Treating obesity in children and adolescents is complex, given the dynamic nature of growth and development during this life stage. The role of pharmacological treatments in the management of pediatric obesity remains uncertain, particularly with respect to outcomes beyond weight reduction, including quality of life and long-term adverse events. To assess the benefits and harms of pharmacological interventions for the treatment of obesity in children and adolescents. We searched CENTRAL, MEDLINE, the World Health Organization (WHO) International Clinical Trials Registry Platform, and ClinicalTrials.gov on 3 July 2023 without language restrictions. In June 2025, we checked the status of ongoing studies and updated results accordingly. We included randomized controlled trials (RCTs) evaluating pharmacological interventions in children (0 to 9 years) and adolescents (10 to 19 years) with essential obesity. Eligible studies administered any medication, at any dose, as monotherapy or in combination, for at least three months and reported outcomes after a minimum follow-up of six months. Critical outcomes were change in body mass index (BMI), change in weight, any adverse events, discontinuation due to adverse events, and incidence or severity of obesity-related outcomes. Important outcomes were health-related quality of life, mental and physical well-being, and obesity-related disability. We used the RoB 2 tool to assess bias in the included RCTs. We calculated mean differences (MDs) and standardized mean differences (SMDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes, with their corresponding 95% confidence intervals (CIs). We used GRADE to assess the certainty of evidence for critical outcomes and quality of life. We included 37 RCTs with a total of 4218 participants. Two were cross-over trials; 35 were parallel-group trials. We identified seven ongoing studies and six studies as awaiting classification. Of the included studies, 25 involved adolescents only. Eleven studies planned to include both children and adolescents, but only eight actually did. One study intended to include children but did not specify participants' age at inclusion. Trials randomized participants to pharmacological interventions or control alongside common baseline treatments (e.g. behavioral or lifestyle approaches, diet, and physical activity). Of the 37 included studies, 31 used placebo and six used no intervention (baseline treatment alone) as the comparator. The studies were conducted across 17 high-income, six middle-income, and three low-income countries. Length of follow-up ranged from six to 31 months, with a median of 11 months. Pharmacological interventions versus placebo Compared to placebo, pharmacological interventions (glucagon-like peptide-1 [GLP-1] receptor agonists, metformin, orlistat, sibutramine, topiramate, phentermine plus topiramate) may reduce BMI (change from baseline) by 1.80 kg/m2 (95% CI -2.36 to -1.24; I2 = 87%; 25 studies, 3091 participants; low-certainty evidence) and weight (change from baseline) by 5.47 kg (95% CI -7.45 to -3.50; I2 = 89%; 20 studies, 2380 participants; low-certainty evidence). Adverse events were frequent. Pharmacological interventions (GLP-1 agonists, sibutramine, phentermine, topiramate) likely make little to no difference in the risk of any adverse events compared to placebo (RR 1.03, 95% CI 1.00 to 1.07; I2 = 0%; 8 studies, 1877 participants; moderate-certainty evidence). Pharmacological interventions (GLP-1 agonists, metformin, orlistat, sibutramine, phentermine, topiramate) may make little to no difference in the risk of discontinuation due to adverse events, although the risk was slightly higher with the medications (RR 1.50, 95% CI 0.82 to 2.75; I2 = 17%; 13 studies, 2213 participants; low-certainty evidence). One study (46 participants), comparing sibutramine to placebo, found that there may be little to no difference in the incidence of obesity-related outcomes for adolescents with comorbidities (assessed as changes in glycemia, blood pressure, total cholesterol, and triglycerides). We were unable to pool other data on incidence or severity of obesity-related outcomes. Compared to placebo, pharmacological interventions (GLP-1 agonists, phentermine plus topiramate) likely result in little to no difference in quality of life, assessed with the Impact of Weight on Quality of Life-Kids (IWQOL) questionnaire (MD 1.02, 95% CI -1.94 to 3.98; I2 = 48%; 4 studies, 741 participants; moderate-certainty evidence). Pharmacological interventions versus no intervention Compared to no intervention, metformin may reduce BMI (change from baseline) by 1.51 kg/m2 (95% CI -2.29 to -0.73; I2 = 0%; 3 studies, 151 participants) and weight (change from baseline) by 3.20 kg (95% CI -6.12 to -0.28; 1 study, 42 participants), but the evidence for both outcomes is very uncertain. Compared to no intervention, pharmacological interventions (metformin and orlistat) may increase the risk of discontinuations due to adverse events, but the evidence is very uncertain (RR 13.70, 95% CI 0.83 to 225.43; 2 studies, 84 participants). None of the studies comparing pharmacological interventions to no intervention reported data on adverse events, obesity-related outcomes, and quality of life that could be pooled in meta-analysis. Only eight of the 37 included studies enrolled children, and data were seldom disaggregated by age, limiting the ability to draw conclusions about benefits or harms in children. This review includes clinical trials assessing the benefits and harms of pharmacological treatments - including GLP-1 agonists, metformin, orlistat, phentermine, sibutramine, and topiramate - for weight management in adolescents with obesity. Evidence suggests that pharmacological treatments may result in small reductions in BMI and weight, which could be clinically important, although effects vary by medication. Evidence on desirable and undesirable effects in children is scant. Uncertainties remain about the optimal duration of treatment, consequences of treatment discontinuation, and long-term benefits and harms, particularly considering the physiology of children and impact on growth. Studies with longer follow-up are needed to evaluate outcomes beyond BMI and weight change, including the potential effects of treatment discontinuation. The Department of Nutrition and Food Safety at the WHO commissioned and provided financial support for this work. WHO acknowledges financial support from the Norwegian Agency for Development Cooperation (NORAD), the Swedish International Development Cooperation Agency (SIDA), the Government of the Grand Duchy of Luxembourg, the Government of Germany (BMG), and the Government of Greece to the WHO Department of Nutrition and Food Safety. Our protocol is registered in PROSPERO: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023433123.
High-grade serous ovarian cancer (HGSOC) is the most aggressive type of ovarian cancer, with a high mortality rate. Testing for alterations in BRCA1/2 genes from tumor tissue is currently recommended as a companion diagnostic procedure for selection of patients eligible for therapy with poly (ADP-ribose) polymerase inhibitors. However, tumor testing alone does not allow for identification of patients who may have a hereditary form of the disease, whereas unselected reflex testing for germline variants is not feasible in resource-limited settings. We report real-world data from the consecutive unselected HGSOC patient population (n = 893) referred for BRCA1/2 mutation testing between 2016 and 2023. First, we evaluated the prevalence and distribution of germline and somatic BRCA1/2 mutations in the Serbian population. Second, we performed independent validation of the probabilistic model, LOH-Germline Inference Calculator (LOHGIC), for inference of germline origin of these alterations based on tumor purity, depth of sequencing, and allele frequency. The Serbian cohort shows approximately 21% overall prevalence of BRCA1/2 pathogenic mutations in HGSOC, of which 30%-50% are germline, none detected in women over 60 years. Concordance of the LOHGIC model for prediction of germline variants with test results from a subset of 121 patients with matched tumor and blood demonstrated a sensitivity of 0.44 (95% CI, 0.14 to 0.79) and a specificity of 0.67 (95% CI, 0.41 to 0.87). The moderate prevalence of germline variants in the Serbian population indicates the need for selection of patients for confirmatory testing from blood. However, probabilistic models alone are not sufficiently accurate and should be complemented with information on patient history and age of onset to rule out patients with likely somatic variant origin for a cost-effective testing program.
The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.
Cyclin-dependent kinase (CDK)4/6 inhibitors (CDK4/6i) have been shown to improve the outcome of patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) advanced/metastatic breast cancer (a/mBC). This study aimed to demonstrate the safety and effectiveness of CDK4/6i in HR+/HER2- a/mBC patients, in a single-center study in Cyprus and to confirm whether these are in line with data derived from randomized clinical trials and other real-world data studies. This retrospective study included 269 patients treated with endocrine therapy (ΕΤ) combined with palbociclib or ribociclib or abemaciclib as first-, second- or third-line treatment at the Bank of Cyprus Oncology Center (2018-2021). Seventy patients from the retrospective study who continued to receive treatment with CDK4/6i-containing regimens, were enrolled in the prospective study (follow-up period: 2021-2024) whereby patients were monitored in real time. Statistical evaluation was performed for differences in progression-free survival (PFS), overall survival (OS), adverse events (AEs)/toxicity, and prognostic factors for effectiveness. The majority of patients received CDK4/6i in the first-line setting (68%, n = 182/269), whilst 25% and 7.8% of patients received CDK4/6i as second and third line of treatment, respectively. The median progression-free survival (mPFS) was 31, 25 and 19 months, with median overall survival (mOS) of 60, 54 and 44 months for palbociclib, ribociclib and abemaciclib, respectively. Neutropenia was the most commonly reported AE, followed by diarrhea, alanine aminotransferase (ALT)/aspartate aminotransferase (AST) increase, pneumonia, thrombocytopenia, erythematous rash and prolonged QT interval. Following subgroup analyses, age > 65 years, higher BC grade, de novo metastatic cancer at initial diagnosis, presence of lymph node/liver or brain metastasis and the larger number of metastatic sites at time of CDK4/6i treatment and the later-line use of CDK4/6i, were associated with a significantly shorter mPFS/mOS. The combination of CDK4/6i with ET is the gold standard treatment in HR+/HER2- a/mBC. Our study results confirm the effectiveness and tolerability of CDK4/6i in clinical routine practice with prognostic factors aligning with those identified in previous studies. This is the first real-world data (RWD) describing the effectiveness and toxicity of three CDK4/6i in the Cypriot patients.
Children undergoing cancer treatment experience a range of treatment-related toxicities that significantly affect quality of life and adherence to therapy. Current methods for symptom reporting rely heavily on clinician interpretation of caregiver or child verbal reports, which can result in incomplete or inaccurate records. The Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (Pediatric PRO-CTCAE; National Cancer Institute) provides a validated mechanism for direct symptom reporting by children and caregivers, yet its traditional administration and preselection of questions limit the breadth of symptom capture. This research aimed to co-design and conduct formative usability testing of the Smart Pediatric Oncology Tracker of Symptoms (SPOTS), a novel, web-based interface for the Pediatric PRO-CTCAE to allow children with cancer and their caregivers to comprehensively report symptoms. The research comprised 2 sequential phases: co-design and usability testing. Guided by child-computer interaction theory and participatory design methods, child-caregiver dyads collaborated with the research team to iteratively design and refine the SPOTS prototype. Nine participant dyads engaged in up to 3 co-design sessions that informed system features, layout, and content. During the usability phase, 12 additional dyads (6 with children aged 7-12 years and 6 with adolescents aged 13-17 years, each with a caregiver) completed structured usability tasks using the SPOTS prototype. Task completion, pathway efficiency, and user feedback were recorded through screen capture, field notes, and think-aloud protocols. Quantitative data were analyzed descriptively, and qualitative feedback was analyzed thematically. SPOTS was described by users as "very clear" and "easy to navigate." Participants valued the visual design, the use of a customizable character, and the opportunity for children to report symptoms independently. Key usability challenges included confusing terminology, navigation redundancy, and visual complexities. Quantitative task analyses indicated that while most structured tasks were completed successfully, many required excess steps or assistance. When not directed to use a specific screen, participants' symptom reporting methods varied, with caregivers and adolescents preferring the Body Parts Screen and younger children favoring the Search Screen. The formative development of SPOTS demonstrates the feasibility and value of co-designing pediatric health technologies directly with children and caregivers. SPOTS has the potential to enhance the implementation of the Pediatric PRO-CTCAE by offering an engaging, child-friendly digital format that facilitates more direct symptom reporting. Future work will include a pilot study to further assess real-world usability, the quality of symptom capture (ie, completeness and accuracy), and integration with clinical workflows.
The aim of this study was to estimate the economic burden of radiotherapy (RT) from the perspectives of payers, the healthcare system, patients, and society, and to assess associated quality-of-life (QoL) outcomes. The analysis examined direct medical and non-medical costs, as well as QoL, before, during, and up to six months after RT. Given the inclusion of multiple cancer types, the study reflects a heterogeneous real-world population. An exploratory comparison across RT techniques was also conducted to provide contextual economic insight. This analysis included data from 301 cancer patients undergoing RT using various techniques, including two-dimensional radiotherapy (2D), 3D conformal radiotherapy (3D-CRT), volumetric-modulated arc therapy (VMAT), and intensity-modulated radiotherapy (IMRT), at the University General Hospital of Heraklion, Crete, Greece. Clinical and cost data were collected retrospectively, while QoL data were collected prospectively using validated instruments at baseline, end of treatment, and six months post-treatment. Quality-adjusted life years (QALYs) were estimated. The primary analysis compared RT with a hypothetical "no RT" comparator derived from published evidence, while comparisons across RT techniques were conducted as exploratory analyses. Costs and QALYs were evaluated over a 6-month time horizon; therefore, discounting was not applied. Incremental cost-effectiveness ratios (ICERs) were calculated, and probabilistic sensitivity analysis was performed to account for parameter uncertainty. The cost per QALY gained with RT compared with the hypothetical "no RT" comparator varied substantially across techniques and cancer types. In the primary analysis, 2D radiotherapy yielded the lowest ICER (€13,043.27/QALY), while VMAT demonstrated an ICER of €29,945.12/QALY. In contrast, IMRT was associated with a substantially higher ICER (€135,529.51/QALY), suggesting limited cost-effectiveness under commonly accepted willingness-to-pay thresholds, whereas 3D-CRT was found to be dominant. Subgroup analyses revealed marked heterogeneity, with ICERs ranging from €3234.45 to €30,232.50 per QALY gained across cancer types. In certain subgroups, RT was either cost-saving or dominant, particularly in breast cancer (cost-saving with similar QALYs) and in skin cancer and sarcoma (dominant strategies). Sensitivity analyses highlighted considerable uncertainty, especially for 2D radiotherapy, primarily driven by small sample sizes and variability in QALY estimates. This study provides short-term, real-world evidence on the cost-effectiveness and quality-of-life outcomes of radiotherapy in a Greek healthcare setting. While simpler techniques such as 2D radiotherapy may appear economically favorable, their limited effectiveness and substantial uncertainty may reduce their overall value. In contrast, advanced techniques-particularly VMAT-demonstrate a more consistent balance between cost and clinical outcomes, supporting their role within value-based, patient-centered oncology care. However, the findings should be interpreted with caution due to population heterogeneity, small subgroup sizes, the short (6-month) time horizon, and the use of a hypothetical comparator. Further research with longer follow-up and disease-specific analyses is warranted.
To investigate how early manual lymphatic drainage can prevent lower limb lymphedema (LLL) following real-world gynecological cancer surgery. A total of 342 patients with gynecological cancers underwent radical surgery at a Guangxi cancer hospital between January 3 and February 15, 2025 were included. In order to ascertain the implementation of preventive manual lymphatic drainage (MLD) following surgery, patients were categorized into a prophylaxis group and a control group according to their selection. To control for potential confounding factors, a 1:1 propensity score-matching (PSM) method was used. Using the gynecological lymphedema questionnaire (GLQ) at least 6 months after surgery, we investigated the incidence of LLL and the status of preventive strategies after the intervention. After PSM, 111 pairs of score-matched patients were generated. The prophylaxis group's LLL incidence was 10.81%, substantially lower than the control group's 21.62% (P = 0.04). 15.6% of patients in the control group and 38.9% of patients in the prophylaxis group engaged in preventive activities (P < 0.001). 71.7% of patients with GCLQ scores ≥ 4 took action to prevent LLL progression. The prophylaxis group showed a significantly reduced risk of LLL (risk ratio, 0.50; 95% confidence interval (CI) [0.263-0.949]; P = 0.034). The occurrence of postoperative lower limb lymphedema is reduced in gynecologic cancer patients who undergo early manual lymphatic drainage. This offers compelling evidence to inform clinical treatment decisions.
The optimal endoscopic technique for esophageal squamous cell carcinoma (ESCC) screening remains uncertain. This study aimed to evaluate the diagnostic performance of Lugol's chromoendoscopy (LCE), electronic chromoendoscopy (ECE), and white light imaging (WLI) in identifying esophageal precancerous and early malignant lesions through a large-scale self-controlled study. Between 2019 and 2023, outpatients aged 45-69 years were enrolled at Endoscopy Center of Anyang Cancer Hospital and underwent a sequential endoscopic examination comprising WLI, ECE, and LCE with complete epidemiological, endoscopic, and pathological data. Per-lesion sensitivity, specificity, positive predictive value, and negative predictive value were evaluated for detecting esophageal intraepithelial neoplasia and above (INA), high-grade intraepithelial neoplasia and above (HGINA), and ESCC. Subgroup analyses stratified by epidemiological data were performed. Among the 2167 included participants, histopathology identified 53 cases of low-grade intraepithelial neoplasia (LGIN), 111 of high-grade intraepithelial neoplasia (HGIN), and 63 of ESCC. LCE showed 100% sensitivity across all lesion categories, outperforming ECE (89.3%, 94.9%, 98.5%) and WLI (68.1%, 79.1%, 87.7%) for INA, HGINA, and ESCC, with significantly better sensitivity for INA and HGINA. Specificity of LCE (74.6%-82.2%) was lower than ECE (84.5%-91.8%) and WLI (90.4%-95.8%) (all P < 0.05). Compared with the LCE-for-all strategy, in which LCE was applied to all endoscopic examinations, the two-step strategy, which restricted LCE to lesions positive on either WLI or ECE, missed 21.6% of LGIN, 6.1% of HGIN, and 1.5% of ESCC lesions. Subgroup analysis showed that senior endoscopists (> 5 years of experience) achieved significantly higher ECE sensitivity for INA detection. An LCE-for-all strategy may be preferable when the priority is to maximize detection of early precancerous lesions such as LGIN, whereas a two-step strategy may achieve adequate detection of HGINA. With adequate training and strict quality control, ECE could serve as an alternative, while WLI alone is not recommended for EC screening.
Management of the axilla in early-stage breast cancer has progressively evolved toward less invasive approaches, as advances in tumor biology, imaging, and local and systemic therapies have improved outcomes while highlighting the morbidity associated with axillary surgery. Sentinel lymph node biopsy, once considered essential for staging, is increasingly being questioned in select patients with clinically node-negative disease. This review summarizes current evidence evaluating omission of sentinel lymph node biopsy in early-stage breast cancer, including its impact on oncologic outcomes, quality of life, and implementation in clinical practice. Multiple retrospective studies and randomized controlled trials have demonstrated that omission of axillary surgery does not compromise survival outcomes in carefully selected patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors. These findings informed the 2016 Choosing Wisely® recommendation by the Society of Surgical Oncology to avoid routine sentinel lymph node biopsy in women over 70 years of age with clinically node-negative disease. While implementation of this guideline was slower than expected, subsequent studies have explored whether sentinel lymph node biopsy can be safely omitted in a broader group of women with early-stage, HR-positive/HER2-negative invasive breast cancers, who are clinically node-negative on physical exam and preoperative axillary ultrasound. This led to the development of several prospective trials, including SOUND (Sentinel Node vs Observation After Axillary Ultra-Sound), INSEMA (Intergroup Sentinel Mamma), NAUTILUS (No Axillary Surgical Treatment in Clinically Lymph Node Negative Patients on Ultrasonography After Neoadjuvant Chemotherapy), BOOG 2013-08 (Dutch Breast Cancer Research Group 2013-08), OMSLNB (Omission of Sentinel Lymph Node Biopsy), VENUS, and SOAPET (Sentinel node biopsy vs. observation after axillary PET). While many of these trials remain ongoing, results of the SOUND and INSEMA trials demonstrate no difference in survival outcomes following omission of sentinel lymph node biopsy in postmenopausal women with low grade, HR-positive/HER2-negative tumors less than 2 cm in size, and these findings are increasingly being incorporated into clinical practice. Advancements in neoadjuvant therapies have resulted in increasing rates of pathologic complete response in the breast in clinically node-negative women with HER2-positive and triple-negative breast cancers, raising the possibility that sentinel lymph node biopsy may be safely omitted in this population as well. This is being investigated in the EUBREAST-01 (European Breast Cancer Research Association of Surgical Trialists), ASICS (Avoiding Sentinel lymph node biopsy In select Clinical node negative breast cancer patients after neoadjuvant Systemic therapy), ASLAN (Avoid Axillary Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy), and Neo-NAUTILUS trials. While these trials are ongoing, the results are promising to change the scope of current clinical practice and reduce the morbidity associated with axillary surgery in appropriately selected patients with breast cancer.
Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor. Although patient survival has been significantly improved by immune checkpoint inhibitors combined with chemotherapy, three major unmet needs remain in SCLC management. First, while prophylactic cranial irradiation (PCI) can reduce the risk of brain metastases, its neurotoxicity limits its use, particularly in elderly patients or those with neurological deficits. Whole-brain radiotherapy (WBRT) remains the primary approach for brain metastases, and hippocampal-avoidance WBRT (HA-WBRT) combined with neuroprotective agents can significantly reduce cognitive risks. Stereotactic radiosurgery (SRS) has shown survival benefits and less cognitive damage for patients with up to 10 brain metastatic lesions. Emerging therapies, such as antibody-drug conjugates targeting B7-H3/DLL3 (I-Dxd, ZL-1310) and bispecific antibody tarlatamab, have demonstrated intracranial response rates of 62.5%-71%. Regardless of whether the brain metastases had previously undergone radiation therapy, the novel drugs showed consistent activity, indicating promising improvements in the prognosis of brain metastases. Second, the rapid progression and severe treatment-related toxicity of SCLC greatly affect patients' physical and mental well-being. Therefore, quality of life (QoL) should be prioritised. Strategies to improve QoL include early palliative care, proactive symptom management, application of HA-WBRT or SRS to preserve neurocognitive function, and novel agents such as tarlatamab to alleviate symptoms including cough and dyspnoea. Third, real-world evidence (RWE), which complements clinical trial data by reflecting treatment efficacy and safety in routine clinical practice, is gaining increasing recognition but faces challenges due to data heterogeneity, bias, and lack of methodological standardization. Future directions involve developing new drugs with high blood-brain barrier penetration, such as radioligand therapy, conducting prospective studies to optimize HA and SRS applications, establishing high-quality RWE databases to support personalized treatments, exploring molecular subtypes (SCLC-A/N/P/I) and leveraging AI technologies to advance precision radiotherapy. SCLC management needs to be patient-centered, integrating precise treatment of brain metastases, QoL improvement, and the application of RWE to achieve a balance between survival benefits and QoL.
Patients living with advanced cancer often benefit from palliative care. Timely referral to specialist palliative care improves quality of life and reduces potentially inappropriate end-of-life care. Despite these benefits, specialist palliative care is frequently introduced late and inconsistently. This study evaluates whether systematically offering a consultation with the hospital palliative care consultation team (PCCT) to all patients referred for radiotherapy for symptomatic bone metastases improves satisfaction with care. The Timely Integration of Palliative Care in Oncology care for patients referred for palliative RadioTherapy (TIPZO-RT) trial follows the Trials within Cohorts design and is embedded within the PRospective Evaluation of interventional StudiEs on boNe meTastases (PRESENT+) cohort. Following cohort enrollment, 246 patients will be randomized (1:1) to either the intervention or control group. Patients in the intervention group are offered a PCCT consultation, which they may accept or refrain from. Patients in the control group are not informed about the trial and continue to receive usual care. After four weeks, patient satisfaction with care (affective behavior, EORTC Satisfaction with Cancer Care core questionnaire (EORTC PATSAT-C33)) will be compared between the groups. Secondary outcomes include symptom burden, quality of life, overall survival, and palliative care utilization. Additionally, in the intervention group, patients' experiences with the consultation are evaluated. Integrating palliative care into oncological care for patients with advanced cancer is essential to deliver comprehensive, patient-centered care that addresses physical, psychosocial and spiritual needs. This pragmatic study may provide evidence to support timely integration of specialist palliative care for all patients with bone metastases who may benefit from specialist palliative care. Using the Trials within Cohorts design, this study generates real-world evidence on the acceptance or need for a consultation with the PCCT, while minimizing disappointment or response bias, as patients in the control group are not informed. ClinicalTrials.gov ID NCT06805396. Registered on 25-03-2025.
Chronic hepatitis delta (CHD) is the most severe form of viral hepatitis and is associated with accelerated progression to cirrhosis and liver failure. Bulevirtide has shown promising results in trials, but real-world data on its effectiveness, safety and impact on patient-reported outcomes (PROs) remain limited. To evaluate the effectiveness, safety, and PROs (quality-of life-QoL; adherence) of bulevirtide therapy in CHD patients undergoing a dedicated pharmacist-led patient-education program (PEP). A prospective observational study enrolled 31 consecutive CHD patients receiving bulevirtide 2 mg daily at a tertiary referral centre. Virological, biochemical and combined responses were assessed at weeks 24, 48 and 60. QoL (through EQ-5D-5L questionnaire), adherence (proportion of days covered), and adverse events were monitored during follow-up. Bulevirtide significantly reduced HDV-RNA by week 24 (p < 0.01), with further reductions at week 48 (p = 0.05) and 60 (p < 0.01). Liver tests improved significantly from baseline to week 24 (p < 0.01) and remained stable. Combined response was achieved in 43.7% of patients by week 60. QoL improved significantly (p = 0.03), and adherence was excellent (≥ 90%). Adverse events were mostly mild and transient. In real-world clinical practice, bulevirtide achieved sustained virological and biochemical improvements with favourable safety and quality-of-life outcomes, confirming its effectiveness in routine management of CHD. While the 60-week data (n = 16) are exploratory due to the sample size, these findings confirm its effectiveness and safety in routine management of CHD.
Small intestinal adenocarcinoma (SIA) is a rare cancer with a poor prognosis. Optimal treatment strategies are unclear as biological understanding of the disease is limited and randomized controlled trials are lacking. Current management is based on protocols for other gastrointestinal cancers. Therefore, the AdenoCarcinoma of the Small Intestine (ACSI) cohort was initiated, a subcohort of the nationwide Prospective Dutch ColoRectal Cancer cohort (PLCRC) study. The ACSI cohort aims to provide a large-scale, prospective SIA cohort, where clinical and molecular data will be combined to improve knowledge on tumor biology, treatment responsiveness, disease outcome and patient reported outcomes (PROs). Patient/material and methods: All adult SIA patients in the Netherlands are eligible for inclusion. Nationwide inclusion is facilitated by 68 hospitals. Clinical data are collected, as well as optional PROs, pathology- and blood samples. Until June 2025, 143 patients have been enrolled. Data of the first 105 patients show a median age of 65 years (interquartile range 58-73) at diagnosis with a slight male predominance (60%). Most tumors are located in the duodenum (57%) and 27% of patients present with stage IV disease, with a majority having single-site metastases (64%). Primary tumor resection is performed in 80%, while systemic treatment is administered in 42%. Four patients did not receive any anti-tumor treatment (14%). Mismatch repair deficiency is detected in 28% of patients. The ACSI cohort enables structured national collection of clinical data, tumor samples and PROs of SIA patients. These data provide a valuable source for further research and improvement of care for this patient group.
Real-world data (RWD) are increasingly recognized as essential for understanding patient populations underrepresented in clinical trials and for supporting data-driven learning in healthcare. For smaller subgroups, the value of RWD depends on standardization and interoperability that enable meaningful reuse across institutions. This study examines how clinicians perceive the reuse and standardization of RWD within a federated Learning Health System (LHS), with emphasis on data quality, clinical relevance, and implications for continuous learning. A qualitative case study was conducted at Oslo University Hospital, informed by Learning Health System theory. Ten oncologists representing seven cancer subspecialties participated in focused, semi structured interviews. Data were analyzed using the stepwise deductive inductive (SDI) method to support empirically grounded conceptual development. The study was situated in the hospital's implementation of the OMOP Common Data Model (CDM) for oncology data. Clinicians highlighted the value of RWD for capturing patient groups often excluded from clinical trials. They described substantial variation in documentation practices, noting that clinically relevant information is frequently unstructured or inconsistently recorded. Time constraints and uncertainty about documentation requirements were identified as barriers to data quality. When reviewing data transformed into the OMOP CDM, participants generally found the mappings accurate but expressed concerns about loss of nuance and semantic drift. Across interviews, there was strong support for involving domain experts in validation and for using standardized data to enable collaboration and learning across institutions. RWD can strengthen oncology practice by supporting insights into diverse patient populations and enabling continuous learning. Standardization through models such as OMOP CDM facilitates reuse and cross institutional collaboration, but success depends on structured documentation, semantic fidelity, clinician engagement, and robust technical infrastructure. These findings underscore the sociotechnical conditions required to realize the potential of RWD within emerging frameworks such as the European Health Data Space.
Next generation sequencing (NGS) impacted on clinical algorithm of solid tumor patients. A heterogeneous series of NGS platforms have been implemented in clinical practice but challenging handling procedures, high technical costs, and scant affordability on sequencing diagnostic routine specimens can leave behind some patients who could benefit from target drugs. Here, we sought to evaluate technical feasibility of Oxford Nanopore Technologies (ONT) sequencing accurate identification of tumor-associated molecular alterations, in a pilot series of real-world samples. We developed a technical workflow adapting the SiRe® NGS panel, originally designed for Ion semiconductor sequencing, on MinION platform (Oxford nanopore technologies), a portable, cost effective long read sequencer. The SiRe® panel enables detection of ٥٦٨ clinically actionable somatic mutations across six key genes (EGFR, KRAS, NRAS, BRAF, cKIT, PDGFRα) relevant to targeted therapies in several solid tumors. We implemented a multiplexed assay using pooled and barcoded samples, processed on a single MinION flow cell. Performance was benchmarked from a pilot series of nine FFPE samples against Ion Torrent sequencing data. A single liquid biopsy sample was also analyzed testing accuracy of MinION technology. The adapted ONT workflow demonstrated high concordance ratei in detecting clinically relevant molecular alterations on short-read fragments, achieving comparable accuracy with standardized second generation NGS platforms on tissue and liquid biopsy samples. This proof of concept aimed to integrate ONT sequencing into molecular oncology workflows, providing practical, low-cost, and scalable alternative to conventional NGS platforms. The results support the potential of ONT technology to democratize access to precision oncology, particularly in laboratories with limited resources.
Adjuvant radiation (AR) remains a controversial treatment modality for pancreatic ductal adenocarcinoma (PDAC). This study aimed to evaluate the findings of the RTOG 0848 trial assessing the benefits of adjuvant radiation in node-negative disease utilizing a national database. Utilizing the National Cancer Database, all patients diagnosed with non-metastatic PDAC, who underwent pancreatectomy, were included (2004-2019). The trend of adjuvant radiation utilization was evaluated. Overall survival in a cohort of patients mimicking the RTOG 0848 protocol was examined as were clinicodemographic and pathologic predictors of adjuvant radiation. Overall rates of adjuvant radiation decreased from 45 to 12%, while neoadjuvant radiation rates simultaneously increased from 4 to 12%. Positive margins and nodal disease were the strongest predictors of adjuvant radiation receipt (OR 1.7[ 95% CI: 1.6-1.7] p < 0.001 and OR: 1.1 [95% CI: 1.1-1.2] p < 0.001; respectively). Both high-risk pathologic groups experienced a decline in the use of adjuvant radiation over time, even after exclusion of patients who received neoadjuvant radiation. After application of the RTOG 0848 criteria, improved overall survival was observed in patients with node-negative and positive margins (adjuvant radiation: 28.6 [95% CI: 25.4-31.8] vs 23.0 [95% CI: 19.4-26.7] months; p = 0.005). In the margin positive cohort, adjuvant radiation was significantly associated with reduced mortality (HR: 0.791 [95% CI: 0.7-0.9]; p < 0.001). Evaluation of RTOG 0848 in the setting of real-world data indicates a role for adjuvant radiation for patients with margin-positive, node-negative pancreatic cancer. This highlights the essential role of multidisciplinary discussions regarding patients with PDAC care.
We previously reported the 10-year effects of colonoscopy screening on colorectal cancer incidence and mortality. Here, we report the effects after 13 years of follow-up. In this multicountry, population-based randomised controlled trial, 84 583 men and women aged 55-64 years at enrolment from Norway, Poland, and Sweden were randomly allocated (1:2) to colonoscopy screening or no screening and analysed. The primary outcomes were colorectal cancer incidence and mortality after 10-15 years of follow-up in intention-to-screen analyses, with first analysis after 10 years, and repeated every other year or at longer intervals. This trial is registered with ClinicalTrials.gov, NCT00883792, and is ongoing. At 13 years of follow-up, colorectal cancer incidence was 375 colorectal cancers (1·46%) of 28 217 individuals in the screening group and 912 colorectal cancers (1·80%) of 56 366 individuals in the no-screening group. The risk ratio (RR) was 0·81 (95% CI 0·71-0·90) in intention-to-screen analyses and 0·55 (0·33-0·81) in per-protocol analyses. The risk for proximal colorectal cancer was 129 (0·51%) in the screening group versus 283 (0·56%) in the no-screening group (RR 0·91 [0·71-1·09]), and the risk for distal colorectal cancer was 224 (0·87%) in the screening group versus 563 (1·11%) in the no-screening group (RR 0·79 [0·65-0·89]; interaction p<0·0001). In men, the colorectal cancer risk was 214 (1·69%) of 14 154 in the screening group and 541 (2·19%) of 28 247 in the no-screening group (RR 0·77 [0·64 to -0·88]); in women, the risk was 161 (1·24%) of 14 063 in the screening group versus 371 (1·43%) of 28 119 in the no-screening group (RR 0·87 [0·70 to 1·02]; interaction p<0·0001). Colorectal cancer mortality was 106 (0·41%) of 28 217 in the screening group and 236 (0·47%) of 56 366 in the no-screening group (intention-to-screen RR 0·88 [0·68-1·08], per-protocol RR 0·70 [0·26-1·25]). The observed colorectal cancer mortality in the non-screening group (0·47%) was substantially lower than expected at the time of designing the trial (0·82%). One colonoscopy significantly reduced colorectal cancer incidence but not mortality over 13 years. Colorectal cancer mortality was lower in both study groups than when the trial was designed. The Norwegian Research Council, the Nordic Cancer Union, the Norwegian Cancer Society, and the Health Fund of South-East Norway.
Comorbidities, common in patients with advanced breast cancer (ABC), may impact survival outcomes and health-related quality of life (HRQoL). Here, we report subgroup analyses on the basis of comorbidities of patients from POLARIS (NCT03280303), a prospective, observational study of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) ABC who were treated with palbociclib plus endocrine therapy in routine clinical practice in North America. Real-world progression-free survival (rwPFS) and overall survival (OS) were evaluated by line of therapy (1 LOT, ≥ 2 LOT), Charlson Comorbidity Index (CCI) score (0, 1-2, and 3+), and common comorbid disorder categories (cardiovascular, psychiatric, metabolic and nutritional, and blood and lymphatic disorders). HRQoL was assessed using the global health status (GHS)/QoL subscale of the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30. From January 2017 to October 2019, 1250 patients (median age, 64 years) initiated palbociclib-based therapy. Median rwPFS (95% CI) for patients with CCI scores of 0, 1-2, and 3+ were 20.3 (17.1-24.8), 24.2 (19.4-29.5), and 16.8 (11.2-20.8) months in 1 LOT and 13.7 (6.2-19.7), 13.2 (9.4-17.5), and 14.9 (8.0-21.9) months in ≥ 2 LOT, respectively. Median OS durations (95% CI) were 48.8 (37.3-not estimable [NE]), not reached (43.0-NE), and 34.8 (29.1-44.1) months in 1 LOT and 39.0 (30.6-50.5), 37.9 (26.5-42.6), and 31.6 (20.9-45.2) months in ≥ 2 LOT, respectively. Patients with blood and lymphatic disorders had shorter rwPFS and OS than those with other common comorbidities. GHS/QoL was maintained irrespective of CCI score. Patients with a CCI score of 0 had clinically meaningful and statistically significantly higher mean GHS/QoL scores than patients with a CCI score of 3+ at each assessment. Patients with HR+/HER2- ABC receiving palbociclib with higher comorbidity burden, especially blood and lymphatic system disorders, had poorer clinical outcomes. GHS/QoL was preserved regardless of comorbidity burden. Clinical trial number: NCT03280303.
Inflammatory bowel disease (IBD) encompasses chronic gastrointestinal disorders that significantly impact patients' quality of life (QoL). While clinical trials support the efficacy and safety of vedolizumab, real-world data linking its effectiveness to QoL-related patient-reported outcomes remain limited. This prospective observational study assessed the effects of 14-week vedolizumab induction therapy on QoL (i.e., fatigue, mood, and sleep disturbances), clinical response, safety, and predictors of response. A total of 257 patients with ulcerative colitis (UC; n = 205) and Crohn's disease (CD; n = 52) received 14-week vedolizumab induction therapy. Disease activity, QoL (assessed using the total Inflammatory Bowel Disease Questionnaire [IBDQ]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue]), mood and sleep disturbances (PROMIS Depression and Sleep Disturbance scales), and selected biomarkers were evaluated. Clinical response was assessed using the Mayo score for UC and Crohn's Disease Activity Index (CDAI) score for CD. At Week 14, clinical response was observed in 82% of UC patients and 82.7% of CD patients. Median total IBDQ scores increased by 45.0 points in UC and 31.5 points in CD (p < 0.001). Median prorated FACIT-Fatigue scores increased by 5.0 points in both groups (p < 0.001), while median prorated PROMIS Sleep Disturbance and Depression T-scores decreased (p < 0.05). Improvement in QoL was moderately correlated with clinical response (r = 0.5). In logistic regression analysis, baseline patient characteristics indicative of advanced disease were associated with a reduced likelihood of clinical and QoL response to treatment. A total of 28 adverse events were reported, including 11 serious events and four treatment-related events. Vedolizumab reduced disease activity and led to a rapid improvement in QoL during the 14-week induction therapy in patients with IBD. Clinical response was positively correlated with QoL improvement. Predictors of reduced response were consistent with features of advanced disease.
Alternating electric fields (AEF) therapy has been shown to improve the overall survival of patients with WHO grade 4 astrocytoma. Few have explored its impact on health-related quality-of-life (HRQoL) and caregiver stress. This was a prospective, multi-centre, registry-based study of adult patients with WHO grade 4 astrocytoma who received either AEF plus temozolomide chemoradiotherapy (AEF + CRT) or CRT alone, with EORTC QLQ-C30/BN20, CSI, and HK-MoCA assessments at baseline and every three months. The primary outcome was the global QLQ-30 score at 3 months after CRT. Secondary outcomes included the QLQ-30 functional score, symptom scores and the caregiver stress index (CSI) at 3 months. 88 patients, 48 AEF + CRT and 40 CRT-alone, were reviewed. The mean AEF duration was 10 ± 8 months. At 3 months, AEF + CRT patients had significantly lower global QLQ-C30 scores than CRT-alone patients (44 ± 22 vs. 66 ± 20; between-group difference 22 points; p < 0.001), exceeding the established minimally important difference of 4-6 points for glioma. On multivariable analysis, AEF therapy (adjusted OR 0.09, 95% CI 0.006-0.7) and preoperative KPS ≥ 80 (adjusted OR 0.09, 95% CI 0.01-0.5) were associated with lower odds of high global QoL (≥ 60). Functional and symptom scores were comparable between groups, apart from higher scalp pruritus in AEF + CRT patients. Mean caregiver CSI scores remained < 7 at all time points. In this prospective real-world cohort of Chinese patients with WHO grade 4 astrocytoma, AEF therapy was independently associated with a reduction in global HRQoL at 3 months compared with CRT alone, while functional and symptom domains and caregiver stress remained largely stable. These data should inform shared decision-making when weighing the survival benefit of AEF against its short-term QoL burden, especially in subtropical climates where scalp-related adverse effects may be more pronounced.