Erasmus MC Cancer Institute

Telomere biology disorders (TBD) are a group of diseases that interfere with normal maintenance of telomeres, the ends of chromosomes that protect them from DNA damage. The most common manifestations are bone marrow failure, pulmonary and liver fibrosis. Systematic data on bone health in patients with TBD are scarce. Our aim was to elucidate the bone phenotype of these patients. The cohort comprises 36 adult patients (20 women and 16 men), with genetically confirmed TBD. Demographic, clinical and genetic characteristics, dual-energy X-ray absorptiometry (DXA) scans, spine X-rays and treatment details were reviewed. Median age of patients was 53.5 (43.0, 64.2) years. (Likely) pathogenic variants of the TERT gene were present in most patients. Osteopenia was diagnosed in 38.9% and osteoporosis in 25.0% of patients, 25.0% had a clinical fracture within the past 5years, and 40.0% had at least one prevalent vertebral fracture (grade 1-3). T-score at the lumbar spine (-0.98±1.48SD) was lower than at the femoral neck (-0.60±1.09SD). Mean trabecular bone score (TBS) T-score was -1.32±1.29SD. Bone-active therapy was used by 44.4% of the population, mostly oral bisphosphonates (85.7%). To conclude, we reported a high prevalence of osteopenia, osteoporosis, recent fractures and prevalent vertebral fractures, in patients with TBD. These results highlight the necessity of addressing the risk of osteoporosis and fractures in these patients during medical assessments. Most importantly, additionally to a DXA scan, a vertebral fracture assessment (VFA) or spine X-ray, is recommended to evaluate vertebral fractures.

Azacitidine/venetoclax is the standard treatment for patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy. Cytochrome P450 3A4 (CYP3A4) is the major metabolizing enzyme for venetoclax, and its inhibition can boost venetoclax. In the HOVON 171 phase 2 trial, patients with AML were treated with azacitidine/venetoclax/cobicistat. This 2-stage, open-label, multicenter phase 2 trial included a crossover run-in phase followed by an ongoing extension phase. In cycle 1, patients received standard-dose azacitidine/venetoclax. In cycle 2, cobicistat was added, and venetoclax was reduced to 50 mg. The primary end point was pharmacokinetic equivalence, defined as 90% confidence interval (CI) of geometric mean ratios (GMRs) >0.8 for area under the curve over 24 hours (AUC0-24h) and maximum plasma concentration (Cmax). Polymorphisms in genes encoding for CYP enzymes were determined. In vitro assays were performed to assess cobicistat's impact on the antileukemic effect of azacitidine/venetoclax in AML cell lines. In 13 evaluable patients, cobicistat-boosted venetoclax at 50 mg achieved higher exposure than standard 400-mg dosing. GMRs were 2.0 (90% CI, 1.4-2.8) for AUC0-24h and 1.4 (90% CI, 1.0-2.0) for Cmax. In the intention-to-treat population, 65% achieved complete remission (CR) or CR with incomplete hematologic recovery. Interpatient variability in venetoclax exposure because of CYP3A4 polymorphisms was reduced by cobicistat. No unexpected toxicities were observed. In in vitro, cobicistat enhanced azacitidine/venetoclax antileukemic effects. In conclusion, cobicistat enhances and optimizes venetoclax exposure, enabling an eightfold dose reduction while maintaining efficacy. The potentiated antileukemic activity positions cobicistat as a promising complementary agent in AML therapy. This trial was registered at www.clinicaltrials.gov as NCT06014489.

'Breast Implant Illness' (BII) refers to non-specific constitutional, rheumatic, mental and cognitive symptoms experienced by women with silicone breast implants (SBIs). This potential late effect of SBIs challenges the safety of SBI-use in oncologic breast reconstruction (BR). Previous studies on BII mainly focused on women with cosmetic SBIs. It remains unclear whether symptoms reported in this population differ from those reported by breast cancer (BC) survivors with SBI-based BR. We conducted a cross-sectional survey in a Dutch cohort including 578 breast augmentation recipients and 2,884 BC survivors, of whom 1,039 had an SBI-based BR. Eighteen BII-related symptoms were assessed. Multivariable logistic regression was used to compare breast augmentation recipients with BC survivors with and without SBIs. Median follow-up time was 8.0 (IQR, 3.9) years. Overall, breast augmentation recipients had a higher risk of myalgia (Odds ratio (OR) 2.10, 95%CI [1.25-3.54]) and food intolerance (OR 1.77, 95%CI [1.01-3.09]) than BC survivors with SBIs, whereas the latter group did not report more BII-associated symptoms than BC survivors without SBIs. In a sensitivity analysis excluding BC patients treated with (neo)adjuvant systemic therapy, breast augmentation recipients reported more BII-related symptoms-headache, myalgia, hair loss, muscle weakness, sleep impairment, and morning stiffness (ORs 1.69-3.35; all p < 0.05) compared to BC survivors with SBIs. Breast augmentation recipients report more BII-related symptoms than BC survivors with or without SBIs. These findings do not support the hypothesis that BII is a distinct disease entity mediated by a generic SBI-related pathogenesis that exists across different populations.Trial registration: This study was preregistered at ClinicalTrials.gov on June 2 nd 2022 (NCT05400954).

Intravascular imaging modalities such as optical coherence tomography (OCT), intravascular ultrasound (IVUS) and near-infrared spectroscopy allow the detection of vulnerable coronary plaques, which may predict the risk of future major adverse cardiovascular events (MACEs). However, the prognostic relevance of specific plaque characteristics remains incompletely defined. This updated meta-analysis aimed to identify the most reliable intracoronary imaging-derived parameters for predicting MACE in untreated coronary lesions. A systematic search of PubMed, Scopus and Google Scholar was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines to identify adjusted observational studies reporting the prognostic impact of plaque vulnerability features assessed by OCT or IVUS. The primary outcome was study-defined MACE. HRs were pooled using random-effects or fixed-effects models depending on heterogeneity. Subgroup and sensitivity analyses were conducted to explore the impact of imaging modality and plaque feature definitions. 12 studies including 8453 patients and 22 319 lesions were analysed. All investigated plaque features were significantly associated with an increased risk of MACE. Among predictors, thin-cap fibroatheroma (TCFA) demonstrated the lower positive association (HR 3.06, 95% CI 1.97 to 4.77), while plaque burden showed the highest (HR 3.92, 95% CI 1.45 to 10.59). IVUS-derived parameters (minimum lumen area and high-risk plaque definition) were superior to their OCT counterparts, whereas OCT better discriminated prognostic TCFA. The combination of minimum lumen area, TCFA and lipid arc yielded the strongest predictive performance for MACE risk. Intracoronary imaging-derived plaque features are significantly associated with future cardiovascular events. Multiparametric models integrating compositional and morphological features apparently enhance risk stratification compared with single parameters. CRD420251047286.

Abstract Objectives Using qualitative methods, this study aimed to provide a comparative overview of the similarities and differences in perspectives towards AI in healthcare in two different stakeholder groups: healthcare practitioners and patients. It also aimed to investigate whether these perspectives may influence the adoption of AI in healthcare. Design This study was conducted using semi-structured interviews. Qualitative data from the interviews were analyzed using both deductive and inductive coding, followed by a thematic analysis to identify the prevailing categories for further discussion. Setting The study was conducted within the Department of Surgical Oncology and Gastrointestinal Surgery of Erasmus Medical Center in Rotterdam, the Netherlands. Participants A total of 30 participants were recruited using purposive sampling based on predefined inclusion characteristics. This included 18 healthcare professionals (subdivided into 10 surgeons and 8 nurses), and 12 patients. The inclusion criterion for healthcare professionals included surgeons specializing in gastro-intestinal surgery, while the inclusion criterion for patients included those patients who had undergone gastro-intestinal surgery within the past 12 months at the time interviews were conducted. Exclusion criteria involved excluding patients with major health complications. Outcome measures The study’s central objective was to develop a set of thematic domains that characterize how both groups of stakeholders view the integration of AI in healthcare, encompassing their attitudes towards trust, acceptance, and responsibility. Additionally, it aimed to compare perspectives between healthcare professionals and patients in order to identify areas of convergence and divergence. Results The analysis comprised a total of 3 main thematic categories, with 10 subcategories. The main thematic categories which emerged were AI Knowledge, Ethics, and Operational and Clinical Implications. While clinicians largely focused on validation, monitoring, administrative labor, and clinical integration, patients emphasized the importance of human attention, of being heard, and of maintaining trust in their clinician. Conclusion Comparing the attitudes and perspectives of both healthcare practitioners and patients revealed the importance of taking into consideration both groups of stakeholders. While both groups tend to raise concerns about similar themes connected to responsibility, it is clear that this concern involves complex dynamics present in the epistemic environment of healthcare. Strengths and limitations This study uniquely compared healthcare practitioners’ and patients’ perspectives within a single qualitative design, using similar interview guides to enable direct cross-stakeholder comparison. The study examined perceptions of an AI model that had been designed and validated for clinical use, enhancing the practical relevance of the findings. The relatively small sample size may have limited the diversity of perspectives captured and reduced transferability. As the study was conducted in a single academic hospital in the Netherlands, the findings may not be generalizable to other healthcare settings or national contexts.

BackgroundPancreatic cancer treatment significantly impacts patients’ quality of life, making both safety and patient preference key considerations. Central venous access devices (CVADs) are indispensable for chemotherapy administration in pancreatic cancer, yet device selection varies widely. This study explored which CVADs oncology specialists use in pancreatic cancer care, focusing on the basis for their recommendations.Materials and methodsA nationwide expert survey was distributed among Dutch medical oncologists and nurse specialists involved in pancreatic cancer care via the Dutch Pancreatic Cancer Group, the Dutch Association for Medical Oncology, the Dutch association for nurses, and the study committee’s network.ResultsNinety-one clinicians responded. Most (88%) had access to both port-a-caths (PORTs) and peripherally inserted central catheters (PICCs), while 12% could only offer one device. Decision-making autonomy varied: 53% reported full autonomy, while others followed hospital-wide preferences (39%) or guidelines (9%). Even within these subgroups, preferred CVAD varied greatly. Although 60% listed patient preference among the top five influential factors, only 28% incorporated patients in that decision. Logistical constraints were key barriers influencing device choice.ConclusionSubstantial variability exists in CVAD selection, availability, and clinician autonomy in pancreatic cancer care. While evidence supports PORTs as the safer option, PICCs remain widely used in daily practice. This discrepancy appears driven by disease-specific and logistical factors, including poor prognosis and uncertainty regarding treatment tolerance. Addressing real-world barriers through improved access to PORTs, clearer guideline recommendations, and enhanced patient counseling may help align clinical practice with evidence and ensure high-quality care for patients receiving chemotherapy.

The HYpofractionated irradiation for PROstate cancer trial was a multicenter, randomized, phase 3, superiority trial comparing dose escalated hypofractionation (HF) with conventional fractionation (CF) for the treatment of localized intermediate- and high-risk prostate cancer. This trial aimed to demonstrate equivalent toxicity of HF. In prior publications, noninferiority of acute and late toxicity could not be established. Here, we report the long-term survival outcomes. We randomly assigned patients (1:1) with intermediate- to high-risk T1b-T4NX-N0MX-M0 localized prostate cancer to receive either HF (64.4 Gy in 19 fractions of 3.4 Gy, 3 fractions per week) or CF (78.0 Gy in 39 fractions of 2 Gy, 5 fractions per week) radiation therapy. The HF schedule was a dose escalation compared with CF, based on a α/β ratio of prostate cancer of ∼1.5 Gy, the equivalent total dose in fractions of 2 Gy is 90.4 Gy for HF versus 78.0 Gy for CF. The primary endpoint of this paper was relapse-free survival at 10 years and secondary outcome was overall survival. Of the 820 patients, 804 were included in the current evaluation, 407 patients received HF and 397 CF radiation therapy. The 10-year relapse-free survival was 64.5% (95% CI, 58.6-69.7) in the HF arm compared with 60.1% (95% CI, 53.9-65.8) in the CF arm (hazard ratio, 0.89; 95% CI, 0.69-1.14; P = .35). The 10-year overall survival in the HF arm was 69.2% (95% CI, 64.1-73.7) versus 61.2% (95% CI, 55.7-66.2) in the CF arm (hazard ratio, 0.82; 95% CI, 0.65-1.05; P = .11). In the updated findings, we could not demonstrate a statistically significant improvement in 10-year relapse-free survival following dose escalated HF compared with CF. Although patients in the HF arm showed a favorable 10-year overall survival, this difference did not remain statistically significant in the multivariable analysis.

Kidney transplant recipients (KTRs) often exhibit impaired immune responses to vaccination, necessitating multiple doses to obtain sufficient protection from severe disease. This study compared immunological mechanisms underlying the vaccine-induced response between KTRs who responded to primary vaccination (primary responders) and those who only responded to a booster vaccination (booster responders). Humoral immune responses, including binding and Fc-mediated functionalities, and T cell responses, were generally comparable in primary and booster responders. More in-depth analyses revealed that booster responders had an expanded memory B cell pool and stronger omicron BA.1 neutralization, while primary responders had more IL-21-producing T cells and a distinct SARS-CoV-2-specific CD4 T cell phenotype. Principal component analysis demonstrated that booster responders exhibited a more refined immune network integration. These results suggest that the delayed immune response of booster responders is not functionally impaired and that repeated vaccination is an effective strategy to achieve adequate protection in this population.