Rijnstate Hospital

To determine the safety and efficacy of taselisib, a selective PI3K inhibitor, in combination with tamoxifen. POSEIDON is a phase II, randomized, placebo-controlled trial conducted from June 2016 to March 2020. Eligible patients were refractory upon prior endocrine therapy. Prior treatment with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and everolimus was allowed. Patients were randomized (1:1) to receive either taselisib (4 mg) + tamoxifen (20 mg) or placebo + tamoxifen. The primary endpoint of the trial was investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) population (two-sided α 0.2, 90% power). Exploratory biomarker analysis with regards to prognosis and treatment resistance was conducted in circulating tumor (ct)DNA. POSEIDON met its primary endpoint, in which patients treated with taselisib + tamoxifen had improved PFS compared with patients treated with placebo + tamoxifen in the ITT population (median PFS 4.8 months vs. 3.2 months; stratified hazard ratio 0.69; 80% confidence interval, 0.49-0.98, P = 0.17). However, toxicity of taselisib was significant, with diarrhea (40% any grade) as the most common adverse event. Exploratory analyses indicated that high tumor fraction (TF) determined in ctDNA at baseline is associated with worse PFS and overall survival (P < 0.0001). Our findings suggest efficacy of PI3K inhibition + tamoxifen beyond second-line treatment and after prior targeted therapies, including CDK4/6 inhibition in metastatic HR+/HER2- breast cancer, although the magnitude of benefit did not outweigh the tolerability of this combination. Exploratory biomarker analysis indicates that TF determined in ctDNA differentiates patients based on prognosis and may help optimize patient selection for targeted treatment strategies.

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.

Electroconvulsive therapy (ECT) is an effective treatment for major depressive episodes, though its mechanisms remain unclear. Its use is limited by stigma and potential cognitive side-effects. Repeated magnetic resonance imaging (MRI) may provide further insights into brain changes related to ECT’s efficacy and cognitive outcomes. We analyzed cognitive, efficacy, and MRI data from depressed patients undergoing ECT in two prospective longitudinal trials (NCT04028596, NL-OMON43040), using 26 matched healthy controls (2020-BC-12375) to control for test-retest effects. All participants were scanned on the same MRI system. Structural and diffusion tensor imaging (DTI) scans were acquired at baseline, after the initial ECT sessions, within two weeks post-treatment, and at three-month follow-up. Linear and nonlinear changes in grey matter (GM) volume, white matter (WM) volume, mean diffusivity (MD), and fractional anisotropy (FA) were assessed. Early brain changes were examined in relation to clinical outcomes. After the 3rd ECT session (n = 19), subcortical GM volume increased with a right-lateralized MD decrease. Two weeks post-ECT (n = 30), cortical GM volume increased, returning to baseline by three months. In WM, MD increased linearly post-ECT and remained elevated at follow-up, with no widespread FA changes (n = 30). ECT transiently impaired verbal learning (n = 23, pbonferroni = 0.04), letter fluency (n = 22, pbonferroni = 0.04), and animal fluency (n = 62, pbonferroni = 0.02). Early brain changes were not associated with cognitive or efficacy outcomes. These results suggest that ECT induces rapid changes in brain macrostructure and microstructure. While macrostructural increases are temporary, microstructural changes in brain structure are longer-lasting.

Abstract Background: In early-stage breast cancer, surgical de-escalation from axillary lymph node dissection (ALND) to sentinel lymph node biopsy (SLNB) did not compromise oncologic safety. This has led to the realization that SLNB predominantly provides prognostic information and may itself not influence recurrence or survival. The BOOG 2013-08 trial was therefore designed to evaluate whether omission of SLNB in clinically T1-2N0 patients treated with breast-conserving surgery and whole-breast irradiation (summarized together as BCT) is safe with respect to regional recurrence rates (RR) and distant disease-free survival (DDFS). Methods: The BOOG 2013-08 (NCT02271828) is a multicenter, non-inferiority, randomized phase-3 trial including women with unilateral cT1-2N0 breast cancer treated with BCT. Clinically node-negative was based on negative findings on physical examination and preoperative axillary ultrasound (including negative cyto- or histopathology in case of a suspicious findings). The trial was conducted in the Netherlands between 2015 and 2022 across 25 centers. Patients were randomized (1:1) to SLNB or omission of SLNB. Randomization was stratified by clinical tumor size (&amp;lt;3 cm vs ≥3 cm), histological grade (grade I-II vs III), hormone receptor status (HR), HER2 status, age (≤50, 50 ≤ 75, &amp;gt;75 years), primary systemic therapy (PST) and participating center. The primary endpoint was 5-year RR; secondary endpoints as presented here were 3-year RR and DDFS. Cumulative probabilities of RR and DDFS were estimated using the Kaplan-Meier method. Non-inferiority was defined as an absolute difference in RR ≤5% in favor of the control group at 5 years. Analyses were performed per-protocol. Results: A total of 1,733 patients were enrolled across 25 centers. After excluding 159 patients (n=106 due to radiation therapy protocol violations), 1574 patients were included (SLNB: n=749; no-SLNB: n=825). At the time of analysis, 100% of patients had reached 3 years and 73% 5-year follow-up. Median follow-up was 5.0 years (range 0.78-6.86, IQR 1.94). Mean age was 61.5 years, 83% had cT1 tumors and 17% cT2 tumors. Tumor grade was I in 28.7%, II in 54.1% and III in 17.2%. Breast cancer subtype was HR+HER2- in 86.8%, triple negative in 5.8% and HER2+ in 7.4% of patients. In the SLNB arm, micro- and macrometastatic disease was detected in 6.0% and 7.7%, respectively. Preliminary data at a median 5-year follow-up showed that the estimated probability of RR was 0.5% in the SLNB arm (95% CI 0.0-1.1) and 1.2% in the no-SLNB arm (95% CI 0.4-2.0), corresponding to an absolute difference of 0.7% (95% CI -0.3 to 1.7). The confidence interval ranges from -0.3 to 0.7, indicating that the 5% non-inferiority margin is not exceeded. Five-year DDFS was 98.3% (95% CI 97.3-99.3) in the SLNB arm versus 96.1% (95% CI 94.5-97.7) in the no-SLNB arm (log-rank p=0.071).Chemo- or endocrine therapy was administered in 11.3% of patients as PST (12.3% SLNB arm vs. 10.3 no-SLNB arm, p=0.214). In total, 50.0% of patients received systemic therapy (51.2% SLNB vs. 49.0% no-SLNB, p 0.202). Of these 50.0%, 39.4% received chemotherapy with or without targeted therapy. Among ER-positive patients, adjuvant endocrine therapy was administered in 48.6% (SLNB) and 46.6% (no-SLNB), p=0.732, while chemotherapy was given in 9.8% and 8.2%, respectively (p=0.532). Conclusions: In cT1-2N0 breast cancer patients treated with BCT, omission of SLNB resulted in a non-inferior median 5-year RR and DDFS compared with SLNB. These premature findings support the omission of SLNB, at least in case of cT1N0, ER+, grade 1-2 breast cancer. This study further demonstrates that adjuvant hormonal therapy should not be a prerequisite for omission of the SLNB. Citation Format: R. J. Schipper, L. M. van Roozendaal, V. M. Wintraecken, J. M. Simons, M. Moossdorff, E. J. T. Luiten, F. van Duijnhoven, L. de Munck, L. F. C. Dols, R. Koelemij, R. van Eekeren, A. B. Francken, T. van Dalen, K. Keymeulen, J. Volders, J. A. van der Hage, H. Torrenga, P. A. Neijenhuis, P. Nijhuis, D. van Uden, E. Heuts, M. A. Bessems, C. D. Dirksen, M. H. Martens, M. F. Bouwmeester, K. Schenk, A. V. R. J. Bell, S. Maaskant-Braat, L. J. A. Strobbe, S. C. Linn, P. M. P. Poortmans, M. L. G. Vane, V. C. G. Tjan-Heijnen, K. K. B. T. van der Vijver, M. B. I. Lobbes, J. de Vries, L. Emelianova-Hiddink, J. Kandt, L. J. Boersma, J. H. W. de Wilt, S. M. J. van Kuijk, M. L. Smidt, BOOG 2013-08 Study Group. Omission of sentinel lymph node biopsy in clinically T1-2 node-negative breast cancer patients treated with breast-conserving therapy: results of the Dutch BOOG 2013-08 randomized controlled trial after a median follow-up of 5 years [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS2-11.

Previous research has highlighted the benefits of reducing contrast media (CM), demonstrating positive impacts on patient safety, environmental sustainability, and health care costs. The 10-to-10 rule, introduced by a single-center study, adjusts CM dose to total body weight and tube voltage. This approach resulted in a reduced overall CM volume, with homogeneous attenuation and consistent diagnostic image quality (IQ) across varying tube voltages. This study aimed to evaluate the effectiveness of the 10-to-10 rule in achieving consistent and homogeneous attenuation in vascular and parenchymal CT in a multicenter clinical practice setting across Europe. A total of 1,037 patients scheduled for CT of the coronary arteries (high-pitch and sequential CCTA), pulmonary arteries (CTPA), aorta (CTA aorta), and abdominal CT in portal venous phase or venous phase scans of the neck were included in this nonrandomized multicenter trial, conducted at 5 centers in the Netherlands, Germany, and Switzerland. Each center followed its standard scan and reconstruction protocol based on the clinical request. CM protocols were based on the 10-to-10 rule: A 10kV reduction in tube voltage should be accompanied by a 10% decrease in iodine delivery rate for vascular studies or total iodine load in parenchymal studies, and vice versa. Objective image quality (IQ) was assessed by drawing region of interests, measuring attenuation [Hounsfield Unit (HU)], and calculating signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). In vascular studies, a reference line was included, representing the threshold for sufficient diagnostic IQ (CCTA-325HU, CTPA-200HU, and CTA Aorta-250HU). 95% CI of the mean attenuation was calculated, and the lower bound of each 95% CI was used as the reference to assess whether attenuation met these thresholds. Generalized mixed models tested for significant differences in objective IQ across varying tube voltages, presented both unadjusted and multivariate adjusted by age and gender. Results demonstrated no significant differences in attenuation for distal high-pitch CCTA, proximal sequential CCTA, distal CTPA, CTA aorta, abdominal portal venous phase scans, and the thyroid gland and sternocleidomastoid muscle in venous phase scans of the neck after adjusting for age and gender. Proximal high-pitch CCTA, distal sequential CCTA, and proximal CTPA yielded significant results ( P =0.030, P <0.001, and P =0.002, respectively). SNR and CNR showed no significant differences for all scan protocols. The majority of 95% CI lower bounds exceeded the predefined threshold for sufficient diagnostic IQ. Exceptions included high-pitch CCTA scans, where only the 90kV level met the threshold, as well as in sequential CCTA at 120kV, and CTPA at 110 and 120kV, for which the lower bounds remained below the threshold. This study demonstrates the generalizability and effectiveness of the 10-to-10 rule in a multicenter trial setting and a large patient population, showing limited significant deviations in iodine attenuation across varying tube voltages for both vascular and parenchymal CT studies.

Work-related musculoskeletal disorders are a growing concern in surgical practice, particularly in the context of robot-assisted surgery. Physical strain can significantly impact the well-being and performance of surgeons and surgical staff. This study aimed to evaluate the prevalence and severity of surgical strain among urologists using different available surgical platforms. An anonymized, web-based survey was conducted between March and October 2024 using the REDCap platform. Distributed via professional networks and social media, the survey collected data on demographics, surgical experience, platform usage, and self-reported physical discomfort. Statistical analysis included Mann-Whitney U and Chi-squared tests, with P<0.05 considered significant. A total of 427 urologists participated. Most console surgeons (up to 83% for one robotic system variant) reported some level of physical discomfort. Discomfort was also reported by 83% of open surgeons and 80% of bedside assistants, the latter of whom had the highest incidence of injury (53%) from robotic arms. A noteworthy subset of survey respondents required physiotherapy (13-15%), medical (6-11%), or surgical (2-3.8%) interventions due to physical strain. No significant differences were observed by age or sex among console users. Ergonomic strain is prevalent among urologic surgeons, regardless of surgical platform, with bedside assistants particularly vulnerable. These findings underscore the need for ergonomic training, physical conditioning, and design improvements in surgical systems to safeguard surgeon health and maintain procedural efficacy.