Boris Hadaschik

Background: Pulmonary metastasectomy (PM) is an established component of multimodal oncological treatment, but its perioperative safety and long-term outcomes in patients with chronic obstructive pulmonary disease (COPD) remain insufficiently defined. We aimed to evaluate the impact of COPD on perioperative morbidity, mortality and long-term survival after PM. Methods: We retrospectively analysed 692 patients who underwent PM with curative intent. COPD severity was graded using the GOLD spirometric classification. Patients were classified according to their postbronchodilator FEV1/FVC ratio into a COPD group (p < 0.001). Overall morbidity and 30-day mortality, however, did not differ. With a median follow-up of 76.7 months, survival was similar between groups (3-year survival 76.5% vs. 78.4%, p = 0.495) and was unaffected by GOLD severity. Independent predictors of worse survival were preoperative systemic therapy (HR 2.18), repeat metastasectomy (HR 1.60) and increasing age (HR 1.02 per year). After propensity matching, survival remained comparable (HR 1.05, p = 0.835). Conclusions: Among carefully selected patients, COPD was not associated with increased mortality or reduced survival after PM, although persistent air leak was significantly more frequent. COPD alone should not, by itself, be considered a contraindication to curative-intent surgery in appropriately selected patients, and these findings should not be generalized to patients with severe or end-stage COPD.

Adverse drug effects remain a major barrier to safe and effective cancer therapy, underscoring the need for tools that predict treatment-related toxicities. We analyzed multimodal real-world data from 14,596 cancer patients across 38 cancer entities, encompassing 330 clinical, tumor, and imaging characteristics, along with 89 anticancer agents. Hematological adverse events (HAE), defined by nadirs of hemoglobin, leukocyte, neutrophil, and platelet values within two months of treatment initiation, were highly prevalent (87.7%; 33.1% severe). We developed Toxix , an explainable artificial intelligence (xAI) framework modeling interactions between patient characteristics and drug combinations. Toxix achieved strong predictive performance for severe toxicities (median AUROC 0.85 for anemia; >0.76 for leukopenia, neutropenia, and thrombocytopenia) and was validated in an external cohort of 2,768 patients with non-small cell lung cancer. Model explainability enabled systematic characterization of drug-patient interactions underlying HAEs. Toxix provides a real-world informed framework for personalized and toxicity-aware cancer therapy planning.

Summary: Radioligand therapy exemplifies precision oncology, yet its consequences remain incompletely understood. A recent article shows that [177Lu]Lu-PSMA promotes emergence and expansion of clonal hematopoiesis enriched for DNA damage response gene mutations, reframing bone marrow effects as treatment-emergent clonal selection rather than collateral toxicity and informing biology-guided patient monitoring and theranostics. See related article by Munzur et al., p. 2644

Background/Objectives: Stress urinary incontinence (SUI) remains a common and functionally relevant complication after radical prostatectomy (RP) and substantially impairs quality of life (QoL). Although pelvic floor muscle training (PFMT) is guideline-recommended, its real-world effectiveness is often limited by accessibility, standardization, and adherence. Digital health interventions may improve adherence to PFMT, potentially influencing continence recovery. We conducted a multicenter randomized controlled trial to evaluate whether a structured, modular app-based PFMT program improves early continence recovery compared with conventional physiotherapist-guided training. Methods: Between September 2022 and September 2024, 62 preoperatively continent men undergoing radical prostatectomy were enrolled in this multicenter randomized controlled trial (Pelvintense). Both groups received perioperative PFMT: Patients were randomized 1:1 to either a modular app-based PFMT program (intervention group) or a standard physiotherapist-guided PFMT (control group). Both app-based PFMT and standard physiotherapist-guided PFMT started three weeks before surgery and continued for 90 days postoperatively. The primary endpoint was continence at 90 days, defined as ICIQ-SF Q1 = 0 (absence of involuntary SUI). Secondary endpoints included continence sub-scores, QoL, erectile function, adherence, and decision regret. Analyses were performed using a modified intention-to-treat approach applying logistic regression and non-parametric tests with sensitivity analyses. Results: A total of 62 patients were included in the study and randomized, with 31 allocated to the app-based PFMT arm and 31 to the standard physiotherapist-guided arm. Three patients in the control arm withdrew consent for data usage after randomization, resulting in a modified intention-to-treat population of 59 patients. At 90 days, continence rates were higher in the app-based group compared with the control group (74.2% versus 21.4%; p < 0.001), corresponding to an absolute risk reduction of 52.8% and a number needed to treat of two. In multivariable analysis, participation in the app-based program was independently associated with higher odds of continence recovery (odds ratio 13.80, 95%-confidence interval 3.22–59.12; p < 0.001). Continence at 30 days and continence-related QoL favored the intervention, whereas no significant differences were observed in erectile function at 90 days. Adherence to the PFMT was higher in the intervention group. Sensitivity analyses confirmed the robustness of the primary outcome. Conclusions: In this randomized controlled trial, a modular app-based PFMT program was associated with early continence recovery after prostatectomy compared with the standard-of-care physiotherapist-guided PFMT. Improved adherence, modular progression of exercises, and a more structured training delivery may have contributed to the effect. App-based PFMT might represent a scalable strategy to implement guideline-recommended supportive care. These findings warrant confirmation in studies with a longer follow-up.

Chronic pyelonephritis is characterized by persistent bacterial infection of the kidney and a dysregulated immune response that promotes disease progression. Macrophages are central regulators of antibacterial immunity in the urinary tract. However, the mechanisms underlying their functional reprogramming in chronic infection remain poorly understood. Here, we identify lactate as a key metabolic determinant of macrophage polarization in human pyelonephritis. Proteomic analysis of human kidney tissue revealed extensive metabolic remodelling, including upregulation of enzymes involved in glycolysis. Consistent with this, lactate levels were significantly elevated in urine and plasma of pyelonephritis patients. Concomitantly, we observed a pronounced accumulation of CD163 macrophages in infected kidneys, representing a distinct macrophage subset with immunomodulatory function. Correlation-based network analysis revealed a strong association between CD163 and lactate dehydrogenase A, supporting a functional association between lactate metabolism and macrophage polarization. Mechanistically, exposure of murine bone marrow-derived macrophages to lactate induced intracellular protein lactylation and promoted polarization toward a CD163 phenotype, defining a metabolically imprinted macrophage state distinct from classical activation paradigms. Proteomic profiling demonstrated extensive remodelling of macrophage protein expression in response to lactate with significant alteration of mediators of phagocytosis, Toll-like receptor signalling, and interferon response. Together, these findings identify lactate as a potent metabolic driver of macrophage reprogramming and establish a foundation for investigating lactylation-dependent immune dysfunction in chronic pyelonephritis.

BAP1 is a tumor suppressor and epigenetic modifier that is frequently mutated in cancer, leading to increased aggressiveness and metastasis, as well as poor patient survival. Unfortunately, there are currently no specific therapies for metastatic tumors harboring BAP1 mutations. In this study, we have identified a new targetable BAP1-associated autophagic vulnerability. We demonstrate that BAP1 transcriptionally regulates the proto-oncogene SRC, a non-receptor tyrosine kinase. SRC then binds to, phosphorylates, and inactivates BECN1 (Beclin 1), an essential autophagy protein. This inhibits autophagy in cells derived from various cancer types with BAP1 mutations. Treatment of these cells with SRC inhibitors (such as dasatinib, bosutinib and saracatinib) and autophagy-inducing drugs (such as Tat-BECN1, SW076956 and SW063058) demonstrated a synergistic interaction between these compounds both in vitro and in ovo using a chick Chorioallantoic Membrane (CAM) assay. Furthermore, ex vivo studies employing patient-derived tumor organoids (PDTOs) of uveal melanoma (UM) and clear-cell renal cell carcinoma (ccRCC) as preclinical models have substantiated the synergism of these drugs, preferentially in the context of BAP1 loss. Our findings elucidate a novel BAP1-SRC-BECN1-autophagy regulatory axis that can be exploited therapeutically in precision oncology through the combination of SRC inhibitors and autophagy inducers, contingent upon patient stratification for BAP1 loss.Significance: Deadly cancers with BAP1 mutations suppress autophagy by phosphorylating the autophagy regulator BECN1 via the proto-oncogene SRC. Treatment with SRC inhibitors and autophagy inducers exhibited synergism in vitro, in ovo and in patient-derived tumor organoids with BAP1 loss, paving the way for treating BAP1-deficient cancers with autophagy inducers and kinase inhibitors.

Cancer worry and risk perception are relevant psychological factors that influence preventive health behaviors. Therefore, a thorough understanding of the factors that impact their occurrence and manifestation is critical. The objective of this study was to assess prevalence and factors associated with worry about prostate cancer (PCa) and absolute/comparative risk perception in a community-based sample of 45-year-old men. Data were collected within the German PCa screening trial PROBASE. Variables were assessed by self-report questionnaires and a clinical interview. Worry about PCa and absolute/comparative risk perception were assessed each on a 5-point-Likert scale. Multivariable logistic regression was used to identify factors associated with the outcomes of interest. Data were available for 33,476 (72.0%) of 46,495 men at enrollment. 7.3% had sometimes/(very) often worry about PCa. 3.7% and 9.9% perceived their absolute risk and comparative risk as somewhat high/very high and somewhat higher/much higher, respectively. 18.8% reported a positive PCa family history. Important factors of worry about PCa, absolute risk perception, and comparative risk perception were lower urinary tract symptoms (LUTS) (OR 3.00, 95% CI 2.63–3.42; OR 2.09, CI 1.71–2.56; OR 2.41, CI 2.10–2.76) and a positive PCa family history (OR 2.35, CI 2.08–2.65; OR 15.13, CI 12.73–17.97; OR 9.69, CI 8.76–10.72). A positive history of urological (OR 3.85, CI 2.63–5.63) and non-urological cancers (OR 1.97, CI 1.52–2.54) were associated with a higher comparative risk perception. In conclusion, worry about PCa and risk perception are influenced by non-cancer-related symptoms as well as by a positive PCa family history. These findings need to be addressed in risk communication with patients.