Radiotherapy (RT) is a central treatment for prostate cancer (PCa), relying on the induction of DNA double-strand breaks (DSBs). Tumor ability to repair these breaks limits RT efficacy, making DSB repair inhibitors potential radiosensitizers. However, many of these inhibitors lack tumor specificity and harm normal cells. Therefore, tumor-specific radiosensitization strategies are critically needed for PCa. Approximately 50% of PCa cases harbor the TMPRSS2-ERG gene fusion, leading to overexpression of the ERG transcription factor (ERG+). In this study, we demonstrate that ERG+ tumors shift DSB repair toward the poly(ADP-ribose) polymerase 1-dependent end-joining (PARP1-EJ) pathway. Proteomic and Western blot analyses revealed elevated PARP1, XRCC1, and LIG3 levels in ERG+ cells. Notably, PARP inhibition with olaparib increased residual γH2AX/53BP1 foci postirradiation in ERG+ cells, indicating enhanced radiosensitization. In tissue slice cultures (TSCs) from 53 tumors of patients with high-risk PCa, olaparib selectively increased γH2AX/53BP1 foci selectively in ERG+ samples. ERG+ patient-derived organoids also showed significantly delayed growth when treated with olaparib plus RT, compared with either treatment alone. Interestingly, ERG-negative cells within ERG+ TSCs were similarly radiosensitized by olaparib, likely through bystander effect, with residual 53BP1 foci levels comparable to those in ERG+ cells. This was confirmed by medium exchange experiments. These findings suggest that ERG expression promotes dependency on the PARP1-EJ pathway, rendering ERG+ PCa more susceptible to PARP inhibition. This supports combining PARP inhibitors with RT for tumor-selective radiosensitization in ERG+ patients.

INTRODUCTION:Molecular tumor boards (MTBs) integrate clinical, pathological, and molecular data to prioritize therapy options. Because MTB-guided treatment starts at varying time points after MTB discussion, vulnerabilities to immortal time bias occur if treatment delay is ignored. METHODS:Retrospective survival analysis of 949 consecutive individuals discussed at the University Cancer Center Hamburg MTB (2016-2022). Index date (t0) was the first MTB discussion. Therapy initiation was modeled as a time-dependent exposure using Mantel-Byar methods and visualized with Simon-Makuch plots. Therapy strata were priority 1 targeted, priority 2 targeted, and non-targeted therapy. RESULTS:Among solid tumors (n = 854), targeted therapy was implemented in 24% and was off-label in 51%. ORR/DCR were 30.8%/61% for priority 1, 11.4%/36.4% for priority 2, and 37.5%/52.1% for non-targeted therapy (P = .017). The progression-free survival ratio (MTB-directed therapy vs immediately preceding line) exceeded 1.3 in 63% of targeted therapy recipients. From the MTB date, median survivalMTB was 16.5 months (priority 1), 15.5 months (priority 2), and 11.0 months (non-targeted). In Mantel-Byar analysis, progression-free survivalSimonMakuch favored priority 1 (P = .002) with 1-year rates of 28%, 12%, and 15% for priority 1, priority 2, and non-targeted therapy, respectively. One-year overall survivalSimonMakuch was 52%, 34%, and 42%. In a time-dependent Cox model, priority 1 was associated with lower risk of death versus no targeted post-MTB therapy (hazard ratio 0.80, 95% confidence interval 0.64-0.99, P = .038). CONCLUSIONS:After correction for immortal time bias, implementation of the top-priority MTB recommendation was associated with improved disease control and survival signals, although confounding and selection effects remain key limitations.

Exhaled breath condensate (EBC) has emerged as a noninvasive liquid biopsy medium that captures aerosolized material from the respiratory tract and may provide insight into local lung biology. Within this matrix, extracellular vesicles (EVs) can carry DNA, RNA, proteins, and lipids that reflect cellular origin and may report tumor-associated inflammation, airway remodeling, and microenvironmental changes. This review summarizes current evidence on the molecular composition, origin, and biogenesis of EVs detected in EBC, with emphasis on their potential for early lung cancer detection and longitudinal disease monitoring. Proteomic, transcriptomic, and genomic analyses have identified tumor-associated signatures, including cytokines, driver mutations, and epigenetic alterations, whereas lipidomic profiling may capture oxidative, inflammatory, and metabolic stress. Recent methodological advances in EV enrichment, microfluidics, single-vesicle analytics, and digital assays are improving the sensitivity of low-biomass EBC analyses. However, EBC-derived EV research remains technically challenging, and standardization of collection, EV isolation, molecular analysis, and reporting is essential. Artificial intelligence (AI) and machine learning (ML) may support integration of multiomic and clinical data, particularly when validated in prospective cohorts. Together, these developments position EBC-derived EVs as an emerging, patient-friendly, lung-proximal platform for biomarker discovery and future precision oncology applications, while underscoring the need for source-resolved validation and clinical translation studies.

Background The advent of B-cell maturation antigen (BCMA)-targeted immunotherapies has markedly transformed the prognosis for patients with relapsed/refractory multiple myeloma (r/r MM). However, the emergence of therapeutic resistance, frequently driven by tumor-intrinsic alterations in the TNFRSF17 (tumor necrosis factor receptor superfamily member 17) gene encoding BCMA, remains a critical clinical challenge. While the event of complete antigen loss via biallelic gene deletion is well-described, the functional impact of novel, non-truncating variants of uncertain significance (VUS) discovered through comprehensive sequencing is often unclear, complicating therapeutic decisions. Methods Whole-genome sequencing (WGS) was performed on purified CD138 + plasma cells from two patients with r/r MM who experienced disease progression after treatment with the anti-BCMA chimeric antigen receptor (CAR) T-cell therapy idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel). We developed a novel AI-based computational workflow to assess the impact of identified TNFRSF17 mutations on protein structure response to treatment across a panel of clinically relevant BCMA-directed agents. Our method combines AI-based protein-complex structure prediction with binding free energy calculations. Results WGS revealed a monoallelic deletion of 16p13, encompassing the TNFRSF17 gene locus, in both patients, accompanied by distinct subclones on the remaining allele: three VUS (p.Cys37Tyr, p.Cys24_Cys28del, and p.Pro23delins9) in patient #1, and the p.Cys8Trp VUS in patient #2. All detected variants in the protein sequence are localized within the extracellular, epitope-bearing domain of BCMA. Our AI-driven structural analysis predicted that these mutations induce significant conformational changes, primarily by disrupting the stabilizing disulfide bond network. Quantitative energetic calculations demonstrated that these variants would severely impair or completely abrogate binding of specific therapeutic agents, including ide-cel and belantamab cilta-cel, consistent with the patients’ clinical course of relapse. Notably, our analysis showed differential effects across various agents, with the binding affinity of some therapeutics predicted to remain robust to the structural changes. Conclusion The integration of WGS into diagnostics with AI-driven structural and energetic modeling provides a powerful framework for the functional interpretation of VUS in TNFRSF17 . This approach can rapidly elucidate patient-specific, epitope-dependent resistance mechanisms and has the potential to guide the rational sequencing of BCMA-targeted therapies. By transforming VUS from a diagnostic challenge into an actionable clinical biomarker, this methodology represents a critical step toward precision immunotherapy in MM.

Keimzelltumoren des Hodens betreffen überwiegend junge Männer bis zu einem Alter von 40 Jahren. Selbst in fortgeschritten metastasierten Erkrankungsstadien werden hohe Heilungsraten erzielt, sodass die Zahl Keimzelltumorüberlebender stetig steigt. Ziel der vorliegenden Arbeit war es, die Diskussion des aktuellen Wissensstands zu chemotherapieassoziierten Langzeitfolgen darzustellen und einen Überblick über relevante Nachsorgeaspekte für die klinische Praxis zu geben. Es handelt sich um eine narrative Übersichtsarbeit, basierend auf einer selektiven Literaturrecherche in der Datenbank PubMed, zur Zusammenfassung der vorliegenden Evidenz für Folgeerkrankungen und Nachsorgeempfehlungen für Keimzelltumorüberlebende. Cisplatin-basierte Chemotherapie ist mit diversen Nebenwirkungen assoziiert, von denen einige von maßgeblicher Bedeutung für die Tumornachsorge sind. Hierzu zählen ein erhöhtes Risiko für kardiovaskuläre Ereignisse, die Entwicklung eines metabolischen Syndroms und therapieassoziierte Zweitmalignome. Weitere Langzeitfolgen betreffen eine eingeschränkte Nierenfunktion, sensorische Polyneuropathie und Hörminderung, Hypogonadismus, Fertilitätsminderung sowie chronische Fatigue, die die Lebensqualität nachhaltig negativ beeinflussen können. Auch nach Ende der onkologischen Tumornachsorge, i. d. R. nach 5 Jahren, sind die genannten Folgeerscheinungen von lebenslanger Relevanz für die Patienten. Die Früherkennung und zielgerichtete Prävention sind für Keimzelltumorüberlebende daher hochrelevant zum Erhalt der Lebensqualität, des allgemeinen Gesundheitszustands und einer normalen Lebenserwartung.

Smoking may influence cancer treatment outcomes; however, there is conflicting evidence on the efficacy of immune checkpoint inhibitors (ICIs) in active smokers. It has been suggested that smokers receiving ICIs may achieve improved outcomes compared with non-smokers. The present study aimed to challenge this assumption by investigating the prognostic impact of smoking status and other characteristics in patients with metastatic or advanced cancer undergoing ICI therapy. In the present study, patients with predetermined solid tumors who received ICIs either as a monotherapy or in combination regimens in a palliative treatment setting were retrospectively evaluated. Patients were included if they had received >1 dose of an ICI and had an available smoking status. Kaplan-Meier estimates were used to analyze the associations between smoking status and overall survival (OS) and progression-free survival (PFS). The patient baseline characteristics were assessed as potential prognostic markers using univariate and multivariate analyses. Of the 464 patients evaluated, 180 met the inclusion criteria. The cohort included patients with lung cancer (n=94), renal cell carcinoma (n=18), urothelial cancer (n=21), melanoma (n=3), and head and neck cancer (n=44). The median OS and PFS times for the whole cohort were 39.1 and 5.5 months, respectively. Patients were categorized as never-smokers (n=45, 25%), former smokers (n=81, 45%) and active smokers (n=54, 30%). The median OS times for the never, former and active smokers were 66.4, 31.6 and 13.9 months, respectively. When comparing the active smokers with the former and never smokers, the median OS times were 13.9 vs. 41.1 months (P=0.069, trend). Multivariate analyses identified Eastern Cooperative Oncology Group (ECOG) performance status ≥3 [hazard ratio (HR), 5.85; P=0.002], neutrophil-to-lymphocyte ratio (NLR; HR, 1.11; P=0.017), lactate dehydrogenase (LDH; HR, 1.00; P<0.001) and C-reactive protein (CRP) levels as continuous variables (HR, 1.01; P=0.002) as significant predictors of a poorer OS. For PFS, multivariate analysis identified sex (HR, 0.69; P=0.049), age (HR, 0.98; P=0.014) and ECOG performance status ≥3 (HR, 5.83; P<0.001) as independent predictors of a shorter PFS. In conclusion, contrary to prior hypotheses suggesting improved outcomes for smokers undergoing ICI therapy, the results of the present study demonstrated a trend towards impaired survival outcomes in active smokers compared with never and former smokers. The independent prognostic factors for a poorer OS included a poor ECOG performance status, CRP level, LDH level and NLR.

Supplementary Figure 2: Emotional distress and tumor burden do not explain the systemic inflammatory signature.

Background Malignancy-associated hemophagocytic lymphohistiocytosis (M-HLH) carries a poor prognosis and is often complicated by overlapping infection, cytopenias, organ failure, and progressive disease. Methods We retrospectively analyzed 49 adults with M-HLH at a single tertiary cancer center (2013-2026), summarizing malignancy spectrum, diagnostic features, treatment, and survival outcomes. HLH probability was assessed by HScore and modified HLH-2004 criteria. Results Lymphoma was the main underlying disease (34/49; 69.4%), led by aggressive B-cell (17/49; 34.7%) and T-cell NHL (12/49; 24.5%). HLH coincided with initial malignancy recognition in 17 of 49 patients (34.7%). The median HScore was 231 (IQR 202-256); 44 of 49 patients (89.8%) met the ≥ 169 threshold, and 42 of 49 patients (85.7%) fulfilled ≥ 5 of 7 modified HLH-2004 criteria. HLH-directed therapy included corticosteroids (41/49; 83.7%), etoposide (21/49; 42.9%), and anakinra (16/49; 32.7%); 21 of 49 patients (42.9%) received concurrent malignancy-directed chemotherapy. Mortality was 59.2% (29/49) with a median overall survival of 56 days (median follow-up 612 days for the cohort; 574 days among survivors, n = 20). De novo presentation carried substantially lower mortality than HLH in previously known malignancy (23.5% vs. 78.1%; hazard ratio [HR] 5.38, 95% confidence interval [CI], 1.85-15.61; P = .002). Malignancy-directed chemotherapy was associated with lower mortality than HLH-directed therapy alone (HR 3.11, 95% CI, 1.36-7.09; P = .007). All 6 patients with invasive mold infection died. Conclusions M-HLH was predominantly lymphoma-associated, met diagnostic criteria with high probability, and carried poor short-term survival. De novo presentation had better outcomes, likely because lymphoma-directed chemotherapy can simultaneously address the underlying malignant trigger and the hyperinflammatory state. Invasive mold infection was uniformly fatal, illustrating the lethal combination of profound immunosuppression and uncontrolled opportunistic infection in this setting.

Antiangiogenic treatment with ramucirumab (RAM) is a standard second-line option in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. However, reliable biomarkers are lacking. The phase II RAMIRIS trial compared RAM plus paclitaxel with RAM plus FOLFIRI (5-fluororuracil, leucovorin and irinotecan) in this setting. We present the exploratory biomarker analysis evaluating placental growth factor (PlGF), carbonic anhydrase IX (CAIX), and tryptase. Plasma samples from 99 patients enrolled in RAMIRIS were collected at predefined timepoints (baseline, Cycle 2 Day 1, and Cycle 4 Day 1). PlGF, CAIX, and tryptase were quantified by ELISA. Associations with progression-free survival (PFS) and overall survival (OS) were analyzed using dichotomized biomarker levels and Cox regression models. PlGF levels increased substantially under treatment, whereas CAIX showed a transient rise, followed by a slight decline, and tryptase remained stable. Elevated PlGF levels at baseline and early-treatment (c2d1) were associated with shorter OS in univariate analysis (baseline HRu = 1.75; p = 0.020; c2d1 HRu = 1.69; p = 0.054). After multivariate adjustment, the association remained directionally consistent; although statistical support was retained only for c2d1 (baseline HRm = 1.41, p = 0.198; c2d1 HRm = 1.85, p = 0.030). CAIX and tryptase showed no consistent associations with survival. Elevated PlGF-particularly its early increase during RAM-based therapy-was associated with shortened survival and may represent a dynamic marker of unfavorable prognosis in advanced gastric/GEJ adenocarcinoma. Given the exploratory nature of this analysis, these findings should be considered hypothesis-generating and require validation in independent biomarker-driven studies.

BACKGROUND:The selection of biologic therapies in metastatic colorectal cancer (mCRC) is traditionally guided by right-left classification; however, this binary classification may not fully capture heterogeneity in responsiveness to anti-epidermal growth factor receptor (EGFR) therapy. We evaluated whether treatment efficacy varies across detailed anatomical tumour segments. METHODS:Individual patient-level data from 12 randomised controlled trials in the ARCAD database were analysed. Patients with RAS wild-type (RAS-WT) mCRC receiving first-line doublet chemotherapy plus anti-EGFR therapy or bevacizumab were included. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS) and objective response rate (ORR). RESULTS:A total of 2867 patients were included (815 right-sided colon cancer [RSC]; 2052 left-sided colorectal cancer [LSC]). In RAS-WT RSCs, anti-EGFR therapy was not associated with improved OS or PFS versus bevacizumab. In RAS/BRAF-WT RSCs, anti-EGFR therapy was associated with inferior PFS. In contrast, in RAS-WT LSCs, anti-EGFR therapy significantly improved OS and ORR, without a significant difference in PFS. Segment-level analyses (N = 1491) showed no significant heterogeneity within RSCs, although median OS numerically varied across subsites. Within LSCs, the OS benefit was most pronounced in the rectum. CONCLUSIONS:The efficacy of anti-EGFR therapy in mCRC appears to exhibit additional intraregional heterogeneity beyond the conventional right-left classification. These findings suggest that anatomical tumour location may reflect underlying biological differences not fully captured by this binary classification.

Supplementary Figure 1: The duration of response to various therapy lines for patients in the Ipi arm is depicted. For each line of therapy, the duration of response (DOR) is indicated if applicable. Active therapy is represented by an arrow, and dashed arrows are used for patients who were lost to follow-up. Monotherapy with trastuzumab (T), ramucirumab (R), radiotherapy (#), or surgery (*) is also indicated.

BACKGROUND:Two PARP inhibitors (PARPis), olaparib and talazoparib, have been approved in combination with androgen receptor pathway inhibitors (ARPIs) for metastatic castration-resistant prostate cancer (mCRPC) in Europe, regardless of homologous-recombination repair (HRR) status. However, the mechanism in HRR-negative patients remains unclear. METHODS:We assessed PARP inhibitors (PARPis; olaparib, talazoparib) alone and with ARPIs (abiraterone, enzalutamide, apalutamide) in prostate cancer cell lines, metastatic patient-derived organoids (mPDOs), and LN-metastatic tissue slice cultures. HRDetect and multi-omics analyses were used to investigate response mechanisms. RESULTS:PARPi-ARPI combinations significantly reduced survival in LNCaP, DU145, and 22RV1 cells and produced greater cytotoxicity than either agent alone in all models. In three metastatic mPDOs, olaparib alone had no effect, whereas talazoparib reduced survival in one mPDO and ARPIs reduced survival in two. In all tested models, PARPi-ARPI combinations produced greater cytotoxicity than either agent alone. None of the mPDOs showed BRCAness by HRDetect. ARPIs downregulated RAD51 and induced a BRCAness-like state, with reduced RAD51 foci formation at DNA double-strand break sites and impaired repair capacity, thereby sensitizing cells to PARPis. In LN-metastatic tissue slice cultures, combination therapy reduced double-strand break repair capacity in 67% of samples. Proteomic analysis showed that olaparib suppressed prometastatic pathways, including epithelial-mesenchymal transition and angiogenesis. CONCLUSION:ARPIs induce a BRCAness-like phenotype through RAD51 downregulation and enhance PARPi sensitivity in metastatic prostate cancer models, supporting combined ARPI-PARPi therapy.

PURPOSE:Traditional adverse event (AE) reporting in oncology trials focuses on the single worst CTCAE grade, which may underrepresent chronic or recurrent toxicity burden. We applied a longitudinal toxicity framework to compare toxicity profiles of chemotherapy with or without cetuximab in metastatic colorectal cancer. PATIENTS AND METHODS:We pooled two randomized first-line trials in the ARCAD database. AEs examined were diarrhea, rash, hand-foot syndrome (HFS), fatigue, anorexia, and mucositis. Outcomes included grade ≥3 AE, time to first occurrence of maximum grade, early onset (≤6 weeks), and AEL, a normalized measure of cumulative toxicity burden over treatment. Analyses were adjusted for chemotherapy backbone, ECOG performance status, sex, primary tumor location, dose reduction, and treatment duration. RESULTS:Compared with Chemotherapy alone (n = 564), Chemotherapy plus cetuximab (n = 738) was associated with higher grade ≥3 rash (21% vs 0.5%; adjusted odds ratio [OR] 49.89, 95% CI 15.8-157.4), higher rash AEL (0.257 vs 0.069; adjusted mean difference 0.22, 95% CI 0.21-0.23), and more frequent early-onset maximum rash (67% vs 34%; adjusted OR 4.28, 95% CI 2.72-6.74). Rash AEL remained higher with cetuximab within maximum-grade strata. HFS showed higher grade ≥3 risk and overall AEL with cetuximab, but no within-grade AEL difference, indicating higher overall HFS burden reflected grade distribution rather than within-grade chronicity. No consistent differences were observed for other AEs. CONCLUSIONS:Incorporating onset timing and AEL distinguished persistent toxicity burden from isolated peak events. This framework may support comparative tolerability assessment when chronic toxicity burden is central to decision-making.

Abstract Background As improvements in anti-cancer treatments have extended survival, patients with advanced cancer and their family caregivers face existential tension between engaging in life and coping with uncertainty about illness trajectory and the course of treatment. For a subgroup, this tension is associated with overwhelming fear and existential distress. Such adjustment difficulties may increase the risk of mental disorders, poor quality of life, and suicidality, and impair prognostic awareness and patient-clinician communication. Despite growing interest in open conversations about end-of-life issues, systematic evidence on effective psychotherapies to best support psychological adaptation in patients with high levels of existential distress is still scarce. We aim to evaluate the effectiveness of a short-term psychodynamic therapy (ORPHYS) to mitigate existential distress compared to usual psycho-oncological treatment (TAU). Methods We conduct a two-arm parallel randomized controlled trial with an active control group. ORPHYS is a manualized individual face-to-face psychotherapy focusing on emotional and relational conflicts specific to cancer patients’ illness situation. Treatment lasts between 5 and 11 months with 15 to 31 weekly sessions (50 min). TAU includes at least one individual session provided by physicians or psychologists with experience in psycho-oncological care. Patients will be assessed pre-intervention and 3, 6, 9, and 12 months after baseline. Target sample size is 160 randomized participants. We recruit patients with stage III/IV solid tumors or advanced hematological cancer and clinically significant existential distress from psycho-oncology clinics and referring oncologists at Hamburg, Düsseldorf, and Würzburg Comprehensive Cancer Centers, Germany. The primary outcome is demoralization (Demoralization Scale-II). Secondary outcomes include diagnoses of affective, anxiety and stress-related disorders, death anxiety, dignity-related distress, and quality of life. Outcome assessments are conducted via self-report questionnaires and diagnostic interviews. Linear mixed models examine outcome differences between trial arms. A confirmatory test of the group contrast at 6-month follow-up after baseline is conducted. Discussion Due to an aging population and prolonged survival, there is a growing demand to help patients deal with existential challenges undergoing palliative cancer care. The study will contribute to knowledge about how clinicians can best help patients with advanced cancer who substantially struggle with uncertainty at the end of life. Trial registration German Clinical Trials Registry, DRKS00038173. Registered October 20th, 2025, https://drks.de/search/en/trial/DRKS00038173 . ClinicalTrials.gov, NCT07312760. Registered December 30, 2025, https://clinicaltrials.gov/study/NCT07312760 .

Supplementary Figure 3: Low NLR defines patients with superior survival in the Ipi arm.