Comprehensive Cancer Center Erlangen

C-X-C motif chemokine receptor 4 (CXCR4) is a transmembrane chemokine receptor involved in various biologic processes, including tumor growth, metastasis, and the homing and retention of hematopoietic stem cells or progenitors in hematopoietic sites ([1][1]). Under physiologic conditions, CXCR4 is

Sildenafil, a selective phosphodiesterase-5 (PDE5) inhibitor, supports vascular remodeling, but its effects on angiogenesis and regeneration of ischemic muscle tissue are not fully understood. We investigated the function of sildenafil by employing a murine hindlimb model of ischemia, in which ischemia and angiogenesis is induced by femoral artery ligation (FAL) in the lower leg of mice. Then, 7 days after FAL or sham operation, gastrocnemius muscles of sildenafil-treated and control mice were isolated and processed for histological and immunofluorescence analyses. Sildenafil treatment led to reduced apoptotic areas within the ischemic tissue (ascertained via TUNEL assay) and increased angiogenesis, evidenced by a higher capillary-to-muscle fiber ratio and an augmented number of proliferating capillary cells (CD31+/CD45-/BrdU+), compared to controls. We observed a decrease in the total count of leukocytes (CD45+) in sildenafil-treated mice. Regarding macrophage infiltration, we found a reduced total number of macrophages (CD68+), along with a shift in macrophage polarization toward the pro-angiogenic and anti-inflammatory M2-like phenotype (CD68+/MRC1+). In summary, we show that sildenafil treatment contributes to angiogenesis and the regeneration of ischemic muscle tissue, most likely by attenuating inflammatory responses and influencing macrophage polarization in direction to regenerative M2-like polarized macrophages.

Abstract Background: In the KEYNOTE-522 study (NCT03036488), neoadjuvant pembrolizumab (pembro) plus chemotherapy (chemo) followed by adjuvant pembro plus chemo significantly improved pathological complete response (pCR), event-free survival, and OS compared with placebo (pbo) plus chemo in participants (pts) with early-stage TNBC. Following neoadjuvant therapy, the estimated treatment difference in pCR for pembro plus chemo vs pbo plus chemo was 13.6% (95% CI, 5.4%‒21.8%; P < 0.001) at the first interim analysis (N=602). Although pCR provides a definitive indicator of neoadjuvant treatment success, other measures, such as RECIST v1.1 and functional tumor volume (FTV), may offer an earlier signal of therapeutic activity. This prespecified exploratory analysis evaluated associations of pCR with ORR at different time points per MRI by RECIST v1.1 and FTV by blinded independent central review. Methods: Pts with previously untreated TNBC (stage T1c N1-N2 or T2-T4 N0-N2) were randomized 2:1 to neoadjuvant pembro 200 mg Q3W or pbo, each with 4 cycles of paclitaxel plus carboplatin (treatment 1) then with 4 cycles of doxorubicin or epirubicin plus cyclophosphamide (treatment 2). After definitive surgery, pts received adjuvant pembro or pbo for 9 cycles or until recurrence/unacceptable toxicity. Breast MRI was performed for consenting pts at screening and after neoadjuvant treatments 1 and 2. Responders were defined as pts who achieved CR or PR per RECIST v1.1 by blinded independent central radiology review. The subgroup analyses population included the randomized pts who signed MRI consent and had baseline values by central radiology review. Results: At data cutoff (March 23, 2021), MRI subgroup analyses included 162 pts (pembro plus chemo, n = 97; pbo plus chemo, n = 65). After treatment 1, ORR per RECIST v1.1 was 91.8% for pembro plus chemo vs 84.6% for pbo plus chemo, while ORR per MRI FTV was 96.9% vs 93.8%. After treatment 2, ORR per RECIST v1.1 was 82.5% vs 90.8%, and ORR per MRI FTV was 84.5% vs 92.3% for pembro plus chemo and pbo plus chemo, respectively. In the post hoc exploratory analyses for pCR in the MRI subgroup, pCR rate (ypT0/Tis ypN0; 95% CI) was 62.9% (52.5%-72.5%) with pembro plus chemo vs 52.3% (39.5%-64.9%) with pbo plus chemo. Odds ratios (OR) for achieving pCR among pts with ORR per RECIST v1.1 or FTV across all patients (pembro plus chemo and pbo plus chemo combined) are shown in the Table. Conclusions: Across all pts (ie, for pembro plus chemo and pbo plus chemo combined), the odds of achieving pCR were higher among pts who had an objective response per either RECIST v1.1 or FTV. Citation Format: J. Cortés, R. Dent, H. McArthur, L. Pusztai, S. Kümmel, C. Denkert, J. O’Shaughnessy, P. A. Fasching, M. Untch, R. Tarnawaski, M. Mouret-Reynier, S. M. Stemmer, T. Foukakis, J. Boileau, C. Chung, M. Fernandez, J. A. Mejia, F. Beca, S. Hou, P. Schmid. Phase 3 study of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab for early-stage TNBC: KEYNOTE-522 magnetic resonance imaging (MRI) subgroup analysis [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 PS4-07-24.

Abstract Background: RIB demonstrated clinically and statistically significant PFS and overall survival (OS) benefit in all of its phase 3 trials in HR+/HER2− advanced breast cancer (ABC; ML-2, -3, -7). We studied clinical characteristics and biomarkers of pts who derived long-term treatment benefit. We present an exploratory analysis of the ML trials of all 1L pts with long-term response (LTR; PFS >4 y) to RIB and 1L postmenopausal pts with very long-term response (VLTR; PFS >5 y). Methods: In the ML trials, pre- (ML-7) and postmenopausal (ML-2, -3) pts with HR+/HER2− ABC received RIB + ET or placebo + ET. Only pts who received 1L RIB were included in this pooled analysis. Pts with early relapse (treatment-free interval [TFI] ≤12 months on [neo]adjuvant ET) and those in ML-7 treated with tamoxifen were excluded. Overall median follow-up (mfu) was 6.1 y (ML-2, 6.7 y; ML-3, 5.9 y; ML-7, 4.5 y). Given the median PFS of ≈2 y reported with CDK4/6i in 1L ABC, more than doubling that time (PFS >4 y) was considered LTR. VLTR was defined as PFS >5 y, calculated only for postmenopausal pts (ML-2, -3) as mfu in ML-7 was <5 y. Biomarker analyses were performed using baseline ctDNA and tumor samples. Nominal P values (unadjusted) were calculated to compare characteristics of pts with LTR and non-LTR. Results: Of 666 pts treated with 1L RIB + ET included in the analysis, 109 were on treatment at data cutoff. A total of 153 pts (23.0%) had LTR; 164 pts (24.6%) were censored before LTR cutoff. Median PFS (mPFS) in pts with LTR was 6.8 y (95% CI: 6.4 y-NE [not estimable]); median OS (mOS) was NE (95% CI: 7 y-NE). Age, body mass index, and menopausal status were balanced between pts with LTR and non-LTR ( Table ). Similar proportions of premenopausal (34/150 [22.7%]) and postmenopausal pts (119/516 [23.1%]) had LTR. Pts with LTR were less likely than those with non-LTR to have liver metastasis (16.3% vs 25.5%) and less likely to have ≥3 metastatic sites (30.1% vs 43.0%). Similar proportions of pts with LTR vs non-LTR had bone-only disease (24.2% vs 19.5%). ctDNA analysis used a panel of 558 genes; gene expression analysis used 800 genes. Pts with LTR had a lower mean ctDNA fraction and were less likely to have CCND1 or TP53 alteration detected by ctDNA. Additionally, they had lower gene expression of CCNE1 and a higher proportion of luminal A disease (PAM50 based). Of 516 postmenopausal pts, 88 (17.1%) had VLTR; further analysis will be provided in the presentation. Conclusions: In the ML studies, 1 of 4 pts treated with 1L RIB were able to derive LTR (PFS >4 y). Pts with LTR had mPFS of 6.8 y, and mOS was NE. Although LTR was more evident in pts with better prognostic factors, noticeably, some pts with unfavorable prognostic factors were still able to achieve LTR. This exploratory analysis suggests long-term benefit with 1L RIB in keeping a good number of pts with HR+/HER2− ABC free of disease progression for more than 4 y. Citation Format: F. Andre, P. A. Fasching, A. Prat, P. Neven, Y. Lu, A. Bardia, G. Curigliano, V. Kaklamani, P. Razavi, Y. Yap, F. Su, E. Roux, K. Pantoja, J. Wu, A. Lteif, D. Juric. Pooled analysis of patients (pts) treated with 1st-line (1L) ribociclib (RIB) + endocrine therapy (ET) in the MONALEESA (ML) studies: long-term progression-free survival (PFS) [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 PD5-10.

ObjectiveThis study was undertaken to evaluate whether synaptic vesicle protein 2A (SV2A) expression on peripheral immune cells predicts treatment response to levetiracetam in epilepsy.MethodsHigh‐dimensional flow cytometry was used to prospectively assess SV2A expression on immune cells from levetiracetam responders, nonresponders, and healthy controls. SV2A expression levels were further validated using real‐time quantitative polymerase chain reaction (RT‐qPCR) in an independent retrospective cohort. The predictive value of SV2A expression on naive CD8+ T cell‐specific SV2A/CD3+ median fluorescence intensity (MFI) ratio was determined, and correlations with central nervous system (CNS)‐resident cell expression were examined in the wild‐type (WT) C57BL6 mouse model.ResultsNaive CD8+ T cells showed significantly lower SV2A expression (p = .0029) in nonresponders compared to responders, confirmed by RT‐qPCR (p = .0022), with no difference in overall CD8+ T‐cell abundance. The naive CD8+ T cell‐specific SV2A/CD3+ MFI ratio (>.4733) correctly identified most responders, with a positive predictive value of 81.8%. SV2A concentration was stable over time (mean interval = 121.2 days, 95% confidence interval = 93.64–148.7 days), unaffected by age, gender, dose, or treatment duration, and neuronal SV2A expression in the CNS of WT C57BL6 mice correlated with SV2A expression of CD8+ in circulating blood cells (r = .655, p = .008).SignificanceNaive CD8+ T cell‐specific SV2A MFI ratio may represent a potential indicator of treatment response for levetiracetam. Pending further validation, its stability and accessibility suggest that it could potentially support treatment decisions and help to reduce ineffective drug trials.

Penile carcinoma (PC) is a rare malignancy with substantial geographic and etiological heterogeneity. Histologically, it is stratified into HPV-associated and HPV-independent subtypes, each with distinct clinical behaviors and molecular features. Prognostic markers such as histologic tumor stage, grade, nodal involvement, and lymphovascular invasion guide therapeutic decision-making, while emerging predictive biomarkers-HPV status, PD-L1 expression, and tumor mutational burden-show potential to personalize systemic treatment. Advances in tumor microenvironment (TME) profiling have revealed immune and stromal signatures that have the potential to influence treatment response. While immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) show early clinical benefits, biomarker-driven patient selection remains essential to optimize efficacy. This review summarizes current evidence on the TME in PC and novel therapeutic strategies, aiming to guide future personalized treatment strategies.

Targeted therapies (TT) improve outcomes in BRAF-mutant melanoma. Pre-clinical data suggest that anticoagulation (AC) and platelet aggregation inhibition (PAI) may have antitumoral effects. We evaluated the impact of concomitant AC or PAI on outcomes in patients receiving TT. We analyzed 1296 patients with unresectable stage III-IV BRAF-mutant melanoma treated with BRAF plus MEK inhibitors (2016-2024) in the prospective multicenter ADOReg registry. Patients were categorized as receiving no antithrombotic therapy (ATT; n = 1125), PAI (n = 73; acetylsalicylic acid or clopidogrel), or AC (n = 98; direct oral anticoagulants, low-molecular-weight heparin, or vitamin K antagonists). Median follow-up was 1.3 years. Compared with patients without ATT, those receiving AC had significantly improved 12-month progression-free survival (PFS; HR 0.55, 95 % CI 0.39-0.78, p = 0.001) and overall survival (OS; HR 0.35, 95 % CI 0.19-0.64, p = 0.001). Direct oral anticoagulants showed the most pronounced PFS benefit (HR 0.40, 95 % CI 0.25-0.64, p < 0.001). PAI was not associated with a significant difference in PFS, but multivariable Cox regression indicated a reduced hazard of death (HR 0.48, 95 % CI 0.27-0.87, p = 0.015). Concomitant AC, particularly factor Xa-inhibiting direct oral anticoagulants, was associated with improved survival in melanoma patients undergoing TT. These findings support prospective trials evaluating AC as concomitant therapy in advanced melanoma.

BackgroundIntraoperative cone‐beam computed tomography (CBCT) provides a valuable option for accurate three‐dimensional applicator positioning in gynecologic brachytherapy, but is associated with radiation exposure and increased intervention time especially in case of repeated CBCT imaging being required for creating a sufficient implant arrangement.PurposeTo reduce the need for multiple CBCT scans for corresponding applicator verification, this work proposes two methods for needle path navigation, including corrections of potential bending in situ, by combining infrared tracking with planar x‐ray imaging for enabling accurate intraoperative needle guidance.MethodsAn examined 200 mm brachytherapy needle was rigidly mounted on an infrared‐reflective tracking tool to enable real time tracking. Two planar x‐ray images, acquired from varying distinct angles, were used to determine the exact 3D position of the needle tip region via backprojection. A spline was fitted through the obtained coordinates to reconstruct the full needle path. Based on this, only a single initial CBCT scan was required to visualize the predicted needle path within this scan. Additionally, a second approach for needle prediction was presented focusing on only one planar x‐ray image by incorporating prior needle bending information from the initial CBCT scan. Both methods were evaluated in preclinical studies and validated against a corresponding ground‐truth obtained from CBCT.ResultsThe proposed method considering two planar x‐ray images successfully reconstructed the needle path with deviations of less than 1 mm from the CBCT reference scan, when using at least 20° offset between the x‐ray image acquisitions. The single‐scan approach, using prior bending information, yielded promising results with deviations at the tip of below 1.3 mm.ConclusionsBoth described methods demonstrated their feasibility in preclinical studies, showing potential to improve and accelerate clinical implantation workflows by means of needle navigation in the future.