Christoph A. Schatz

This review provides a focused overview of the current cancer landscape in Europe, addressing epidemiological trends, cancer-related costs, prevention and early detection, inequalities in access to care, and the implementation of therapeutic innovation. Recent studies from major European institutions were selected to illustrate key developments. Cancer incidence, mortality, direct and indirect costs vary substantially across countries, although comparisons remain limited by differences in geographical areas included, data collection, registration systems, and methodological approaches. The available evidence highlights the need for more standardized cancer data, greater investment in prevention, equitable implementation of screening programmes, broader access to multidisciplinary care, advanced diagnostic tools, clinical trials, and precision oncology. European funding programmes and collaborative networks may contribute to these objectives by promoting shared research infrastructures and cooperation.

The mammalian sirtuins (SIRTs), consisting of seven members (SIRT 1–7), are NAD⁺-dependent histone deacetylases (HDACs). Similar to other classical NAD⁺-independent HDACs, SIRTs regulate a wide range of key biological processes by deacetylating both histone and non-histone proteins. By linking cellular metabolism to tissue homeostasis, SIRTs play important roles in physiological regulation and are often deregulated in many human diseases including diabetes, neurodegeneration and cancer, particularly sarcomas. Here, we reviewed the expression and roles of SIRTs, especially the most studied family member SIRT 1, across several types of human sarcomas, including both bone and soft tissues sarcomas. We also discussed the clinical relevance of SIRTs and the potential of their modulation as a therapeutic strategy in sarcomas.

Supplementary Tables and Supplementary Methods

Targeted alpha therapies (TAT) are an innovative class of therapies for cancer treatment. The unique mode-of-action of TATs is the induction of deleterious DNA double-strand breaks. Difficult-to-treat cancers, such as gynecologic cancers upregulating the chemoresistance P-glycoprotein (p-gp) and overexpressing the membrane protein mesothelin (MSLN), are promising targets for TATs. Here, based on the previous encouraging findings with monotherapy, we investigated the efficacy of the mesothelin-targeted thorium-227 conjugate (MSLN-TTC) both as monotherapy and in combination with chemotherapies and antiangiogenic compounds in ovarian and cervical cancer models expressing p-gp. MSLN-TTC monotherapy showed equal cytotoxicity in vitro in p-gp–positive and -negative cancer cells, while chemotherapeutics dramatically lost activity on p-gp–positive cancer cells. In vivo, MSLN-TTC exhibited dose-dependent tumor growth inhibition with treatment/control ratios of 0.03–0.44 in various xenograft models irrespective of p-gp expression status. Furthermore, MSLN-TTC was more efficacious in p-gp–expressing tumors than chemotherapeutics. In the MSLN-expressing ST206B ovarian cancer patient-derived xenograft model, MSLN-TTC accumulated specifically in the tumor, which combined with pegylated liposomal doxorubicin (Doxil), docetaxel, bevacizumab, or regorafenib treatment induced additive-to-synergistic antitumor efficacy and substantially increased response rates compared with respective monotherapies. The combination treatments were well tolerated and only transient decreases in white and red blood cells were observed. In summary, we demonstrate that MSLN-TTC treatment shows efficacy in p-gp–expressing models of chemoresistance and has combination potential with chemo- and antiangiogenic therapies.

Increasing evidence showed that altered histone deacetylases ( HDACs ) are involved in, and exert cell type specific roles in sarcomagenesis. Here we reviewed expression and roles of HDACs in several types of human sarcomas, providing a basic guideline for personalized therapy. In sarcomas, overexpression of HDACs was common, including a prevalence in uterine sarcomas. Class I HDAC1–3 , especially HDAC1-2 , were upregulated in most sarcomas and were often associated with poor prognosis. Class I HDACs inhibit tumor suppressor expression and lineage differentiation, but maintain chromatin integrity and oncofusion protein stability. Class II HDACs have specific functions in cellular transformation, long telomeres maintenance, drug resistance, and cytoskeletal organization, and act as negative predictors in some sarcomas; for example, HDAC4 for leiomyosarcoma (LMS) and endometrial stromal sarcoma (ESS), HDAC5 for uterine LMS, HDAC6 for ESS, chondrosarcoma (CHS) and undifferentiated endometrial sarcoma. Moreover, some HDACs play dual, cell-context or cellular localization-dependent roles. HDAC 2 and HDAC5 could promote or suppress osteosarcoma growth. HDAC4 acts as a tumor suppressor in CHS but as an oncogene in other sarcomas. Moreover, HDAC4 is the targets of several microRNAs in osteosarcoma. Cytoplasmic HDAC6 increases self-renewal and cell migration, compared with nuclear HDAC6 enhancing EWSR1-FLI1 transcription. Thus, the diverse expression and roles of HDACs in sarcoma pathogenesis will be a solid foundation to guide personalized therapeutic application of HDAC modulators in sarcomas.

Purpose: Despite the clinical evidence of actinium-225 ( ²²⁵ Ac)-based targeted alpha therapies (TαT) efficacy, optimized treatment regimens are needed to improve overall clinical response rates and decrease toxicities. The nuclear recoil effect of ²²⁵ Ac and its resulting daughter nuclides have been hypothesized to contribute to non-targeted damage. However, a lack of generator concepts for radionuclidically pure francium-221 ( ²²¹ Fr), involvement of strong acids for elution, and its short half-life (4.8 min), has limited in vivo studies. Here, we report on a successful application of an ²²⁵ Ac/ ²²¹ Fr generator concept and the in vivo distribution of ²²¹ Fr and bismuth-213 ( ²¹³ Bi). Methods: The immobilization of ²²⁵ Ac and elution of ²²¹ Fr was performed on a LN2 resin column. The biodistribution of ²²¹ Fr and ²¹³ Bi was investigated in male SCID mice with LNCaP tumors at 5 and 15 min p.i. Results: Our results indicate that LN2 resin is a highly efficient resin for selective separation of ²²⁵ Ac and ²²¹ Fr. The use of 0.1 M NaOAc enabled continuous elution at a constant pH. The biodistribution study revealed a fast distribution of ²²¹ Fr and ²¹³ Bi already 5 min p.i. We observed a strong accumulation of ²²¹ Fr to the kidneys, salivary glands and small intestine. In ²¹³ Bi-injected mice, the highest accumulation was in kidney and liver. Conclusion: We present an unprecedented concept utilizing LN2 resin in ²²⁵ Ac/ ²²¹ Fr generator applications. Successfully eluted and injected ²²¹ Fr fractions showed strong accumulation of ²²¹ Fr and ²¹³ Bi in key organs. Our data provide preliminary evidence of the potential contribution of recoiled progeny radionuclides to side-effects in non-targeted organs.

In June 2024, a 41 year-old woman presented to the infectious diseases outpatient clinic with a left inguinal mass progressing in size. The patient had previously been on vacation in Greece. When a tumor was initially suspected, the mass was surgically removed. Staining with Grocott methenamine silver and Alzian blue were inconspicuous, but histopathologic examination revealed a clear histiocytic demarcation, followed by a confirmation of the suspected diagnosis of dirofilariasis caused by Dirofilaria repens by PCR. Even though still a rare event in Austria, the number of human D. repens cases has been continuously increasing in recent years. This is partly due to the increased spread of the parasite due to climate change and globalization.

Despite treatment, prostate cancer commonly progresses into castration-resistant prostate cancer (CRPC), which remains largely incurable, requiring the development of new interventions. Darolutamide is an orally administered second-generation androgen receptor inhibitor indicated for patients with non-metastatic CRPC or metastatic hormone-sensitive prostate cancer. Here, we evaluated the effect of androgen receptor (AR) inhibition by darolutamide in combination with DNA double-strand-break-inducing targeted radium-223 alpha therapy in vitro and in an intratibial LNCaP xenograft model mimicking prostate cancer metastasized to bone. The results highlight the synergistic antitumor efficacy of darolutamide in combination with radium-223 both in vitro and in vivo. This effect was most likely driven by the downregulation of genes involved in DDR signaling, which was demonstrated in vitro by a gene set enrichment analysis. The combination treatment also reduced pathological tumor-induced effects in bone by decreasing the number of osteoblasts and osteoclasts and reducing abnormal bone formation in tumor-bearing bone. Additionally, it was shown that darolutamide does not affect the uptake of radium-223 into bone tissue. These results support the investigation of darolutamide in combination with radium-223 for the treatment of patients with CRPC metastasized to bone.

Supplementary Tables and Supplementary Methods

Supplementary Tables and Supplementary Methods