e13855 Background: Geriatric oncology (GO) addresses the unique needs of older cancer patients, an increasingly critical population as the demographic shift towards aging continues. However, evidence gaps and a lack of standardized guidelines hinder the integration of GO into daily oncology practice. We conducted a comprehensive survey among physicians evaluate the current status of geriatric oncology in Switzerland . identify positive aspects as well as barriers. Methods: A structured questionnaire was disseminated to approximately 300 oncology professionals including hematologists, pathologists, gynecologic oncologists via email through the Swiss Group for Clinical Cancer Research (SAKK) between July and September 2024. Anonymous responses were collected using MS Forms with follow-up at the SAKK semi-annual meeting. The survey assessed baseline characteristics, utilization of GO guidelines, screening practices, and perceptions regarding the benefits and barriers to implementing GO in clinical settings. Results: A total of 100 responses were analyzed (response rate: > 30%). Key findings include: Participant Profile: 55% female; 45% male. Predominantly professionals managing solid tumors, with 50% utilizing GO guidelines. The majority of participants were senior specialists ( > 10 years of clinical experience). Screening Practices: The G8 tool was the most frequently used (45/68), primarily for patients aged > 65 with geriatric syndromes or > 75 years. Benefits of GO Assessments: Improved treatment personalization (69 mentions), quality of life (61 mentions), and decision-making accuracy (58 mentions) were cited as key advantages. Barriers: Personnel and expertise shortages were noted by 48% of respondents, alongside limited interest in GO workshops and insufficient healthcare policy support. Clinical Impact: Treatment modifications following GO assessments were reported occasionally (85%) or often (8%), with frequent exclusion of chemotherapy when inappropriate. Research Interests: High interest was observed in research domains like gynecological oncology, hematology, and surgery. Conclusions: While Switzerland has a robust network of experienced oncology professionals and supportive services, the integration of GO remains inconsistent and sparse. Addressing barriers such as personnel training, policy frameworks, and fostering research collaboration is essential. Initiatives to promote early education in GO, advocate for patient-centered care, and establish national consensus standards are critical next steps. These efforts will position Switzerland as a leader in geriatric oncology amidst a rapidly aging European population. Future Directions: The Swiss Geriatric Oncology Group (SGOG) aims to expand its efforts in education, research, and policy advocacy to bridge gaps in the implementation of GO, ensuring optimal care for older cancer patients.

PDF file - 209KB, Positivity for SALL4, OCT3/4, keratins, EpCAM and Cellsearch(registered trademark) assay in control cell lines. A, Double fluorescence staining for SALL4 (green) / keratins (orange) and OCT3/4 (green) / EpCAM (orange) counterstained with DAPI (blue) to visualize cells' nuclei in 4 different germ cell tumor cell lines (magnification: 400x). Scale bar, 50 microm. B, Representation of the staining of tumor cells from 4 different germ cell tumor cell lines spiked into blood of healthy donors using the Cellsearch(registered trademark) assay. C, Representative images of primary testicular germ cell tumor samples positive for SALL4, OCT3/4, keratins and EpCAM immunohistochemical staining counterstained with Hematoxylin to visualize cells' nuclei (magnification - 400x, scale bar - 50 microm). (CK, cytokeratin. PE, phycoerythrin. APC, allophycocyanin. DAPI, 4′,6-diamidino-2-phenylindole). D, Dot-like pattern keratin (orange) staining in TCam-2 and NT2 cell lines, counterstained with DAPI (blue) to visualize cells' nuclei (magnification: 1000x). Scale bar, 20 microm.

PDF file - 65KB, Characterization of relapsed, treatment-refractory germ cell tumor patients.

Abstract Purpose: Germ cell tumors (GCTs) represent the most frequent malignancies among young men, but little is known about circulating tumor cells (CTCs) in these tumors. Considering their heterogeneity, CTCs were investigated using two independent assays targeting germ cell tumor and epithelial cell–specific markers, and results were correlated with disease stage, histology, and serum tumor markers. Experimental Design: CTCs were enriched from peripheral blood (n = 143 patients) and testicular vein blood (TVB, n = 19 patients) using Ficoll density gradient centrifugation. For CTC detection, a combination of germ cell tumor (anti-SALL4, anti-OCT3/4) and epithelial cell–specific (anti-keratin, anti-EpCAM) antibodies was used. In parallel, 122 corresponding peripheral blood samples were analyzed using the CellSearch system. Results: In total, CTCs were detected in 25 of 143 (17.5%) peripheral blood samples, whereas only 11.5% of patients were CTC-positive when considering exclusively the CellSearch assay. The presence of CTCs in peripheral blood correlated with clinical stage (P < 0.001) with 41% of CTC positivity in patients with metastasized tumors and 100% in patients with relapsed and chemotherapy-refractory disease. Histologically, CTC-positive patients suffered more frequently from nonseminomatous primary tumors (P < 0.001), with higher percentage of yolk sac (P < 0.001) and teratoma (P = 0.004) components. Furthermore, CTC detection was associated with elevated serum levels of α-fetoprotein (AFP; P = 0.025), β-human chorionic gonadotropin (βHCG; P = 0.002), and lactate dehydrogenase (LDH; P = 0.002). Incidence and numbers of CTCs in TVB were much higher than in peripheral blood. Conclusions: The inclusion of germ cell tumor–specific markers improves CTC detection in GCTs. CTCs occur frequently in patients with more aggressive disease, and there is a gradient of CTCs with decreasing numbers from the tumor-draining vein to the periphery. Clin Cancer Res; 20(14); 3830–41. ©2014 AACR.

Despite recent advances in the treatment of metastatic castration-resistant prostate cancer (CRPC), treatment is inevitably hampered by the development of drug resistance. Thus, new drugs are urgently needed. We investigated the efficacy, toxicity, and mechanism of action of the marine triterpene glycoside cucumarioside A2-2 (CA2-2) using an in vitro CRPC model. CA2-2 induced a G2/M-phase cell cycle arrest in human prostate cancer PC-3 cells and caspase-dependent apoptosis executed via an intrinsic pathway. Additionally, the drug inhibited the formation and growth of CRPC cell colonies at low micromolar concentrations. A global proteome analysis performed using the 2D-PAGE technique, followed by MALDI-MS and bioinformatical evaluation, revealed alterations in the proteins involved in cellular processes such as metastatic potential, invasion, and apoptosis. Among others, the regulation of keratin 81, CrkII, IL-1β, and cathepsin B could be identified by our proteomics approach. The effects were validated on the protein level by a 2D Western blotting analysis. Our results demonstrate the promising anticancer activity of CA2-2 in a prostate cancer model and provide insights on the underlying mode of action.

The field of marine bioactive compounds (marine drugs) has evolved significantly in recent years [...]

PURPOSE Cisplatin is the main systemic treatment modality for male type II germ cell tumors (GCTs). Although generally very effective, 5%-10% of patients suffer from cisplatin-resistant disease. Identification of the driving mechanisms of resistance will enable improved risk stratification and development of alternative treatments. METHODS We developed and characterized cisplatin-resistant GCT cell line models and compared their molecular characteristics with patient samples with cisplatin resistance and/or a poor clinical outcome. Subsequently, the association between the overlapping genetic features and clinical data was assessed. Finally, we used Cox regression to determine the prognostic relevance of these features within the currently used risk classification. RESULTS Gain of chromosome 3p25.3 was detected in all cisplatin-resistant cell lines, and copy number of this region correlated with the level of resistance (R = 0.96, P = 1.5e-04). Gain of this region was detected at low frequencies in primary tumors and at higher frequencies in relapsed and/or cisplatin-resistant tumors. Chromosome 3p25.3 gain was associated with shorter progression-free survival and overall survival, with the strongest association observed in nonseminomas excluding pure teratomas. 3p25.3 gain was more frequently observed in tumors with yolk sac tumor histology and predicted adverse outcome independent of the International Germ Cell Cancer Collaborative Group risk classification and the presence of TP53/MDM2 alterations. CONCLUSION On the basis of both in vitro analyses and clinical data, we found 3p25.3 to be strongly associated with cisplatin resistance and poor clinical outcome in male type II GCTs. Using genomic profiling, 3p25.3 status could help to improve risk stratification in male patients with type II GCT. Further characterization of this locus and underlying mechanisms of resistance is warranted to guide development of novel treatment approaches for cisplatin-resistant disease.

Cisplatin-based chemotherapy has been used for more than four decades as a standard therapeutic option in several tumor entities. However, being a multifaceted and heterogeneous phenomenon, inherent or acquired resistance to cisplatin remains a major obstacle during the treatment of several solid malignancies and inevitably results in disease progression. Hence, we felt there was an urgent need to evaluate common mechanisms between multifarious cancer entities to identify patient-specific therapeutic strategies. We found joint molecular and (epi)genetic resistance mechanisms and specific cisplatin-induced mutational signatures that depended on the developmental origin (endo-, meso-, ectoderm) of the tumor tissue. Based on the findings of thirteen tumor entities, we identified three resistance groups, where Group 1 (endodermal origin) prominently indicates NRF2-pathway activation, Group 2 (mesodermal origin, primordial germ cells) shares elevated DNA repair mechanisms and decreased apoptosis induction, and Group 3 (ectodermal and paraxial mesodermal origin) commonly presents deregulated apoptosis induction and alternating pathways as the main cisplatin-induced resistance mechanisms. This review further proposes potential and novel therapeutic strategies to improve the outcome of cisplatin-based chemotherapy.

Germ cell tumors (GCTs) are developmental cancers, tightly linked to embryogenesis and germ cell development. The recent and expanding field of RNA modifications is being increasingly implicated in such molecular events, as well as in tumor progression and resistance to therapy, but still rarely explored in GCTs. In this work, and as a follow-up of our recent study on this topic in TGCT tissue samples, we aim to investigate the role of N6-methyladenosine (m6A), the most abundant of such modifications in mRNA, in in vitro and in vivo models representative of such tumors. Four cell lines representative of GCTs (three testicular and one mediastinal), including an isogenic cisplatin resistant subline, were used. CRISPR/Cas9-mediated knockdown of VIRMA was established and the chorioallantoic membrane assay was used to study its phenotypic effect in vivo. We demonstrated the differential expression of the various m6A writers, readers and erasers in GCT cell lines representative of the major classes of these tumors, seminomas and non-seminomas, and we evidenced changes occurring upon differentiation with all-trans retinoic acid treatment. We showed differential expression also among cells sensitive and resistant to cisplatin treatment, implicating these players in acquisition of cisplatin resistant phenotype. Knockdown of VIRMA led to disruption of the remaining methyltransferase complex and decrease in m6A abundance, as well as overall reduced tumor aggressiveness (with decreased cell viability, tumor cell proliferation, migration, and invasion) and increased sensitivity to cisplatin treatment, both in vitro and confirmed in vivo. Enhanced response to cisplatin after VIRMA knockdown was related to significant increase in DNA damage (with higher γH2AX and GADD45B levels) and downregulation of XLF and MRE11. VIRMA has an oncogenic role in GCTs confirming our previous tissue-based study and is further involved in response to cisplatin by interfering with DNA repair. These data contribute to our better understanding of the emergence of cisplatin resistance in GCTs and support recent attempts to therapeutically target elements of the m6A writer complex.

Approximately 420 men are diagnosed with germ-cell cancer (GCC) in Switzerland each year. Recent international guidelines outline management issues, but many aspects remain controversial in an area of highly individualised treatments. Even more than in other tumour types, in GCC the challenge is to choose exactly the correct treatment for an individual patient. Overtreatment in patients likely to be cured must be avoided to reduce long-term toxicities. On the other hand, treatment intensification is required in patients presenting with adverse prognostic factors. Therefore, referral to expert centres or consultations with an expert for a second opinion is strongly recommended. In 2020, Swiss experts discussed their strategies in a consensus meeting during the virtual Swiss Oncology and Haematology Congress (SOHC) in order to harmonise their concepts and to suggest optimal strategies for the management of GCC patients in Switzerland. Votes on controversial issues were obtained and are presented in this review wherever applicable.

Novel treatment options are needed for testicular germ cell tumor (TGCT) patients, particularly important for those showing or developing cisplatin resistance, the major cause of cancer-related deaths. As TGCTs pathobiology is highly related to epigenetic (de)regulation, epidrugs are potentially effective therapies. Hence, we sought to explore, for the first time, the effect of the two most recently FDA-approved HDAC inhibitors (HDACis), belinostat and panobinostat, in (T)GCT cell lines including those resistant to cisplatin. In silico results were validated in 261 patient samples and differential expression of HDACs was also observed across cell lines. Belinostat and panobinostat reduced cell viability in both cisplatin-sensitive cells (NCCIT-P, 2102Ep-P, and NT2-P) and, importantly, also in matched cisplatin-resistant subclones (NCCIT-R, 2102Ep-R, and NT2-R), with IC50s in the low nanomolar range for all cell lines. Treatment of NCCIT-R with both drugs increased acetylation, induced cell cycle arrest, reduced proliferation, decreased Ki67 index, and increased p21, while increasing cell death by apoptosis, with upregulation of cleaved caspase 3. These findings support the effectiveness of HDACis for treating TGCT patients in general, including those developing cisplatin resistance. Future studies should explore them as single or combination agents.

While the majority of patients with advanced testicular germ cell tumors (GCT) achieve complete responses after chemotherapy and if indicated after postchemotherapy resection of residual lesions, about 20% of patients have incomplete responses or show relapses. Moreover, toxicity of chemotherapy is high, and severe adverse chronic effects have been described. Therefore, there is an urgent need for biomarkers that could help to improve tumor staging, and support decision-making, ideally including monitoring of therapy response and prediction of relapse. Besides the well-established serum markers lactate dehydrogenase, α-fetoprotein, and β-subunit of human chorionic gonadotropin, during recent years new noninvasive liquid biopsy markers have been investigated in GCT, including cell-free nucleic acids like microRNAs, and circulating tumor cells (CTCs).Prognostic relevance has been demonstrated for circulating tumor cells (CTCs) in patients with different cancers. However, little is known in GCT patients. Histologically, GCT are a very heterogeneous group of tumors comprising pure seminomas (consisting of cells that remember primordial germ cells) and nonseminomas, which are either undifferentiated (embryonal carcinoma) or differentiated, exhibiting different degrees of embryonic (teratoma) or extraembryonic (yolk sac tumor and choriocarcinoma) differentiation. This heterogeneity hampers capture and detection of CTCs deriving from those tumors using a single method or a single antibody. To date, label-independent capture methods that enrich tumor cells according to the density of GCT cells, which is similar to that of mononuclear cells, have been successfully applied. Since testicular GCT might also express epithelial proteins, methods based on enrichment of CTCs using epithelial markers are promising to detect CTCs in certain subgroups of patients with GCTs as well.Here, we describe and discuss a combination of methods to capture and detect GCT cells with epithelial and germ cell characteristics in blood.

Autophagy (Ancient Greek αὐτόφαγος [autóphagos]—“self-devouring”) is defined as a regulated mechanism of the degradation of unnecessary or dysfunctional cellular components [...]

By the end of the year 2020, there are nine marine-derived anticancer drugs available on the market, and the field is currently growing exponentially [...]

The role of subcellular survivin compartmentalization in the biology and prognosis of prostate cancer is unclear. We therefore investigated subcellular localization of survivin in more than 3000 prostate cancer patients by quantitative immunohistochemistry and performed transcriptomics of 250 prostate cancer patients and healthy donors using publicly available datasets. Survivin (BIRC5) gene expression was increased in primary prostate cancers and metastases, but did not differ in recurrent vs non-recurrent prostate cancers. Survivin immunohistochemistry (IHC) staining was limited exclusively to the nucleus in 900 prostate cancers (40.0%), and accompanied by various levels of cytoplasmic positivity in 1338 tumors (59.4%). 0.5% of prostate cancers did not express survivin. Nuclear and cytoplasmic survivin staining intensities were strongly associated with each other, pT category, and higher Gleason scores. Cytoplasmic but not nuclear survivin staining correlated with high tumor cell proliferation in prostate cancers. Strong cytoplasmic survivin staining, but not nuclear staining predicted an unfavorable outcome in univariate analyses. Multivariate Cox regression analysis showed that survivin is not an independent prognostic marker. In conclusion, we provide evidence that survivin expression is increased in prostate cancers, especially in metastatic disease, resulting in higher aggressiveness and tumor progression. In addition, subcellular compartmentalization is an important aspect of survivin cancer biology, as only cytoplasmic, but not nuclear survivin accumulation is linked to biological aggressiveness and prognosis of prostate cancers.

In 2019, the scientific and medical community celebrated the 50th anniversary of the introduction of the very first marine-derived drug, Cytarabine, into clinics [...]

Malignant germ cell tumors (GCT) are the most common malignant tumors in young men between 18 and 40 years. The correct identification of histological subtypes, in difficult cases supported by immunohistochemistry, is essential for therapeutic management. Furthermore, biomarkers may help to understand pathophysiological processes in these tumor types. Two GCT cell lines, TCam-2 with seminoma-like characteristics, and NTERA-2, an embryonal carcinoma-like cell line, were compared by a quantitative proteomic approach using high-resolution mass spectrometry (MS) in combination with stable isotope labelling by amino acid in cell culture (SILAC). We were able to identify 4856 proteins and quantify the expression of 3936. 347 were significantly differentially expressed between the two cell lines. For further validation, CD81, CBX-3, PHF6, and ENSA were analyzed by western blot analysis. The results confirmed the MS results. Immunohistochemical analysis on 59 formalin-fixed and paraffin-embedded (FFPE) normal and GCT tissue samples (normal testis, GCNIS, seminomas, and embryonal carcinomas) of these proteins demonstrated the ability to distinguish different GCT subtypes, especially seminomas and embryonal carcinomas. In addition, siRNA-mediated knockdown of these proteins resulted in an antiproliferative effect in TCam-2, NTERA-2, and an additional embryonal carcinoma-like cell line, NCCIT. In summary, this study represents a proteomic resource for the discrimination of malignant germ cell tumor subtypes and the observed antiproliferative effect after knockdown of selected proteins paves the way for the identification of new potential drug targets.

Background Treatment options for patients (pts) with multiply relapsed or refractory metastatic germ cell cancer (GCC) are limited. The mTOR inhibitor everolimus has been approved for the treatment of different solid tumors and was assessed in refractory GCC within this phase II RADIT trial of the German Testicular Cancer Study Group. Methods GCC pts progressing during cisplatin-based salvage chemotherapy, or relapsing after high-dose chemotherapy, or failing at least two lines of cisplatin-based chemotherapy were eligible. Prior combination chemotherapy with gemcitabine, oxaliplatin and paclitaxel, or a doublet combination of these drugs was mandatory. Primary endpoint was the progression-free survival rate at 12 weeks. Twenty-five evaluable pts were needed, assuming a 20% two-sided type 1 error and 95% power to reject the null hypothesis of 5% of patients being progression-free after 12 weeks. At least one pt among the first 13 pts being progression-free after 6 weeks was mandatory to complete recruitment. Secondary endpoints were objective response rate, disease control rate (SD + PR + CR), median progression-free survival (PFS), median overall survival (OS), and safety. The trial was registered at http://clinicaltrials.gov as NCT01242631. Results Twenty-five pts from six German centers were treated with everolimus 10 mg orally once daily until disease progression or unacceptable toxicity between December 2010 and January 2014. 12-week PFS rate was 0%, no objective responses were achieved, and only one pt had stable disease after 6 weeks on treatment as a prerequisite of completing patient accrual accounting for a 6-week disease control rate of 5.4%. Median PFS and OS were estimated at 7.4 weeks and 8.3 weeks, respectively. Toxicity was acceptable, with one treatment discontinuation due to adverse events, and no new safety signals detected. Conclusions Targeting the mTOR pathway with single-agent everolimus failed to produce clinically relevant responses in pts with heavily pretreated and/or cisplatin-refractory GCC.

To gain knowledge about the factors associated with discontinuation of scheduled treatment in elderly men with castration-resistant prostate cancer (CRPC).