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Many intracellular pathogens, such as mammalian reovirus, mimic extracellular matrix motifs to specifically interact with the host membrane. Whether and how cell-matrix interactions influence virus particle uptake is unknown, as it is usually studied from the dorsal side. Here we show that the forces exerted at the ventral side of adherent cells during reovirus uptake exceed the binding strength of biotin-neutravidin anchoring viruses to a biofunctionalized substrate. Analysis of virus dissociation kinetics using the Bell model revealed mean forces higher than 30 pN per virus, preferentially applied in the cell periphery where close matrix contacts form. Utilizing 100 nm-sized nanoparticles decorated with integrin adhesion motifs, we demonstrate that the uptake forces scale with the adhesion energy, while actin/myosin inhibitions strongly reduce the uptake frequency, but not uptake kinetics. We hypothesize that particle adhesion and the push by the substrate provide the main driving forces for uptake. Many intracellular pathogens mimic extracellular matrix motifs to specifically interact with the host membrane which may influences virus particle uptake. Here authors use single molecule tension sensors to reveal the minimal forces exerted on single virus particles and demonstrate that the uptake forces scale with the adhesion energy.

Salivary gland carcinomas are rare, heterogeneous, and often resistant to conventional treatments, highlighting the need for new therapeutic strategies. This retrospective study evaluated the expression of three immunologically relevant biomarkers—PRAME, FOLR1, and CLDN18.2—as potential therapeutic targets in salivary gland carcinomas. Tumor samples from 54 patients with seven histological subtypes treated at Saarland University Medical Center between 2013 and 2023 were analyzed using immunohistochemistry and scored with the Immunoreactive Score. PRAME was strongly expressed in 89% of cases, while FOLR1 and CLDN18.2 showed markedly lower expression at 41% and 6%, respectively. High PRAME expression was significantly associated with the presence of distant metastases, regardless of histological subtype. Patients with low PRAME expression tended to have improved overall survival, as indicated by Kaplan–Meier analysis and Log‐Rank testing. These findings suggest PRAME as a promising immunotherapeutic and diagnostic target for salivary gland carcinomas, particularly through T‐cell‐based therapies already under investigation in other malignancies such as acute myeloid leukemia. Further preclinical studies are needed to validate the functional and therapeutic significance of PRAME, FOLR1, and CLDN18.2 in this context.

Hepatocellular cancer (HCC) therapy is in need for an ideal companion diagnostic. Preclinical experimental studies have identified the insulin receptor (IR) and its synergistic counterpart, the IGF1 receptor (IGF1R), as relevant in HCC development, and the ligands IGF1 and IGF2 have been found to be elevated in HCC. This study aimed to bridge the gap to the clinical setting and explore whether the IR or the IGF1R would be of prognostic significance and would be associated with clinicopathologic parameters in HCC patients. In our retrospective cohort study located at the University Hospital Schleswig-Holstein, Campus Kiel, Germany, HCC samples of 139 patients were examined for IR and IGF1R expression by immunohistochemistry. A HistoScore was correlated with clinicopathological characteristics and survival. IR overexpression was frequently observed and was associated with clinicopathological parameters and survival. Membranous IR expression was associated with worse tumor specific survival ( p  = 0.043). Intriguingly, membranous IR expression was associated with worse tumor specific survival ( p  = 0.017) in the subgroup of patients undergoing sorafenib therapy. IGF1R expression was not associated with survival. In conclusion, our results suggest that membranous IR expression plays a role in HCC prognosis and treatment resistance, inspiring future validation as a potential companion diagnostic in HCC.

fusion-associated carcinomas of the sinonasal tract are exceedingly rare, with fewer than 100 cases reported worldwide, but probably underrecognized. Recently classified by the WHO as a distinct provisional subtype of non-keratinizing squamous cell carcinoma, these tumors pose significant diagnostic and therapeutic challenges. Their histological resemblance to inverted papillomas and their bland histology in most cases often leads to misdiagnosis, while their aggressive behavior underscores the need for a tailored treatment approach. We report two cases of fusion-associated carcinomas managed at Saarland University Medical Center. The first case involved a 46-year-old woman who initially presented with recurrent sinonasal inverted papilloma, confirmed through multiple surgical interventions over nearly a decade. In 2023, reevaluation and genetic analysis revealed a fusion. The patient demonstrated an exceptional response to three cycles of neoadjuvant gemcitabine and cisplatin, achieving complete remission on MRI restaging. This allowed a shift to definitive chemoradiotherapy, with sustained disease-free status confirmed by a PET-CT three months post-treatment in July 2024. The second case involved a 66-year-old woman presenting with recurrent inverted papilloma affecting the sinonasal and tympanic regions. Despite multiple surgeries, malignant transformation to invasive squamous cell carcinoma occurred, with lymph node metastasis and intracranial spread. A combined otolaryngological and neurosurgical approach was undertaken, but the disease progressed. The patient passed away in January 2020, with postmortem review of the prior histology and genetic analysis confirming fusion carcinoma that showed bland-looking papilloma-like morphology in the initial specimens and later a high-grade cytology indicating biological progression to poorly differentiated carcinoma. These cases highlight the aggressive nature of fusion-associated carcinomas and the critical role of genetic profiling in diagnosis and management. The exceptional, first ever reported response to neoadjuvant chemotherapy in one case underscores the potential for personalized treatment strategies, warranting further investigation into targeted therapies for this rare malignancy.

Background The incidence of Cholangiocellular Carcinoma (CCA) is increasing in the western world. The tumour has a high proportion of desmoplastic stroma and is correlated with a worse prognosis when cancer associated myofibroblasts (CAFs) are present. Recent studies showed promising results after liver transplantation (LTx) in non-resectable early stage CCA. Mycophenolic acid (MPA) and the mTor inhibitor Everolimus are used to prevent organ rejection but recently were shown to exhibit an antiproliferative effect on CCA-cells. Little is known about the influence of immunosuppressive drugs on tumour cell proliferation and migration after paracrine stimulation by CAFs. Moreover, it is still unknown, which signaling pathways are activated following these specific cell-cell interactions. Methods CCA cell lines HuCCT1 and TFK1 were utilized for the study. CAFs were derived from resected CCA cancer tissue. Cell viability was measured by the crystal violet assay and tumour cell invasion was quantified using a modified co-culture transmigration assay. Semiquantitative cytokine-expression was measured using a cytokine-array. Protein expression and phosphorylation of ERK, STAT3 and AKT was determined by Western-blot analysis. Results CCA cells treated with MPA exhibited a dose related decrease in cell viability in contrast to Cyclosporine A (CSA) treatment which had no effect on cell viability. Everolimus significantly inhibited proliferation at very low concentrations. The pro-invasive effect of CAFs in co-culture transmigration assay was significantly reduced by Everolimus at a concentration of 1nM ( p  = 0.047). In contrast, MPA and CSA showed no effect on tumour cell invasion. Treatment of CAFs with 1nM Everolimus showed a significant reduction in the expression of IL 8, IL 13, MCP1, MIF and Serpin E1. CCA-cells showed significant increases in phosphorylation of ERK, STAT3 and AKT under the influence of conditioned CAF-media. This effect was suppressed by Everolimus. Conclusions The secretion of proinflammatory cytokines by CAFs may lead to increased activation of JAK/STAT3-, ERK- and AKT-signaling and increased migration of CCA-cells. Everolimus abrogates this effect and inhibits proliferation of CCA-cells even at low concentrations. LTx for non-resectable early stage CCA is currently performed in several clinical studies. Consistent with a role for common immunosuppressants in inhibiting tumour cell-proliferation and -invasion, our study indicates that a combination of standard therapies with Everolimus and MPA is a promising therapy option to treat CCA following LTx.

Recent developments in robotic surgery have led to an increasing number of robot-assisted hepatobiliary procedures. However, a limitation of robotic surgery is the missing haptic feedback. The fluorescent dye indocyanine green (ICG) may help in this context, which accumulates in hepatocellular cancers and around hepatic metastasis. ICG accumulation may be visualized by a near-infrared camera integrated into some robotic systems, helping to perform surgery more accurately. We aimed to test the feasibility of preoperative ICG application and its intraoperative use in patients suffering from hepatocellular carcinoma and metastasis of colorectal cancer, but also of other origins. In a single-arm, single-center feasibility study, we tested preoperative ICG application and its intraoperative use in patients undergoing robot-assisted hepatic resections. Twenty patients were included in the final analysis. ICG staining helped in most cases by detecting a clear lesion or additional metastases or when performing an R0 resection. However, it has limitations if applied too late before surgery and in patients suffering from severe liver cirrhosis. ICG staining may serve as a beneficial intraoperative aid in patients undergoing robot-assisted hepatic surgery. Dose and time of application and standardized fluorescence intensity need to be further determined.

Background Obesity in the recipient is linked to inferior transplant outcome. Consequently, access to kidney transplantation (KT) is often restricted by body mass index (BMI) thresholds. Bariatric surgery (BS) has been established as a superior treatment for obesity compared to conservative measures, but it is unclear whether it is beneficial for patients on the waiting list. Methods A national survey consisting of 16 questions was sent to all heads of German KT centers. Current situation of KT candidates with obesity and the status of BS were queried. Results Center response rate was 100%. Obesity in KT candidates was considered an important issue (96.1%; n  = 49/51) and 68.6% ( n  = 35/51) of departments responded to use absolute BMI thresholds for KT waiting list access with ≥ 35 kg/m 2 (45.1%; n  = 23/51) as the most common threshold. BS was considered an appropriate weight loss therapy (92.2%; n  = 47/51), in particular before KT (88.2%; n  = 45/51). Sleeve gastrectomy was the most favored procedure (77.1%; n  = 37/51). Twenty-one (41.2%) departments responded to evaluate KT candidates with obesity by default but only 11 (21.6%) had experience with ≥  n  = 5 transplants after BS. Concerns against BS were malabsorption of immunosuppressive therapy (39.2%; n  = 20/51), perioperative morbidity (17.6%; n  = 9/51), and malnutrition (13.7%; n  = 7/51). Conclusions Obesity is potentially limiting access for KT. Despite commonly used BMI limits, only few German centers consider BS for obesity treatment in KT candidates by default. A national multicenter study is desired by nearly all heads of German transplant centers to prospectively assess the potentials, risks, and safety of BS in KT waitlisted patients. Graphical abstract

Background Head and neck squamous cell carcinomas (HNSCC) pose significant clinical challenges, particularly in high‐risk cases with positive lymph node status. Current prognostic biomarkers are often costly and methodologically demanding. In this regard, histomorphological biomarkers such as tumor buds (TB) and poorly differentiated clusters (PDC) represent promising, cost‐effective prognostic indicators that are relatively straightforward to implement. Methods The prognostic significance of TB and PDC, in conjunction with stromal tumor‐infiltrating lymphocytes (sTILs) and the tumor‐stroma ratio (TSR), was evaluated in a cohort of 50 high‐risk, nodal‐positive HNSCC patients. Histomorphological features were assessed using standard hematoxylin and eosin (H&E) staining, while HPV association and PD‐L1 expression were determined by means of immunohistochemistry (IHC) and/or PCR. All variables collected were subsequently correlated with traditional histopathological and clinical parameters. Finally, a novel scoring system incorporating TB and PDC was developed, and its association with overall survival (OS) was analyzed. Results TB and PDC both demonstrated a significant impact on patients' OS (TB Log‐rank test, p = 0.0499, PDC Log‐rank test, p = 0.0235). A novel scoring system based on these features had strong association with patients' OS (Log‐rank test, p = 0.0200) in contrast to the conventional and routinely performed grading system, which evaluates the degree of differentiation within neoplastic cells (Log‐rank test, p = 0.3325). PD‐L1 expression was not associated with TB and PDC formation. HPV‐negative status was associated with a higher number of tumor buds. Conclusion This study reveals the potential prognostic value of TB and PDC in high‐risk HNSCC, which may offer a practical and cost‐effective alternative to traditional markers. Our proposed practicable and straightforward employable scoring system significantly correlates with OS, suggesting its potential benefit in clinical practice. These findings advocate for further validation to enhance prognostic accuracy and guide treatment strategies in HNSCC.

Introduction: Robotic-assisted liver surgery (RALS) with its known limitations is gaining more importance. The fluorescent dye, indocyanine green (ICG), is a way to overcome some of these limitations. It accumulates in or around hepatic masses. The integrated near-infrared cameras help to visualize this accumulation. We aimed to compare the influence of ICG staining on the surgical and oncological outcomes in patients undergoing RALS. Material and Methods: Patients who underwent RALS between 2014 and 2021 at the Department of General Surgery at the University Hospital Schleswig-Holstein, Campus Kiel, were included. In 2019, ICG-supported RALS was introduced. Results: Fifty-four patients were included, with twenty-eight patients (50.9%) receiving preoperative ICG. Hepatocellular carcinoma (32.1%) was the main entity resected, followed by the metastasis of colorectal cancers (17%) and focal nodular hyperplasia (15.1%). ICG staining worked for different tumor entities, but diffuse staining was noted in patients with liver cirrhosis. However, ICG-supported RALS lasted shorter (142.7 ± 61.8 min vs. 246.4 ± 98.6 min, p < 0.001), tumors resected in the ICG cohort were significantly smaller (27.1 ± 25.0 mm vs. 47.6 ± 35.2 mm, p = 0.021) and more R0 resections were achieved by ICG-supported RALS (96.3% vs. 80.8%, p = 0.075). Conclusions: ICG-supported RALS achieve surgically and oncologically safe results, while overcoming the limitations of RALS.