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Background: We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites., Methods: For this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the updated version of the classifier on a validation set, which consisted of a biological cohort (n = 3579) and a technical one (n = 15). We then assessed the performance of the classifier on a test set, which included a positive control cohort of 16 PAAD metastases from various sites and a cohort of 124 negative control samples consisting of 96 breast cancer metastases from 18 anatomical sites and 28 carcinoma metastases to the brain., Results: The updated PAAD-iCCA-Classifier achieved 98.21% accuracy on the biological validation samples, and on the technical validation ones it reached 100%. The classifier also correctly identified 15/16 (93.75%) metastases of the positive control as PAAD, and on the negative control, it correctly classified 122/124 samples (98.39%) for a 97.85% overall accuracy on the test set. We used this DNA methylation dataset to explore the organotropism of PAAD metastases and observed that PAAD liver metastases are distinct from PAAD peritoneal carcinomatosis and primary PAAD, and are characterized by specific copy number alterations and hypomethylation of enhancers involved in epithelial-mesenchymal-transition., Conclusions: The updated PAAD-iCCA-Classifier (available at https://classifier.tgc-research.de/ ) can accurately classify PAAD samples from various metastatic sites and it can serve as a diagnostic aid., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the ethics commissions of Charité, Universitätsmedizin Berlin (EA1/079/22 and EA1/157/21). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) remains a particularly aggressive disease with few effective treatments. The PDAC tumor immune microenvironment (TIME) is known to be immune suppressive. Oncolytic viruses can increase tumor immunogenicity via immunogenic cell death (ICD). We focused on tumor-selective (vvDD) and cytokine-armed Western-reserve vaccinia viruses (vvDD-IL2 and vvDD-IL15) and infected carcinoma cell lines as well as patient-derived primary PDAC cells. In co-culture experiments, we investigated the cytotoxic response and the activation of human natural killer (NK). Infection and virus replication were assessed by measuring virus encoded YFP. We then analyzed intracellular signaling processes and oncolysis via in-depth proteomic analysis, immunoblotting and TUNEL assay. Following the co-culture of mock or virus infected carcinoma cell lines with allogenic PBMCs or NK cell lines, CD56 + NK cells were analyzed with respect to their activation, cytotoxicity and effector function. Both, dose- and time-dependent release of danger signals following infection were measured. Viruses effectively entered PDAC cells, emitted YFP signals and resulted in concomitant oncolysis. The proteome showed reprogramming of normally active core signaling pathways in PDAC (e.g., MAPK-ERK signaling). Danger-associated molecular patterns were released upon infection and stimulated co-cultured NK cells for enhanced effector cytotoxicity. NK cell subtyping revealed enhanced numbers and activation of a rare CD56 dim CD16 dim population. Tumor cell killing was primarily triggered via Fas ligands rather than granule release, resulting in marked apoptosis. Overall, the cytokine-armed vaccinia viruses induced NK cell activation and enhanced cytotoxicity toward human PDAC cells in vitro. We could show that cytokine-armed virus targets the carcinoma cells and thus has great potential to modulate the TIME in PDAC., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: Pre-operative assessment of surgical risk is essential for patient counselling in the elderly patient population. Our purpose was to compare validated geriatric assessment scores (GAS) in predicting postoperative morbidity and mortality in patients ≥ 80 years., Methods: Overall, eight preoperative GAS were assessed for each patient who received RC from 2016 to 2021. Postoperative morbidity was recorded according to the Clavien-Dindo classification (CDC) of surgical complications. Binary logistic regression analyses were used to determine prediction of 30-d morbidity and 90-d mortality in patients ≥ 80 years., Results: In total, 424 patients were analysed (77.4% male) with median age of 71 years (IQR: 68.82;70.69), of which 67 (15.8%) were ≥ 80 years. Patients age ≥ 80 years showed more 30-d CDC grade ≥ IIIb (41.07% vs. 27.74% compared to < 80 years, p < .001) and worse 90-d mortality (26.87% vs. 4.76%, p < .001). In patients ≥ 80 years, morbidity was predicted by simplified Frailty Index (sFI)  ≥ 2 (OR: 2.06, 95% CI: 1.27-3.34, p = .004), Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2 (OR: 2.78, 95% CI: 1.18-6.54, p = .019) and severe Adult Comorbidity Evaluation (ACE)-27 score (OR: 2.07, 95% CI: 1.13-3.79, p = .019), while 90-d mortality was predicted by CDC grade ≥ IIIb (OR: 22.91, 95% CI: 8.74-60.09, p < .001) and ECOG ≥ 2 (OR: 2.87, 95% CI: 1.05-7.86, p = .04)., Conclusion: Even in a high-volume center of RC, 90-d mortality is significantly higher in patients age ≥ 80. Our results suggest in patient age ≥ 80, sFI ≥ 2, ECOG performance status ≥ 2 and severe ACE-27 score as clinical cut-off value to evaluate alternative bladder-sparing concepts., (© 2024. The Author(s).)

Artificial intelligence (AI) promises to be the next revolutionary step in modern society. Yet, its role in all fields of industry and science need to be determined. One very promising field is represented by AI-based decision-making tools in clinical oncology leading to more comprehensive, personalized therapy approaches. In this review, the authors provide an overview on all relevant technical applications of AI in oncology, which are required to understand the future challenges and realistic perspectives for decision-making tools. In recent years, various applications of AI in medicine have been developed focusing on the analysis of radiological and pathological images. AI applications encompass large amounts of complex data supporting clinical decision-making and reducing errors by objectively quantifying all aspects of the data collected. In clinical oncology, almost all patients receive a treatment recommendation in a multidisciplinary cancer conference at the beginning and during their treatment periods. These highly complex decisions are based on a large amount of information (of the patients and of the various treatment options), which need to be analyzed and correctly classified in a short time. In this review, the authors describe the technical and medical requirements of AI to address these scientific challenges in a multidisciplinary manner. Major challenges in the use of AI in oncology and decision-making tools are data security, data representation, and explainability of AI-based outcome predictions, in particular for decision-making processes in multidisciplinary cancer conferences. Finally, limitations and potential solutions are described and compared for current and future research attempts., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: We evaluate differences of patient-reported outcome measurements (PROM) based urinary continence and sexual function 12 months after radical prostatectomy (RPE) based on perioperative, surgical, and patient-specific characteristics in a large European academic urology center., Materials and Methods: All men enrolled in the Prostate Cancer Outcome Study (PCO) study who were treated with RPE between 2017 and 2021 completed EPIC-26 information surveys before and 12 months after RPE. Survey data were linked to clinical data of our institution. Logistic regression analyses were performed to examine the correlation between individual surgeons, patient characteristics, patient clinical data, and their urinary continence and sexual function., Results: In total, data of 429 men were analyzed: unstratified mean (SD) EPIC-26 domain score for urinary function decreased from 93.3 (0.7) to 60.4 (1.5) one year after RPE, respectively for sexual function from 64.95 (1.6) to 23.24 (1.1). Patients with preoperative adequate urinary function (EPIC-26 score > 80) reported significantly different mean urinary function scores between 53.35 (28.88) and 66.25 (25.15), p= 0.001, stratified by surgeons experience. On binary logistic regression analyses, only nerve sparing techniques (OR: 1,83, 95% CI: 1.01;3.21; p = 0.045) and low body mass index (OR: 0.91, CI: 0.85;0.99, p= 0.032) predicted adequate postoperative urinary function., Conclusions: The results show how using provider-specific data from a larger cohort study enables to develop institution-specific analysis for functional outcomes after RPE. These models can be used for internal quality improvement as well as enhanced and provider-specific patient communication and shared decision making., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Pancreatic adenocarcinoma (PDAC) is still a complex, devastating disease. Cachexia symptoms frequently impair patient survival. This accompanying syndrome is commonly diagnosed late, when clinical signs become evident. Early diagnosis using conventional measurement methods is often difficult, and the discrimination of this disease from cancer progression is challenging and often overlaps. The aim of this study was to analyze whether conventional nutritional assessments or laboratory biomarkers are better predictive tools for the early detection of patients at risk of reduced survival., Methods: We analyzed a prospective predefined cohort of 182 patients with gastrointestinal cancer, 120 patients with PDAC and-as controls-62 patients with other gastrointestinal adenocarcinoma (oAC), from whom we have sufficient data of protocol-defined conventional nutritional assessments, clinical data, and specific laboratory parameters., Results: at the time of tumor diagnosis, high inflammatory biomarkers (c-reactive protein (CRP), interleukin-6 (IL-6)) and albumin serum levels were associated with impaired OS in PDAC patients, but not in patients with oAC. Hemoglobin, body mass index (BMI), and bioelectrical assessments alone did not have a prognostic impact at the time of diagnosis. In a multivariate analysis, only CRP (HR 1.91 (1.25-2.92), p = 0.003) was found to be an independent prognostic factor in PDAC patients. Over the course of the disease in PDAC patients, inflammatory biomarkers, albumin, hemoglobin, and bioelectrical assessments were associated with impaired OS. In multivariate testing, CRP (HR 2.21 (1.38-3.55), p < 0.001) and albumin (HR 1.71 (1.05-2.77), p = 0.030) were found to be independent prognostic factors in PDAC patients., Conclusion: Specifically for PDAC patients, high inflammatory index and albumin serum levels potentially represent a sufficient early surrogate marker to detect patients at high risk of impaired OS better than complex conventional methods. These findings could help to identify patients who may benefit from early therapeutic interventions.

Background: In the treatment of advanced urothelial (aUC) and renal cell carcinoma (aRCC), biomarkers such as PD-1 and PD-L1 are not robust prognostic markers for immunotherapy (IO) response. Previously, a significant association between IO and a change in splenic volume (SV) was described for several tumour entities. To the best of our knowledge, this study presents the first correlation of SV to IO in aUC and aRCC., Methods: All patients with aUC (05/2017-10/2021) and aRCC (01/2012-05/2022) treated with IO at our academic centre were included. SV was measured at baseline, 3 and 9 months after initiation of IO using an in-house developed convolutional neural network-based spleen segmentation method. Uni- and multivariate Cox regression models for overall survival (OS) and progression-free survival (PFS) were used., Results: In total, 35 patients with aUC and 30 patients with aRCC were included in the analysis. Lower SV at the three-month follow-up was significantly associated with improved OS in the aRCC group., Conclusions: We describe a new, innovative artificial intelligence-based approach of a radiological surrogate marker for IO response in aUC and aRCC which presents a promising new predictive imaging marker. The data presented implicate improved OS with lower follow-up SV in patients with aRCC.

In addition to being risk factors for pancreatic cancer, parameters such as smoking, diabetes, or obesity might also act as potential prognostic factors for the survival of patients initially diagnosed with pancreatic cancer. By implementing one of the largest retrospective study cohorts of 2323 pancreatic adenocarcinoma (PDAC) patients treated at a single high-volume center, potential prognostic factors for survival were evaluated on the basis of 863 cases. Since parameters such as smoking, obesity, diabetes, and hypertension can cause severe chronic kidney dysfunction, the glomerular filtration rate was also considered. In the univariate analyses, albumin ( p < 0.001), active smoking ( p = 0.024), BMI ( p = 0.018), and GFR ( p = 0.002) were identified as metabolic prognostic markers for overall survival. In multivariate analyses, albumin ( p < 0.001) and chronic kidney disease stage 2 (GFR < 90 mL/min/1.37 m 2 ; p = 0.042) were identified as independent metabolic prognostic markers for survival. Smoking presented a nearly statistically significant independent prognostic factor for survival with a p -value of 0.052. In summary, low BMI, status of active smoking, and reduced kidney function at the time of diagnosis were associated with lower overall survival. No prognostic association could be observed for presence of diabetes or hypertension.

Inflammatory properties are known to promote tumor progression leading to an impaired median overall survival (mOS). Various small studies have focused on a wide range of inflammation-based prognostic indicators. By using sufficient data from 1294 out of 2323 patients diagnosed with pancreatic cancer between 2009 and 2021 at our cancer center, inflammatory markers such as the neutrophil to lymphocyte ratio (NRL), the platelet to lymphocyte ratio (PLR), the lymphocyte to monocyte ratio (LMR) and the CRP to albumin ratio (CAR) were evaluated. We identified a new combined score, termed the inflammatory benchmark index (IBI). We performed univariate and multivariate overall survival analyses and identified optimal prognostic cut-off values for each parameter. In univariate analyses, advanced age ( p < 0.001), gender ( p < 0.001), tumor stage ( p < 0.001), CA19-9 ( p = 0.001), NLR ( p = 0.001), LMR ( p = 0.004), PLR ( p = 0.004), CAR ( p = 0.001) and IBI ( p = 0.001) were identified as prognostic markers. In multivariate analyses advanced age ( p < 0.001), gender ( p = 0.001), tumor stage ( p < 0.001), CA19-9 ( p < 0.001), NLR ( p = 0.001), LMR ( p = 0.038), CAR ( p < 0.001) and IBI ( p < 0.001) were independent prognostic markers. These findings emphasize the impact of inflammation in pancreatic cancer, provide easily accessible prognostic values for the clinician, and may be useful as stratification parameters for trials aimed at patient inflammation or immune response.

Background: Primary objective of this present trial was to define the maximum tolerable dose of lapatinib in combination with oxaliplatin, 5-fluorouracil, and folinic acid (OFF) in refractory pancreatic cancer. The secondary objective was to assess the safety and efficacy of lapatinib plus OFF., Methods: We conducted a phase I trial using an accelerated dose escalation design in patients with refractory pancreatic cancer. Lapatinib was given on days 1 to 42 in combination with folinic acid 200 mg/m 2 day + 5-fluorouracil 2000 mg/m 2 (24 h) on days 1, 8, 15, and 22, and oxaliplatin 85 mg/m 2 days 8 and 22 of a 43-day cycle (OFF). Toxicity and efficacy were evaluated., Results: In total, eighteen patients were enrolled: dose level 1 (1000 mg) was assigned to seven patients, dose level 2 (1250 mg), five patients; and dose level 3 (1500 mg), six patients. Dose-limiting toxicities were diarrhea and/or neutropenic enterocolitis observed in two of six patients: one diarrhea III°, one diarrhea IV°, as well as neutropenic enterocolitis. The maximum tolerable dose of lapatinib was 1250 mg OD., Conclusions: The combination of lapatinib 1250 mg OD with platinum-containing chemotherapy is safe and feasible in patients with refractory pancreatic cancer and warrants further investigation.

Pancreatic cancer is the seventh leading cause of cancer death in both sexes. The aim of this study is to analyze baseline CT body composition using artificial intelligence to identify possible imaging predictors of survival. We retrospectively included 103 patients. First, the presence of surgical treatment and cut-off values for sarcopenia and obesity served as independent variates. Second, the presence of surgery, subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle index (SMI) served as independent variates. Cox regression analysis was performed for 1-year, 2-year, and 3-year survival. Possible differences between patients undergoing surgical versus nonsurgical treatment were analyzed. Presence of surgery significantly predicted 1-year, 2-year, and 3-year survival (p = 0.01, <0.001, and <0.001, respectively). Across the follow-up periods of 1-year, 2-year, and 3-year survival, the presence of sarcopenia became an equally important predictor of survival (p = 0.25, 0.07, and <0.001, respectively). Additionally, increased VAT predicted 2-year and 3-year survival (p = 0.02 and 0.04, respectively). The impact of sarcopenia on 3-year survival was higher in the surgical treatment group (p = 0.02 and odds ratio = 2.57) compared with the nonsurgical treatment group (p = 0.04 and odds ratio = 1.92). Fittingly, a lower SMI significantly affected 3-year survival only in patients who underwent surgery (p = 0.02). Especially if surgery is performed, AI-derived sarcopenia and reduced muscle mass are unfavorable imaging predictors.

Background/aim: Pancreatic ductal adenocarcinoma (PDAC) shows poor survival and early systemic dissemination. Cancer associated fibroblasts (CAFs) enhance migration and invasion of cancer cells. We aimed to investigate the role of CAFs in cell migration and their underlying paracrine effects., Materials and Methods: Using Transwell ® migration assays, PDAC cells (PANC-1) and three distinct types of fibroblasts were analyzed: CAFs, genetically transformed human foreskin-fibroblasts (BJeLR), and non-transformed human foreskin-fibroblasts (VH7). IL6 in the culture supernatant was measured to investigate paracrine communication in monocultures and direct/indirect cocultures., Results: CAFs showed a significantly higher capacity to migrate in vitro when compared to benign fibroblasts (p=0.009). They also facilitated the migration of PDAC cells in coculture (p=0.001). Neither BJeLR, nor VH7 displayed such features. This was accompanied by a significant increase in IL-6 when CAFs were cocultured with PANC-1 (p=0.009)., Conclusion: CAFs are a key element of intra-tumoral migration and should be further investigated as a potential therapeutic target., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the tumor's high chemoresistance. Cancer associated fibroblasts (CAFs) have previously been identified to be the key stromal players. This is the first time we provide detailed in vitro experiments investigating tumor-stromal interactions when exposed to three well-known chemotherapeutic agents., Methods: Monocultures, indirect and direct co-cultures of two PDAC cell lines (AsPC and Panc-1) and six primary patients derived CAFs were treated with gemcitabine, nab-paclitaxel and the γ-secretase-inhibitor (GSI) DAPT. The cell viability of each component was measured with XTT. Finally, IL-6 concentrations of the supernatants were analyzed., Results: On the contrary to PDAC cell lines, CAF monocultures hardly responded to any treatment which suggested that stroma (CAFs) itself is more resistant to standard chemo-treatments than the epithelial cancer cells. Moreover, only a weak chemotherapeutic response was observed in direct co-cultures of cancer cells with CAFs. A change in the morphology of direct co-cultures was accompanied with the chemoresistance. CAFs were observed to build cage-like structures around agglomerates of tumor cells. High levels of IL-6 were also associated with a reduced response to therapy. Indirect co-cultures make the tumor-stromal interaction more complex., Conclusions: CAFs are highly chemoresistant. Direct cell-cell contact and high levels of IL-6 correlate with a high chemoresistance., (Copyright © 2018 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)