Search

Supplementary Table from Safety and Efficacy of 90Y-FAPI-46 Radioligand Therapy in Patients with Advanced Sarcoma and Other Cancer Entities

Supplementary Figure from Safety and Efficacy of 90Y-FAPI-46 Radioligand Therapy in Patients with Advanced Sarcoma and Other Cancer Entities

Purpose:We report efficacy and safety of 90Y-labeled FAPI-46 (90Y-FAPI-46-RLT) in patients with advanced sarcoma, pancreatic cancer, and other cancer entities.Experimental Design:Up to four cycles of radioligand therapy (RLT) were offered to patients with (i) progressive metastatic malignancy, (ii) exhaustion of approved therapies, and (iii) high fibroblast activation protein (FAP) expression, defined as SUVmax ≥ 10 in more than 50% of tumor. Primary endpoint was RECIST response after RLT. Secondary endpoints included PET response (PERCIST), overall survival (OS), dosimetry, and safety of FAP-RLT.Results:Among 119 screened patients, 21 (18%) were found eligible [n = 16/3/1/1 sarcoma/pancreatic cancer/prostate/gastric cancer; 38% Eastern Cooperative Oncology Group (ECOG) ≥ 2] and received 47 90Y-FAPI-46-RLT cycles; 16 of 21 (76%) patients underwent repeat RLT. By RECIST, disease control was confirmed in 8 of 21 patients [38%; 8/16 (50%) of evaluable patients). There was one partial response (PR) and seven stable diseases after RLT. Disease control was associated with prolonged OS (P = 0.013). PERCIST response was noted in 8 of 21 patients [38%; 8/15 (53%) of evaluable patients]. Dosimetry was acquired in 19 (90%) patients. Mean absorbed dose was 0.53 Gy/GBq in kidney, 0.04 Gy/GBq in bone marrow, and n = 6) and anemia (n = 6) being most prevalent.Conclusions:90Y-FAPI-46-RLT was safe and led to RECIST PR in one case as well as stable disease in about one third of patients with initially progressive sarcomas, pancreatic cancer, and other cancers. Discontinuation after the first cycle and a low rate of PR requires future improvement of FAP-RLT.

The phosphoinositide-3-kinase (PI3K)/AKT signaling pathway controls fundamental processes of cancer cell biology like proliferation and cell survival. The PI3K/AKT pathway is activated in pancreatic ductal adenocarcinoma (PDAC) cells. The molecular mechanisms linking PI3K signaling to the cell cycle machinery in PDAC cells are not investigated in detail. Using the PI3K inhibitor Ly294002 as well as small interfering RNA targeting AKT1 expression, we show that PI3K controls the proliferation and G1 phase progression of PDAC cells. Gene profiling revealed several important regulators of G1-S phase progression controlled by PI3K signaling like p21Cip1, S-phase kinase–associated protein 2 (SKP2), CDC25a, cyclin A, cyclin D2, CDK2, and cyclin E. We show that the F-box protein SKP2, an oncogene up-regulated in PDAC, is transcriptionally regulated by the PI3K/AKT1 pathway in PDAC cells. At the molecular level, the control of the SKP2 gene by PI3K is due to the regulation of E2F1 binding to the proximal SKP2 gene promoter. The complex and profound connection of PI3K/AKT1 signaling to the cell cycle qualifies this pathway as a suitable target for therapeutic intervention in PDAC. [Cancer Res 2007;67(9):4149–56]

Supplementary Figure 1 from Phosphoinositide-3-Kinase Signaling Controls S-Phase Kinase–Associated Protein 2 Transcription via E2F1 in Pancreatic Ductal Adenocarcinoma Cells

Electroencephalographic neurofeedback (EEG NF) can improve quality of life (QoL) and reduce distress by modifying the amplitude of selected brain frequencies. This study aims to investigate the effects of NF therapy on QoL and self-efficacy in cancer patients and to explore age-related reactions. In a waitlist control paradigm, psychometric data (EORTC QLQ-C30, General Self-Efficacy Scale) of 20 patients were collected at three different time points, each five weeks apart. An outpatient 10-session NF intervention (mobile) was conducted between the second and third measurement point. QoL and self-efficacy changed significantly over time (QoL: F(2,36) = 5.294, p η2 = .227; Self-efficacy: F(2,26) = 8.178, p η2 = .386). While QoL increased in younger patients, older patients initially showed a decrease in QoL, which then increased during intervention. Younger patients did not differ from older patients in QoL in both waitlist control (T0-T1) and intervention phase (T1–T2). QoL in older patients significantly differed between waitlist control and intervention phase (Z = − 2.023, p d = 1.085). Self-efficacy increased in both age categories. Younger and older patients did not differ in self-efficacy in waitlist control, but in intervention phase (F(1,16) = 7.014, p η2 = .319). The current findings suggest that NF therapy is a promising treatment modality for improving QoL in cancer patients. Our study reveals NF being a tool to influence self-efficacy, which should receive more appreciation in clinical care. However, the effect of NF in different age groups as well as the influence on further cancer-related symptoms should be investigated in future research.

In the setting of ongoing SARS-CoV-2 vaccination, vaccine-related tracer uptake in locoregional lymph nodes has become a well-known issue in tumor staging by

Fibroblast activation protein inhibitor (FAPI) PET/CT is a new tool in the diagnostic workup of cancer. With a growing volume of applications, pitfalls and common findings need to be considered for (68)Ga-FAPI PET/CT image interpretation. The aim of this study was to summarize common findings and report pitfalls in (68)Ga-FAPI PET/CT. Methods: Ninety-one patients underwent whole-body PET/CT with either FAPI-04 (n = 25) or FAPI-46 (n = 66). Findings were rated in a consensus session of 2 experienced readers. Pitfalls and common findings were defined as focal or localized uptake above the background level and categorized as unspecific or nonmalignant and grouped into degenerative, muscular, scarring/wound-healing, uterine, mammary gland, and head-and-neck findings. The frequency of findings was reported on a per-patient and per-group basis, and SUV(max), SUV(mean), and SUV(peak) were measured. Results: Non–tumor-specific uptake was found in 81.3% of patients. The most frequent finding was uptake in degenerative lesions (51.6%), with a mean SUV(max) of 7.7 ± 2.9, and head-and-neck findings (45.1%). Except for the salivary glands, the uptake values did not differ between 10 and 60 min after injection in most findings. Uterine uptake was found in most women (66.7%), with a mean SUV(max) of 12.2 ± 7.3, and uptake correlated negatively with age (SUV(max), r = −0.6, P < 0.01; SUV(peak), r = −0.57, P < 0.01; SUV(mean), r = −0.58, P < 0.01). Conclusion: Pitfalls include non–tumor-specific (68)Ga-FAPI uptake in degenerative lesions, muscle, the head and neck, scarring, the mammary glands, or the uterus. Here, we summarize the findings to help readers avoid common mistakes at centers introducing (68)Ga-FAPI PET/CT.

Introduction Positron emission tomography (PET) using small ligands of the fibroblast activation protein (FAP) was recently introduced. However, optimal uptake time has not been defined yet. Here, we systematically compare early (~ 10 min p.i.) and late (~ 60 min p.i.) FAPI-46 imaging in patients with various types of cancer. Methods This is a retrospective single-institutional study. Imaging was performed at the Essen University Hospital, Germany. A total of 69 patients who underwent dual time-point imaging for either restaging (n = 52, 75%) or staging (n = 17, 25%) of cancer were included. Patients underwent PET with two acquisitions: early (mean 11 min, SD 4) and late (mean 66 min, SD 9). Mean injected activity was 148 MBq (SD 33). Results In total, 400 lesions were detected in 69 patients. Two of 400 (0.5%) lesions were only seen in early time-point imaging but not in late time-point imaging. On a per-patient level, there was no significant difference between SUVmax of hottest tumor lesions (Wilcoxon: P = 0.73). Organ uptake demonstrated significant early to late decrease in SUVmean (average ∆SUVmean: − 0.48, − 0.14, − 0.27 for gluteus, liver, and mediastinum, respectively; Wilcoxon: P max was observed (average ∆SUVmax: + 0.4, Wilcoxon: P = 0.03). Conclusion In conclusion, early (~ 10 min p.i.) versus late (~ 60 min p.i.) FAPI-46 imaging resulted in equivalent lesion uptake and tumor detection. For improved feasibility and scan volume, we implement early FAPI-46 PET in future clinical and research protocols.

We report a case of a 75-year-old man with facial edema that also affected the periorbital area who was admitted to the hospital with the suspected diagnosis of Quincke's edema. The diagnosis of cutaneous angiosarcoma was made by microscopic examination and immunohistochemical staining. Chemotherapy was initially initiated because the angiosarcoma was unresectable and the radiation situation was difficult. Therapy has to be switched to second and third line therapy due to disease progression. The case illustrates the complexity of diagnosis and therapy in patients with cutaneous angiosarcoma.Es wird über den Fall eines 75-jährigen Patienten mit einer Gesichtsschwellung v. a. periorbital berichtet, der unter der Verdachtsdiagnose eines Quincke-Ödems stationär aufgenommen wurde. Probebiopsien ergaben das Vorliegen eines kutanen Angiosarkoms. Bei nicht resezierbarem Befund und schwieriger Bestrahlungssituation wurde zunächst eine Chemotherapie eingeleitet. Im Verlauf erfolgte bei Befundprogress die Therapieumstellung auf Zweit- und Drittlinientherapie. Der geschilderte Fall verdeutlicht die Komplexität bei der Diagnostik und Therapie bei Patienten mit kutanem Angiosarkom.

Introduction The treatment of soft tissue and bone sarcoma of the hand and wrist are based on general principles rather than on specific data due to the rare incidence of cases. The current study was conducted to analyze the survival and functional outcomes of patients with sarcoma of the distal part of the upper extremity. Methods Outcome of 168 consecutive patients with soft tissue and bone sarcoma of the hand and wrist were treated over a 34 year period by a single surgeon were retrospectively reviewed. The survivorship was determined using the Kaplan Meyer method. Functional outcomes were evaluated using the Michigan Hand Questionnaire. Results The overall survival demonstrates the statistical significance (p = 0,002) between patients with low (94,7% (95% CI, 92,9–96,5)) and high (72,7% (95% CI, 71,9–73,5)) grade tumors. There is no statistical significance in overall survival among different subgroups of high-grade sarcomas. Despite the predominant number of patients after external R1/R2 resection, local recurrences and a high number of high-grade sarcoma, the incidence of regional relapse was 12,5% using multimodal approach. The overall hand function reached 72,3 points for the treated hand compared to 92,3 for uninvolved hand (p Conclusion The series describes the treatment of consecutive cases since 1983 using limb-preserving therapy in single site location. The patients suffering from sarcoma of the hand and wrist should be treated in high volume centers with a sufficient diagnostic and therapeutic infrastructure, including specialized hand and reconstructive plastic surgical specialists.

Purpose: We report efficacy and safety of 90Y-labeled FAPI-46 (90Y-FAPI-46-RLT) in patients with advanced sarcoma, pancreatic cancer, and other cancer entities. Experimental Design: Up to four cycles of radioligand therapy (RLT) were offered to patients with (i) progressive metastatic malignancy, (ii) exhaustion of approved therapies, and (iii) high fibroblast activation protein (FAP) expression, defined as SUVmax ≥ 10 in more than 50% of tumor. Primary endpoint was RECIST response after RLT. Secondary endpoints included PET response (PERCIST), overall survival (OS), dosimetry, and safety of FAP-RLT. Results: Among 119 screened patients, 21 (18%) were found eligible [n = 16/3/1/1 sarcoma/pancreatic cancer/prostate/gastric cancer; 38% Eastern Cooperative Oncology Group (ECOG) ≥ 2] and received 47 90Y-FAPI-46-RLT cycles; 16 of 21 (76%) patients underwent repeat RLT. By RECIST, disease control was confirmed in 8 of 21 patients [38%; 8/16 (50%) of evaluable patients). There was one partial response (PR) and seven stable diseases after RLT. Disease control was associated with prolonged OS (P = 0.013). PERCIST response was noted in 8 of 21 patients [38%; 8/15 (53%) of evaluable patients]. Dosimetry was acquired in 19 (90%) patients. Mean absorbed dose was 0.53 Gy/GBq in kidney, 0.04 Gy/GBq in bone marrow, and Conclusions: 90Y-FAPI-46-RLT was safe and led to RECIST PR in one case as well as stable disease in about one third of patients with initially progressive sarcomas, pancreatic cancer, and other cancers. Discontinuation after the first cycle and a low rate of PR requires future improvement of FAP-RLT.

The multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug.We analysed the molecular profiles and clinical outcomes of patients with pazopanib-treated sarcoma enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing and transcriptome sequencing to inform the care of young adults with advanced cancer across histology and patients with rare cancers.Among 109 patients with available whole-genome/exome sequencing data, there was no correlation between clinical parameters, specific genetic alterations or mutational signatures and clinical outcome. In contrast, the analysis of a subcohort of 62 patients who underwent molecular analysis before pazopanib treatment and had transcriptome sequencing data available showed that mRNA levels of NTRK3 (hazard ratio [HR] = 0.53, p = 0.021), IGF1R (HR = 1.82, p = 0.027) and KDR (HR = 0.50, p = 0.011) were independently associated with progression-free survival (PFS). Based on the expression of these receptor tyrosine kinase genes, i.e. the features NTRK3-high, IGF1R-low and KDR-high, we developed a pazopanib efficacy predictor that stratified patients into three groups with significantly different PFS (p lt; 0.0001). Application of the pazopanib efficacy predictor to an independent cohort of patients with pazopanib-treated sarcoma from DKTK MASTER (n = 43) confirmed its potential to separate patient groups with significantly different PFS (p = 0.02), whereas no such association was observed in patients with sarcoma from DKTK MASTER (n = 97) or The Cancer Genome Atlas sarcoma cohort (n = 256) who were not treated with pazopanib.A score based on the combined expression of NTRK3, IGF1R and KDR allows the identification of patients with sarcoma and with good, intermediate and poor outcome following pazopanib therapy and warrants prospective investigation as a predictive tool to optimise the use of this drug in the clinic.

Background Leiomyosarcoma (LMS) most frequently metastasizes to the lung. Metastatic LMS is considered incurable. Selected patients may benefit from pulmonary metastasectomy (PM) within multimodal therapy. This study analyzed the prognostic relevance of clinicopathologic factors in these patients. Methods Patients with metastatic LMS to the lung treated in our center from 2004 to 2020 were included in this single-center retrospective study. Overall survival (OS), progression-free survival (PFS), and prognostic factors were analyzed. Results The study had 64 patients (33 males, 52%) with metastatic LMS to the lung. The 5-year OS was 55% after the diagnosis of pulmonary metastases. Age older than 60 years at the primary tumor diagnosis, primary tumor larger than 70 mm, and five or more lung metastases were associated with poorer OS. Of the 64 patients, 44 underwent PM. The postoperative mortality rate was 0%. The patients selected for PM were younger and had smaller primary tumors, fewer metastases, and metastases that more often were metachronous. Metastasis grade (G1 vs. G2/3) and size (20-mm cutoff) were significant prognostic factors for OS (p = 0.05) and PFS (p = 0.028) after PM, respectively. The 44 patients who underwent PM had a survival benefit compared with the patients who were selected but did not undergo PM (n = 6) and the patients who were not selected for PM (n = 14). Three patients (7%) were alive and free of disease at the last follow-up visit respectively 5.5, 9, and 12 years after PM. Conclusions For patients with leiomyosarcoma, PM is safe. Despite aggressive multimodal treatment, most patients will experience recurrence and eventually die of their disease. However, a small subgroup of patients could potentially be cured after PM.

OA Förderung 2022 Background: Transcriptome profiling provides large data on tumor biology, which is particularly valuable in translational research and is becoming more and more important for clinical decision-making as well. RNA sequencing is considered to be the gold standard for this. However, FFPE material, as the most available material in routine pathology, has been an undefeatable obstacle for RNAseq. Extraction-free nuclease protection assays have the potential to be a reliable alternative method for large-scale expression profiling. The aim of this study was to validate and test the basic feasibility, technical applicability robustness, and reliability of the HTG transcriptome profiling (HTP) assay on clinical tumor samples. Methods: FFPE samples from 44 synovial sarcomas (SyS) and 20 spindle cell sarcomas (SpcS) were used. The HTP assay was performed on 10 µm thin FFPE slides. After nuclease protection in the HTG Edge Seq System, libraries were generated for sequencing on an Illumina NextSeq 500 platform. Fastq data were parsed and then analyzed by using the HTG analysis platform EdgeSeq REVEAL. Immunohistochemistry was performed to validate the expression of TLE1. Results: The technical application of the HTP Panel revealed robust and reliable results with 62 samples, and only 2 samples failed due to an incomplete digestion of gDNA. The analysis, performed at the analysis platform REVEAL, showed 5964 genes being significantly differentially expressed between SpcS and SyS. In particular, overexpression of the known marker TLE1 in synovial sarcoma could be recovered, which underlines the reliability of this system. Discussion: Transcriptome profiling gets more and more important for tumor research and diagnostics. Among other established technologies, the HTP Panel has shown to be a feasible method to get robust and reliable results. Thereby, this method needs very few sample-input by getting a success-rate of 96.88%, which indicates the upper average range, compared to other technologies working with FFPE tissue. Conclusion: The nuclease protection assay-based HTP Panel is a feasible method for adequate transcriptome profiling with low sample input and therefore is suitable for further research of biomarkers.

The aim of this study was to provide an update on the most recent developments regarding systemic treatments in the various molecular subtypes of gastrointestinal stromal tumour (GIST).Several novel direct inhibitors of KIT and PDGFRA have entered the advanced clinical development in later treatment lines based on promising early clinical trial experience. Both avapritinib and ripretinib are more potent and more specific against various KIT and PDGFRA mutations. For patients with PDGFRA D842V mutations, the next generation of drugs may become the first active treatment options.Comprehensive molecular testing of KIT/PDGFRA-wildtype GIST may unmask clinically relevant targets, including NTRK fusions.The treatment landscape in GIST is expected to undergo a profound transformation with more potent drugs currently in late-stage clinical development.

Die Behandlung gastrointestinaler Strumatumoren (GIST) ist seit Einfuhrung von KIT-Inhibitoren dramatisch verbessert worden. Eine Heilung gelingt allerdings unverandert nur auf der Grundlage einer operativen Therapie des Primartumors. Auch in der metastasierten Situation erscheint die Chance auf eine langfristige Tumorkontrolle durch Tyrosinkinaseinhibitoren (TKI) nach dem Erreichen einer ggf. chirurgischen kompletten Resektion hoher zu sein. Die Entscheidung, welche Patienten am ehesten von multimodalen Konzepten profitieren, basiert inzwischen neben klinischen Faktoren auch auf einer Vielzahl molekularer Pradiktoren und verlangt eine Besprechung in multidisziplinaren, erfahrenen Behandlungsteams. Neue, breiter wirksame Inhibitoren ermoglichen ein Therapieansprechen auch bei bislang refraktaren GIST-Subtypen wie den PDGFR-D842V-mutierten GIST, aber scheinen auch bei KIT-mutierten GIST nach dem Versagen aller zugelassenen Therapien einen therapeutischen Nutzen aufzuweisen. Hier ist eine grundlegende Anderung der Behandlungssequenzen in naher Zukunft zu erwarten.

Fibroblast activation protein (FAP) is overexpressed in several solid tumors and therefore represents an attractive target for radiotheranostic applications. Recent investigations demonstrated rapid and high uptake of small-molecule inhibitors of FAP (

11564 Background: Alveolar soft-part sarcoma (ASPS) is a highly metastasizing ultra-rare sarcoma subtype, frequently affecting young adults. Conventional cytotoxic drugs are not effective in ASPS, but antiangiogenics demonstrated significant improvement in tumor burden reduction and PFS in the only ever conducted comparative trial. Immune check-point (PD-1/PD-L1) inhibitors (ICI) are emerging promising drugs in the therapy of ASPS, from small reported retrospective and prospective series. A world-wide registry has been set up with the aim of exploring the efficacy of ICI in ASPS. Methods: Data from adult patients (pts) diagnosed with ASPS and treated with PD- 1/PD-L1 inhibitors for advanced disease in expert sarcoma centers from Europe, Australia and US was retrospectively collected. IRB approval was obtained. Demographics, data related to treatments and outcome were considered. Radiologic assessment was based on RECIST 1.1. Progression-free (PFS) and overall survival (OS) were calculated with Kaplan-Meier method. An updated analysis of this series is presented here. Results: Sixty ASPS pts (27 female/33 male) with a median age at diagnosis of 25y (range 3-61) were registered. Primary tumor arose in limbs in 47 pts (78%) and 41 pts (68%) were metastatic at diagnosis. 52/60 pts (87%) had received previous systemic therapy (including chemotherapy in 19 pts and antiangiogenics in 47pts), with a median of one previous line (0-6). All pts received ICI for metastatic disease. Immunotherapy regimens consisted of monotherapy in 31 pts (52%) and combination in 29 pts (48%) (23 with an antiangiogenic agent). 29/60 pts (48%) received ICI within a clinical trial. Among the 52 evaluable pts, there was 1 complete response (CR) and 20 partial responses (PR) (ORR 40.4%). After a median follow-up of 21 months -mos- (range 4-59), 37/60 pts have progressed to ICI, with a median PFS of 13.4 mos (95% CI 10.1-16.7). Eleven pts received a subsequent line of ICI with a median PFS of 26 mos (95%CI 0-57). 16 pts have died, being the median OS from ICI initiation 38 mos (95% CI 33-43). The 12-mos and 24-mos OS rates were 94% and 70% respectively. Conclusions: This registry constitutes the largest available series of ASPS treated with immune check-point inhibitors. Our results suggest that treatment with ICI provide long-lasting disease control and prolonged OS in pts with advanced ASPS, an ultra-rare entity with limited active therapeutic options. The results on subsequent ICI lines suggest a lack of cross-resistance among different ICI therapies.

Background. Angiosarcomas are rare and heterogeneous tumors with poor prognosis. The clinical subtypes are classified depending on the primary site and etiology. Methods. We conducted a retrospective, monocentric study of 136 patients with localized AS between May 1985 and November 2018. Overall survival (OS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS) were estimated using the Kaplan–Meier method. To identify prognostic factors, univariate and multivariate analyses were performed based on Cox regressions. Results. The median age was 67 years (19–72.8 years). Primary sites were cutaneous (27.2%), breast (38.2%), and deep soft tissue (34.6%). The majority was primary angiosarcomas (55.9%) followed by postradiation (40.4%) and chronic lymphedema angiosarcomas (2.9%). Prognosis significantly differed depending on the primary site and etiology. Shortest median OS and MFS were observed in deep soft tissue angiosarcomas, whereas cutaneous angiosarcomas, angiosarcomas of the breast, and radiation-associated angiosarcomas displayed worse median LRFS. Univariate analyses showed better OS for tumor size p = 0.009), negative surgical margins ( p = 0.021), and negative lymph node status ( p = 0.007). LRFS and MFS were longer for tumor size p = 0.012 and p = 0.013). In multivariate analyses, age p = 0.035). Conclusions. Different behaviors and prognoses depending on the primary site and etiology should be considered for the treatment of this heterogeneous disease. In cutaneous angiosarcomas of the head/neck and postradiation angiosarcomas of the breast, local recurrence seems to have a crucial impact on OS. Therefore, improved local therapies and local tumor staging may have to be implemented. However, in deep soft tissue angiosarcomas, distant recurrence seems to have a major influence on prognosis, which indicates a benefit of additional perioperative chemotherapy.

Regorafenib significantly prolonged progression-free survival (PFS) in pretreated patients with advanced non-adipocytic sarcoma (HR = 0.46, p &lt, 0.001) in a placebo-controlled, randomized, phase-II trial (NCT01900743). Thus, here, we assessed the prevalence of 57 biomarkers and their prognostic and predictive values for PFS and overall survival (OS). We analyzed 134/182 patients included in this trial, treated with regorafenib (n = 71, 53%) or placebo (n = 63, 47%). Mutational analyses were performed via full coding sequence analysis for 10 genes, and mutation hotspot panel for 50 genes (four genes in common). H19 was studied with RNA in-situ hybridization. The prognostic and predictive biomarkers&rsquo, values were studied only for biomarkers found positive/mutated in at least 10 patients. Overall, 25 out of 57 studied biomarkers, including five out of seven genes involved in angiogenesis, were found mutated/positive in at least one patient, of which 23 biomarkers had low prevalence (fewer than eight out of 134 patients), contrasting with H19 (n = 24, 18%), and TP53 (n = 35, 26%). However, in multivariable models of PFS and OS, including treatment effects and interactions, no significant prognostic or predictive values of the tested biomarkers were observed. Though several promising biomarkers were found to be positive/mutated, none of them were identified as viable predictive and prognostic biomarkers.

Cancers of unknown primary site (CUPs) represent a heterogeneous group of metastatic tumors, which accounts for 3-5% of malignancies. Due to the poor prognosis and limited local and systemic treatment options, there is an urgent need for improvement of molecularly driven treatment strategies. We investigated the molecular profile and clinical course of 70 patients enrolled in a prospective precision oncology registry trial conducted by the National Center for Tumor Diseases (NCT) Heidelberg/Dresden and the German Cancer Consortium (DKTK) that addresses younger adults with advanced-stage cancer across histologies as well as patients with rare tumors (NCT/DKTK MASTER). Molecular analyses included whole genome sequencing (WGS, n=29), whole exome sequencing (WES, n=41) and transcriptome analysis (n=55). All patients were diagnosed with CUP-syndrome, 61/70 (87.1%) of diagnoses fulfilled the ESMO Clinical Practice Guidelines. Progression free survival (PFS) of the first treatment based on MASTER (PFS2) was compared to the PFS of the last prior systemic treatment (PFS1) in each individual patient. Within the coding sequence, we identified 0 to 1386 nonsynonymous point mutations (SNVs, median=41) and 0 to 38 insertions/deletions (indels, median=3) per sample. Hypermutation (≥100 SNVs and indels) was observed in 14 samples. Mutations of TP53 and KRAS were significantly enriched. Analysis of copy-number changes (CNVs) was performed in 51 samples (27 WGS and 24 WES) and revealed complex CNV profiles in most cases. Gains and losses involved single arms or whole chromosomes. Gains in chromosome 8q, 1q and 7 and losses in chromosome 6q and 17p occurred in more than 40% of the patients. Fusions of EML4-ALK and FGFR2 were found in three and six cases, respectively. In one case, pathological reevaluation for NUT midline carcinoma was recommended based on a NUTM1-MXI1 fusion. In total, pathological reevaluation based on characteristic genetic events was recommended in five cases. Germline analysis of 70 cases revealed five pathogenic variants (ACMG Class 5) in CHEK2, BRCA1, CDKN2A, NBN and ERCC3. In addition, one likely pathogenic variant (ACMG Class 4) was found in FH. The molecular tumor board recommended targeted therapy in 56/70 (80.0%) patients which could be applied in 20/56 (35.7%) cases. The molecularly driven treatment approaches translated into a median PFS2/1 ratio of 2.25 (n=17). Median PFS1 was 89 days (range 31-304, n=17) compared to a median PFS2 of 180 days (range 50-805, n=17). For three patients in which PFS1 could not be determined median PFS2 was 305 days (range 182-336). We demonstrate that a comprehensive molecular analysis of CUPs provides clinically relevant information and additional, molecularly stratified treatment approaches in many cases. These targeted therapies can be highly beneficial even in heavily pretreated patients. Citation Format: Maximilian Werner, Lino Möhrmann, Małgorzata Oleś, Andreas Mock, Arne Jahn, Simon Kreutzfeldt, Sebastian Uhrig, Martina Fröhlich, Barbara Hutter, Daniela Richter, Gina Rüter, Ivan Jelas, Rainer Hamacher, Johanna Falkenhorst, Sebastian Wagner, Christian Brandts, Melanie Börries, Anna Illert, Klaus Metzeler, Benedikt Westphalen, Alexander Desuki, Thomas Kindler, Albrecht Stenzinger, Evelin Schröck, Benedikt Brors, Peter Horak, Christoph Heining, Stefan Fröhling, Hanno Glimm. Genomics based personalized oncology of cancer of unknown primary [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 820.

Sarcoma is a basket term for mesenchymal tumors for which more than 75 genetically and histologically distinct subtypes are recognized. Therapeutic progress has largely been achieved with classical chemotherapeutic drugs that were tested in empirical clinical trials. However, outcome in metastatic patients remains poor and with few exceptions numerous trials have failed or only provided limited improvement in recent years. Given the genomic heterogeneity, preclinical model systems will be indispensable to identify new molecular targets and to prioritize drugs and drug combinations. Cell culture is still widely used in preclinical sarcoma research to identify potential novel therapeutic approaches and resistance mechanisms. New and improved techniques in genome-wide and proteome-wide screens enable a better characterization. In addition to cell line xenograft mouse models, patient-derived xenografts crucially broadened and improved preclinical studies using primary human samples. Finally, novel strategies for genome editing, like CRISPR/Cas and sleeping beauty transposon, lead to development of novel genetically engineered cell lines and mouse models. The present review gives a non-comprehensive overview on current model systems used in sarcoma research and discusses their translational relevance. Those include cell lines, subtype-specific patient-derived cell lines and xenografts as well as developments in genome editing and genetically engineered cell lines and mouse models.

Soft tissue sarcomas (STS) are a rare and heterogeneous disease sharing mesenchymal origin. While classification of different STS subtypes has generated insight into their molecular pathogenesis, treatment response, and prognosis, oncological management still poses major clinical challenges. Despite considerable evolution in definition of optimal treatment strategies over the past decade there is a critical need of new and less toxic therapeutic approaches for the treatment of metastatic sarcoma. This review covers the latest clinical study highlights for soft tissue sarcomas and gastroinestinal stromal tumours (GIST) presented at ASCO 2016, demonstrating a constant progress from conventional chemotherapy to histology-tailored therapy as well as immunotherapy approaches.

Primary heart tumors are an extremely rare oncological entity with primary cardiac sarcomas usually representing 20% of all primary cardiac tumorous lesions [Shanmugam: Eur J Cardiothorac Surg 2006;29: 925–932; Orlandi et al.: J Thorac Oncol 2010;5: 1483–1489]. Angiosarcoma is the most prevalent histology and despite a multidisciplinary approach tends to have a dismal prognosis [Shanmugam: Eur J Cardiothorac Surg 2006;29: 925–932; Fury et al.: Cancer J 2005;11: 241–247]. Based on the prevailing literature, we report a 48-year-old woman diagnosed with primary metastatic cardiac angiosarcoma who showed a severe hypersensitivity reaction to conventional chemotherapy with taxanes but an excellent response to treatment with the multitargeted receptor tyrosine kinase inhibitor pazopanib.

Hepatocellular cancers arise in a background of liver damage and inflammation. Bakiri et al. describe the function of the transcription factor c-Fos/AP-1 using mouse models and human data. c-Fos affects cholesterol and bile acid metabolism and induces DNA damage and inflammation, thus promoting liver cancer., Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos–expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.

The phosphoinositide-3-kinase (PI3K)/AKT signaling pathway controls fundamental processes of cancer cell biology like proliferation and cell survival. The PI3K/AKT pathway is activated in pancreatic ductal adenocarcinoma (PDAC) cells. The molecular mechanisms linking PI3K signaling to the cell cycle machinery in PDAC cells are not investigated in detail. Using the PI3K inhibitor Ly294002 as well as small interfering RNA targeting AKT1 expression, we show that PI3K controls the proliferation and G1 phase progression of PDAC cells. Gene profiling revealed several important regulators of G1-S phase progression controlled by PI3K signaling like p21Cip1, S-phase kinase–associated protein 2 (SKP2), CDC25a, cyclin A, cyclin D2, CDK2, and cyclin E. We show that the F-box protein SKP2, an oncogene up-regulated in PDAC, is transcriptionally regulated by the PI3K/AKT1 pathway in PDAC cells. At the molecular level, the control of the SKP2 gene by PI3K is due to the regulation of E2F1 binding to the proximal SKP2 gene promoter. The complex and profound connection of PI3K/AKT1 signaling to the cell cycle qualifies this pathway as a suitable target for therapeutic intervention in PDAC. [Cancer Res 2007;67(9):4149–56]

The Activator Protein 1 (AP-1) transcription factor subunit Fos-related antigen 1 (Fra-1) has been implicated in liver fibrosis. Here we used loss-of-function as well as switchable, cell type-specific, gain-of-function alleles for Fra-1 to investigate the relevance of Fra-1 expression in cholestatic liver injury and fibrosis. Our results indicate that Fra-1 is dispensable in three well-established, complementary models of liver fibrosis. However, broad Fra-1 expression in adult mice results in liver fibrosis, which is reversible, when ectopic Fra-1 is switched off. Interestingly, hepatocyte-specific Fra-1 expression is not sufficient to trigger the disease, although Fra-1 expression leads to dysregulation of fibrosis-associated genes. Both opn and cxcl9 are controlled by Fra-1 in gain-of-function and loss-of-function experiments. Importantly, Fra-1 attenuates liver damage in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine-feeding cholestatic liver injury model. Strikingly, manipulating Fra-1 expression affects genes involved in hepatic transport and detoxification, in particular glutathione S-transferases. Molecular analyses indicate that Fra-1 binds to the promoters of cxcl9 and gstp1 in vivo. Furthermore, loss of Fra-1 sensitizes, while hepatic Fra-1 expression protects from acetaminophen-induced liver damage, a paradigm for glutathione-mediated acute liver failure. Conclusion: These data define a novel function of Fra-1/AP-1 in modulating the expression of detoxification genes and the adaptive response of the liver to bile acids/xenobiotic overload. (Hepatology 2014;58:261–273)

Understanding the molecular pathogenesis of inflammatory liver disease is essential to design efficient therapeutic approaches. In hepatocytes, the dimeric transcription factor c-JUN/AP-1 is a major mediator of cell survival during hepatitis, although functions for other JUN proteins in liver disease are less defined. Here, we found that JUNB was specifically expressed in human and murine immune cells during acute liver injury. We analyzed the molecular function of JUNB in experimental models of hepatitis, including administration of concanavalin A (ConA) or α-galactosyl-ceramide, which induce liver inflammation and injury. Mice specifically lacking JUNB in hepatocytes displayed a mild increase in ConA-induced liver damage. However, targeted deletion of Junb in immune cells and hepatocytes protected against hepatitis in experimental models that involved NK/NKT cells. The absence of JUNB in immune cells decreased IFN-γ expression and secretion from NK and NKT cells, leading to reduced STAT1 pathway activation. Systemic IFN-γ treatment or adenovirus-based IRF1 delivery to Junb-deficient mice restored hepatotoxicity, and we demonstrate that Ifng is a direct transcriptional target of JUNB. These findings demonstrate that JUNB/AP-1 promotes cell death during acute hepatitis by regulating IFN-γ production in NK and NKT cells and thus functionally antagonizes the hepatoprotective function of c-JUN/AP-1 in hepatocytes.

Epidemiological and experimental data demonstrate, that inflammation contributes significantly to pancreatic carcinogenesis. IL1beta, a pleiotropic cytokine produced by inflammatory cells and tumor cells, promotes cancer progression. Single nucleotide polymorphisms (SNPs) of the IL1beta promoter were found to be associated with an increased risk for certain cancers. In this case-control study we determined IL1beta promoter SNPs in 73 patients with pancreatic cancer and 235 controls. We found that the IL1beta -511CT/-31TC genotype was significantly associated with an increased risk for pancreatic cancer (OR 1.42, p=0.0456). Among pancreatic cancer cases, patients with the -511CT/-31TC genotype had less frequently resectable disease than patients with other IL1beta -511/-31 genotypes (p=0.0323). Furthermore, the IL1beta -511CT/-31TC genotype was more frequent observed in UICC stage IV (p=0.039) and undifferentiated tumors (G3) (p=0.019). In addition, we found that the proinflammatory IL1beta -511CT/-31TC alleles define an IL1beta secretory phenotype in pancreatic cancer cell lines in vitro. These findings provide a first evidence for an association of the IL1beta gene promoter SNPs with risk for pancreatic cancer.

Pancreatic ductal adenocarcinoma is a dismal disease with a median survival of less than 6 months and an overall 5-year survival rate less than 1%. This bad prognosis is due to early lymphatic and hematogenic dissemination. Effective therapies for locally advanced or metastatic tumors are very limited and curatively resected patients experience relapse in over 80% of cases. Together, these findings reflect the aggressive biology of the disease. Here, we describe molecular mechanisms leading to unrestrained proliferation, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential, tissue invasion, metastasis and sustained angiogenesis. Potential therapeutic targets are highlighted.