Neoadjuvant concurrent chemoradiotherapy with and without hyperthermia in retroperitoneal sarcomas: feasibility, efficacy, toxicity, and long-term outcome.

PURPOSE: Retroperitoneal (RPS) sarcomas are associated with poor local and abdominal tumor control. However, the benefit of preoperative radio- or chemotherapy alone for these entities is currently unclear. Moreover, as intermediate- and high-grade sarcomas have a tendency toward early metastasis, exploration of neoadjuvant strategies is of high importance. This analysis reports the results of our 20-year single-institution experience with preoperative neoadjuvant concurrent chemoradiation. METHODS: From 2000-2019, 27 patients with intermediate- or high-grade RPS (12 dedifferentiated liposarcoma, 10 leiomyosarcoma, 5 others) were treated with radiotherapy (median dose: 50.4 Gy; range 45-75 Gy) and two cycles of chemotherapy (doxorubicin 50 mg/m2 BSA/d3 q28 and ifosfamide 1.5 g/m2 BSA/d1­5 q28) in neoadjuvant intent. Chemotherapy consisted of doxorubicin alone in two cases and ifosfamide alone in one case. Fifteen patients (56%) additionally received deep regional hyperthermia. RESULTS: The median follow-up time was 53 months (±56.7 months). 92% of patients received two cycles of chemotherapy as planned and 92% underwent surgery. At 5 and 10 years, abdominal-recurrence-free survival was 74.6% (±10.1%) and 66.3% (±11.9%), distant metastasis-free survival was 67.2% (±9.7%) and 59.7% (±11.1%), and overall survival was 60.3% (±10.5%) and 60.3% (±10.5%), respectively. CTC grade III and IV toxicities were leukocytopenia (85%), thrombocytopenia (33%), and anemia (11%). There were no treatment-related deaths. CONCLUSION: Neoadjuvant chemoradiotherapy with and without hyperthermia for retroperitoneal sarcomas is feasible and provided high local control of intermediate- and high-grade sarcoma.

[Sinonasal tumors : News from the WHO with special reference to mesenchymal entities]. / Sinunasale Tumoren : Neues aus der WHO mit besonderem Fokus auf neue mesenchymale Entitäten.

The last two decades have seen significant advances in the pathology of sinonasal tract neoplasms. This was the consequence of the availability of several innovative diagnostic tools, which resulted in a dynamic evolution of entities and splitting of newly defined or conceptualized entities and subtypes that have been included in the spectrum of old heterogeneous diseases. Most of these new tumor subtypes have distinctive demographic, clinicopathologic, and biological characteristics with prognostic and therapeutic implications for individual patients. NUT carcinoma (NUT midline carcinoma) was separated from the spectrum of sinonasal undifferentiated carcinoma (SNUC) and is defined by specific recurrent translocation. On the other hand, the recently described SMARCB1-deficient carcinoma (while probably representing a distinctive clinicopathologic entity) remained as a variant in the SNUC spectrum. A new neoplasm in the spectrum of non-keratinizing carcinomas is the human papillomavirus(HPV)-related adenoid-cystic-like sinonasal carcinoma with its distinctive, albeit diverse, morphology. In the group of small round-cell malignancies, adamantinoma-like Ewing sarcoma has been delineated as an important diagnostic pitfall given its prominent epithelial differentiation. Inclusion of the biphenotypic (myoneural) sinonasal sarcoma (BSS) as a low-grade malignancy defined by recurrent PAX3/MAML3-translocation represents an important feature of the new WHO classification given the distinctive biological behavior of this low-grade non-metastasizing rare entity, which has been uniformly misclassified as a peripheral nerve sheath tumor or leiomyosarcoma in the past. Recognition of CTNNB1 mutations and STAT6/NAB2 gene fusions as defining genetic markers for sinonasal hemangio­/glomangiopericytoma and solitary fibrous tumors, respectively, represents another important achievement in recent years. This review summarizes the new aspects in the WHO classification and also addresses recently described entities that have not been included in the WHO classification.

[Diagnostic and predictive molecular pathology of head and neck neoplasms]. / Diagnostische und prädiktive Molekularpathologie von Kopf-Hals-Tumoren.

As a result of some seminal observations as well as a consequence of increasing use of modern and innovative molecular diagnostic technologies, a variety of new genetic aberrations have been discovered in head and neck neoplasms of different anatomic locations and histogenetic origins. These advances resulted in the establishment of new molecularly defined disease entities. On the other hand, some of these new genetic biomarkers paved the way to potentially promising novel therapeutic opportunities. Diverse old (well known in other entities) and newly discovered translocations and gene fusions represent the leading subgroup of these genetic aberrations. They have been detected not only in malignant epithelial neoplasms (carcinomas) of the salivary glands, but also in carcinomas from other head and neck sites as well as diverse mesenchymal tumors. In addition to these gene fusions, several activating mutations (such as CTNNB1 in sinonasal glomangiopericytoma) as well as inactivating mutations or deletions (like SMARCB1 loss in sinonasal carcinomas) were detected as new molecular markers. In the present review we summarize the relevant molecular alterations in topographically and histopathologically distinct tumors of the head and neck region with emphasis on recently established molecular markers.

Heparosan-coated liposomes for drug delivery.

Liposomal encapsulation is a useful drug delivery strategy for small molecules, especially chemotherapeutic agents such as doxorubicin. Doxil® is a doxorubicin-containing liposome ("dox-liposome") that passively targets drug to tumors while reducing side effects caused by free drug permeating and poisoning healthy tissues. Polyethylene glycol (PEG) is the hydrophilic coating of Doxil® that protects the formulation from triggering the mononuclear phagocyte system (MPS). Evading the MPS prolongs dox-liposome circulation time thus increasing drug deposition at the tumor site. However, multiple doses of Doxil® sometimes activate an anti-PEG immune response that enhances liposome clearance from circulation and causes hypersensitivity, further limiting its effectiveness against disease. These side effects constrain the utility of PEG-coated liposomes in certain populations, justifying the need for investigation into alternative coatings that could improve drug delivery for better patient quality of life and outcome. We hypothesized that heparosan (HEP; [-4-GlcA-ß1-4-GlcNAc-α1-]n) may serve as a PEG alternative for coating liposomes. HEP is a natural precursor to heparin biosynthesis in mammals. Also, bacteria expressing an HEP extracellular capsule during infection escape detection and are recognized as "self," not a foreign threat. By analogy, coating drug-carrying liposomes with HEP should camouflage the delivery vehicle from the MPS, extending circulation time and potentially avoiding immune-mediated clearance. In this study, we characterize the postmodification insertion of HEP-lipids into liposomes by dynamic light scattering and coarse-grain computer modeling, test HEP-lipid immunogenicity in rats, and compare the efficacy of drug delivered by HEP-coated liposomes to PEG-coated liposomes in a human breast cancer xenograft mouse model.

An update on the management of sporadic desmoid-type fibromatosis: a European Consensus Initiative between Sarcoma PAtients EuroNet (SPAEN) and European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG).

Desmoid-type fibromatosis is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Currently, there is no established or evidence-based treatment approach available for this disease. Therefore, in 2015 the European Desmoid Working Group published a position paper giving recommendations on the treatment of this intriguing disease. Here, we present an update of this consensus approach based on professionals' AND patients' expertise following a round table meeting bringing together sarcoma experts from the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group with patients and patient advocates from Sarcoma PAtients EuroNet. In this paper, we focus on new findings regarding the prognostic value of mutational analysis in desmoid-type fibromatosis patients and new systemic treatment options.

[Gastrointestinal stromal tumours (GIST)--development in pathology, surgery and medical therapy. Developed during the 10th German GIST-meeting, Göttingen]. / Gastrointestinale Stromatumoren (GIST)--Neues zu Pathologie, Chirurgie und medikamentöser Therapie. Erarbeitet im Rahmen des 10. Deutschen GIST-Treffens, Göttingen.

The first description of ligand-independent activating mutations in the KIT gene, which encodes the tyrosine-kinase KIT, greatly improved our understanding of gastrointestinal stromal tumour (GIST) biology. The therapeutic success in GIST has made tyrosine kinase inhibitors a "paradigm of targeted therapy". Deciphering resistance mechanisms in GIST has had implications for many other kinase-driven cancers. To exchange current knowledge within the field of GIST, the German GIST Meeting has taken place for now 10 years, traditionally in Göttingen. Subjects discussed include clinical diagnostics, pathology, surgery, and medical therapy. The following presentation gives an overview of the last meeting held in December 2013, including distinctive features in GIST and current data on the different topics.

Irreversible heavy chain transfer to hyaluronan oligosaccharides by tumor necrosis factor-stimulated gene-6.

The covalent transfer of heavy chains (HCs) from inter-α-inhibitor (IαI) to hyaluronan (HA) via the protein product of tumor necrosis factor-stimulated gene-6 (TSG-6) forms the HC-HA complex, a pathological form of HA that promotes the adhesion of leukocytes to HA matrices. The transfer of HCs to high molecular weight (HMW) HA is a reversible event whereby TSG-6 can shuffle HCs from one HA molecule to another. Therefore, HMW HA can serve as both an HC acceptor and an HC donor. In the present study, we show that transfer of HCs to low molecular weight HA oligosaccharides is an irreversible event where subsequent shuffling does not occur, i.e. HA oligosaccharides from 8 to 21 monosaccharide units in length can serve as HC acceptors, but are unable to function as HC donors. We show that the HC-HA complex is present in the synovial fluid of mice subjected to systemic and monoarticular mouse models of rheumatoid arthritis. Furthermore, we demonstrate that HA oligosaccharides can be used, with TSG-6, to irreversibly shuffle HCs from pathological, HMW HC-HA to HA oligosaccharides, thereby restoring HC-HA matrices from the inflamed joint to their normal state, unmodified with HCs. This process was also effective for HC-HA in the synovial fluid of human rheumatoid arthritis patients (in vitro).

The inflammation-associated protein TSG-6 cross-links hyaluronan via hyaluronan-induced TSG-6 oligomers.

Tumor necrosis factor-stimulated gene-6 (TSG-6) is a hyaluronan (HA)-binding protein that plays important roles in inflammation and ovulation. TSG-6-mediated cross-linking of HA has been proposed as a functional mechanism (e.g. for regulating leukocyte adhesion), but direct evidence for cross-linking is lacking, and we know very little about its impact on HA ultrastructure. Here we used films of polymeric and oligomeric HA chains, end-grafted to a solid support, and a combination of surface-sensitive biophysical techniques to quantify the binding of TSG-6 into HA films and to correlate binding to morphological changes. We find that full-length TSG-6 binds with pronounced positive cooperativity and demonstrate that it can cross-link HA at physiologically relevant concentrations. Our data indicate that cooperative binding of full-length TSG-6 arises from HA-induced protein oligomerization and that the TSG-6 oligomers act as cross-linkers. In contrast, the HA-binding domain of TSG-6 (the Link module) alone binds without positive cooperativity and weaker than the full-length protein. Both the Link module and full-length TSG-6 condensed and rigidified HA films, and the degree of condensation scaled with the affinity between the TSG-6 constructs and HA. We propose that condensation is the result of protein-mediated HA cross-linking. Our findings firmly establish that TSG-6 is a potent HA cross-linking agent and might hence have important implications for the mechanistic understanding of the biological function of TSG-6 (e.g. in inflammation).

Risk factors for incident mild cognitive impairment--results from the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe).

OBJECTIVES: To provide age- and gender-specific incidence rates of MCI among elderly general practitioner (GP) patients (75+ years) and to identify risk factors for incident MCI. METHOD: Data were derived from the longitudinal German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe). Incidence was calculated according to the 'person-years-at-risk' method. Risk factors were analysed using multivariate logistic regression models. RESULTS: During the 3-year follow-up period, 350 (15.0%) of the 2331 patients whose data were included in the calculation of incidence developed MCI [person-years (PY) = 6198.20]. The overall incidence of MCI was 56.5 (95% confidence interval = 50.7-62.7) per 1000 PY. Older age, vascular diseases, the apoE epsilon4 allele and subjective memory complaints were identified as significant risk factors for future MCI. CONCLUSION: Mild cognitive impairment is frequent in older GP patients. Subjective memory complaints predict incident MCI. Especially vascular risk factors provide the opportunity of preventive approaches.

[Molecular biological evaluation of prognostic parameters in GIST. Development of an integrative model of tumor progression]. / Molekularbiologische Evaluation prognostischer Parameter in GIST. Entwicklung eines integrativen Modells der Tumorprogression.

Prognosis evaluation in gastrointestinal stromal tumors (GIST) is currently based on tumor diameter, mitotic counts and anatomic localisation. There are two risk classifications as well as the first ever TNM classification for GISTs, whereby the risk classification according to the Armed Forces Institute of Pathology (AFIP) has the best correlation with clinical follow-up according to own experiences. "Very low/low risk" GISTs are almost benign, while the majority of "high risk" GISTs metastasize and benefit from adjuvant therapy. Careful evaluation of mitotic counts in 50 high-power fields is of particular relevance for correct risk classification. Apart from these classical prognostic factors, many molecular genetic parameters with correlation to follow-up have been evaluated and may help to improve prognosis evaluation of GISTs in the future. Since most of the molecular genetic parameters are associated or even determined by the clinico-pathological parameters, an integrated model for tumor progression of GISTs is helpful to interpret the different factors in correlation to one another. In particular for "intermediate risk" GISTs, additional parameters are needed for improved prognosis evaluation.

[Multilayer analysis of signal transduction and cell cycle control in GIST. Identifying new interaction partners with differential regulation]. / Multilayer-Analyse der Signaltransduktion und Zellzykluskontrolle in GIST. Identifizierung neuer Interaktionspartner mit differenzieller Regulation.

To identify new interactions as well as diagnostically, prognostically and therapeutically relevant differences in the regulation of gene expression in gastrointestinal stromal tumors (GISTs), we analyzed the methylation status, mRNA expression, microRNA expression, protein expression and protein phosphorylation in parallel in identical tumor tissue samples. The data were analyzed in a multilayer approach and were correlated to each other and to clinico-pathological parameters. Differentially regulated genes were mapped to signal transduction pathways which are already known to play a major role in GISTs. A functionally orientated overview of the different data layers was constructed, which enabled new insights into gene regulation in GISTs.

Increased KIT signalling with up-regulation of cyclin D correlates to accelerated proliferation and shorter disease-free survival in gastrointestinal stromal tumours (GISTs) with KIT exon 11 deletions.

Gastrointestinal stromal tumours (GISTs) with deletions in KIT exon 11 are characterized by higher proliferation rates and shorter disease-free survival times, compared to GISTs with KIT exon 11 point mutations. Up-regulation of cyclin D is a crucial event for entry into the G1 phase of the cell cycle, and links mitogenic signalling to cell proliferation. Signalling from activated KIT to cyclin D is directed through the RAS/RAF/ERK, PI3K/AKT/mTOR/EIF4E, and JAK/STATs cascades. ERK and STATs initiate mRNA transcription of cyclin D, whereas EIF4E activation leads to increased translation efficiency and reduced degradation of cyclin D protein. The aim of the current study was to analyse the mRNA and protein expression as well as protein phosphorylation of central hubs of these signalling cascades in primary GISTs, to evaluate whether tumours with KIT exon 11 deletions and point mutations differently utilize these pathways. GISTs with KIT exon 11 deletions had significantly higher mitotic counts, higher proliferation rates, and shorter disease-free survival times. In line with this, they had significantly higher expression of cyclin D on the mRNA and protein level. Furthermore, there was a significantly higher amount of phosphorylated ERK1/2, and a higher protein amount of STAT3, mTOR, and EIF4E. PI3K and phosphorylated AKT were also up-regulated, but this was not significant. Ultimately, GISTs with KIT exon 11 deletions had significantly higher phosphorylation of the central negative cell-cycle regulator RB. Phosphorylation of RB is accomplished by activated cyclin D/CDK4/6 complex, and marks a central event in the release of the cell cycle. Altogether, these observations suggest increased KIT signalling with up-regulation of cyclin D as the basis for the unfavourable clinical course in GISTs with KIT exon 11 deletions.

Coding and Non-coding: Molecular Portrait of GIST and its Clinical Implication.

Gastrointestinal stromal tumours are the most common mesenchymal tumours of the gastrointestinal tract. Despite similar mutation pattern of activating mutations in KIT or PDGFRA receptors in 85% of cases, they demonstrate significantly heterogeneous clinical behaviour and pathological characteristics. This heterogeneity opens the question of the role of other factors and mechanisms of regulation in the development of GIST. Additional mutations in downstream effectors of GIST related signalling pathways or aberrant expression of non-coding RNAs may be additional contributing factors, the latter being increasingly recognized in carcinogenesis in general. Recently, a substantial progress has been achieved in understanding the functional roles of lncRNAs in GIST suggesting their potential employment as biomarkers and therapeutic targets in GIST. Moreover, some miRNAs have recently been found to be able to sensitize cells to imatinib, which could be an attractive option to overcome the resistance to the drug, which hampers the efficacy of GIST treatment. Therefore, the advantage can be taken of both coding and non-coding parts of the genome in order to significantly improve prognostication and help find personalized therapy for patients, depending on a subtype of GIST and personal characteristics.

[R1 resection for pancreatic carcinoma]. / R1-Resektion beim Pankreaskarzinom.

BACKGROUND: Surgery is the only potentially curative therapeutic approach in patients with pancreatic ductal adenocarcinoma (PDAC); however, achieving a negative (R0) resection margin is not always possible. OBJECTIVE: The impact of R1 resection margins on survival rates and treatment options (surgical and multimodal) for intraoperatively and postoperatively identified R1 resection margins. RESULTS: For intraoperatively diagnosed R1 resection margins, a re-resection (e.g. pancreas, main bile duct, stomach, superior mesenteric and portal vein) can be performed to achieve R0 resection margins. Arterial resections and the resection of additional organs are occasionally technically feasible and can be performed in an individual approach. New neoadjuvant and adjuvant treatment strategies have increased the rate of resectable PDAC and have improved the outcome of patients with R0/R1 resected PDACs. CONCLUSION: An R0 resection is the primary goal of surgery in patients with PDAC as R1 resections are correlated with a poor outcome.

Androgen metabolism via 17beta-hydroxysteroid dehydrogenase type 3 in mammalian and non-mammalian vertebrates: comparison of the human and the zebrafish enzyme.

Formation and inactivation of testosterone is performed by various members of the 17beta-hydroxysteroid dehydrogenase (17beta-HSD) family. The main player in testosterone formation is considered to be 17beta-HSD type 3, which catalyzes the reduction of androstenedione to testosterone with high efficiency and is almost exclusively expressed in testis. So far, only the mammalian homologs have been characterized but nothing is known about the role of 17beta-HSD type 3 in other vertebrates. In this study, we describe the identification and characterization of the zebrafish homolog. We found zebrafish 17beta-HSD type 3 to be expressed in embryogenesis from sphere to 84 h post-fertilization. Expression was also detected in various tissues of both male and female adults, but displayed sexual dimorphism. Interestingly, expression was not highest in male testis but in male liver. In female adults, strongest expression was observed in ovaries. At the subcellular level, both human and zebrafish 17beta-HSD type 3 localize to the endoplasmic reticulum. The zebrafish enzyme in vitro effectively catalyzed the conversion of androstenedione to testosterone by use of NADPH as cofactor. Among further tested androgens epiandrosterone and dehydroepiandrosterone were accepted as substrates and reduced at C-17 by the human and the zebrafish enzyme. Androsterone and androstanedione though, were only substrates of human 17beta-HSD type 3, not the zebrafish enzyme. Furthermore, we found that both enzymes can reduce 11-ketoandrostenedione as well as 11beta-hydroxyandrostenedione at C-17 to the respective testosterone forms. Our results suggest that 17beta-HSD type 3 might play slightly different roles in zebrafish compared with human although testosterone itself is likely to have similar functions in both organisms.