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Local recurrences (LR) and distant metastases (DM) are common in retroperitoneal soft tissue sarcoma (RPS). Longer time to recurrence and resection of the recurrent lesion have been identified as beneficial prognostic factors for overall survival (OS) upon first tumor relapse. However, prognostic factors concerning OS upon subsequent recurrences are scarcely defined. In this study, we aimed to identify prognostic factors for post-relapse outcome in multiple recurrent RPS.Patients undergoing resection of primary and recurrent RPS at the University Hospital Heidelberg were retrospectively analyzed. Multivariable Cox regression analyses were performed to identify predictors of overall, LR- and DM-free survival. Subgroup analyses were performed for liposarcoma and leiomyosarcoma patients.201 patients with primary disease, 101 patients with first, 66 patients with second and 43 patients with third LR as well as 75 patients with DM were analyzed. More than 12 months to recurrence and resection of recurrence were associated with improved OS after resection of first and second LR (5-year OS for first/second LR; resection: 64%/62%, no resection: 20%/46%). Gross macroscopic incomplete resection of first (p 0.001), second (p = 0.001), and third recurrences (p 0.001) was an independent prognostic factor for poor OS.Development of LR and DM is frequent in RPS. Once a tumor relapsed, patients benefit from tumor resection not only in case of first, but also in case of subsequent recurrences.

The genetic hallmark of epithelioid hemangioma (EH) is the presence of recurrent gene fusions involving FOS and FOSB transcription factors, which occur in one-third of the cases. Certain clinical, pathologic, and genotypic correlations have been described, with FOS-related fusions being more often detected in skeletal and cellular variants of EH, while FOSB gene rearrangements are more commonly associated with atypical histologic features and penile location. These fusions are infrequently detected in the cutaneous or head and neck EH. Overall, two-thirds of EH lack these canonical fusions and remain difficult to classify, especially when associated with atypical features and/or clinical presentations. Triggered by an index case of an intravascular soft tissue EH with a novel GATA6-FOXO1 gene fusion by targeted RNA sequencing (Archer® FusionPlex® Sarcoma Panel), we have investigated 27 additional EH cases negative for FOS and FOSB gene rearrangements for this novel abnormality to determine its recurrent potential, and its association with clinical and pathologic features. Four additional EH cases were found to display GATA6-FOXO1 fusions (18%). There were three females and two males, with a mean age of 32 years old. Three lesions occurred in the head and neck (dura, nasopharyngeal, and cheek), one in the back and one in the leg. Two of these lesions were cutaneous and one was intravascular in the subcutis of the leg. Microscopically, the tumors showed a variegated morphology, with alternating vasoformative and solid components, extravasated red blood cells and mild to moderate cytologic atypia. None showed brisk mitotic activity or necrosis. Tumors were negative for FOS and FOSB by immunohistochemistry. In conclusion, we report a new GATA6-FOXO1 fusion in a subset of EH, with a predilection for skin, and head and neck location. The relationship of this novel molecular subset with the more common FOS/FOSB fusion-positive EH remains to be determined.

Background: While subtyping of the majority of malignant chromophobe renal cell carcinoma (cRCC) and benign renal oncocytoma (rO) is possible on morphology alone, additional histochemical, immunohistochemical or molecular investigations are required in a subset of cases. As currently used histochemical and immunohistological stains as well as genetic aberrations show considerable overlap in both tumors, additional techniques are required for differential diagnostics. Mass spectrometry imaging (MSI) combining the detection of multiple peptides with information about their localization in tissue may be a suitable technology to overcome this diagnostic challenge. Patients and Methods: Formalin-fixed paraffin embedded (FFPE) tissue specimens from cRCC (n=71) and rO (n=64) were analyzed by MSI. Data were classified by linear discriminant analysis (LDA), classification and regression trees (CART), k-nearest neighbors (KNN), support vector machine (SVM), and random forest (RF) algorithm with internal cross validation and visualized by t-distributed stochastic neighbor embedding (t-SNE). Most important variables for classification were identified and the classification algorithm was optimized. Results: Applying different machine learning algorithms on all m/z peaks, classification accuracy between cRCC and rO was 85%, 82%, 84%, 77% and 64% for RF, SVM, KNN, CART and LDA. Under the assumption that a reduction of m/z peaks would lead to improved classification accuracy, m/z peaks were ranked based on their variable importance. Reduction to six most important m/z peaks resulted in improved accuracy of 89%, 85%, 85% and 85% for RF, SVM, KNN, and LDA and remained at the level of 77% for CART. t-SNE showed clear separation of cRCC and rO after algorithm improvement. Conclusion: In summary, we acquired MSI data on FFPE tissue specimens of cRCC and rO, performed classification and detected most relevant biomarkers for the differential diagnosis of both diseases. MSI data might be a useful adjunct method in the differential diagnosis of cRCC and rO.

Background Desmoid-type fibromatosis is a rare, potentially locally aggressive disease. Herein we present our experience in the treatment with radiotherapy. Methods and materials In total 40 patients who received 44 treatments from 2009 to 2018 at the Heidelberg University Hospital with photons (N = 28) as well as protons (N = 15) and carbon ions (N = 1) were investigated. The median age at radiotherapy was 41 years [range 8–78]. Familial adenomatous polyposis (FAP) was confirmed for nine patients and 30 had a unifocal desmoid tumor. The localizations were abdominal wall, abdominopelvic cavity, thoracic wall, extremity, head and neck and trunk. The median prescribed dose was 54 Gy/ Gy (RBE) [range 39.6–66, IQR 50–60]. Eleven treatments were performed at the time of first diagnosis; 33 at the time of progression or recurrence. Post-operative radiotherapy was performed in 17 cases. The median planning target volume was 967 ml [84–4364 ml, IQR 447–1988]. Survival analysis was performed by the Kaplan-Meier Method. Results The median follow-up time was 32 months [1–153]. At the end of the follow-up interval all patients but one were alive. The estimated local progression free survival of the treated lesion in 3 and 5 years was 76.4% and 63,8%, respectively. The progression-free survival in 3 and 5 years was 72.3 and 58.4% and the overall survival was 97.4 and 97.4%, respectively. In case of macroscopic tumor (N = 31) before radiotherapy a partial remission was observed in 12 cases (38.7%) and a complete remission in 4 cases (12.9%). Progression was observed in 13 (29.5%) cases, predominantly at the margin of the planning target volume (PTV, N = 5, 38,4%) followed by progression within the PTV (N = 4, 30.8%). In univariate analysis multifocal localization was associated with impaired progression-free survival (p = 0.013). One patient developed a grade V gastrointestinal bleeding, otherwise no acute toxicity >°III was observed. Late toxicity was depending on the localization of the desmoid tumor and was especially severe in patients with FAP and abdominopelvine desmoids including gastrointesinal fistula, perforation and abscess. Conclusion Radiotherapy in the treatment of desmoids can lead to long term control. Treatment of patients with abdominopelvine desmoids should be avoided, as the risk of higher-grade complications is substantial.

Uterine neoplasms comprise a broad spectrum of lesions, some of which may pose a diagnostic challenge even to experienced pathologists. Recently, genome-wide DNA methylation-based classification of central nervous system tumors has been shown to increase diagnostic precision in clinical practice when combined with standard histopathology. In this study, we describe DNA methylation patterns of a diverse set of uterine neoplasms and test the applicability of array-based DNA methylation profiling. A multicenter cohort including prototypical epithelial and mesenchymal uterine neoplasms was collected. Tumors were subject to pathology review and array-based DNA methylation profiling (Illumina Infinium HumanMethylation450 or EPIC [850k] BeadChip). Methylation data were analyzed by unsupervised hierarchical clustering and t-SNE analysis. After sample retrieval and pathology review the study cohort consisted of 49 endometrial carcinomas (EC), 5 carcinosarcomas (MMMT), 8 uterine leiomyomas (ULMO), 7 uterine leiomyosarcomas (ULMS), 15 uterine tumor resembling ovarian sex cord tumors (UTROSCT), 17 low-grade endometrial stromal sarcomas (LGESS) and 9 high-grade endometrial stromal sarcomas (HGESS). Analysis of methylation data identified distinct methylation clusters, which correlated with established diagnostic categories of uterine neoplasms. MMMT clustered together with EC, while ULMO, ULMS and UTROSCT each formed distinct clusters. The LGESS cluster differed from that of HGESS, and within the branch of HGESS, we observed a notable subgrouping of YWHAE- and BCOR-rearranged tumors. Herein, we describe distinct DNA methylation signatures in uterine neoplasms and show that array-based DNA methylation analysis holds promise as an ancillary tool to further characterize uterine neoplasms, especially in cases which are diagnostically challenging by conventional techniques.

Simple Summary Histopathological examination of lymph node (LN) specimens allows the detection of hematological diseases. The identification and the classification of lymphoma, a blood cancer with a manifestation in LNs, are difficult and require many years of training, as well as additional expensive investigations. Today, artificial intelligence (AI) can be used to support the pathologist in identifying abnormalities in LN specimens. In this article, we trained and optimized an AI algorithm to automatically detect two common lymphoma subtypes that require different therapies using normal LN parenchyma as a control. The balanced accuracy in an independent test cohort was above 95%, which means that the vast majority of cases were classified correctly and only a few cases were misclassified. We applied specific methods to explain which parts of the image were important for the AI algorithm and to ensure a reliable result. Our study shows that classifications of lymphoma subtypes is possible with high accuracy. We think that routine histopathological applications for AI should be pursued. Abstract The diagnosis and the subtyping of non-Hodgkin lymphoma (NHL) are challenging and require expert knowledge, great experience, thorough morphological analysis, and often additional expensive immunohistological and molecular methods. As these requirements are not always available, supplemental methods supporting morphological-based decision making and potentially entity subtyping are required. Deep learning methods have been shown to classify histopathological images with high accuracy, but data on NHL subtyping are limited. After annotation of histopathological whole-slide images and image patch extraction, we trained and optimized an EfficientNet convolutional neuronal network algorithm on 84,139 image patches from 629 patients and evaluated its potential to classify tumor-free reference lymph nodes, nodal small lymphocytic lymphoma/chronic lymphocytic leukemia, and nodal diffuse large B-cell lymphoma. The optimized algorithm achieved an accuracy of 95.56% on an independent test set including 16,960 image patches from 125 patients after the application of quality controls. Automatic classification of NHL is possible with high accuracy using deep learning on histopathological images and routine diagnostic applications should be pursued.

Background: Low-grade myofibroblastic sarcoma (LGMS) is a rare subtype of soft tissue sarcoma of intermediate grade often representing fibromatosis-like features with a rare metastasing behavior. This type of tumor has a predilection for the head and neck region, but also occurs in the extremities. Confirming the diagnosis is difficult and treatment strategies have to be chosen individually.Methods: The objective of this study was to conduct a systematic review for LGMS of the extremities. The electronic databases PubMed and the Cochrane Library were searched for eligible studies. 141 abstracts were screened on PubMed, while 10 studies were identified as eligible. Cases were summarized in terms of clinical aspects, therapeutic regimen with the primary endpoint of follow-up controls regarding local recurrence or distant metastasis. In addition, we present the rare case and surgical management of a 28-year-old male patient with residual LGMS of the thumb after initial incomplete resection. Results: 33 cases of LGMS in the extremities were identified on PubMed. Cochrane library didn’t show any results. All of them were surgically resected. Only two cases of LGMS in the hand were described in literature so far. Treatment options varied from local excision to wide resection without exact definition of the safety distance. 26 cases provided follow-up information with local recurrence in 6 cases (23 %), while 4 cases (15 %) showed distant metastasis. Conclusions: Wide resection should be the surgical aim to avoid local recurrence and distant metastases. While the excision of tumors of the thumb and hand often require closer resection margins, due to the close proximity of anatomical structures, tumor-free margins are elementary even if tissue transfer from a donor site is needed for reconstruction.

AIMS Non-small-cell lung cancer (NSCLC) and breast cancer are common entities. Staining for oestrogen receptor (ER), progesterone receptor (PgR), mammaglobin (MAMG) and GATA-binding protein 3 (GATA3) is frequently performed to confirm a mammary origin in the appropriate diagnostic setting. However, comprehensive data on the immunohistological expression of these markers in NSCLC are limited. Therefore, the aim of this study was to analyse a large cohort of NSCLCs and correlate the staining results with clinicopathological variables. METHODS AND RESULTS A tissue microarray was stained for ER, PgR, MAMG, human epidermal growth factor receptor 2 (HER2), and GATA3, and included 636 adenocarcinomas (ADCs), 536 squamous cell carcinomas (SqCCs), 65 large-cell-carcinomas, 34 pleomorphic carcinomas, and 20 large-cell neuroendocrine carcinomas. HER2 status was determined for immunohistochemically positive cases with chromogenic in-situ hybridisation. Markers with a proportion of ≥5% positive cases in ADC and SqCC were considered for survival analysis. Among ADCs, 62 (10%), 17 (3%), one (

Pancreatic acinar cell carcinoma (PAC) is a rare disease with a poor prognosis. Treatment options for metastatic PAC are limited and often follow chemotherapeutic regimens for pancreatic ductal adenocarcinoma. Although recurrent genomic alterations, such as BRAF fusions and defects in genes involved in homologous recombination DNA repair, have been described in PAC, data on the clinical efficacy of molecularly guided, targeted treatment are scarce. Here we describe the case of a 27-yr-old patient with BRAFV600E-mutated PAC who was successfully treated with a combination of BRAF and MEK inhibitors. The patient presented to our clinic with abdominal pain and weight loss. Imaging showed extensive retroperitoneal disease as well as mediastinal lymphadenopathy. Because of elevated α-fetoprotein (AFP) levels and inconclusive histologic findings, a germ cell tumor was suspected; however, PEI chemotherapy was unsuccessful. A repeat biopsy yielded the diagnosis of PAC and treatment with FOLFIRINOX was initiated. Comprehensive molecular profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program revealed a somatic BRAFV600E mutation and a germline PALB2 stop-gain mutation. Therapy was therefore switched to BRAF/MEK inhibition, resulting in almost complete remission and disease control for 12 mo and a remarkable improvement in the patient's general condition. These results indicate that BRAF alterations are a valid therapeutic target in PAC that should be routinely assessed in this patient population.

Background Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year. In contrast to many other malignancies, no substantial therapeutic breakthrough has been made in the past few decades, thereby limiting the treatment to cytotoxic chemotherapy with little beneficial effect for most patients. Targeted therapy tailored to the individual has shown substantial success in the recent past as a promising avenue for cancer therapy. Methods In this study, we determined the frequency of amplification of the HER2 gene in a comprehensive and well-characterized European cholangiocarcinoma cohort encompassing 436 patients including intrahepatic (n = 155), proximal (n = 155) and distal (n = 126) cholangiocarcinoma by strict application of a combined immunohistochemical and in situ hybridization algorithm following the current guidelines for HER2 assessment in gastric cancer. Results We identified a proportion of 1.4% (n = 6) patients that demonstrated HER2 gene amplification, with the highest rate among the distal cholangiocarcinoma patients (2.4%). None of the patients with equivocal (2+) immunohistochemical staining results exhibited gene amplification molecularly. In four of the five patients with HER2 positivity, gene amplification was already present in concomitantly tested high-grade biliary intraepithelial neoplasia (80%). HER2 gene amplification was not significantly associated with other clinical parameters, including survival. Conclusions This study identifies HER2 gene amplification as a rare event in cholangiocarcinoma of the Western population, occurring already in high-grade BilIN in a subset of patients. Furthermore, we provide a robust testing algorithm that may be used prior to therapy administration in future clinical trials evaluating the role of HER2 as a predictive marker in cholangiocarcinoma.

A 50 year old woman underwent laparoscopic supracervical hysterectomy because of symptomatic fibroids. Histologic examination of samples obtained after morcellation revealed typical uterine leiomyomas in all samples investigated. 28 and 47 months later, respectively, the patient presented with peritoneal spreading of nodules that were surgically removed and histologically classified as leiomyosarcoma. In 3/4 of samples obtained after morcellation copy number/SNP-array hybridization showed complex genomic alterations widely identical to the pattern characterizing the sarcoma. Therefore, we conclude that the leiomyosarcoma had unambiguously developed from one of the leiomyomas as a result of secondary genetic alterations i.e. a rearrangement of ALK and a del(14q). The case is challenging the current risk estimates for spreading of unexpected malignant uterine tumors due to power morcellation and highlights the relevance of certain genetic alterations for rare malignant transformation of uterine benign smooth muscle tumors.

USP6, auch als Tre-2 und TRE17 bekannt, ist eine ubiquitinspezifische Protease, die nach Uberexpression in NIH-3T3-Zellen vor uber 2 Jahrzehnten als potenzielles Onkogen identifiziert wurde. Bis vor einigen Jahren war wenig uber Funktion und Mechanismen der onkogenen Aktivierung von USP6 bekannt. Der Nachweis von USP6-Rearrangements in aneurysmatischen Knochenzysten und in nodularen Fasziitiden hat nicht nur zu einem besseren Verstandnis der Pathogenese dieser Entitaten beigetragen, sondern stellt auch ein nutzliches Werkzeug in ihrer Diagnose und in der differenzialdiagnostischen Abgrenzung von morphologisch ahnlichen Lasionen dar. In dieser Ubersicht werden die klinischen, pathologischen und molekulargenetischen Aspekte der aneurysmatischen Knochenzyste und der nodularen Fasziitis sowie der mit diesen Entitaten verwandten Lasionen vorgestellt und diskutiert.

Introduction: The treatment of patients (pts) with rrMM remains challenging and response is often limited in depth and duration. In contrast to many other malignant diseases, targeted therapy in MM is hampered by the limited number of actionable targets. Activating mutations of BRAF have been found in 2-4% of newly diagnosed MM and in up to 8% of rrMM. Several case reports have reported clinical efficacy of downstream pathway inhibition in MM. This phase II trial is evaluating the safety and efficacy of combined BRAF/MEK inhibition in rrMM pts with BRAF V600E mutation. Aims: The primary objective of this study was to demonstrate the therapeutic efficacy of encorafenib in combination with binimetinib. The primary endpoint was the overall response rate (ORR), defined as best response within 1 year of treatment. Main secondary endpoints included progression-free survival (PFS) and duration of response. Safety analyses included all adverse events (AEs) with those of grade 1/2 only being assessed further if considered to be related to study medications by the investigator. Methods: A total of 15 pts with rrMM who have failed at least 2 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMID), were planned to be enrolled in this open-label phase II multicenter trial. Key inclusion criteria were presence of a BRAF V600E/K mutation confirmed by both mutation-specific immunohistochemistry (IHC) and next-generation sequencing in more than 50% of MM cells. Exclusion criteria included plasma cell leukemia, CNS involvement, cardiac dysfunction, or a history of retinal vein occlusion. Pts received encorafenib 450mg p.o. daily and binimetinib 45mg p.o. twice daily. Responses were assessed using IMWG 2016 criteria. The primary endpoint was analyzed by testing the one-sided null hypothesis of ORR Results: As of July 2020, 12 pts have been enrolled and were evaluable for safety and 11 pts were evaluable for response as 1 pt had just completed cycle 1 with confirmation of response pending at the time of data lock. Subtypes of MM were IgG in 6 pts, IgA in 2 pts, and Bence Jones in 4 pts. Pts had received a median of 5 prior lines of therapy (range 2-14). All pts had failed previous treatment with both a PI and an IMID and in addition carfilzomib, pomalidomid, and/or anti-CD38 antibodies in 8/4/6 pts, respectively. The study already reached its primary endpoint. The ORR was 82% (lower limit of the 95% CI 56.4%, one-sided exact binomial test, p Adverse events of all grades, assessed to be at least possibly related to a study drug, occurred in 9/12 pts and included blurred vision, macula edema, cramps, arthralgia, diarrhea, skin rash, and decreased left ventricular function. Grade 3 or 4 AEs irrespective of causality occurring in more than 1 pt were reported in 8 pts with anemia, hypertension and thrombocytopenia (3/ 3/ 2 pts, respectively). SAEs were reported in 2 pts, respiratory tract infection in both pts and tooth decay in 1 pt that was not related to the study medication. No deaths occurred while on treatment or within 30 days of the end of treatment. Preliminary results of biomarker assessments reveal new RAS mutations and amplification of the BRAF locus at the time of relapse while on study treatment as potential markers of resistance. Analysis of pharmacodynamic markers by phospho-IHC reveals suppression of BRAF/MEK signaling at cycle 1 / day 28 and restoration of expression at the time of relapse. Conclusion: Targeting activating BRAF mutations in rrMM by combining the BRAF inhibitor, encorafenib, and the MEK inhibitor, binimetinib, induces rapid and deep responses in the majority of pts. No new safety signal has been observed when compared to prior reports on these compounds. The study reached its primary endpoint with fewer pts than expected. The primary efficacy and safety analysis will be presented at the conference. Disclosures Raab: Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Scheid:BMS: Honoraria; Amgen: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Besemer:GSK: Honoraria; Janssen: Honoraria. Metzler:Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; GSK: Consultancy; BMS: Consultancy. Khandanpour:Astra Zeneca: Research Funding; Sanofi: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy. Trautmann-Grill:Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Honoraria; GSK: Consultancy; BMS: Honoraria. Goldschmidt:Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp and Dohme (MSD): Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Novartis: Honoraria, Research Funding; Molecular Partners: Research Funding; Incyte: Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:. Weisel:Abbvie: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. OffLabel Disclosure: Encorafenib and Binimetinib in BRAF V600E mutant multiple myeloma

Contains fulltext : 175089.pdf (Publisher’s version ) (Open Access) BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) 62012 study was a Phase III trial of doxorubicin versus doxorubicin-ifosfamide chemotherapy in 455 patients with advanced soft tissue sarcoma (STS). Analysis of the main study showed that combination chemotherapy improved tumor response and progression-free survival, but differences in overall survival (OS) were not statistically significant. We analyzed factors prognostic for tumor response and OS, and assessed histological subgroup and tumor grade as predictive factors to identify patients more likely to benefit from combination chemotherapy. METHODS: Central pathology review was performed by six reference pathologists. Gender, age, performance status, time from first presentation with sarcoma to starting palliative chemotherapy, tumor grade, histological subgroup, primary tumor site involvement, and sites of metastases were assessed as prognostic factors. RESULTS: Three hundred and ten patients were included in this study. Discordance between local and central pathology opinion of tumor histology and tumor grade was observed in 98 (32%) and 122 (39%) cases, respectively. In multivariate analysis, liposarcoma patients had improved tumor response compared to other histological subgroups, whilst patients with metastases other than lung, liver or bone had a poorer response [odds ratio (OR) 0.42, 95% confidence interval (CI) 0.23-0.78; p = 0.006]. Patients with bone metastases had reduced OS [hazard ratio (HR) 1.56, 95% CI 1.16-2.09; p = 0.003]. By central pathology review, patients with undifferentiated pleomorphic sarcoma (UPS) had improved tumor response and OS with doxorubicin-ifosfamide compared to single-agent doxorubicin (OR 9.90, 95% CI 1.93-50.7 and HR 0.44, 95% CI 0.26-0.79, respectively). Grade III tumors had improved response with combination chemotherapy but there was no interaction between chemotherapy and grade on OS. CONCLUSIONS: Prospective central pathology review of tumor histology should be integrated into future STS clinical trials. Doxorubicin-ifosfamide may be most appropriate for young, fit patients with poorly differentiated Grade III tumors including UPS.

Es wird uber den Fall einer 47-jahrigen Patientin mit einseitiger, polyostotischer fibroser Dysplasie und drei intramuskularen Raumforderungen berichtet. Die bildgebende Diagnostik war suspekt auf intramuskulare Myxome, sodass die Verdachtsdiagnose eines Mazabraud-Syndroms gestellt wurde. Nach Inzisionsbiopsie konnte dieses histopathologisch und molekularpathologisch bestatigt werden. Es folgte die Exzision der intramuskularen Myxome und aufgrund anamnestisch bestehender endokriner Begleitanomalien der zusatzliche Nachweis eines McCune-Albright-Syndroms.

Ein 10-jahriger Junge leidet seit 2 Monaten zunehmend an Schmerzen im Oberschenkel. Im Rontgen und CT ist eine Osteolyse des Os ilium zu erkennen. Eine Knochenbiopsie fuhrt zur richtigen Diagnose.

Introduction In retroperitoneal soft tissue sarcoma (STS) local recurrence (LR) rates remain high despite more aggressive surgical approaches. Since wide resection margins cannot be achieved in all patients, application of intraoperative radiation therapy (IORT) has been frequently discussed. Still, the significance of IORT in multimodal treatment of retroperitoneal STS remains unclear. Material and methods Patients undergoing resection of primary or recurrent retroperitoneal STS at the University of Heidelberg Department of General, Visceral and Transplantation Surgery were retrospectively analyzed. Univariate Kaplan-Meyer and multivariate Cox regression analyses were performed to identify predictors of LR-free survival and to investigate the impact of IORT and high cumulative radiation doses. Analyses with propensity-score matched subgroups for IORT and cumulative radiation dose were performed to control for selection bias. Subgroup analyses for patients with retroperitoneal liposarcoma were likewise performed. Results 272 patients were identified. Recurrent tumors, histology of dedifferentiated liposarcoma or unclassified sarcoma and microscopically incomplete resection were associated with decreased LR-free survival. In liposarcoma, only recurrent and dedifferentiated tumors were confirmed as poor prognostic factors concerning LR. IORT and cumulative radiation doses exceeding 60 Gy did not influence LR rates (estimated 5-year LR-free survival: IORT: 39%, non-IORT: 46%; p = 0.79). Conclusion In this retrospective evaluation, additional application of IORT does not significantly influence oncological outcome in retroperitoneal soft tissue sarcoma. Randomized trials are needed to clarify the benefit of IORT.

Tumors of soft tissue and bone represent a heterogeneous group of neoplasias characterized by a wide variety of genetic aberrations. Albeit knowledge on tumorigenesis in mesenchymal tumors is continuously increasing, specific insights on altered signaling pathways as a basis for molecularly targeted therapeutic strategies are still sparse. The aim of this study was to determine the involvement of YAP1/TAZ-mediated signals in tumors of soft tissue and bone. Expression levels of YAP1 and TAZ were analyzed by immunohistochemistry in a large cohort of 486 tumor specimens, comprising angiosarcomas (AS), Ewing sarcomas, leiomyosarcomas, malignant peripheral nerve sheath tumors (MPNST), solitary fibrous tumors, synovial sarcomas (SySa), well-differentiated/dedifferentiated/pleomorphic and myxoid liposarcomas (MLS). Moderate to strong nuclear staining of YAP1 and TAZ was detected in 53% and 33%, respectively. YAP1 nuclear expression was most prevalent in MPNST, SySa and MLS, whereas nuclear TAZ was predominately detected in AS, MLS and MPNST. In a set of sarcoma cell lines, immunoblotting confirmed nuclear localization of YAP1 and TAZ, corresponding to their transcriptionally active pool. Suppression of YAP1/TAZ-TEAD mediated transcriptional activity significantly impaired sarcoma cell viability in vitro and in vivo. Our findings identify nuclear YAP1 and TAZ positivity as a common feature in subsets of sarcomas of soft tissue and bone and provide evidence of YAP1/TAZ-TEAD signaling as a specific liability to be considered as a new target for therapeutic intervention. Nuclear YAP1/TAZ expression may represent a biomarker suited to identify patients that could benefit from YAP1/TAZ-TEAD directed therapeutic approaches within future clinical trials.

Background and purpose To report our experience with limb-sparing surgery, IOERT and EBRT in extremity STS. Materials and methods 183 patients were retrospectively analyzed. 78% presented in primary situation, with 80% located in the lower limb. Stage at presentation was: I: 6%, IIa: 25%, IIb: 21%, III: 42%, IV: 7%. The majority showed high-grade lesions (grade 1: 5%, 2: 31%, 3: 64%). IOERT was applied to the tumor bed (median 15Gy) and preceded (9%) or followed (91%) by EBRT (median 45Gy) in all patients. Results Median follow-up was 64months (78months in survivors). Surgery was complete in 68%, while 32% had microscopic residual disease. 5- and 10-year-LC was 86% and 84%, respectively. LC was significantly higher in primary compared to recurrent disease and tended to be higher after complete resection. Estimated 5- and 10-year-DC was 68% and 66%, while corresponding OS was 77% and 66%, respectively. OS was significantly affected by grading and stage. Severe postoperative complications and late toxicities were observed in 19% and 20%, respectively. Limb-preservation rate was 95% with good function in 83%. Conclusions Combination of limb-sparing surgery, IOERT and EBRT achieved encouraging LC and OS in this unfavorable patient group with acceptable postoperative complications and low rates of late toxicities resulting in a high limb-preservation rate and good functional outcome.

Das teleangiektatische Osteosarkom ist eine seltene Unterform des Osteosarkoms und macht etwa 4 % aller Osteosarkome aus (ca. 0,1–0,2/1.000.000). Charakteristisch ist die Ausbildung septierter, hamorrhagisch-zystischer Lasionen, welche vorwiegend in den Metaphysen langer Rohrenknochen auftreten. Betroffen sind, wie beim konventionellen Osteosarkom, v. a. Patienten im 2. Lebensjahrzehnt [1].

At present, there is not a commonly used and generally accepted standardized approach for the pathologic evaluation of pretreated soft tissue sarcomas. Also, it is still unclear whether the cut-off for prognostic relevance is similar in the many different histological subtypes of STS. This manuscript, produced by a European Organization for Research and Treatment of Cancer - Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) endorsed task force, aims to propose standardization of the pathological examination process and the reporting of STS resection specimens after neoadjuvant radio- and/or chemotherapy.

Introduction New treatment options for patients with metastatic Soft Tissue Sarcoma are urgently needed. Preclinical studies suggested activity of vorinostat, a histone deacetylase inhibitor. Methods A multi-centre, open-label, non-randomised phase II trial to investigate the efficacy and safety of vorinostat in patients with locally advanced or metastatic Soft Tissue Sarcoma failing 1st-line anthracycline-based chemotherapy was initiated. Patients were treated with vorinostat 400 mg po qd for 28 d followed by a treatment-free period of 7 d, representing a treatment cycle of 5 weeks. Restaging was performed every three cycles or at clinical progression. Results Between 06/10 and 09/13, 40 Soft Tissue Sarcoma patients were treated with vorinostat at seven participating centres. Patients had received 1 (n = 8, 20%), 2 (n = 10, 25%) or ≥3 (n = 22, 55%) previous lines of chemotherapy. Best response after three cycles of treatment was stable disease (n = 9, 23%). Median progression-free survival and overall survival were 3.2 and 12.3 months, respectively. Six patients showed long-lasting disease stabilisation for up to ten cycles. Statistical analyses failed to identify baseline predictive markers in this subgroup. Major toxicities (grade ≥III) included haematological toxicity (n = 6, 15%) gastrointestinal disorders (n = 5, 13%), fatigue (n = 4, 10%), musculoskeletal pain (n = 4, 10%), and pneumonia (n = 2, 5%). Conclusion In a heavily pre-treated patient population, objective response to vorinostat was low. However, a small subgroup of patients had long-lasting disease stabilisation. Further studies aiming to identify predictive markers for treatment response as well as exploration of combination regimens are warranted. Trial registration: NCT00918489 ( ClinicalTrials.gov ) EudraCT-number: 2008-008513-19

To establish precise diagnostic algorithms and standardised treatment of sarcomas in specialized centers, the interdisciplinary research group KoSar (sarcoma competence network) has been funded by German Cancer Aid. A sarcoma tissue repository and a diagnostic reference center have been set up, presently containing about 1000 accurately diagnosed sarcomas of different entities. Significant gene expression profiles for synovial sarcomas, leiomyosarcomas, myxoid liposarcomas and a small profile for myxofibrosarcomas as well as a new classification of angiosarcomas were defined. We systematically searched for activated signal transduction pathways in sarcoma cell lines and xenograft transplant models and candidate targets for molecular therapies were identified. Based on these results first clinical studies have been initiated by the German Interdisciplinary Sarcoma Study Group (GISG).

Anaplastic large cell lymphoma (ALCL) accounts for approximately 15% of childhood NHL. Relapsed ALCL represents a formidable challenge because outcome is poor despite the use of high-dose chemotherapy regimens. We report two patients with relapsed T-type and 0-type ALCL who achieved long-term 3rd and 4th remissions with 4-weekly oral dexamethasone (DEX) and etoposide pulses for 2 years. This regimen also induced and maintained remission in a third patient with Nijmegen breakage syndrome (NBS) with secondary T-type ALCL. These patients demonstrate that low-intensity oral chemotherapy can induce long-term remissions and offer a curative perspective in refractory, relapsed and secondary ALCL.

Positron emission tomography (PET) using 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) is used as a functional imaging technique for the staging and follow-up of lymphomas. However, additional information about the tumor proliferation rate using 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) may be useful for the assessment of prognosis. We enrolled 48 patients with Hodgkin's (n = 15) and non-Hodgkin's lymphoma (n = 33) with residual masses2 cm examined by tracer studies with FDG and FLT. The results were related to median overall and progression-free survival. In 15 out of 48 patients analysed using FDG, positive results were found. Using FLT, 10 out of 48 patients were positive. 33 patients were FDG negative. Eight patients were positive both using FDG and FLT. Overall survival for patients with a negative PET scan was significantly higher than for patients with positive PET, irrespective of the tracer used. FLT alone was able to discriminate between patients with long or short overall survival. However, there was no statistical significance comparing FDG/FLT negative versus FDG negative alone. Although FDG detected more lesions than did FLT, the additional biological characterization of tumor tissue with respect to proliferation by FLT might be useful by providing complementary information for the identification of recurrence. However, the present data show no advantage of combined FDG/FLT studies over FDG alone with respect to the prediction of survival.

Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Surgery has been the only effective therapy. However, many patients still eventually die of disease recurrence. Chemotherapy and radiation therapy have been of limited value. Imatinib mesylate (Glivec®) is an orally administered competitive inhibitor of tyrosine kinases associated with the KIT, ABL protein, licensed for the treatment of metastatic GIST since 2002 in Germany. Methods: We summarized the data of 16 patients with advanced or metastatic GIST treated with imatinib mesylate in palliative and neoadjuvant settings. Results: Overall response was 81%, with no evidence of disease (NED) in 3/16 (19%), partial response (PR) in 9/16 (56%) and stable disease (SD) in 1/16 (6%), whereas 3/16 patients (19%) suffered from progressive disease (PD). Mean follow-up was 18.6 months [range: 4–30]. Mean progression-free survival (PFS) was 17.6 months [range: 0–30], mean overall survival (OS) from initial diagnosis was 32.3 months [range: 5–122]. Most common side effects were periorbital edema and skin rash. Conclusion: Imatinib mesylate is well tolerated in a dose of up to 800 mg/day and has significant activity during long- term treatment of patients with advanced or metastatic GIST.

The aim of this study was to analyze the presentation of, surgery for, and prognosis of malignant vascular tumors (MVTs).This was an observational single-center study. Patients who underwent operation for MVTs between 1988 and 2004 were included. Data were gathered prospectively in a computerized registry.Of 568 adult patients with soft tissue malignancies, 43 (7.6%) were treated for MVTs. Twenty-four men and 19 women (median age, 55.3 years) were referred for 30 primary tumors and 13 recurrences. Symptoms were observed in 90.7% of the cases (swelling [37.2%], pain [34.9%], extrusion [11.6%], hemorrhage [7%], weight loss [4.7%], loss of energy [4.7%], impaired function [4.7%], and others [30.2%]). Tumors were located in the extremities (n = 16), trunk (n = 3), abdomen (n = 15), retroperitoneum (n = 7), and thyroid gland (n = 2). Twenty-two (51.2%) angiosarcomas, nine (20.9%) malignant hemangiopericytomas, eight (18.6%) malignant epithelioid hemangioendotheliomas, and four (9.3%) lymphangiosarcomas were seen. The median overall survival after surgery was 21.4 months, with 2-, 5-, and 10-year overall survival rates of 41.5%, 38.3%, and 18.8%, respectively. MVTs of the extremities and trunk and localized disease indicated a better prognosis than abdominal or retroperitoneal MVTs (univariate and multivariate analyses: P = .0122 and P = .0287) and metastasized stages (univariate and multivariate analyses: P = .0187 and P = .0287).A considerable number of patients with soft tissue malignancies undergo surgery for MVT. Various symptoms and a multilocular occurrence are typical. The course of MVTs is aggressive. Tumor site and stage are important prognostic factors. Surgery is potentially curative, especially for localized disease of the extremities and trunk.

Objective To evaluate limb-salvage surgery with vascular resection for lower extremity soft tissue sarcomas (STS) in adult patients and to classify blood vessel involvement. Methods Subjects were consecutive patients (median age, 56 years) who underwent vascular replacement during surgery of STS in the lower limb between January 1988 and December 2003. Blood vessel involvement by STS was classified as follows: type I, artery and vein; type II, artery only; type III, vein only; and type IV, neither artery nor vein (excluded from the analysis). Patient data were prospectively gathered in a computerized database. Results Twenty-one (9.9%) of 213 patients underwent vascular resections for lower limb STS. Besides 17 type I tumors (81.0%), 3 (14.3%) type II and 1 (4.7%) type III STS were diagnosed. Arterial reconstruction was performed for all type I and II tumors. Venous replacement in type I and III tumors was performed in 66.7% of patients. Autologous vein (n = 8) and synthetic (Dacron and expanded polytetrafluoroethylene; n=12) bypasses were used with comparable frequency for arterial repair, whereas expanded polytetrafluoroethylene prostheses were implanted in veins. Morbidity was 57.2% (hematoma, thrombosis, and infection), and mortality was 5% (embolism). At a median follow-up of 34 months, the primary and secondary patency rates of arterial (venous) reconstructions were 58.3% (54.9%) and 78.3% (54.9%). Limb salvage was achieved in 94.1% of all cases. The 5-year local control rate and survival rate were 80.4% and 52%, respectively. We observed a 5-year metastasis-free survival rate of 37.7% and found vessel infiltration and higher tumor grade (low-grade vs intermediate grade and high grade tumors) to be negative prognostic factors at univariate and multivariate analysis. Conclusions Long-term bypass patency rates, the high percentage of limb salvage, and the oncologic outcome underline the efficacy of en bloc resection of STS involving major vessels in the lower limb. Disease-specific morbidity must be anticipated. The classification of vascular involvement (type I to IV) is useful for surgical management.

Thymic cysts are rare lesions located along the anatomical course of the third pharyngeal pouch. While most of the cases represent congenital cysts, they may also be related to neoplasms. We report a case of a micronodular thymoma with lymphoid stroma, which was completely built of small cysts, discuss the pathologic features of this tumor type and review the etiology and other aspects of thymic cysts.

The role of high-dose chemotherapy (HDCT) with PBSCT in the treatment of bone and soft-tissue sarcomas is not established. In total, 27 patients (15 female, median age at TPL 30.6 years (range: 13-59)) were analyzed (Ewing sarcoma family n=8, osteosarcoma n=6, MPNST (malignant peripheral nerve sheath tumor) n=4, synovial sarcoma n=3, liposarcoma n=2, leiomyosarcoma n=2, rhabdomyosarcoma n=1, meningosarcoma n=1). Following chemotherapy and surgery complete remission (CR) (n=9), partial remission (PR) (n=10), stable disease (SD) (n=2) and progressive disease (PD) (n=6) were reached prior HDCT. Different HDCT conditioning regimens were used. One patient died due to cardiac arrest after HDCT. Except hematologic side effects, no WHO grade III-IV complications were observed. Four patients died within 6 months due to PD, disease recurred in another seven patients and led to death, 15 patients are alive with/without disease. The median progression-free survival (PFS) is 12.0 months (range: 0-58), in nine CR patients median PFS is 25.8 months (range: 3-58). Although the role of HDCT in the treatment of sarcomas is not defined, a subgroup of patients who achieved CR before HDCT could benefit from this therapy.

Aims: Benign neurofibromas and malignant peripheral nerve sheath tumours (MPNST) commonly develop in patients with neurofibromatosis. Differentiation of benign from malignant tumours by conventional preoperative imaging is unreliable. FDG-PET is a non-invasive technique for biological tumour evaluation. The aim of this study was to assess the value of FDG-PET in patients with neurogenic tumours suspicious for MPNST. Methods: Benign and malignant neurogenic soft tissue tumours were prospectively evaluated by computed tomography or magnetic resonance imaging. Three-dimensional qualitative and quantitative FDG-PET was performed. Standard uptake value (SUV) was analyzed with respect to histological diagnosis and follow-up data. Results: Twenty-five neurogenic soft tissue tumours were included. FDG-PET identified all primary (n=6) and recurrent MPNST (n=7). Benign lesions (n=12) did not demonstrate high FDG uptake. The SUV was significantly higher in MPNST (median 2.9; range 1.8–12.3), than in benign tumours (median 1.1; range 0.5–1.8) (p

Neuere morphologische und molekulare Befunde haben unser Verstandnis uber gastrointestinale Stromatumoren (GIST) betrachtlich erweitert. Gastrointestinale Stromatumoren werden gegenwartig uber ihre Uberexpression von CD117 (KIT), dem Rezeptor des Stammzellfaktors, definiert und so gegenuber glattmuskularen Tumoren abgegrenzt. Zytogenetisch sind GIST bereits in fruhen Stadien durch haufige komplette oder partielle Verluste der Chromosomen 14 und 22 und terminale Deletionen des Chromosomenarms 1p charakterisiert. Im Verlauf der Tumorprogression wird eine Akkumulation von zusatzlichen chromosomalen Anomalien beobachtet. Basierend auf der Erstbeschreibung von aktivierenden KIT-Mutationen in GIST haben sich zahlreiche Studien mit der Rolle von wildtypischem und mutiertem KIT in GIST beschaftigt. Inzwischen wurden in der uberwiegenden Mehrheit der GIST KIT-Mutationen identifiziert und selbst in KIT-Mutation-negativen GIST eine konstitutive Phosphorylierung der KIT-Rezeptor-Tyrosinkinase nachgewiesen. Diese Befunde lassen darauf schliesen, dass KIT eine zentrale Rolle bei der Pathogenese von GIST spielt. Imatinib (STI571/Glivec®) inhibiert selektiv die BCR/ABL-, die PDGFR- und die KIT-Rezeptor-Tyrosinkinasen. Erste therapeutische Anwendungen von Imatinib bei Patienten mit progredienten GIST haben in dieser chemo- und radiotherapieresistenten Tumorentitat beachtliche Ergebnisse erzielt. In dieser Ubersicht werden die morphologischen Befunde und molekularen Grundlagen von GIST dargestellt, die eine neue therapeutische Perspektive eroffnet haben.

PURPOSE: To evaluate the clinical relevance of genomic aberrations in follicular lymphomas (FLs). PATIENTS AND METHODS: In this study, we analyzed 124 biopsy samples of patients with FL using comparative genomic hybridization. RESULTS: In 87 cases (70%), genomic imbalances were detectable. The most frequent aberrations were gains of chromosome arms 7p (21 patients), 7q (21 patients), Xp (16 patients), 12q (15 patients), and 18q (14 patients) as well as losses on 6q (21 patients). Grades 2 and 3 according to the World Health Organization classification correlated with a more complex karyotype (P < .0001). In a subset of 82 patients, a comprehensive clinical data set was available. In a multivariate analysis including all clinical risk factors of the International Prognostic Index as well as genomic aberrations, the loss of material on chromosomal bands 6q25q27 was the strongest predictor of a shorter survival (P = .0001; hazard ratio, 6.5), followed by elevated serum lactate dehydrogenase level (P = .0009; hazard ratio, 4.9), the presence of more than one extranodal manifestation (P = .017; hazard ratio, 4.2), and age greater than 60 years (P = .022; hazard ratio, 2.6). CONCLUSION: These data indicate that genomic aberrations may contribute significantly to risk assessment in patients with FL, the majority of whom are included in low-risk groups using established clinical prognostic scores.

Infantile myofibromatosis is a proliferative disorder characterized by the development of single or multiple nodular lesions in the soft tissue, skeleton, and internal organs. These tumors can occur at any anatomic site, but in one third of the cases, the head and neck region is involved. Here, we report a case of an infantile myofibroma occurring in a 7-year-old girl presented as a solitary lesion in the head and neck area. The clinical heterogeneity and the misleading histopathologic appearances may render the diagnosis difficult. Usually, treatment of choice is surgical removal of the tumor; however, the low rate of recurrence and the possibility of spontaneous regression may lead to conservative surgery or therapeutic abstention.

Ein 64-jahriger Mann entwickelte bei der Gartenarbeit einen akuten Brustschmerz. Aortendissektion und koronare Herzerkrankung konnten ausgeschlossen werden, die thorakale Computertomographie zeigte jedoch eine aneurysmatische Vergroserung der Pulmonalarterie mit einer intraluminal flottierenden Struktur. Der Patient wurde zum Ersatz der Pulmonalarterie unmittelbar sternotomiert. Die Histologie ergab ein intimales Sarkom der beiden Pulmonalarterienaste. Die Pulmonalarterie wurde mittels einer T-formigen Gore-Tex-Prothese ersetzt.

Background To report the results of a subgroup analysis of a prospective phase II trial focussing on radiation therapy and outcome in patients with extremity soft tissue sarcomas (STS). Methods Between 2005 and 2010, 50 patients (pts) with high risk STS (size ≥ 5 cm, deep/extracompartimental location, grade II-III (FNCLCC)) were enrolled. The protocol comprised 4 cycles of neoadjuvant chemotherapy with EIA (etoposide, ifosfamide and doxorubicin), definitive surgery with IOERT, postoperative EBRT and 4 adjuvant cycles of EIA. 34 pts, who suffered from extremity tumors and received radiation therapy after limb-sparing surgery, formed the basis of this subgroup analysis. Results Median follow-up from inclusion was 48 months in survivors. Margin status was R0 in 30 pts (88%) and R1 in 4 pts (12%). IOERT was performed as planned in 31 pts (91%) with a median dose of 15 Gy, a median electron energy of 6 MeV and a median cone size of 9 cm. All patients received postoperative EBRT with a median dose of 46 Gy after IOERT or 60 Gy without IOERT. Median time from surgery to EBRT and median EBRT duration was 36 days, respectively. One patient developed a local recurrence while 11 patients showed nodal or distant failures. The estimated 5-year rates of local control, distant control and overall survival were 97%, 66% and 79%, respectively. Postoperative wound complications were found in 7 pts (20%), resulting in delayed EBRT (>60 day interval) in 3 pts. Acute radiation toxicity mainly consisted of radiation dermatitis (grade II: 24%, no grade III reactions). 4 pts developed grade I/II radiation recall dermatitis during adjuvant chemotherapy, which resolved during the following cycles. Severe late toxicity was observed in 6 pts (18%). Long-term limb preservation was achieved in 32 pts (94%) with good functional outcome in 81%. Conclusion Multimodal therapy including IOERT and postoperative EBRT resulted in excellent local control and good overall survival in patients with high risk STS of the extremities with acceptable acute and late radiation side effects. Limb preservation with good functional outcome was achieved in the majority of patients. Trial registration ClinicalTrials.gov NCT01382030, EudraCT 2004-002501-72, 17.06.2011

Hintergrund: Weichgewebesarkome werden haufig als gutartige Tumoren beurteilt und ohne Sicherheitsabstand oder inkomplett reseziert. Fur die Sicherstellung der lokalen Tumorkontrolle wird die onkologische Nachresektion (weite-, kompartimentale Resektion oder Amputation) als Therapie der Wahl empfohlen. Um die Ergebnisse nach onkologischer Nachresektion zu uberprufen, erfolgte eine Analyse im eigenen Patientengut. Methoden: Prospektiv erhobene Daten von 67 konsekutiven Patienten, die wegen eines nicht-onkologisch (intracapsulare oder marginale Resektion) operierten primaren Weichgewebesarkoms der Extremitaten oder des Stammes eine Nachresektion erhielten, wurden ausgewertet. Ergebnisse: 85 % der Tumoren waren an den Extremitaten und 15 % am Korperstamm lokalisiert. Lokal fortgeschrittene Tumorstadien (UICC (1992, 4. Aufl., 2. Rev.), IIB-IIIB) dominierten (66 %). 25 Patienten erhielten eine additive intraoperative Strahlentherapie. Die Morbiditat der Nachresektion betrug 28,4 %. Ein Resttumor wurde in 64 % der Nachresektate vorgefunden. Durch die Nachresektion wurden 60 Sarkome (90 %) komplett mit histopathologisch tumorfreien Absetzungsrandern (R0-Resektion) reseziert. Bei einem medianen Follow-up von 57 Monaten betrug die lokale Tumorkontrolle nach R0-Nachresektion 88 % (UICC IA-IIA, 100 %, IIB-IIIB, 82 %). Patienten der UICC-Stadien IIB-IIIB, die nach R0-Nachresektion mit einer intraoperativen Strahlentherapie therapiert wurden, erreichten eine lokale Kontrolle von 90 %. Die 5-Jahres-Uberlebensrate betrug 87 % nach R0-Nachresektion. Schlusfolgerungen: Diese Ergebnisse verdeutlichen den Stellenwert der onkologischen Nachresektion und implizieren, das die onkologische Nachresektion die therapeutische Grundlage fur eine effektive adjuvante Zusatztherapie darstellt.

Deciduosen der Appendix konnen in seltenen Fallen Ursache einer akuten Appendicitis wahrend der Schwangerschaft sein. Im submesothelialen Stroma lokalisierte Deciduazellverbande sind dem derzeitigen Kenntnisstand zufolge physiologische Reaktionen der pluripotenten Stromazellen auf progestationsdominierte hormonelle Stimuli. Seltener ist die Deciduose eine unter Schwangerschaftshormonen decidualisierte praexistente Endometriose, erkennbar an einer Lokalisation abweichend von der streng submesothelialen, an Residuen zyklisch rezidivierender Proliferation und Blutung und an eingestreuten endometrialen Drusenformationen.

Purpose: Soft-tissue sarcomas (STS) are highly diverse, devastating and clinically challenging malignancies. In advanced-stage STS, conventional chemotherapy provides symptom palliation but not prolonged survival, which typically ranges from 11-15 months after development of distant metastases. Thus, there is an urgent need for more effective, well-tolerated and targeted STS therapies. Alterations of the FGFR1 receptor tyrosine kinase are under investigation as biomarker of FGFR inhibitor sensitivity in several epithelial cancers. Prompted by the detection of high-level FGFR1 amplification in a patient with metastatic leiomyosarcoma through clinical exome sequencing, we investigated the role of FGFR1 as oncogenic driver and potential drug target in STS. Specific aims were to (i) determine the frequency of FGFR1 amplification and overexpression in adult STS, (ii) evaluate the sensitivity of FGFR1-altered STS cells to genetic and pharmacologic FGFR1 inhibition, and (iii) delineate the signaling pathways engaged by FGFR1 in these cells. Experimental design: The frequency of FGFR1 amplification and overexpression was established in a cohort of patients with treatment-näive high-grade STS using array-based comparative genomic hybridization and mRNA expression profiling, respectively, and results were validated using data from The Cancer Genome Atlas (TCGA). FGFR1 dependence was assessed in STS cell lines with and without FGFR1 alteration through RNA interference (RNAi)-mediated knockdown and selective small-molecule FGFR inhibitors. FGFR ligand and pharmacologic inhibitors were employed to dissect FGFR signaling in FGFR1-altered STS cells. Results: FGFR1 amplification and overexpression were present in 31% and 34% of cases in the untreated high-grade STS cohort (n = 176) and in 16% and 15% of cases in the TCGA cohort (n = 256). Interestingly, FGFR1 overexpression was detected in a substantial proportion of cases with no amplification (high-grade sarcoma cohort, 26%; TCGA cohort, 6.6%) comprising seven STS subtypes. Functional studies employing RNAi and different FGFR inhibitors (PD173074, AZD4547, BGJ398) demonstrated that the degree of dependence on FGFR1 for proliferation, survival, and anchorage-independent growth was primarily determined by FGFR1 expression levels. Furthermore, we identified the MAPK-ERK1/2 signaling axis as critical FGFR1 effector pathway whose suppression dictates the sensitivity of FGFR1-driven STS cells to FGFR-targeted therapy. Conclusions: FGFR1 amplification and overexpression are frequent events in multiple STS subtypes, and high FGFR1-expressing STS cells are sensitive to FGFR inhibition. These findings support FGFR1 as novel therapeutic target in STS and point to FGFR1 overexpression as a more reliable biomarker of sensitivity to FGFR pathway inhibition than genomic amplification, which might be of value for enrichment of future clinical trial populations. Citation Format: Priya Chudasama, Marcus Renner, Katja Specht, Sadaf Mughal, Barbara Hutter, Ingo Alldinger, Simon Schimmack, Dirk Jäger, Christof von Kalle, Stefan Gröschel, Stephan Wolf, Benedikt Brors, Wilko Weichert, Hanno Glimm, Gunhild Mechtersheimer, Claudia Scholl, Stefan Fröhling. FGFR1 overexpression is frequent in adult soft tissue sarcoma and predicts sensitivity to FGFR inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 457.

We present the case of a 62-year-old woman who consulted her physician in December 2005, suffering from a mass at the left lower anterior neck with rapid enlargement. Intraoperative frozen section was highly suspicious of a CASTLE tumour (carcinomas showing thymus-like differentiation). Finally, immunohistochemical investigation revealing positivity for CK5/6, c-kit (CD117) and CD5 as well as negativity for thyroglobulin, calcitonin, vimentin and TTF-1 confirmed the diagnosis. Due to lymph node metastases, radiochemotherapy was performed. Fifteen months after the initial diagnosis disseminated pulmonary metastases were found and treated with cisplatin based chemotherapy, which led to a stabilisation of the disease. In June 2008, computed tomography showed progress of the pulmonary metastases, making further chemotherapeutical treatment necessary. Although treatment was changed in October 2008, the staging evaluation in January 2009 revealed further progress of the metastatic disease. Currently, the patient is still alive, but receives no medical treatment at the moment.