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Abstract Background Soft tissue sarcomas (STSs) are a heterogeneous group of tumors. Wide surgical resection is standard, often combined with neoadjuvant chemotherapy, radiotherapy, or both. Studies have shown the predictive value of tumor necrosis in bone sarcoma (BS); however, the role of necrosis in STS after neoadjuvant therapies is still unclear. This study aimed to investigate the role of chemo- and radiotherapy in the formation of tumor necrosis and to evaluate the influence of tumor necrosis on overall survival and local recurrence-free survival. Data from BS patients and patients who did not receive neoadjuvant therapy were compared. Methods A total of 779 patients with STS or BS were treated surgically. In all patients, tumor-specific factors such as type, size, or grading and the type of adjuvant therapy were documented. Local recurrence (LR), the diagnosis of metastatic disease, and survival during follow-up were evaluated. Results A total of 565 patients with STS and 214 with BS were investigated. In STS, 24.1% G1 lesions, 34.1% G2 lesions, and 41.8% G3 lesions were observed. Two hundred twenty-four of the patients with STS and neoadjuvant therapy had either radiotherapy (RTx) (n = 80), chemotherapy (CTx) (n = 93), or both (n = 51). Three hundred forty-one had no neoadjuvant therapy at all. In STS, tumor necrosis after neoadjuvant treatment was significantly higher (53.5%) than in patients without neoadjuvant therapy (15.7%) (p

CDC42 controls intestinal epithelial (IEC) stem cell (IESC) division. How aberrant CDC42 initiates intestinal inflammation or neoplasia is unclear. We utilized models of inflammatory bowel diseases (IBD), colorectal cancer, aging, and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and neoplasia. Intestinal specimens were collected to determine the levels of CDC42 in IBD or colorectal cancer. Cdc42 floxed mice were crossed with Villin-Cre, Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2, or Bmi1-CreERT2 mice to generate Cdc42 deficient mice. Irradiation, colitis, aging, and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation, IESC/progenitor regenerative capacity, and IEC repair. Our studies revealed that increased CDC42 in colorectal cancer correlated with lower survival; in contrast, lower levels of CDC42 were found in the inflamed IBD colon. Colonic Cdc42 depletion significantly reduced Lgr5+ IESCs, increased progenitors' hyperplasia, and induced mucosal inflammation, which led to crypt dysplasia. Colonic Cdc42 depletion markedly enhanced irradiation- or chemical-induced colitis. Depletion or inhibition of Cdc42 reduced colonic Lgr5+ IESC regeneration. In conclusion, depletion of Cdc42 reduces the IESC regeneration and IEC repair, leading to prolonged mucosal inflammation. Constitutive monogenic loss of Cdc42 induces mucosal inflammation, which could result in intestinal neoplasia in the context of aging.

Abstract Background Hyperplasia of the hematopoietic bone marrow in the appendicular skeleton is common. In contrast, focal hematopoietic islands within the axial skeleton are a rare entity and can confuse with osteoblastic metastases. This study aimed to characterize typical MRI and CT findings of hematopoietic islands in distinction from osteoblastic metastases to help both radiologists and clinicians, on the one hand, not to overdiagnose this entity and, on the other hand, to decide on a reasonable work-up. Methods We retrospectively analyzed the imaging findings of 14 hematopoietic islands of the axial skeleton in ten patients (nine females, median age = 65.5 years [range, 49–74]) who received both MRI and CT at initial diagnosis between 2006 and 2020. CT-guided biopsy was performed in five cases to confirm the diagnosis, while the other five patients received long-term MRI follow-up (median follow-up = 28 months [range, 6–96 months]). Diffusion-weighted imaging was available in three, chemical shift imaging respectively 18F- fluorodeoxyglucose PET/CT in two, and Technetium 99 m skeletal scintigraphy in one of the patients. Results All lesions were small (mean size = 1.72 cm2) and showed moderate hypointense signals on T1- and T2-weighted MRI sequences. They appeared isointense to slightly hyperintense on STIR images and slightly enhanced after gadolinium administration. To differentiate this entity from osteoblastic metastases, CT provides important additional information, as hematopoietic islands do not show sclerosis. Conclusions Hematopoietic islands within the axial skeleton can occur and mimic osteoblastic metastases. However, the combination of MRI and CT allows for making the correct diagnosis in most cases.

Sarcomas are a heterogeneous group of rare mesenchymal tumors. The migration of immune cells into these tumors and the prognostic impact of tumor-specific factors determining their interaction with these tumors remain poorly understood. The current risk stratification system is insufficient to provide a precise survival prediction and treatment response. Thus, valid prognostic models are needed to guide treatment. This study analyzed the gene expression and outcome of 980 sarcoma patients from seven public datasets. The abundance of immune cells and the response to immunotherapy was calculated. Immune-related genes (IRGs) were screened through a weighted gene co-expression network analysis (WGCNA). A least absolute shrinkage and selection operator (LASSO) Cox regression was used to establish a powerful IRG signature predicting prognosis. The identified IRG signature incorporated 14 genes and identified high-risk patients in sarcoma cohorts. The 14-IRG signature was identified as an independent risk factor for overall and disease-free survival. Moreover, the IRG signature acted as a potential indicator for immunotherapy. The nomogram based on the risk score was built to provide a more accurate survival prediction. The decision tree with IRG risk score discriminated risk subgroups powerfully. This proposed IRG signature is a robust biomarker to predict outcomes and treatment responses in sarcoma patients.

Progressive respiratory failure is the primary cause of death in patients with COVID-19, but pathologies in other tissues may also occur. Here the authors report that adrenal tropism of SARS-CoV-2 is associated with adrenalitis, reduced adrenal cortisol levels and severe adrenal damage in a post-mortem case series of patients with severe fatal COVID-19.

Abstract Background The degree of contamination of healthy tissue with tumor cells during a biopsy in bone or soft tissue sarcomas is clearly dependant on the type of biopsy. Some studies have confirmed a clinically relevant contamination of the biopsy tract after incisional biopsies, as opposed to core-needle biopsies. The aim of our prospective study was to evaluate the risk of local recurrence depending on the biopsy type in extremity and pelvis sarcomas. Methods We included 162 patients with a minimum follow-up of 6 months after wide resection of extremity sarcomas. All diagnostic and therapeutic procedures were performed at a single, dedicated sarcoma center. The excision of the biopsy tract after an incisional biopsy was performed as a standard with all tumor resections. All patients received their follow-up after the conclusion of therapy at our center by means of regional MRI studies and, at a minimum, CT of the thorax to rule out pulmonary metastatic disease. The aim of the study was the evaluation of the influence of the biopsy type and of several other clinical factors on the rate of local recurrence and on the time of local recurrence-free survival. Results One hundred sixty-two patients with bone or soft tissue tumors of the extremities and the pelvis underwent either an incisional or a core-needle biopsy of their tumor, with 70 sarcomas (43.2%) being located in the bone. 84.6% of all biopsies were performed as core-needle biopsies. The median follow-up time was 55.6 months, and 22 patients (13.6%) developed a local recurrence after a median time of 22.4 months. There were no significant differences between incisional and core-needle biopsy regarding the risk of local recurrence in our subgroup analysis with differentiation by kind of tissue, grading of the sarcoma, and perioperative multimodal therapy. Conclusions In a large and homogenous cohort of extremity and pelvic sarcomas, we did not find significant differences between the groups of incisional and core-needle biopsy regarding the risk of local recurrence. The excision of the biopsy tract after incisional biopsy in the context of the definitive tumor resection seems to be the decisive factor for this result.

PurposeSomatostatin analogues (SSA) are frequently used in the treatment of neuroendocrine tumours. Recently, [18F]SiTATE entered the field of somatostatin receptor (SSR) positron emission tomography (PET)/computed tomography (CT) imaging. The purpose of this study was to compare the SSR-expression of differentiated gastroentero-pancreatic neuroendocrine tumours (GEP-NET) measured by [18F]SiTATE-PET/CT in patients with and without previous treatment with long-acting SSAs to evaluate if SSA treatment needs to be paused prior to [18F]SiTATE-PET/CT.Methods77 patients were examined with standardised [18F]SiTATE-PET/CT within clinical routine: 40 patients with long-acting SSAs up to 28 days prior to PET/CT examination and 37 patients without pre-treatment with SSAs. Maximum and mean standardized uptake values (SUVmax and SUVmean) of tumours and metastases (liver, lymphnode, mesenteric/peritoneal and bones) as well as representative background tissues (liver, spleen, adrenal gland, blood pool, small intestine, lung, bone) were measured, SUV ratios (SUVR) were calculated between tumours/metastases and liver, likewise between tumours/metastases and corresponding specific background, and compared between the two groups.ResultsSUVmean of liver (5.4 ± 1.5 vs. 6.8 ± 1.8) and spleen (17.5 ± 6.8 vs. 36.7 ± 10.3) were significantly lower (p < 0.001) and SUVmean of blood pool (1.7 ± 0.6 vs. 1.3 ± 0.3) was significantly higher (p < 0.001) in patients with SSA pre-treatment compared to patients without. No significant differences between tumour-to-liver and specific tumour-to-background SUVRs were observed between both groups (all p > 0.05).ConclusionIn patients previously treated with SSAs, a significantly lower SSR expression ([18F]SiTATE uptake) in normal liver and spleen tissue was observed, as previously reported for 68Ga-labelled SSAs, without significant reduction of tumour-to-background contrast. Therefore, there is no evidence that SSA treatment needs to be paused prior to [18F]SiTATE-PET/CT.

IntroductionAdrenal vein sampling (AVS) is not a routine procedure in patients with primary bilateral macronodular adrenocortical hyperplasia (PBMAH), but has been used to determine lateralization of cortisol secretion in order to guide decision of unilateral adrenalectomy. Our aim was to characterize the steroid fingerprints in AVS samples of patients with PBMAH and hypercortisolism and to identify a reference hormone for AVS interpretation.MethodRetrospectively, we included 17 patients with PBMAH from the German Cushing’s registry who underwent AVS. 15 steroids were quantified in AVS and peripheral blood samples using LC-MS/MS. We calculated lateralization indices and conversion ratios indicative of steroidogenic enzyme activity to elucidate differences between individual adrenal steroidomes and in steroidogenic pathways.ResultsAdrenal volume was negatively correlated with peripheral cortisone (r=0.62, p

In most cases, invasive aspergillosis (IA) is caused by A. fumigatus, though infections with other Aspergillus spp. with lower susceptibilities to amphotericin B (AmB) gain ground. A. terreus, for instance, is the second leading cause of IA in humans and of serious concern because of its high propensity to disseminate and its in vitro and in vivo resistance to AmB. An early differentiation between A. fumigatus and non-A. fumigatus infections could swiftly recognize a potentially ineffective treatment with AmB and lead to the lifesaving change to a more appropriate drug regime in high-risk patients. In this study, we present the characteristics of the monoclonal IgG1-antibody AB90-E8 that specifically recognizes a surface antigen of A. fumigatus and the closely related, but not human pathogenic A. fischeri. We show immunostainings on fresh frozen sections as well as on incipient mycelium picked from agar plates with tweezers or by using the expeditious tape mount technique. All three methods have a time advantage over the common procedures currently used in the routine diagnosis of IA and outline the potential of AB90-E8 as a rapid diagnostic tool.

Introduction: Struma ovarii is a teratoma of the ovaries predominantly composed of thyroid tissue. Hyperthyroidism associated with struma ovarii is rare, occurring in approximately 8% of cases. Due to the rarity of struma ovarii, available data are limited to case reports and small case series. Methods and results: We report on a 61-year-old female patient with known Hashimoto’s thyroiditis on levothyroxine replacement therapy for years with transition to clinical and biochemical hyperthyroidism despite antithyroid medication with carbimazole (10 mg/day), new diagnosis of urothelial carcinoma and an adnexal mass suspicious of ovarian cancer. The patient underwent resection of the adnexal mass and histopathology revealed a mature teratoma predominantly composed of thyroid tissue showing high levels of sodium iodide symporter protein expression. Following struma ovarii resection and disappearance of autonomous production of thyroid hormones, the patient developed hypothyroidism with severely decreased thyroid hormone levels fT4 and fT3 (fT4 0.4 ng/dL, reference interval 0.9–1.7 and fT3 < 1.0 pg/mL, reference interval 2.0–4.4). This has previously been masked by continued thyroid-stimulating hormone suppression due to long-term hyperthyroidism pre-surgery indicating secondary hypothyroidism, in addition to primary hypothyroidism based on the known co-existing chronic lymphocytic thyroiditis of the orthotopic thyroid gland. Levothyroxine administration was started immediately restoring euthyroidism. Conclusion: This case illustrates possible diagnostic pitfalls in a patient with two concurrent causes of abnormal thyroid function.

BackgroundTreatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising.Materials and MethodsPrimary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable.ResultsPD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p

The potential of cancer drugs is not fully exploited due to low tumor uptake and occurrence of systemic side effects, limiting maximum tolerated dose. Actively targeted nanocarriers improve efficacy while minimizing off‐target toxicity. Herein, it is the first time a drug‐delivery platform for heat‐triggered intravascular drug release is described, based on synthetic phosphatidyl‐(oligo)‐glycerols from organic synthesis to preclinical investigation in feline patients. For the nanocarrier formulated doxorubicin (DOX), superior tumor drug delivery and antitumor activity compared with free DOX, conventional liposomal DOX (Caelyx), and temperature‐sensitive lysolipid‐containing DOX‐liposomes in rat sarcoma are demonstrated. In a comparative oncological study with neoadjuvant treatment of feline sarcoma, a metabolic response determined with 18 F‐FDG‐positron emission tomography/magnetic resonance imaging (PET/MRI) and histopathological response after tumor resection are significantly better compared with free DOX, potentially by overcoming drug resistance based on improved intratumoral drug distribution. This novel drug‐delivery platform has great potential for the treatment of locally advanced tumors in humans.

Abstract Background The treatment of aneurysmal bone cysts (ABCs) has evolved and less invasive methods have been tried. Denosumab is a monoclonal antibody which inhibits osteoclasts. It has been shown to be effective in giant cell tumour of bone (GCT) of bone and hence promises some effect also in ABC. We report on 6 patients treated with Denosumab and compare our results to the cases already published. Methods Data of 6 patients with ABCs and patients whose treatment included Denosumab were retrospectively analyzed. Denosumab was used at a dose of 120 mg on days 1, 8, 15 and 29, and every 4 weeks thereafter. In some of these patients the dose was reduced at the end of the treatment. Clinical and radiological responses were evaluated. Results In 4 female and 2 male patients with a mean age of 17 years (range: 6–30 years) the lesions were located in the sacrum (2), in distal radius, distal femur, talus and pelvis. One of the sacral lesions healed after 12 months and has stayed stable for 3 years since. The second patient received 2 years of therapy with recalcification, but recurred 1 year later and is under renewed therapy. The pelvic lesion improved but recurred. This patient has a 13-years history of intermittent therapy including surgery, two pregnancies and remains in a stable situation. The lesion of the talus did not improve with Denosumab after surgery and was complicated by destruction of the ankle joint with osteoarthritis. Recurrent lesions of the distal femur and the distal radius, previously treated by curettage and bone grafting healed under Denosumab and have remained stable for 2 and 3 years, respectively. One case of severe hypercalcemia was observed in a 7-year old child 6 months after discontinuation of Denosumab. Conclusion Denosumab provides a treatment option for ABCs in anatomically critical locations. Adjuvant application might reduce the rate of local recurrence. In young patients, severe rebound hypercalcemia months after discontinuation of Denosumab may occur.

Abstract Background Chondrosarcoma is the second most frequent malignant bone tumor. Grade I chondrosarcoma (syn.: atypical cartilaginous tumor) is classified as an intermediately and locally aggressive neoplasm and typically is treated less aggressively (i.e., by intralesional curettage). Does the data regarding local recurrence (LR) and metastatic disease justify this? Methods From 1982 to 2014, 37 consecutive patients with G1 chondrosarcoma had been resected or curetted. The margin was defined as R0 (wide resection) or R1 (marginal resection). All patients were followed for evidence of local recurrence or metastatic disease. Overall and recurrence-free survival were calculated, and various potentially prognostic factors were evaluated. Results In 23 patients (62%), the tumor was widely (R0) resected, whereas in 14 patients, (38%) the resection was marginal (R1). Overall survival was 97% after 5 years, 92% after 10 years, and 67% after 20 years. Five-year local recurrence-free survival was 96%. Ten-year local recurrence-free survival was 83%. Local recurrence-free survival showed a significant correlation to margin status but no correlation to location or age. None of the patients with local recurrence died during the follow-up. One patient had metastatic disease at initial presentation, and a further five patients developed metastatic disease during follow-up. Metastatic disease proofed to be a highly significant factor for survival but was not correlated to local recurrence. Conclusions There was no significant correlation between the outcome and the primary tumor location. Marginal resection was a risk factor for LR, but there was no significant difference in the overall survival in patients with or without LR. Metastatic disease (16%) was more common than expected from the literature and a significant predictor for poor overall survival.

Abstract Background Distant metastases frequently occur in gastroenteropancreatic neuroendocrine tumors. If hepatic surgery is not feasible, patients are treated with somatostatin analogs. However, the underlying mechanisms of action of this treatment remain to be defined. The aim of the present study was to analyze the micro-RNA expression profile inter-individually before and after the treatment with somatostatin analogs. Material and methods Tumor specimens of all included patients (n = 8) before and after the onset of a therapy with somatostatin analogs were analyzed and a micro-RNA expression profile (754 micro-RNAs) of each probe was generated. This analysis in an intra-individual setting was selected to avoid bias from inter-individual differences. The micro-RNA expression profiles were validated by qPCR. Patients with any other systemic treatment were excluded from the present study. Results Eight patients were included in the present study of which all had neuroendocrine tumors of the small intestine with diffuse hepatic metastases. Grouped analyses revealed that 15 micro-RNAs were differentially expressed (3 up- and 12 downregulated) after the exposure to somatostatin analogs. Additionally, let-7c-5p and mir-3137 are concordantly regulated in the inter-individually analysis. Conclusions This is the first study analyzing the individual micro-RNA expression profile before and after a therapy with somatostatin analogs. Data from this study reveal that somatostatin analogs may in part exert their beneficial effects through an alteration in the micro-RNA expression profile.

Background: Cytosolic 5′-nucleotidase 1A (NT5C1A) dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Here, we investigate NT5C1A expression in pancreatic ductal adenocarcinoma (PDAC) and its impact on gemcitabine metabolism and therapeutic efficacy. Methods: NT5C1A expression was determined by semiquantitative immunohistochemistry using tissue microarrays. Gemcitabine metabolites and response were assessed in several human and murine PDAC cell lines using crystal violet assays, Western blot, viability assays, and liquid chromatography tandem mass-spectrometry (LC-MS/MS). Findings: NT5C1A was strongly expressed in tumor cells of a large subgroup of resected PDAC patients in two independent patient cohorts (44–56% score 2 and 8–26% score 3, n = 414). In contrast, NT5C1A was expressed at very low levels in the tumor stroma, and neither stromal nor tumoral expression was a prognostic marker for postoperative survival. In vitro, NT5C1A overexpression increased gemcitabine resistance by reducing apoptosis levels and significantly decreased intracellular amounts of cytotoxic dFdCTP in +NT5C1A tumor cells. Co-culture experiments with conditioned media from +NT5C1A PSCs improved gemcitabine efficacy in tumor cells. In vivo, therapeutic efficacy of gemcitabine was significantly decreased and serum levels of the inactive gemcitabine metabolite dFdU significantly increased in mice bearing NT5C1A overexpressing tumors. Interpretation: NT5C1A is robustly expressed in tumor cells of resected PDAC patients. Moreover, NT5C1A mediates gemcitabine resistance by decreasing the amount of intracellular dFdCTP, leading to reduced tumor cell apoptosis and larger pancreatic tumors in mice. Further studies should clarify the role of NT5C1A as novel predictor for gemcitabine treatment response in patients with PDAC. Keywords: Cytosolic 5′-nucleotidase 1A, Chemotherapeutic resistance, Gemcitabine, Pancreatic cancer

Background: Primary lymphoma of bone (PBL) is a rare entity. Due to unspecific clinical signs and equivocal radiographs diagnosis may be delayed. This retrospective report of 109 PBL cases demonstrates typical aspects of the lesion. Treatment and prognostic factors are evaluated. Methods: Retrospectively patient records were reviewed. All patients were followed for evidence of local or distant recurrence. Overall survival (OS) was used as clinical outcome. Results: The median age of the 109 patients was 62.8 years. The most common symptoms were pain (76%), swelling (29%), neurologic symptoms and pathological fracture (16% each). Mean duration of symptoms was 8 months (0–197 months).19% of patients had indolent NHL subtypes, 72% aggressive NHL subtypes and 7% cases Hodgkin disease. Cyclophosphamid, doxorubicin, vincristine and prednisone (CHOP) or CHOP plus rituximab (RCHOP) were given in 88 (81%) of patients. Radiotherapy was delivered in 67 (61%) of cases. 51 (47%) patients received both. Surgical interventions were restricted to cases with complications as fractures.The 5-year OS was 66%. The 5-year OS was 66%. In the subgroup of 78 patients with aggressive NHL subtype there was a highly significant benefit for chemotherapy or chemotherapy and radiation in comparison to no treatment or radiation alone. Raised LDH, age, IPI and ECOG performance were prognostic factors. In multivariate analysis, age and raised LDH levels only kept significance. Conclusions: In our series of primary bone lymphoma, chemotherapy resulted in a better outcome than Radiotherapy alone. Long-term survival is based on the stage of the disease, favoring younger (

Patients with localized relapse of soft-tissue sarcoma (STS) after anthracycline-based chemotherapy have a dismal prognosis, particularly when surgery is not possible. To facilitate resection and improve long-term tumor control, we applied an intensified perioperative treatment consisting of ICE (ifosfamide 6 g/m2, carboplatin 400 mg/m2, and etoposide 600 mg/m2) in combination with regional hyperthermia (RHT) to maximize local control. Here, we retrospectively evaluate the safety and efficacy of this strategy. Patients aged ≥18 years with locally advanced high-risk STS, either with or without metastasis, treated with ICE + RHT after the failure of first-line anthracycline-based chemotherapy were included in this analysis. Radiographic response, toxicity, progression-free survival (PFS), and overall survival (OS) were assessed. Between 1996 and 2018, 213 sarcoma patients received ICE at our centre. Of these, 110 patients met the selection criteria (progressive disease, suitable high-grade STS histology, anthracycline pretreatment, RHT treatment) for this analysis. Fifty-four patients had locally advanced disease without metastases (LA-STS), and 56 patients had additional metastatic disease (M-STS). Disease control was achieved in 59% of LA-STS patients and in 47% of M-STS patients. For LA-STS, 21% of the patients achieved radiographic response, facilitating resection in 4 patients (7%), compared with 11% of the M-STS patients, facilitating resection in 5 patients (9%). PFS was significantly longer in LA-STS than in M-STS (10 vs. 4 months, p

Abstract Background The relevance of estrogen receptor (ER) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Clinical trials targeting ER with selective estrogen receptor modulators in pancreatic cancer did not show any benefit. Here, we analyze the impact of recently characterized ER isoform beta on survival in a cohort of patients with resected PDAC. Methods Eighty-four patients having undergone pancreatic resection for PDAC at a single institution were identified. Tissue microarrays were constructed of archival tumor specimens. The expression of ER beta was determined by immunohistochemistry and quantified by a system established for estrogen receptor expression in breast cancer. ER beta expression was then correlated with clinicopathological parameters, and univariate and multivariate survival analyses were performed. Results Nuclear expression of ER beta was found in 31% of tumors. No significant correlation was found between ER beta expression and TNM status, tumor grade, age or sex. Univariate analysis revealed nodal metastasis and the expression of ER beta as factors correlating with a shorter overall survival and disease free survival. When comparing ER beta expression in patients surviving more than 24 months with those who died from the tumor within 12 or 24 months, respectively, a significantly lower ER beta expression was found in the long term survivors. In multivariate analysis, ER beta expression was demonstrated to be an independent predictor of shorter overall survival. Conclusions In resected PDAC, expression of ER beta seems to correlate with poor prognosis. These data may help to identify patients who may benefit from additional systemic therapy including selective estrogen receptor modulators.

Introduction: Clear cell chondrosarcoma (CCC) is a rare subtype of chondrosarcoma and it is commonly considered a low-grade tumor and less aggressive than atypical cartilaginous tumor (grade 1 central chondrosarcoma). However, the experience even of musculoskeletal tumor centres with this rare entity is limited. The aim of this study is to analyse our own treatment results and those of the literature regarding the therapy and outcome of this lesion. Material and Methods: 7 cases of CCC have been treated in our department between 2003 and 2015. Their follow-up data were collected retrospectively. 187 literature cases with histopathological and clinical characteristics were retrieved by means of a PubMed search with the key word “clear cell chondrosarcoma”. The data pertaining to treatment and follow up were extracted. We analysed the survival of patient and the risk factors for local recurrence (LR) as well as metastatic disease (MD). Results: The mean age at the time of diagnosis was 40 years. Two thirds of the patients were male. The mean follow-up time was 109 months. To our surprise, there was a high rate of LR (30%) and of MD (20%) when compared to low-grade conventional chondrosarcomas. 15% of LR and 20% of metastatic disease were observed after more than 10 years follow-up. Uncommon locations of MD such as in the spine is a unique observation in chondrosarcomas and underlines the high aggressiveness of this tumor. 10-year overall survival was almost 80%, 10-years disease free survival 60%. Positive margins (p = 0.038) and metastases (p = 0.006) impaired the overall survival significantly. The rate of local recurrence was significantly dependent on resection margin (p

Abstract Background Chondrosarcoma is the second most frequent primary malignant bone tumor. Treatment is mainly based on surgery. In general, wide resection is advocated at least in G2 and G3 tumors. But which margins should be achieved? Does localization as for example in the pelvis have a higher impact on survival than surgical margins themselves? Methods From 1982 to 2014, 87 consecutive patients were treated by resection. The margin was defined as R0 (wide resection), R1 (marginal resection) or, R2 if the tumor was left intentionally. All patients were followed for evidence of local recurrence or distant metastasis. Overall and recurrence-free survival were calculated, significance analysis was performed. Results In 54 (62%) cases a R0 resection, in 31 (36%) a R1 and in 2 (2%) patients a R2-resection was achieved. Histology proved to be G1 in 37 patients (43%), G2 in 41 (47%) and G3 in 9 cases (10%). 5-year local recurrence-free survival (LRFS) was 75%. Local recurrence-free survival showed a significant association with the margin status and the localization of the tumor with pelvic lesions doing worst. Metastatic disease was initially seen in 4 patients (4.6%), 19 others developed metastatic disease during follow-up. Overall survival of the entire group at 5 and 10 years were 79 and 75%, respectively. The quality of surgical margins and the presence of local recurrence did not influence overall survival in a multivariate analysis. Pelvic lesions had a worse prognosis as did higher grades of the tumor, metastatic disease and age. Conclusions The mainstay of therapy in Chondrosarcoma remains surgery. Risk factors as grading, metastatic disease, age and location significantly influence overall survival. Margin status (R0 vs. R1) did influence local recurrence-free survival but not overall survival. Chondrosarcomas of the pelvis have a higher risk of local recurrence and should be treated more aggressively.

Abstract Background Atypical lipomatous tumours (ALT) are common adipocytic tumours. Due to their large size and deep-seated location, wide resection might result in severe functional deficits. The question which margins should be aimed is hence discussed controversially. Methods Forty consecutive patients underwent limb-sparing resections. Margins were defined as R0 (wide resection), R1 (marginal resection) or R2 if tumour was left. All patients were followed for evidence of local recurrence or remote metastases. Overall and recurrence-free survival was calculated. Results The mean age at the time of surgery was 61.9 years. The mean tumour diameter was 17 cm with no patient having metastatic disease. In 8 cases a wide (R0) resection, in 31 cases a marginal (R1) and in one patient a R2-resection was performed. The median follow-up time was 40 months. Four patients died due to causes that were not tumour-related. 3 (7.5%) patients (all R1) developed local recurrences. Two of our 3 recurrences in this series occurred in 6 already recurring cases. We observed no dedifferentiation of tumours and no metastatic disease. Conclusions ALT represents a comparatively common diagnosis in large deep-seated lesions of the extremities, especially in patients over 60 years. Marginal resection shows an acceptable rate of local recurrence. The risk of dedifferentiation as proven also in a metaanalysis of the English literature of the last 30 years is close to 1%, metastatic disease is exceedingly rare.

Abstract Background Liposarcomas are the second most common type of soft tissue sarcomas, 30–50% of these are of myxoid subtype. The aim of this retrospective study was to analyze the local control rate, the metastatic pattern and survival of patients in a consecutive single-institution series. Methods From 1983 to 2015, 43 patients with myxoid liposarcoma of the extremities and trunk wall underwent resections. The margin was defined as R0 (wide) or R1 (marginal). Patients were followed for evidence of local recurrence or distant metastasis. Overall and recurrence-free survival was calculated. Results The mean age was 48.6 years. The lower extremity was involved in 40 cases, the mean tumour size was 12 cm. In 31 cases a wide and in 12 cases a marginal resection was performed. Grading was G1 in 14, G2 in 25 and G3 in 4 cases. Nine patient died in follow-up, 4 of them with metastatic disease, all nonpulmonary. 5-year local recurrence (LR) free survival was 82%. 4 (9.3%) patients developed LR (all R1). Overall survival (OS) was 81% after 5 and 72% after 10 years. In multivariate analysis age and Grading proved to be significant on OS. According to univariate analysis, only age over 48 years and distant metastasis had a significant impact on overall survival. Conclusions Patients with myxoid liposarcomas have a good prognosis. Myxoid liposarcoma has a distinct pattern of nonpulmonary metastatic disease. Therefore, patients with high-risk extremity myxoid liposarcoma should undergo imaging studies of the chest, abdomen, spine and pelvis as part of their staging and follow-up examinations preferably with whole body MRI, or CT scans and MRI of the spine and pelvic region for detection of suspected metastatic disease.

Abstract Background Desmoid-type fibromatosis (DF) is a aggressive (myo)fibroblastic neoplasm with an infiltrative growth and a tendency to local recurrence. Resection of the tumour and/or radiation were proposed as principal treatment. The aim of this retrospective study was to analyze the local control rates focusing on the effect of surgical margins and radiotherapy. Methods From 1981 to 2014, 44 patients had been treated. Fifty four therapies had been applied, in 50 cases surgery +/− radiation therapy, NSAIDs or chemotherapy. In 4 cases a conservative approach was chosen. Thirty seven patients had primary, 17 recurrent disease. Endpoint was either local recurrence (LR), progression of residual disease or rare non-metastatic secondary lesions at the same extremity. Results The mean age was 39,4 years. In 17 cases a R0, in 27 a R1 and in 6 cases a R2 resection was achieved. Four patients were treated conservatively. All together in 21 cases radiotherapy, in 5 NSAIDs, in 3 imatinib and in 2 cases each tamoxifen or chemotherapy had been applied. The median follow-up was 119 months. 5-year recurrence free survival after resection was 78%. 10 (20.4%) patients developed LR between 5 and 42 months after therapy. Recurrent disease was a negative factor on LR. Margins, radiotherapy, sex, or size of the tumour had no significant impact on LR. Patients younger than 40 years had a significant higher risk of LR. Conclusions Surgical margins are less important than keeping function. Radiotherapy might be an option in unresectable lesions, the role of adjuvant radiotherapy is controversially discussed.

Background: The aim of this paper was to assess and compare the accuracy of common magnetic resonance imaging (MRI) pulse sequences in measuring the lesion sizes of hepatocellular carcinomas (HCCs) with respect to the Milan criteria and histopathology as a standard of reference. Methods: We included 45 patients with known HCC who underwent contrast-enhanced MRI of the liver prior to liver transplantation or tumor resection. Tumor size was assessed pathologically for all patients. The MRI protocol contained axial T2-weighted images as well as T1-weighted imaging sequences before and after application of Gd-EOB-DTPA. Tumor diameters, the sharpness of lesions, and the presence of artifacts were evaluated visually on all available MRI sequences. MRI measurements and pathologically assessed tumor dimensions were correlated using Pearson’s correlation coefficient and Bland–Altman plots. The rate of misclassifications following Milan criteria was assessed. Results: The mean absolute error (in cm) of MRI size measurements in comparison to pathology was the smallest for the hepatobiliary phase T1-weighted acquisition (0.71 ± 0.70 cm, r = 0.96) and largest for the T2w turbo-spin-echo (TSE) sequence (0.85 ± 0.78 cm, r = 0.94). The misclassification rate regarding tumor size under the Milan criteria was lowest for the T2w half-Fourier acquisition single-shot turbo spin-echo sequence and the hepatobiliary phase T1w acquisition (each 8.6%). The highest rate of misclassification occurred in the portal venous phase T1w acquisition and T2w TSE sequence (each 14.3%). Conclusions: The hepatobiliary phase T1-weighted acquisition seems to be most accurate among commonly used MRI sequences for measuring HCC tumor size, resulting in low rates of misclassification with respect to the Milan criteria.

Benign so-called “brown tumors” secondary to hyperparathyroidism are a rare diagnostic pitfall due to their impressively malignant-like character in various imaging modalities. We present the case of a 65-year-old male patient with multiple unclear osteolytic lesions on prior imaging suspicious for metastatic malignant disease. Eventually, findings of 18F-FDG PET/CT staging and 99mTc-MIBI scintigraphy resulted in revision of the initially suspected malignant diagnosis. This case illustrates how molecular imaging findings non-invasively corroborate the correct diagnosis of osteitis fibrosa cystica generalisata with the formation of multiple benign brown tumors.

Background: Aneurysmal bone cysts (ABC) are benign but locally aggressive lesions. The treatment of ABC has evolved over the years, but curettage with or without local adjuvants still represents the standard. Less invasive methods such as embolization, sclerotherapy or RANKL inhibitors (Denosumab) are also established. The aim of this study was to report and compare the results of a series of patients mainly treated with curettage with and without subsequent phenolization. Methods: 65 patients with the unequivocal diagnosis of primary ABC were treated. 61 of them were located within the bone whereas 4 patients had an ABC of the soft tissues. All patient were treated surgically by means of curettage with or without adjuvants, resection, or with minimally invasive methods such as Polidocanol injections, embolizations or Denosumab treatment. In total 80 procedures had been performed. Results: Our patients had a mean age of 25.3 ± 16.0 years, ranging from 4 to 74 years. The most common skeletal locations were the pelvis in 23%, the femur in 18%, the tibia in 16% and the spine in 10%. Six lesions were resected and showed no recurrence. 5 patients were treated with polidocanol injections (n = 3) or embolization plus systemic treatment with Denosumab (n = 2). With embolization and Denosumab both patients showed stable disease and required no further treatment. Polidocanol injections resulted in stable disease with no further treatment required in one patient and in subsequent curettage with adjuvant phenolization in two other patients.In 54 initial curettages 21 were performed with adjuvant phenolization. In this group, 16 lesions healed (76%), 3 showed persistent disease and 2 patients had a local recurrence (9%). Out of 33 patients without phenolization 21 (64%) healed, 3 showed stable persistent disease and 9 (27%) experienced a recurrence. In total we performed 66 curettages, 27 with and 39 without adjuvant phenol treatment. Resolution was achieved in 19 (70%) and 25 (64%) of cases. respectively. Persistent disease was evident in 5 cases each and recurrence in 3 and 9 cases, respectively (n.s.). Conclusion: Curettage is still the standard of treatment for ABC. Local recurrence does not depend on the use of adjuvant phenol as shown in this and other studies. Minimally invasive methods such as selective embolization and injections of sclerosing agents may result in healing or at least in tolerable persistence of residual lesions but needs repetitive treatments and does not show homogenous results throughout the institutions. Denosumab appears to be an additional option, especially in surgically critical locations such as the spine or the sacrum. Keywords: Aneurysmal bone cyst, Curettage, Recurrence, Phenol

Background and objectives: The aim of the present retrospective single-center study is to evaluate the diagnostic performance of contrast-enhanced ultrasound (CEUS) for assessing Bosniak III complex renal cystic lesions with histopathological validation. Materials and Methods: 49 patients with CEUS-categorized Bosniak III renal cystic lesions were included in this retrospective study. All patients underwent native B-mode, Color Doppler, contrast-enhanced ultrasound (CEUS) between 2010–2020. Eight and five patients underwent computed tomography (CT) and magnetic resonance imaging (MRI), respectively. Twenty-nine underwent (partial) nephrectomy allowing for histopathological analysis. The applied contrast agent for CEUS was a second-generation blood pool agent. Ultrasonography examinations were performed and interpreted by a single experienced radiologist with more than 15 years of experience (EFSUMB Level 3). Results: CEUS examinations were successfully performed in all included patients without registering any adverse effects. The malignancy rate of CEUS-categorized Bosniak III renal lesions accounted for 66%. Initially, cystic complexity was visualized in native B-mode. In none of the renal lesions hypervascularization was detected in Color Doppler. CEUS allowed for detection of contrast enhancement patterns in all included Bosniak III renal lesions. Delayed wash-out could be detected in 6/29 renal lesions. In two cases of histopathologically confirmed clear-cell RCC, appropriate up-grading from Bosniak IIF to III was achieved by CEUS. Conclusions: CEUS depicts a promising imaging modality for the precise diagnostic workup and stratification of renal cystic lesions according to the Bosniak classification system, thereby helping guidance of adequate clinical management in the future.

Background: Contrast-enhanced ultrasound (CEUS) allows for dynamic analysis of vascularization patterns of unclear hepatic lesions. Our study aimed to evaluate the diagnostic performance of CEUS for further characterizing suspicious liver lesions by comparing findings from CEUS examinations with corresponding histopathology. Methods: Between 2005 and 2016, 160 patients with unclear liver lesions underwent CEUS followed by liver biopsy. All examinations were performed by an experienced consultant radiologist (EFSUMB Level 3) and included native B-mode ultrasound, Color Doppler, and CEUS. A second-generation blood pool contrast agent was applied for CEUS. Results: CEUS was successfully performed in all patients without occurrence of any adverse side effects. CEUS showed a sensitivity of 94.5%, a specificity of 70.6%, a true positive rate of 87.3%, and a true negative rate of 85.7% compared to histopathological results as the reference standard. Conclusions: CEUS represents a safe imaging modality with a high diagnostic accuracy in assessing both—benign and malignant—liver lesions compared to corresponding histopathological results.

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest tumors worldwide. Understanding the function of gene expression alterations is a prerequisite for developing new strategies in diagnostic and therapy. GPRC5A (RAI3), coding for a seven transmembrane G protein-coupled receptor is known to be overexpressed in pancreatic cancer and might be an interesting candidate for therapeutic intervention. Expression levels of RAI3 were compared using a tissue microarray of 435 resected patients with pancreatic cancer as well as 209 samples from chronic pancreatitis (CP), intra-ductal papillary mucinous neoplasm (IPMN) and normal pancreatic tissue. To elucidate the function of RAI3 overexpression, siRNA based knock-down was used and transfected cells were analyzed using proliferation and migration assays. Pancreatic cancer patients showed a statistically significant overexpression of RAI3 in comparison to normal and chronic pancreatitis tissue. Especially the loss of apical RAI3 expression represents an independent prognostic parameter for overall survival of patients with pancreatic cancer. Suppression of GPRC5a results in decreased cell growth, proliferation and migration in pancreatic cancer cell lines via a STAT3 modulated pathway, independent from ERK activation.

Background and aims: Recent cDNA expression profiling analyses indicate that within specific organ cancers Cytokeratins (CKs) dysregulation may identify subgroups with distinct biological phenotypes. Our objectives in this study were (1) to test whether cytokeratins were also distinct on the protein level, (2) to evaluate these biomarkers in a series of well-characterised CRCs, (3) to apply hierarchical cluster analysis to immunohistochemical data. Methods: Tissue microarrays (TMA) comprising 468 CRC specimens from 203 patients were constructed to evaluate CK5, CK7, CK8, CK13, CK14, CK16, CK17, CK18, CK19 and CK20. In total, 2919 samples were analyzed. Results: Unsupervised hierarchical clustering discovered subgroups represented by reduced CK8 and CK20 expression, that differed by a shorter patients survival. The evaluation of the specific biomarkers by Kaplan–Meier analysis showed that reduced CK8 expression (p < 0.01) was significantly associated with shorter patients’ survival, but was not an independent factor correlated with tumour stage (pT), grading (G) and nodal stage (pN). Conclusions: Reduced coexpression of CK8 and CK20 may indicate an epithelial-mesenchymal transition (EMT) representing an important step in the development of more aggressive CRCs. In addition, multiplex analysis of TMAs together with immunohistochemistry (IHC) supplemented by hierarchical clustering are a useful, promising and very powerful tool for the identification of tumour subgroups with diagnostic and prognostic signatures.

BACKGROUND, AIMS: Genomewide expression profiling has identified a number of genes expressed at higher levels in colorectal cancer (CRC) than in normal tissues. Our objectives in this study were: 1) to test whether genes were also distinct on the protein level; 2) to evaluate these biomarkers in a series of well-characterized CRCs;, 3) to apply hierarchical cluster analysis to the immunohistochemical data. METHODS: Tissue microarrays (TMAs) comprising 351 CRC specimens from 270 patients were constructed to evaluate the genes Adam10, CyclinD1, Annexinll, NFKB, Casein-kinase-2-beta (CK2B), YB-1, P32, Rad51, c-fos, IGFBP4, Connexin26 (Cx26). In total, 3,797 samples were analyzed. RESULTS: Unsupervised hierarchical clustering discovered subgroups of CRC that differed by tumor stage, survival. KaplanMeier analysis showed that reduced Cx26 expression was significantly associated with shorter patient survival, higher tumor grade (G1/G2vs G3, P = .02), Adam10 expression with a higher tumor stage (pT1/2vs pT3/4, P = .04). CONCLUSIONS: Our study highlights the potential of TMAs for a higher-dimensional analysis by evaluating serial sections of the same tissue core (three-dimensional TMA analysis). In addition, it endorses the use of immunohistochemistry supplemented by hierarchical clustering for the identification of tumor subgroups with diagnostic, prognostic signatures.

Comparative genomic hybridization (CGH) was used to screen colorectal carcinomas for chromosomal aberrations that are associated with metastatic phenotype. In total, 63 tumor specimens from 40 patients were investigated, comprising 30 primary tumors, 22 systemic metastases (12 liver, 6 brain, and 4 abdominal wall metastases) and 11 lymph node tumors. Using statistical analysis and histograms to evaluate the chromosomal imbalances, overrepresentations were detected most frequently at 20q11.2-20q13.2, 7q11.17q12, 13q11.2-13q14, 16p12, 19p13, 9q34, and 19q13.1-19q13.2. Deletions were prominent at 18q12-18q23, 4q27-4q28, 4p14, 5q21, 1p21-1p22, 21q21, 6q16-6q21, 3p12, 8p22-8p23, 9p21, 11g22, and 14q13-14q21. Hematogenous metastases showed more alterations than lymph node tumors, particularly more deletions at 1p, 3, 4, 5q, 10q, 14, and 21q21 and gains at 1q, 7p, 12gter, 13, 16, and 22q. Comparing liver metastases with their corresponding primary tumors, particularly deletions at 2q, 5q, 8p, 9p, 10q, and 21q21 and gains at 1q, 11, 12gter, 17g12-q21, 19, and 22q were more often observed. The analysis suggested that the different pathways of tumor dissemination are reflected by a nonrandom accumulation of chromosomal alterations with specific changes being responsible for the different characteristics of the metastatic phenotype.

Predicting the clinical outcome of cancer patients based on the expression of marker genes in their tumors has received increasing interest in the past decade. Accurate predictors of outcome and response to therapy could be used to personalize and thereby improve therapy. However, state of the art methods used so far often found marker genes with limited prediction accuracy, limited reproducibility, and unclear biological relevance. To address this problem, we developed a novel computational approach to identify genes prognostic for outcome that couples gene expression measurements from primary tumor samples with a network of known relationships between the genes. Our approach ranks genes according to their prognostic relevance using both expression and network information in a manner similar to Google's PageRank. We applied this method to gene expression profiles which we obtained from 30 patients with pancreatic cancer, and identified seven candidate marker genes prognostic for outcome. Compared to genes found with state of the art methods, such as Pearson correlation of gene expression with survival time, we improve the prediction accuracy by up to 7%. Accuracies were assessed using support vector machine classifiers and Monte Carlo cross-validation. We then validated the prognostic value of our seven candidate markers using immunohistochemistry on an independent set of 412 pancreatic cancer samples. Notably, signatures derived from our candidate markers were independently predictive of outcome and superior to established clinical prognostic factors such as grade, tumor size, and nodal status. As the amount of genomic data of individual tumors grows rapidly, our algorithm meets the need for powerful computational approaches that are key to exploit these data for personalized cancer therapies in clinical practice.

Transcriptional signatures are an indispensible source of correlative information on disease-related molecular alterations on a genome-wide level. Numerous candidate genes involved in disease and in factors of predictive, as well as of prognostic, value have been deduced from such molecular portraits, e.g. in cancer. However, mechanistic insights into the regulatory principles governing global transcriptional changes are lagging behind extensive compilations of deregulated genes. To identify regulators of transcriptome alterations, we used an integrated approach combining transcriptional profiling of colorectal cancer cell lines treated with inhibitors targeting the receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase pathway, computational prediction of regulatory elements in promoters of co-regulated genes, chromatin-based and functional cellular assays. We identified commonly co-regulated, proliferation-associated target genes that respond to the MAPK pathway. We recognized E2F and NFY transcription factor binding sites as prevalent motifs in those pathway-responsive genes and confirmed the predicted regulatory role of Y-box binding protein 1 (YBX1) by reporter gene, gel shift, and chromatin immunoprecipitation assays. We also validated the MAPK-dependent gene signature in colorectal cancers and provided evidence for the association of YBX1 with poor prognosis in colorectal cancer patients. This suggests that MEK/ERK-dependent, YBX1-regulated target genes are involved in executing malignant properties.