bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results from extended lymphadenectomies with [111In]PSMA-617 for intraoperative detection of PSMA-PET/CT-positive nodal metastatic prostate cancer
Authors: Jilg Cordula A. , Reichel Kathrin , Stoykow Christian , Rischke H. Christian , Bartholomä Mark , Drendel Vanessa , von Büren Moritz , Schultze-Seemann Wolfgang , Meyer Philipp T. , Mix Michael 
Published: March 2020

Abstract
Purpose
Identification of suspicious PSMA-PET/CT-positive lymph node (LN) metastases (LNM) from prostate cancer (PCa) during lymphadenectomy (LA) is challenging. We evaluated an 111In-labelled PSMA ligand (DKFZ-617, referred to as [111In]PSMA-617) as a γ-emitting tracer for intraoperative γ-probe application for resected tissue samples in PCa patients. Forty-eight hours prior to LA, [111In]PSMA-617 was administered intravenously in 23 patients with suspected LNM on PSMA-PET/CT (n = 21 with biochemical relapse, n = 2 at primary therapy). Resected tissue samples (LN, LNM and fibrofatty tissue) were measured ex situ by a γ-probe expressed as counts per second (CPSnorm). [111In]PSMA-617 tissue sample uptake was measured by a germanium detector for verification and calculated as %IAlbm (percent injected activity per kilogram lean body mass at time of surgery). Based on a clinical requirement for a specificity > 95%, thresholds for both ex situ measurements were chosen accordingly. Correlation of the results from PET/CT, γ-probe and germanium detector with histopathology was done.

Results
Eight hundred sixty-four LNs (197 LNM) were removed from 275 subregions in 23 patients, on average 8.6 ± 14.9 LNM per patient. One hundred four of 275 tissue samples showed cancer. Median γ-probe and germanium detector results were significantly different between tumour-affected (33.5 CPSnorm, 0.71 %IAlbm) and tumour-free subregions (3.0 CPSnorm, 0.03 %IAlbm) (each p value < 0.0001). For the chosen γ-probe cut-off (CPSnorm > 23) and germanium detector cut-off (%IAlbm > 0.27), 64 and 74 true-positive and 158 true-negative samples for both measurements were identified. Thirty-nine and 30 false-negative and 6 and 5 false-positive tissue samples were identified by γ-probe and germanium detector measurements.

Conclusion
[111In]PSMA-617 application for LA is feasible in terms of an intraoperative real-time measurement with a γ-probe for detection of tumour-affected tissue samples. γ-probe results can be confirmed by precise germanium detector measurements and were significantly different between tumour-affected and tumour-free samples.
The equivalence of $F_{a}$-frames
Authors: Hussain Tufail , Li Yun-Zhang 
Published: March 2020

AbstractStructured frames such as wavelet and Gabor frames in$L^{2}(\mathbb {R})$L2(R)have been extensively studied. But$L^{2}(\mathbb{ R}_{+})$L2(R+)cannot admit wavelet and Gabor systems due to$\mathbb{R}_{+}$R+being not a group under addition. In practice,$L^{2}(\mathbb{R}_{+})$L2(R+)models the causal signal space. The function-valued inner product-based$F_{a}$Fa-frame for$L^{2}(\mathbb{R}_{+})$L2(R+)was first introduced by Hasankhani Fard and Dehghan, where an$F_{a}$Fa-frame was called a function-valued frame. In this paper, we introduce the notions of$F_{a}$Fa-equivalence and unitary$F_{a}$Fa-equivalence between$F_{a}$Fa-frames, and present a characterization of the$F_{a}$Fa-equivalence and unitary$F_{a}$Fa-equivalence. This characterization looks like that of equivalence and unitary equivalence between frames, but the proof is nontrivial due to the particularity of$F_{a}$Fa-frames.
Trends in survival of stage IV breast cancer (BC) among Caucasian and African American (AA) BC patients (pts)
Authors: Dawood S. S. , Broglio K. , Hortobagyi G. , Giordano S. 
Published: March 2020

1000 Background: The aim of this review was to look at the trends in survival over time in patients(pts) with de novo stage IV BC and to identify factors that impact survival. Methods: We searched the SEER registry to identify pts with de novo stage IV breast cancer diagnosed between 1988 and 2003. Pts who were male, did not have microscopic confirmation of disease, had more than one primary, and who had a prior malignancy were excluded. Pts were divided into three groups based on their year of diagnosis separated into 5-year intervals: 1988 - 1993, 1994 - 1998, and 1999 -2003. Overall survival (OS) and BC specific survival (BCS) were calculated from the date of diagnosis to the date of death, last follow-up, or 12/31/03. Survival outcomes were estimated by the Kaplan-Meier method, and Cox models were fit to determine the characteristics that were independently associated with survival. Follow-up time was censored at 3 years for Cox analyses. Results: 15,438 pts were identified. 3796 pts were diagnosed from 1988–1993, 3954 from 1994–1998, and 7688 from 1999–2003. Median age was 62 years. Median follow-up was 16 months (mos) (range 0–191), 18 mos (range 0–199), and 11 mos (range 0–59) in periods 1988 - 1993, 1994 - 1998, and 1999 - 2003 respectively. Median OS was 18 mos overall and 16, 18, and 20 mos respectively for each time period. Median BCS was 23 mos overall and 20, 21, and 25 mos for each time period. In the multivariable model, more distant year of diagnosis, Grade 3 disease, higher number of positive LN, increasing age, being unmarried, ER- disease, PR- disease, and no surgery were all independently associated with worse BCS. The interaction term between ER and year of diagnosis was of borderline significance, indicating that over time, pts with ER+ disease had decreasing risk of death compared to patients with ER- disease (HR 0.98, 95% CI 0.96–1.00). An interaction term between race and year of diagnosis was significant, such that with each increasing year of diagnosis AA pts had increasing risk of death compared to whites (HR 1.04, 95% CI 1.01–1.07). Conclusions: The survival of de novo stage IV BC pts has modestly improved over time. Of concern, survival disparities between AA and white patients increased rather than diminished over time. No significant financial relationships to disclose.
Sensitivity of myxoid-round cell liposarcoma (MRCL) to trabectedin (T) may be related to a direct effect on the fusion transcript
Authors: Grosso F. , Forni C. , Frapolli R. , Greco A. , Gronchi A. , Jimeno J. , Mantovani R. , D'Incalci M. , Pilotti S. , Casali P. G. 
Published: March 2020

10000 Background: Myxoid-round cell liposarcomas (MRCL) is a variant of liposarcoma, associated with t(12;16)(q13;p11) and the rarer t(12;22)(q13;q12) chromosomal translocation, resulting in the FUS-CHOP and EWS-CHOP fusion proteins, supposed to act as aberrant transcription factors. We reported the exceedingly high clinical efficacy of T against MRCL, which is a magnitude higher in comparison to other liposarcomas and sarcomas. Reasons thereof remain unknown, but a distinct mechanism of action of T in MRCL is suspected on clinical grounds. Methods: Tumor biopsies were taken from 9 MRCL patients (pts) before starting T, and the tumor was fully characterized by cytogenetic and molecular analysis. Primary cultures were set up, and tumor fragments were transplanted in scid mice, to develop an experimental model aimed at investigating the mechanism of action of T. Chromatin immunoprecipitation (ChIP) analysis on the 402–91 myxoid liposarcoma cell line was performed, to characterize the DNA binding capability of FUS-CHOP. Finally, in vivo ChIP analyses are currently ongoing, using tumor samples obtained before and after therapy with T. Tumor samples from 3 patients have been processed so far. Results: All patients had t(12–16) by FISH. Molecular characterization showed that 7 pts had the type II transcript, 1 had the type III, and 1 both type II and III. Primary cultures evaluated after the first 3 passages were morphologically, cytogenetically and molecularly consistent with the original tumor, as well as the 4 tumours grown in mice so far. In the myxoid liposarcoma cell line carrying the type I transcript, selective binding of FUS-CHOP to some promoters was seen. Impairment of this binding activity was observed after treatment with T at concentration 1–4 nM. Conclusions: There is in vitro evidence of a direct effect of T on the fusion protein's ability to bind to promoters. In vivo studies on the experimental model are ongoing, and results will be presented. No significant financial relationships to disclose.
Targeted therapy for osteosarcoma using 17AAG and rapamycin: Identification of new targets using Gene Microarray profiling and MiRNA
Authors: Gazitt Y. , Moncada K. , Thomas C. , Takimoto C. , Tolcher A. 
Published: March 2020

10027 Background: Sarcomas constitute a group of diverse diseases with many subtypes and varying prognoses. Hence, new approaches for therapy involving targeting of specific survival pathways are needed. Methods: We used 17-AAG to block HSP90 and rapamycin (Ra) to block mTOR, in 2 osteosarcoma cell lines, HOS and KHOS/NP. Cells were treated for 24 and 48 hours with 200 nM of 17- AAG or 5 micromolar of rapamycin. Gene profiling (GP) was performed using h-U133 2 Plus Array (Affymetrix). Results were pre-filtered using the GCOS pair-wise comparisons. ANOVA was filtered for >2-fold change between two conditions. We compared control HOS or KHOS vs. 24 H or 48 H treatment with Ra, or 17AAG. Gene identity, ontology and z-scores were derived. For micro RNAs (miRs), we used a miRNA chip (LC Sciences) and data were normalized, adjusted and clustered using t-test (p<0.01). Results and Conclusions: 17-AAG is a good inducer of apoptosis in HOS and KHOS cells (IC50 of ∼50nM) and blocked cells at mitosis. Ra is a weak inducer of apoptosis (IC20 at 5 micromolar) and blocked cells at G1. GP of 17AAG treated HOS/KHOS cells revealed >1,000 and 1,600 gene changes at 24 H and 48 H, respectively, with ∼700 genes affected at 24 and 48H. Ra affected ∼400 and ∼350 genes at 24 and 48H, respectively, with 20 genes affected at 24 and 48H. Of the genes upregulated by 17AAG, >450 were in cell and protein metabolism; >50 genes were in chromatin modifications and >40 in regulation of cell cycle. With 17AAG, changes were found in histones and deacetylases; cytoskeleton proteins; extracellular matrix proteins and MMPs; HSPs; MAP kinase, mTOR, IGF and VEGF pathways; cell cycle and apoptosis. Many targets were validated by by immunoblotting. MiRs were profiled following 24H treatment with 17AAG or Ra. 17AAG upregulated miR122a;145;143 and 663 (4–16 fold) and miR 542–5P was decreased (∼12 fold). Ra upregulated miR 498;145;143;452;663; 602 and miR224 (4–32 fold) and downregulated (4–32 fold) miR1;542–5P and miR335. Taken together, miR changes affect the expression of transcripts related to angiogenesis; cell cycle; cell signaling and apoptosis and are common to the changes observed by GP. In summary, new therapeutic targets were identified by the combination of GP and miRNA following 17AAG or rapamycin. No significant financial relationships to disclose.
STEAP1: A potential marker of metastatic disease for Ewing family tumors
Authors: Cheung I. Y. , Feng Y. , Danis K. , Shukla N. , Meyers P. , Ladanyi M. , Cheung N. 
Published: March 2020

10028 Background: Ewing Family Tumors (EFTs) metastasize by hematogeneous spread. Because of its dismal cure rate, targeting subclinical disease is particularly relevant. Genome-wide gene expression array analysis can uncover novel genes differentially expressed in tumors over normal marrow/blood, which may have clinical potentials as markers of minimal residual disease (MRD). Methods: Gene expression array data were obtained on 28 EFT tumors and 10 EFT cell lines using the Affymetrix U133 gene chip. Ten genes with high tumor to blood ratios were identified. Quantitative RT-PCR was performed to study (1) the dynamic range of detection of rare tumor cells (frequency of 10-7 to 10-4), (2) the gene expression in normal blood and marrow samples, (3) the gene expression among EFT tumors, and (4) the prognostic impact of marker positivity in EFT patients with histologically negative marrows. Results: Of the 10 genes, 5 genes, namely six transmembrane epithelial antigen of the prostate 1 [STEAP1], cyclin D1 [CCND1], plakophilin 1 [PKP1], transmembrane protein 47 [TMEM47], and NKX2.2 transcription factor [NKX2.2] were chosen for further analyses. This was based on their steep linear dynamic range in tumor cells seeded in normal mononuclear cells and consistently high expression among EFT tumor samples. Among 53 EFT patients with histologically negative marrow samples, a marker was classified as positive if the gene transcript level was above the upper limit of normal, defined as mean + 2SD of 26 normal blood and marrow samples. Of the 5 markers tested, STEAP1 positivity in marrow samples was highly correlated with survival with new metastasis in Kaplan Meier analysis (p=0.001). Conclusions: This gene expression array-based approach identified STEAP1 as a promising surrogate MRD marker of metastatic EFT with potential prognostic importance. Its clinical utility will need to be further tested in large patient cohorts. No significant financial relationships to disclose.
A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitinib (AG-013736) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer (MBC)
Authors: Rugo H. S. , Stopeck A. , Joy A. A. , Chan S. , Verma S. , Lluch A. , Liau K. F. , Kim S. , Bycott P. , Soulieres D. 
Published: March 2020

1003 Background: Single-agent DOC is commonly used to treat MBC. Axitinib (AG) is a potent TKI of VEGFRs. A phase I lead-in study identified 80 mg/m2 q3wks of DOC in combination with 5 mg BID of AG as the recommended phase 2 dose. The primary objective was to determine whether the time to progression (TTP) of AG+DOC arm is superior to DOC+PL. Methods: Pts with no prior chemotherapy for MBC and =12 mos from adjuvant chemotherapy (aCT), measurable disease, ECOG performance status (PS) of 0–2, and no uncontrolled brain metastases were randomly assigned (2:1) to receive treatment with either DOC+AG or DOC+PL without prophylactic growth factor in cycle 1. Tumor measurements were performed q9wks. Pts were stratified according to estrogen receptor (ER) status, prior aCT and PS (0–1 or 2). Results: A total of 168 pts were randomized. 92 pts had received prior aCT, 27 of whom received a prior taxane. Treatment arms were well balanced for prior adjuvant and taxane therapy. A median of 7 cycles of AG+DOC (range: 1–18) and 7 cycles of DOC+PL (range: 1–23) were administered. The most common non-hematologic adverse events observed in the AG+DOC arm included diarrhea (60%), nausea (53%), alopecia (51%), fatigue (49%), stomatitis (44%) and vomiting (40%). Grade 3/4 adverse events that were increased with AG+DOC vs DOC included febrile neutropenia (16 vs 7%), fatigue (13 vs 5%), stomatitis (13 vs 2%), diarrhea (11 vs 0%) and hypertension (5 vs 2%). Other grade 3/4 hematologic toxicities were similar in both arms. The median TTP (by RECIST) was 8.2 mo with AG+DOC arm and 7 mo with DOC+PL arm with a hazard ratio of 0.73 (prespecified, one-sided p=0.052). The overall response rate (ORR) was 40% for AG+DOC arm and 23% for DOC+PL arm (p=0.038). In a hypothesis-generating subgroup analysis, the median TTP in patients receiving prior aCT was 9.0 mo with AG+DOC arm and 6.3 mo with DOC+PL arm with a hazard ratio of 0.54 (p=0.012). Within this stratum, ORR was 45% for AG+DOC arm and 13% for DOC+PL arm (p=0.003). Conclusions: The anti-angiogenic TKI AG combined with DOC (80 mg/m2 q3wks) as first line therapy for MBC has an acceptable safety profile and promising anti-tumor activity. No significant financial relationships to disclose.
Paclitaxel in patients (pts) with advanced angiosarcomas
Authors: Schlemmer M. , Reichardt P. , Verweij J. , Hartmann J. T. , Judson I. , Thyss A. , Blay J. Y. 
Published: March 2020

10033 Background: Angiosarcomas represent a heterogenous group of rare sarcomas with specific clinical behaviour and risk factors. Paclitaxel has been suggested to induce tumor control in a proportion of pts with angiosarcoma while being inactive in other soft tissue sarcomas subtypes. The objective of this retrospective study was to investigate the antitumor activity of this compound in a larger series and a multicenter setting. Patients and Methods: Data from pts with angiosarcoma treated with paclitaxel in centers of the EORTC Soft Tissue and Bone Sarcoma Group were collected using a standardized data collection form. Results: Data from 32 pts were collected from 10 centers. There were 17 males and 15 females with a median age of 60.4 years (range 24–91). Eight pts (25%) had angiosarcomas of the face and scalp, 24 pts (75%) at other primary sites. Ten (31 %) pts had a previous cancer history, 7 of whom had been irradiated for breast cancer. Ten (31 %) pts had received 1st line chemotherapy (ctx) and 3 pts 2nd line ctx prior to treatment with paclitaxel. All 13 (40%) pretreated pts had doxorubicin, 5 pts in combination with ifosfamide as 1st line and 3 pts ifosfamide as 2nd line ctx. 21 (66 %) pts received paclitaxel 175 mg/m2 every 3 weeks, and 11 (34 %) received 75–100 mg/m2weekly. The overall response rate (RR) was 62.5 % [including 1 CR (3%) and 19 PR (59%)]; in pts with face and scalp primary sites the RR was 75% (1CR, 5 PR), whereas pts with angiosarcoma at other sites achieved a response in 58% (14 PR). PFS was 7.6 months for all 32 pts. Conclusion: Paclitaxel was an active agent in angiosarcoma in this retrospective multicenter study, also in angiosarcoma originating at other sites than scalp and face. These results need to be confirmed in a controlled, prospective phase II study. No significant financial relationships to disclose.
Retrospective review of treatment for angiosarcoma at Fox Chase Cancer Center over the past 15 years
Authors: Saroha S. , Litwin S. , von Mehren M. 
Published: March 2020

10034 Background: Angiosarcoma is a rare vascular neoplasm that may arise in a variety of anatomic locations. There is limited published data on chemotherapy treatment in angiosarcoma and data on taxane therapy does not utilize contemporary schedules. We present a retrospective analysis of our institution's experience with angiosarcoma over the past 15 years. We reviewed patient characteristics, overall survival and response to various chemotherapeutic agents. We specifically compared the response to weekly paclitaxel with all other chemotherapeutic agents used over the study period. Methods: Medical records of all the patients treated with the diagnosis of angiosarcoma at Fox Chase Cancer Center between January 1990 and June 2005 were reviewed. Overall survival was determined by the Kaplan-Meier method. Response to chemotherapy was determined at two-month follow-up after starting treatment. Clinician judgment was used to define response for superficial lesions. We compared the response to weekly paclitaxel with all other chemotherapy regimens using Fisher's exact test. p <0.10 was considered significant. Results: A total of 39 patients were identified. Most common sites for angiosarcoma were head and neck (including scalp) and breast. Median overall survival was 21 months. Since many patients received several lines of chemotherapy, 40 chemotherapy administrations were identified for analysis. 10 of 13 patients showed response to weekly paclitaxel versus 14 of 27 for non-paclitaxel regimens, which was not statistically significant by Fisher's exact test (2-tail, p=0.18). We also analyzed the response with respect to different anatomic locations of angiosarcoma and individual chemotherapy regimens used, however the numbers were too small for statistical comparisons. Conclusions: Angiosarcoma is an aggressive malignancy with poor survival rates. Our study demonstrated that paclitaxel has efficacy in angiosarcoma, although not statistically superior to non-taxane containing regimens. No significant financial relationships to disclose.
Treosulfan high dose therapy with autologous stem cell rescue in high-risk Ewing tumors
Authors: Dirksen U. , Lanvers-Kaminski C. , Ranft A. , Bremer A. , Boos J. , Jürgens H. 
Published: March 2020

10039 Background: High dose (HD) chemotherapy using a busulfan-containing regimen has been proven advantageous for some high risk Ewing tumor (ET) patients. HD busulfan is not compatible with radiotherapy to central axis sites. Treosulfan is a bifunctional alkylating agent, structurally related to busulfan, that has shown to be safe even in heavily pretreated patients and patients at risk to treatment related toxicity. Methods: In vitro: In order to compare the cytotoxicity of busulfan and treosulfan, growth inhibition was tested by a modified (4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium-bromide (MTT) assay. In vivo: 11 patients with primary disseminated ET and contraindication for busulfan HD treatment and 11 patients with relapsed ET were referred to HD treosulfan (36 g/m2) and melphalan (140 mg/m2) followed by autologous stem cell rescue. Results: In vitro: Busulfan and treosulfan were cytotoxic in a time and dose dependent manner. Treosulfan was 15-fold more cytotoxic compared to busulfan. In vivo: The median age in patients with disseminated ET was 14.3 years, in relapsed ET 22.7 years. Sex distribution was equal. Response status prior to HD treosulfan was: stable disease in 4, partial response in 6, complete remission in 8, progressive disease in 1, not documented in 3 patients. Median follow up time in patients with disseminated ET was 0.91 years. All patients are alive. Four patients have relapsed within 2 years after HD treatment. Median follow up time in relapsed ET was 1.35 years. Seven patients are in remission, one patient is under treatment and two patients have died after relapse. HD was well tolerated with mucositis °3 in seven, °4 in three, stomatitis °3 in four, °4 in three , neutropenic infection °3 in three and reversible myelitis in one patient. Conclusions: Treosulfan HD treatment is a feasible therapeutic option without overt acute toxicity for patients with advanced ET. Efficacy and late effects remain to be evaluated. No significant financial relationships to disclose.