bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of long-term outcome between doublet versus triplet neoadjuvant chemotherapy in nonmetastatic osteosarcoma of extremity
Authors: Hong S. , Rha S. , Jeong J. , Lee Y. , Shin S. , Shin K. , Roh J. 
Published: August 2020

10542 Background: Multimodal approach had improved outcomes of non-metastatic osteosarcoma. This study was to compare outcomes between doublet (AP; doxorubicin and cisplatin) and triplet (IAP; AP and ifosfamide) neoadjuvant chemotherapy for non-meteastatic osteosarcoma of extremity in a single institute. Methods: A total of 124 osteosarcoma patients were enrolled. In AP group, doublet regimen was given to 77 patients from 1991 to 1999, who received intra-arterial cisplatin(120mg/m2) at day 1 and intravenous doxorubicin (25mg/m2) for 3 days. In IAP group, triplet regimen was given to 49 patients from 2000 to 2007, who received ifosfamide additionally at a dose of 2.5g/m2/day for 3 days. After completion of 3 cycles of chemotherapy, patients underwent limb-salvage surgery. We assessed tumor response according to pathologic tumor necrosis, and treated further adjuvant chemotherapy. In AP group, responder received 3 more cycles of AP, while non-responders received 6 cycles of ifosfamide-contaning regimens. In IAP group, all patients had 3 more cycles of IAP chemotherapy. Results: The median follow-up duration was 5.2 years (0.4–16.7). The most frequent site and histology were distal femur and osteoblastic type. Overall pathologic response was more than 90% tumor necrosis in 74.8% of patients. Total necrosis of tumor was also found in 46 patients (37.4%). There was no difference between two groups in pathologic response (76.3% vs. 72.3%; p=0.62) or other clinico-pathologic parameters. Tumor recurrence was occurred in 31.5% of patients with the most common site of lung (84.6%). There was no difference between two groups in recurrence (p=0.17) or lung metastasis (p=0.53). There were no statistical differences in disease free survival (p=0.75) and overall survival (p=0.07) between two groups. In toxicity profiles, there were more hematologic toxicity in IAP group (febrile neutropenia,p<0.001; thrombocytopenia,p<0.05), while there were no statistical differences in treatment related death. Conclusions: The addition of ifosfamide to doxorubicin and cisplatin in neoadjuvant chemotherapy did not show improved outcomes in this study. Further trials are required to elucidate optimal neoadjuvant chemotherapy and effective salvage regimens. No significant financial relationships to disclose.
Ifosfamide, carboplatin, and etoposide as front-line therapy in patients with Ewing sarcoma family tumors (EFT): A study of the Brazil/Uruguay Cooperative Group
Authors: Brunetto A. L. , Castillo L. A. , Petrilli A. S. , Boldrini E. , Gregianin L. J. , Costa C. , Almeida M. T. , Rosario K. , Rodriguez-Galindo C. , Castro C. G. , Dufort G. 
Published: August 2020

10547 Background: Chemotherapy (CT) with ifosfamide, carboplatin, and etoposide (ICE) is effective in refractory solid tumors. The aim of this trial was to determine the efficacy and safety of ICE as front line therapy for patients (pts) with newly-diagnosed EFT. Methods: Induction with 2 courses of ICE (ifosfamide 3g/m2/d ×3, carboplatin 450mg/m2 ×1, etoposide 150mg/m2/d ×3) plus 2 of VDC (vincristine 1,5mg/m2/d ×1, doxorubicin 60mg/m2/d ×1, cyclophosphamide 1,5g/m2/d ×1) was followed by surgery and/or radiotherapy. After induction, pts were allocated to low (LR) or high-risk (HR) according to LDH (<or>1,5×NL), site (pelvic/non-pelvic) and resection (complete/unresectable) or metastatic (mets). Postoperative CT included 10 alternating courses of IE and VDC for LR and 12 alternating courses of ICE and VDC for HR. Toxicity was assessed following 523, 648, 268 and 114 courses of ICE, VDC, IE and VC, respectively; 35 site visits were carried out for data quality control. Results: From 10/2003 to 10/2008, 150 of 159 enrolled pts were evaluable; median age 13y (0.2–29.3y). 44 pts were classified as LR and 101 as HR, 56 mts. Toxicity was mainly grade III-IV neutropenia, thrombocytopenia and febrile neutropenia, and was significantly higher following ICE. The 3y EFS and OS were 65% and 27% for localized pts and 80% and 43% for mets pts. 3y EFS for lung and non-lung mets were 40% and 19% (P=0.013). Multivariate analysis showed that mets disease was the only independent prognostic factor (P=0.006) for the entire group. However, when mts pts were analyzed separately, high LDH (P=0.01) and extra-lung site (P=0.016) had significant negative impact on survival. Conclusions: ICE regimen is safe and despite a high proportion of pts with advanced disease the survival are similar to larger series. Elevated LDH and the presence of extra-lung mets were significant negative prognostic factors in mets pts. Randomized trials to identify pts who may benefit from more intensive CT are warranted. No significant financial relationships to disclose.
Effect of mTOR inhibition on sensitivity of triple-negative breast cancer cells to epidermal growth factor inhibition
Authors: Liu T. , Yacoub R. , Graham T. , Yang L. , Tighiouart M. , O'Regan R. M. 
Published: August 2020

1055 Background: The outcome for patients with triple negative (TN) cancers is poor at least in part because of a lack of targeted therapies. Although 50% of TN breast cancers over-express EGFR, the use of EGFR inhibitors as single agents in patients with unselected and TN metastatic breast cancers has produced disappointing results. Likewise, mTOR inhibitors have modest activity as single agents in metastatic breast cancer. mTOR inhibitors have been demonstrated to activate the Akt pathway by a possible feedback mechanism, which could potentially sensitize TN breast cancer cells to upstream inhibitors. We have previously demonstrated that EGFR inhibitors in combination with rapamycin (RAPA) decrease cell survival, increase apoptosis, and are synergistic in TN breast cancer cells, compared to any of the agents alone (AACR 2008). We, therefore, evaluated the combination of mTOR and EGFR inhibition in vivo. Methods: Athymic mice were inoculated with TN (MDA-MB-231) breast cancer cells. One week after cell inoculation, mice were treated with vehicle, lapatinib 75mg/kg by mouth daily, RAPA 3mg/kg IP biweekly, or the combination. After 4 weeks of treatment, mice were sacrificed and tumors were assessed for target proteins by Western blotting and immunohistochemistry Results: The combination of RAPA and lapatinib resulted in a significant decrease in TN breast tumor volume (76 mm3), compared to rapamycin alone (133 mm3, p = 0.01), lapatinib alone (183 mm3, p < 0.0001) or control (188 mm3, p = 0.005). Neither lapatinib nor RAPA alone inhibited tumor growth significantly compared to control (p > 0.05). Interestingly, in contrast to our findings in vitro, the increase in pAkt noted in RAPA treated tumors was not decreased by lapatinib, despite the significant decrease in tumor size in tumors treated with the combination. Conclusions: These studies demonstrate that the combination of mTOR inhibition and lapatinib significantly inhibit TN breast cancer growth, compared with either agent alone. Given the lack of targeted therapies in TN breast cancers, these data support the possibility that mTOR inhibition can sensitize TN breast cancers to EGFR inhibitors. A clinical trial evaluating the combination of lapatinib and RAD001 as second-line therapy for TN metastatic breast cancer is planned. [Table: see text]
Analysis of an observational registry of gastrointestinal stromal tumor (GIST) patients (pts) in the United States: reGISTry
Authors: Pisters P. W. , Trent J. C. , Blanke C. D. , Picus J. , Stealey E. , McDougall K. , von Mehren M. 
Published: August 2020

10557 Background: This observational reGISTry, initiated 11/04, characterizes the evolving patterns of care for GIST, such as the recent use and approval of Imatinib mesylate (IM) in adjuvant GIST. Methods: Data from consented pts (e.g. demographics, clinical characteristics, therapy, outcomes) are entered onto a web-based database. Updated analyses are performed every 6 months (mo), with data from unique sites being compared to the aggregate. Results: 792 pts enrolled from 121 centers, 55% from community practices. 79% were diagnosed with localized tumor, 87% of which received surgery as primary treatment. 94% had c-kit testing and 4% had mutational analysis performed at any time (1.4% of the pts in the community; 7.8% in Universities). 59% of pts had mutations in KIT Exon 11, 12% in Exon 9, 3% in Exon 17, 9% in PDGFRA Exon 18 and 18% had no detectable mutations. 13% of pts from Universities were enrolled in clinical trials vs 3% in the community. 78% of pts receiving IM at any time started at 400mg qd and 70% of pts receiving Sunitinib malate (SU) started at 50mg (4 wks on, 2 wks off). 6.6% of all pts received neoadjuvant IM, for a median of 4.3 mo for those pts that have completed (81%). 120 pts (15%) received adjuvant IM (13% of the pts in the community; 17% in Universities). Prior to Jun07 (ACOSOG Z9001 adjuvant IM positive results released) 14% of eligible pts received adjuvant IM vs 29% after Jun07. Median duration of adjuvant IM was 361 days for those pts that have completed (43%). Conclusions: reGISTry is a useful tool for measuring evolving pt management patterns in GIST capturing treatment variations from standard guidelines and differentiating management in Universities from that occurring in the community. Mutational analysis and clinical trial participation are still infrequent. The starting dose of IM and SU remains 400mg and 50mg, respectively, for most pts. The use of adjuvant IM has increased after Jun 07, suggesting that prescribing habits may have been influenced by evolving study data in these pts. [Table: see text] [Table: see text]
KIT and PDGFRA mutations of gastrointestinal stromal tumor
Authors: Nishida T. , Takahashi T. , Nakajima K. , Tsujinaka T. , Hirota S. 
Published: August 2020

10560 Background: KIT or PDGFRA mutations are found in gastrointestinal stromal tumors (GIST) and are correlated with imatinib (IM) effects. Most reports studied only hot-spots of each gene using paraffin sections and extracted DNA. Here we examined full sequence of the genes using frozen section of GI mesenchymal tumors. Methods: Histologic Dx was done with HE and immunohistochemistory (IH). Using RNA obtained from fresh samples of serial 209 pts with GIST (n=174), myogenic (21), neurogenic tumors (11), or GI sarcoma (3), KIT or PDGFRA cDNA was amplified by RT-PCR and fully sequenced. Results: Tumors other than GIST showed no KIT-immunoreactivity, and had no-PCR-products of KIT (32) or wild type (WT) (3). PDGFRA of these tumors is WT. In IH, KIT was positive in 94% of GIST and CD34 in 84%. 7 GIST showed no-PCR-products of KIT, 8 WT of the genes, 142 KIT, or 17 PDGFRA mutations. Mutations are mutually exclusive. No-PCR was associated with IM-responded GIST (6 out of 15 IM-treated pts), in which KIT expression in IH was scarcely seen. WT are found in 3 juvenile GIST or 4 NF-1, and only 1 adult GIST showed WT. KIT mutations are found in exon (Ex) 9 (10 pts), Ex 11 (125), Ex 13 (3), or Ex 17 (4). All Ex 9 mutations are typical insertion mutations, found in small intestine (8) or colon (2), and associated with poor prognosis. Ex 13 and 17 mutations are missense and Ex 11 showed various type of mutations including deletion, insertion and missense mutations. These mutations distributed throughout GI tract. Deletion mutations in Ex 11 are associated with high recurrence rates (38/64 pts) and poor prognosis. 7 pts showed insertion mutation in the distal part of Ex 11. PDGFRA mutations found in Ex 12 (4 pts) or Ex18 (13) are missense mutations and associated with gastric location, epithelioid histology (10/16), low mitotic activity and relatively indolent clinical features. Conclusions: KIT mRNA and protein are sometimes depressed in IM-responded lesions, which causes difficulty in mutation research. Mutations in KIT and PDGFRA are specific for GIST and WT GIST is extremely rare in adult pts except NF-1. No significant financial relationships to disclose.
Unusual metastatic sites in gastrointestinal stromal tumor (GIST)
Authors: Bertulli R. , Fumagalli E. , Coco P. , Messina A. , Morosi C. , Dileo P. , Casali P. G. 
Published: August 2020

10566 Background: Metastases from GIST usually affect liver and peritoneum. Extra-abdominal metastases may occur in a limited proportion of pts. Only anecdotal reports describe rare metastatic sites (MS), to lungs, bone and distant soft tissues. Methods: We reviewed a group of 278 pts with advanced/metastatic GIST treated with tyrosine kinase inhibitors over a 7 years period with a view to unusual MS. Results: Thirteen pts (5%), M/F:10/3, median age 50 yrs (34–68 y), developed uncommon MS in a median time of 42 months from their primary diagnosis (0–120 m). Nine pts showed bone metastases along with peritoneal and/or hepatic lesions. All but four pts had also other unusual sites: 2 had pulmonary lesions, 1 had subcutaneous nodules, 1 had a lesion to parotid gland, and pt had lesions to spleen and lungs. In addition to these 9 pts with bone plus other metastases, other two pts had an histologically confirmed bone recurrence as the only metastatization site. In 4 pts, bone metastases were histologically confirmed. In the others, imaging and evidence of progression elsewhere were used as clinical criteria for diagnosis of bone metastatization. With regard to all pts, the most frequent bone sites were spine and pelvis, while ribs and femurs were rare. In four pts, radiation therapy was done, with pain relief. Nine pts died of disease progression after a median time of 17 months (3–40 m) from bone metastases diagnosis. Two pts with a single bone lesion are alive and still on imatinib treatment. Finally, one pt had mediastinal, retrorbital and brain lesions in addition to abdominal metastases, after therapy with imatinib and PTK787. Sunitinib was started with a partial response in all MS. This pt died due to massive bleeding during treatment. Last pt died in few months after parotid gland and subcutaneous metastases diagnosis. Conclusions: Imatinib has dramatically improved GIST prognosis. This is likely to result in a higher number of unusual MS, as observed in other tumors responding to medical therapies in their advanced stages. Rare MS in our series were bones, lungs, subcutaneous tissues, spleen, parotid gland and brain. These cases did not exceed 5% of all cases. [Table: see text]
Dermatofibrosarcoma protuberans (DFSP) in six patients with ADA-SCID
Authors: Kesserwan C. , Sokolic R. , Cowen E. , Garabedian E. , Pittaluga S. , Baird K. , López-Terrada D. , Issekutz A. , Bridge J. , Wayne A. , Candotti F. 
Published: August 2020

10570 Background: DFSP is a rare malignant skin tumor associated with a characteristic chromosomal translocation (t(17;22)(q22;q13)), resulting in the COL1A1-PDGFB fusion gene. We originally diagnosed DFSP in two patients affected with a rare form of severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID). The association of these two rare conditions has been described in two other cases, which prompted us to screen for DFSP systematically in patients with ADA-SCID. Methods: Eight ADA-SCID patients were evaluated with complete dermatological exam and skin biopsy. Molecular analysis (FISH and/or RT-PCR) and karyotype were performed when possible. Results: Six patients (age 2, 2, 5, 9, 12 and 22 years) were found to have DFSP. Five patients had between 4 and 12 multicentric lesions over the trunk and extremities. One patient had a single lesion. Most lesions appeared as 2–15 mm tan atrophic plaques. Nodular lesions were present in 3 patients. All lesions showed a spindle cell proliferation of the dermis, extending into the subcutaneous fat. A storiform pattern was only noticed in one adult patient. In all cases, CD34 expression was diffusely positive and FXIIIa was negative. Karyotype showed t(17;22)(q22;q13) in the 2 patients in whom it was performed. FISH was positive for COL1A1-PDGFB in 2 of 4 patients studied. RT-PCR showed the COL1A1-PDGFB fusion transcript in one case in which FISH was inconclusive.FISH and RT-PCR analyses are being conducted in 2 and 5 remaining cases, respectively. Conclusions: We describe a previously unrecognized association between multicentric DFSP and ADA-SCID. Multicentricity of DFSP to this extent has not previously been reported . We hypothesize that t(17;22)(q22;q13) may arise due to the known DNA repair defect in ADA-SCID and that the known dermal overexpression of PDGFB in this condition may favor the development of fibrotic tumors, as opposed to other skin cancers. Our observations can provide further insight into the pathogenesis of DFSP and should facilitate early diagnosis of DFSP in ADA-SCID. No significant financial relationships to disclose.
Multifocal myxoid liposarcoma: Metastasis or second primary? A molecular biological analysis
Authors: de Vreeze R. S. , de Jong D. , Nederlof P. M. , Ruijter H. J. , Boerrigter L. , Haas R. L. , van Coevorden F. 
Published: August 2020

10576 Background: The metastatic or second primary nature of multifocal myxoid/round cell liposarcoma (MRLS), defined as tumor presentation in at least two separate sites before manifestation in the lungs, is a matter of debate with essential clinical consequences. Characteristic genetic alteration for MRLS include the t(12;16)(q13;p11) or t(12;22)(q13;q12), of which various exon fusion transcripts are described with highly varying incidences, permitting use as a marker for clonality. Moreover, in solid tumors, analysis of loss of heterozygozity (LOH) has proven its value for clonality analysis. Methods: Fifteen patients with features fitting to the criteria of multifocal MRLS with 2–5 metachronous (n= 12) or synchronous (n=3) localizations were investigated. Using RT-PCR, the detailed molecular characteristics of FUS-CHOP and EWS-CHOP breakpoints were determined. LOH analysis at 12 loci on 11 chromosomes was used to further analyze clonal relationships and a dedicated algorithm for interpretation in MRLS was developed. Results: In all patients, tumor sites showed identical FUS-CHOP exon fusion products. In six patients, identical rare fusion transcripts were found, strongly supporting clonal relation. Nine patients had the common exon5-FUS/exon2-CHOP fusion transcript, of which two were identified as clonally related by LOH analysis. In all other patients, LOH analysis was highly suggestive of clonal relation and no evidence for interpretation of a second primary tumor was found. Conclusions: This study supports the metastatic nature of apparent multifocal MRLS. Therefore, in these cases the optimal treatment should be chosen as for this metastasis is preferred, in which case all treatment modalities can be considered. No significant financial relationships to disclose.
Activity of paclitaxel in radiation induced and other secondary angiosarcomas
Authors: Pink D. , Rahm J. , Schoeler D. , Schoenknecht T. M. , Reichardt P. 
Published: August 2020

10578 Background: Angiosarcomas (AS) represent 1–2% of adult soft tissue sarcomas and can arise anywhere in the body. Major predisposing factors are therapeutic radiation and chronic lymphedema. Paclitaxel has shown an exceptionally high activity of 75–89% in angiosarcomas of the face and scalp and to a lesser and less consitent degree of 15–58% in other disease locations. We report on a retrospectice single center experience with chemotherapy in 17 patients (pts.) with secondary angiosarcomas (SAS). Methods: Data from 17 patients were analysed including 15 females and 2 males with a median age of 63 years (range 18–80 years). 12 female patients suffered from angiosarcoma of the breast/thoracic wall following operation and radiation + chemotherapy of a primary breast cancer with an interval of a median of 6 years (range 2–15 years). 1 patient developed a SAS 6 years after resection and radiation of a liposarcoma in the limb. 4 patients were diagnosed with SAS following chronic lymphedema (3 Steward-Treves-Syndrome, interval 8, 9 and 38 years, repectively and 1 connatal lymphedema, interval 18 years). Results: 14/17 pts. received surgery as first treatment for SAS. 10 pts. developed a locoregional recurrence, 1 pt. distant metastases. 3 pts. remain free of disease. 3 pts. were diagnosed with locally advanced/metastatic SAS. Surgery for local recurrence after primary surgery resulted in further recurrence in all cases. All 14 patients with recurrent/metastatic disease were treated with chemotherapy. 12 pts. received paclitaxel at a dose of 175 mg/m2 q3w or 50–70 mg/m2 q1w as first- or second-line therapy. Responses were 8 PR with a median PFS of 6 months (range 3–23 months), and 1 SD (PFS 4 months) with a disease control rate of 75%. 2 pts. are too early to evaluate, 1 pt. showed PD. In only 3/11 cases, pts. responded to Anthracycline-based chemotherapy. Conclusions: Paclitaxel shows high activity in SAS, comparable to the results in face and scalp angiosarcomas and can be considered a standard treatment option. No significant financial relationships to disclose.
Correlation of FDG PET-CT with histologic response after neoadjuvant chemotherapy for soft tissue sarcomas
Authors: Cheng E. Y. , Froelich J. W. , Manivel J. C. , Weigel B. J. , Skubitz K. M. 
Published: August 2020

10583 Background: Surrogate endpoints for survival are needed to allow rapid assessment of new therapies without doing lengthy studies using a survival endpoint. Non-invasive assessment of treatment response is also needed to guide chemotherapy. FDG- PET-CT has potential for assessing response to treatment in sarcoma. This study's goal was to correlate FDG-PET-CT, along with standard CT, with histologic response after chemotherapy for high grade soft tissue sarcomas before resection. Methods: Patients with high grade soft tissue sarcomas > 5 cm were enrolled in a prospective clinical trial and given ifosfamide/doxorubicin before tumor excision. FDG-PET-CT was performed at baseline before treatment, after cycle 1, & just before surgery. Differences in both SUVmax (baseline to cycle 1 [B-1], baseline to surgery [B-3]) and CT criteria (RECIST 1 dimension [1D], RECIST 2D & Choi) were compared to histologic response (> or < 90%) upon excision. Results: 25 patients were enrolled and 4 had disease progression prior to completing all 3 PET-CT's yielding 21 evaluable cases. 5 patients had SUVmax change of <40%: 4/5 (80%) had histologic response < 90% & 1/5 (20%) had histologic response >90%. 16 patients had SUVmax change of >40%: 12/16 (75%) had histologic response >90% & 4/16 (25%) had histologic response <90%. A scatterplot of SUVmax change (baseline to surgery), & histologic response as continuous variables revealed a Spearman's correlation coefficient = 0.55 (p<0.01). Conclusions: A cutoff value of 40% reduction in SUVmax from baseline to surgery appeared to differentiate histologic responders. Using this to define PET response, a correlation between PET response, as well as RECIST 1D and 2D, and histologic response was observed. Additional patient follow-up & further study of FDG-PET-CT as a surrogate endpoint for histologic response and survival is warranted. [Table: see text] [Table: see text]