bluuebunny/crossref_metadata_2025 huggingface dataset:
Denosumab for the treatment of giant cell tumor (GCT) of bone: Final results from a proof-of-concept, phase II study
Authors: Thomas D. M. , Chawla S. , Skubitz K. , Staddon A. , Henshaw R. , Blay J. , Smith J. , Ye Z. , Roudier M. , Jun S.
Published: August 2020

10510

Background: GCT of bone is a primary osteolytic bone tumor with low metastatic potential that is associated with significant skeletal morbidity. GCT is rich in stromal cells that express RANKL, a key mediator of osteoclast activation. In this open-label, study, we investigated whether denosumab, a fully human monoclonal antibody against RANKL, could have a potential therapeutic effect on giant cell histology for patients with GCT. Methods: In this single-arm study, 37 patients with measurable or unresectable GCT received denosumab 120 mg subcutaneously once monthly with loading doses on days 8 and 15 of month 1. The primary endpoint was the proportion of patients with a tumor response (≥90% elimination of giant cells or no radiographic progression of the target lesion) at week 25 as assessed by histology and CT or MRI. A sample size of 35 patients was planned. All 37 enrolled patients were evaluated for safety; 35 were eligible for efficacy evaluation (2 had insufficient histology or radiology data). Results: Thirty of 35 patients (86%; 95% CI 70%-95%) had a tumor response: 20 of 20 by histology and 10 of 15 by radiology. Of 31 patients with data for assessments of clinical benefit, 26 (84%%; 95% CI 66%-95%) reported reduced pain or improvement in functional status. Bone repair was reported in 9 patients (29%; 95% CI 14%-48%). Suppression of the bone turnover markers urinary N-telopeptide and serum C-telopeptide was seen as early as 28 days after the first dose and sustained for the duration of the study. Adverse events (AEs) were reported in 33 patients (89%). One death due to surgical complications (not treatment-related) occurred on-study. No patient experienced treatment-related serious AEs or developed anti-denosumab antibodies. Conclusions: In this study, 86% of patients with measurable or unresectable GCT experienced a tumor response with denosumab. Further clinical trials of denosumab as a new therapy for GCT are warranted.

[Table: see text]
Evaluation of the safety and efficacy of pathotropic nanoparticles bearing a dominant negative cyclin G1 construct for chemoresistant osteosarcoma and other sarcomas: Phase I, II, and III studies
Authors: Chawla S. P. , Chua V. S. , Fernandez L. , Quon D. , Saralou A. , Blackwelder W. C. , Hall F. L. , Gordon E. M.
Published: August 2020

10513

Background: (1) To evaluate the safety/anti-tumor potential of intravenous (i.v.) Rexin-G in chemotherapy-resistant sarcoma (Phase I/II), and (2) to confirm the efficacy/safety of i.v. Rexin-G in chemotherapy-resistant osteosarcoma (Phase II). Methods: Twenty patients in the Phase I/II study and 22 patients in the Phase II study received 1–2 × 10e11 cfu Rexin-G i.v., 2–3 times a week for 4 weeks. Treatment was continued if the patient had < Grade 1 toxicity. Results: Treatment-related adverse events included chills (n=1), presyncope (n=1), photophobia (n=1) of Grade 1 severity, and fatigue (n=4) of Grade 1–2 severity. In the Phase I/II sarcoma study, 3/6 patients had stable disease at Dose Level 0, median progression free survival (PFS) was 5 weeks, and overall survival (OS) was 14 weeks, while 10/14 patients had stable disease at Dose Level I-II, median PFS was 16 weeks and median OS was 34 weeks. Cox regression analysis showed a dose-response relationship between PFS/OS and Rexin-G dosage (p = 0.02 and 0.005, respectively). The Table below shows the results for evaluable patients (n=17) in the Phase II study for osteosarcoma. Kaplan-Meier analysis shows a dose-response relationship between overall survival and Rexin-G dosage in the combined Phase I/II sarcoma and Phase II osteosarcoma studies (p = 0.02; n=42). Two patients achieved surgical remissions which are sustained for >26 weeks. Conclusions: These studies suggest that (i) intravenous Rexin-G is safe and well-tolerated, and (ii) Rexin-G controls tumor growth and prolongs progression-free survival and overall survival in a dose-dependent manner in chemotherapy-resistant osteosarcoma and sarcoma. [Table: see text]

[Table: see text]
Survival in high-grade osteosarcoma: Improvement in a 21-year period at a single institution
Authors: Picci P. , Mercuri M. , Ferrari S. , Alberghini M. , Briccoli A. , Ferrari C. , Pignotti E. , Bacci G.
Published: August 2020

10515

Background: After the introduction of pre-operative chemotherapy in the early 1980s, treatment of osteosarcoma had not advantages from new drugs/modalities. Aim of this work is to analyze improvements in overall survival for patients treated over 21 years (1982–2002), with a 5-year minimum follow-up, in the largest series from a single institute ever reported, including all high grade osteosarcomas, despite histology varieties, age, site, and stage. Data are also analyzed in subgroups to define patients who benefited most. Methods: All diagnoses of high grade osteosarcoma were included. Of the 1,656 consecutive cases observed, 198 patients were excluded (41 consultation only, 129 low-grade varieties and 28 lost to follow-up). Within 1,456 included patients, 1,032 had characteristics to be enrolled in conventional clinical trials (classic histology, age < 41, localized and extremity disease). Results: Considering all patients, with a median follow-up of 12 years (5–25 yrs), 754 (51.7%) are alive, 613 continuously disease-free. Survival at 5, 10, and 15 years is 57%, 52%, and 51% respectively. Patients candidates for clinical trials have a survival rate of 68%, 64%, and 61% respectively. Survival for the other patients is 30%, 25%, and 24% respectively. Jointpoint Statistical Analysis at real 5-year follow-up shows a yearly statistically significant improvement in survival of 1.31% (95% CI 0.5–2.1), from 51% for patients treated in 1982 to 68% for those treated in 2002. Within the subgroups, survival statistically improved in patients candidates to protocols, those who relapsed, or presented with metastatic disease at diagnosis, or had axial tumors. Surgery was also analyzed, with a statistical significant increase in the percentage of limb salvage procedures without an increased rate of local recurrences. Conclusions: Despite the lack of new drugs for osteosarcoma, survival has statistically improved, especially for those patients with the worst outcome. Aggressive treatments are therefore recommended for all patients including those with poor prognosis.

No significant financial relationships to disclose.
Cardiac cormorbidities in women with metastatic breast cancer treated with doxorubicin-based and non-doxorubicin-based chemotherapy
Authors: Watson G. J. , Kugel M. R. , Shih H. , Tak Piech C. , McKenzie R. S.
Published: August 2020

1052

Background: Observational data are sparse regarding cardiac comorbidities in patients with metastatic breast cancer (MBC) newly initiated on chemotherapy. As some MBC treatments are associated with cardiac toxicity, such information would be useful in guiding treatment decisions. The objective of this analysis was to understand the frequency of cardiac comorbidities in MBC patients prior to chemotherapy initiation based on the Medicare 5% standard analytical file (SAF). Methods: The Medicare 5% SAF was used to investigate claims for women with breast neoplasm and > 1 distant metastatic site (based on ICD-9 diagnosis codes) that subsequently received chemotherapy (based on claims with a chemotherapy J code). Cardiac comorbidities [hypertension (HTN), coronary artery disease (CAD), myocardial function (MI), and congestive heart failure (CHF)] prior to initial chemotherapy were reported as non-mutually exclusive categories. The index quarter was based on chemotherapy initiation that occurred between 7/2001 and 12/2006. Patients were categorized based on receipt of non doxorubicin-based chemotherapy (non-DOX) vs DOX-based chemotherapy. Results: The study included 2,587 women with MBC that received cytotoxic chemotherapy subsequent to the diagnosis of MBC. The mean age was higher in the non-DOX group. Both groups reported a significant proportion of patients with cardiac comorbidities prior to chemotherapy, with greater proportions reported in the non-DOX group (table). Conclusions: Cardiac comorbidities were commonly reported in women with MBC prior to chemotherapy. Such information is useful to health care professionals when considering potential interventions for patients with MBC.

[Table: see text]

[Table: see text]
Combined analysis of two phase II trials of imatinib in advanced dermatofibrosarcoma protuberans (DFSP)
Authors: Schuetze S. , Rutkowski P. , Van Glabbeke M. M. , Rankin C. , Rubin B. P. , Lazar A. , Debiec-Rychter M. , Gelderblom H. , Hohenberger P. , van Oosterom A. T.
Published: August 2020

10520

Background: DFSP is an infiltrative, low-grade, dermal tumor with propensity to recur locally and occasionally metastasize. Translocation between COL1A1 on chromosome 17 and PDGFB on chromosome 22, which results in transcriptional upregulation of PDGFB, is characteristic of DFSP. Autocrine/paracrine PDGFB-mediated activation of PDGFRB drives DFSP proliferation. Two distinct phase II trials of imatinib in patients (pts) with locally advanced or metastatic DFSP were conducted, 1 in North America (SWOG) with confirmed objective response rate and 1 in Europe (EORTC) with 14 week progression-free rate as primary end-points. Methods: Pts with locally advanced or metastatic DFSP were eligible. In the EORTC trial confirmation of t(17;22) by FISH was prospectively required for participation, imatinib was started at 400mg bid, surgery was undertaken after 14 weeks if feasible and response was assessed at 14 weeks. Full accrual was to be 44 pts in one step. In the SWOG trial confirmation of t(17;22) by RT-PCR was performed after enrollment, imatinib was started at 400mg daily and response was assessed every 8 weeks. Full accrual was to be 40 pts in 2 steps. Results: 16 pts were enrolled in EORTC and 8 pts enrolled in SWOG trial. The studies were closed early because of slow accrual and regulatory approval of imatinib in DFSP. Pts age ranged from 24 to 70 yrs, DFSP was located on head/neck, trunk and extremity in 7, 11 and 6 pts, respectively, ranged in size from 1.2–49 cm and was classic, pigmented and fibrosarcomatous DFSP in 13, 1 and 7 pts, respectively. One patient did not have DFSP on central review, lacked t(17;22) and thus was ineligible. Metastases were present in 7 pts involving lung in 6 pts. 11 pts (46%) had partial response, 9 pts had stable disease and 4 pts had progressive disease as best response. Median time to progression was 1.7 yrs. Response and progression-free at 1 yr rates were similar between studies. Imatinib was stopped in 11 pts for progression, 1 pt for toxicity, 2 pts resected free of gross disease and 1 pt withdrew. Conclusions: Imatinib is active in DFSP harboring t(17;22) with an objective response rate approaching 50% and is active in fibrosarcomatous DFSP. Response rates and time to progression did not appear to differ between pts taking 400 mg daily versus 400 mg bid.

[Table: see text]
Role of trabectedin (T) in the management of advanced uterine leiomyosarcoma (U-LM)
Authors: Grosso F. , Sanfilippo R. , Jones R. L. , Collini P. , Morosi C. , Raspagliesi F. , Tercero J. C. , D'Incalci M. , Judson I. R. , Casali P. G.
Published: August 2020

10530

Background: To explore the clinical impact of T in U-LM. T has been approved in Europe for second line treatment of advanced soft tissue sarcomas (STS). Efficacy is well established in liposarcoma and leiomyosarcoma. U-LMs display peculiar clinical and genetic features compared to other STS. These differences may be responsible for the sensitivity of this subtype to therapy, thus justifying an evaluation of the activity of T in a relatively homogeneous series of U-LM patients. Methods: From April 2000, 56 patients (pts) with advanced disease, previously exposed to a median of 3 chemotherapy lines (range 1–5), received T within an expanded access programme at two European referral institutions for sarcoma. The clinical records were reviewed focusing on response and treatment outcome. Two pts were excluded from the analysis having received only 1 course of T. Median age was 56 yrs (range 29–73), median number of metastatic sites was 2 (range 1–4), the most frequent metastatic site was lung (88%), 24 patients had a local relapse. Results: A total of 252 courses were delivered (median 3, IQR2–6) and 36% of patients received more than 5 courses of T. Fifty-two patients were evaluable for response. A partial response was observed in 11 patients and stable disease in 15, for a PR rate of 21% and a tumor control rate of 50%. The median progression-free survival was 3.6 months (CI95% 2.6–6.7), with 41% of patients free from progression at 6 months. Conclusions: These results compare favourably with other systemic treatments in advanced U-LMS and support their sensitivity to T. This should prompt further studies to prospectively evaluate the efficacy of T in U-LMS and elucidate possible biological predictive factors (e.g. DNA repair protein expression).

[Table: see text]
Clival chordoma molecular subtypes and clinical behavior
Authors: Park D. M. , Prevedello D. M. , Gardner P. , Lee D. , Henry S. , Snyderman C. , Carrau R. , Horbinski C. , Hamilton R. L. , Kassam A. B.
Published: August 2020

10538

Background: Chordoma is a primary bone cancer of the axial skeleton with predilection for local invasion. Primary treatment modalities consist of surgery and radiation therapy with limited role for chemotherapy. Because patients with chordoma exhibit heterogeneous clinical history and response to therapy, we investigated potential markers predictive of clinical behavior. Methods: This study analyzed 35 clival chordoma specimens with documented immunohistochemistry (IHC) staining for Ki-67 proliferation index from 29 patients. Detailed additional pathologic studies were performed prospectively on 12 consecutive patients. This consisted of the following: IHC for brachyury, cytokeratin, p53, and epidermal growth factor receptor (EGFR); fluorescent in situ hybridization (FISH) analysis for EGFR amplification and presence of 1p36, 9p21, and 19q13 loci; polymerase chain reaction based loss of heterozygosity analysis (LOH) of 1p, 9p, 10q, 17p, and 19p loci. Results: All confirmed chordoma specimens were positive for brachyury and negative for amplification of EGFR. Increase in Ki-67 index was associated with recurrence in 5 of 6 cases. Out of the 12 patients with detailed molecular pathologic studies, 5 had loss of 1p, 2 had deletion of 9p21 (p16), and 2 had loss of 10q (PTEN). The loss of 1p and 9p were detected via both FISH and LOH analyses. 3 of the 12 patients’ tumor specimens showed a Ki-67 index of greater than 10%; the remaining specimens were less than 5%. All 3 patients with high Ki-67 index had loss of either 9p (p16) or 10q (PTEN). The tumor specimen from these 3 patients also exhibited enhanced in vitro propagation. Conclusions: Subtyping of clival chordomas based on molecular phenotype may provide prognostic information. The prospective nature of this study in concert with assessment of residual disease after surgery may allow for identification of distinct subpopulations of patients at greater risk of disease recurrence for consideration of adjuvant therapy. The correlative in vitro study will provide an opportunity to evaluate targeted therapies customized to individual molecular subgroups.

No significant financial relationships to disclose.
Prediction of tumor necrosis fraction using combined volumetric and metabolic indices derived from FDG-PET/CT in osteosarcoma patients receiving neoadjuvant chemotherapy
Authors: Park B. , Park H. , Min H. , Kang H. , Im H. , Kim S.
Published: August 2020

10539

Background: Maximum standardized uptake values (mSUV) might not reliably reflect the chemotherapy response in osteosarcoma especially when treatment response within tumors is heterogenous. The purpose of this study was to compare the usefulnesses of various FDG PET/CT indices for predicting tumor response to neoadjuvant chemotherapy and to identify the most appropriate one in osteosarcoma. Methods: Thirteen patients with primary osteosarcoma (age 14±2.9 yrs, ranged 10–19 yrs) that had undergone FDG PET/CT scans before and after neoadjuvant chemotherapy were enrolled. The authors measured mSUV, metabolic tumor volumes (MTV), and total lesion glycolysis (TLG) in each PET/CT scan. MTVs were calculated by summing voxels with SUV greater than 1.5, 2, 2.5 and 3.0, and with % mSUV greater than 20%, 25%, 30% and 35%. Histopathologic necrosis fractions were compared with the above-mentioned PET/CT parameters and their pre- to post-treatment ratios (MTV ratio, rMTV; mSUV ratio, rSUV; TLG ratio, rTLG). Results: Histopathologic necrosis fractions ranged from 3% to 99% (62.2%±37.7%). rMTV and rTLG values were found to be correlated with histopathologic necrosis fractions (R2=0.45–0.65, p<0.05), whereas, mSUV and MR image volumes (MRV), both before and after treatment, rSUV values, and rMRV values were not. With regard to rMTV and rTLG values obtained using various MTV criteria, the highest correlation was observed for a rTLG value of 2.5 mg/ml (R2=0.65, p=0.001). Five patients were classified as responders and 8 as poor-responders to neoadjuvant chemotherapy defined as those with chemotherapy-induced necrosis fractions of ≥90% and <90%, respectively. The rSUVs of responders and poor-responders were not different, but rMTV and rTLG values showed a trend toward difference, although statistically not significant (p=0.110 and 0.106, respectively). The sensitivity and specificity of rTLG were 100% and 62.5%, respectively, at an SUV cut-off of 0.13. Conclusions: In our osteosarcoma patient population, TLG and MTV, which represent combined metabolic and volumetric indices, were found to predict tumor response better than pre- or post-treatment mSUV or rSUV.

No significant financial relationships to disclose.
Role of MRI in osteosarcoma for chemotherapy response evaluation and prediction: Correlation with histological necrosis
Authors: Bajpai J. , Gamnagatti S. , Sreenivas V. , Phulia R. , Sharma M. , Khan S. A. , Rastogi S. , Safaya R. , Malhotra A. , Bakhshi S.
Published: August 2020

10540

Background:Histologic necrosis (HN), the current gold standard for response evaluation in osteosarcoma (OS), is accessible only after neoadjuvant chemotherapy (NACT) and may get affected by confounding factors. Thus, it would be useful to have surrogate markers of response evaluation and prognostication using magnetic resonance imaging (MRI) to individualize therapy. Method:Thirty-one treatment naïve OS patients received 3 cycles of NACT followed by surgery during 2006–2008. All patients underwent baseline and post-NACT conventional(C), diffusion-weighted (DW) and dynamic contrast enhanced (DCE) MRI. Taking ‘Huvos grading’ (good response >/= 90% HN) as reference standard, various parameters of MRI were compared with it. Tumor considered as ellipsoidal; volume (V), average tumor plane (ATP) and relative(r)-ATP (ATP/body surface area) were calculated using standard formula for ellipse. Receiver operating characteristic curves were generated to assess the best threshold and predictability. Sensitivity and specificity were calculated along with 95% confidence limits. After deriving thresholds for each parameter in univariable analysis, multivariable analysis was carried out. Results: Both pre-and post NACT, absolute and relative size parameters were well correlated with HN, though post NACT change in parameters did not. Apparent diffusion coefficient (ADC), either pre-and post NACT measurements or change following chemotherapy were not correlating well. However, on adjusting for volume, significant correlation was found. Thus, we could derive a new parameter diffusion per unit volume (DV= ADC /V). Change in shape of time intensity curve did not show significant correlation. Conclusions: In OS, NACT response can be assessed and predicted by conventional and DW- MRI early in the disease course which correlates well with HN. DV seems to be a sensitive substitute for response evaluation. For DCE-MRI, more sophisticated models in future studies might be useful. [Table: see text]

No significant financial relationships to disclose.
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 (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]
Clinical features, treatment, and outcome in 108 patients with localized, high-grade synovial sarcoma (SS)
Authors: Gupta A. A. , Al-Hussaini H. , Yu C. , Griffin A. , Tsung V. , Stephens D. , Blackstein M. , Hogg D. , Ferguson P. , Wunder J.
Published: August 2020

10584

Background: There remains ongoing controversy in the treatment of localized SS, with no clear consensus on routine use of chemotherapy. Methods: Between 1986 and 2007, 93 adult (AP) and 15 pediatric (PP) patients were diagnosed with high grade, localized SS at 2 centres in Toronto. Clinical records and pathology reports were examined. Survival distribution functions were estimated by Kaplan-meier and compared using Log-rank test. Results: Median age for AP and PP was 36 (range 14–76) and 14 (range 0.4–18) years, respectively. Sixty-six (61%) patients had large tumours (> 5 cm), 7 (6.5%) had neuro-vascular invasion, and 10 (9.3%) had bone invasion. 76 (82%) AP and 8 (53%) PP received radiation (RT). 16 (17%) AP and 13 (87%) PP received chemotherapy. All patients underwent definitive surgery with gross total resection; 9 patients (8 PP) had positive margins. Some patients received neoadjuvant chemotherapy, and response was evaluable in 15 patients: 10 SD, 2 PR, 1 CR, 1 PD. Relapse occurred in 32 patients: 28 distant, 3 local only, 1 local + distant. With a median follow-up of 5.6 years, EFS and OS was 72 ± 4.6% and 82 ± 4.2%, respectively and was similar for AP and PP. Patients with tumours > 5 cm had significantly worse EFS (63 ± 6.5%) compared to patients with small tumours (88 ± 5.4%, p=0.02), as did those with bone invasion (47 ± 18 vs.75 ± 4.9, p=0.05). The effect of chemotherapy was assessed in the entire cohort. Of 29 who received chemotherapy, 9 (31%) relapsed, and of 79 who did not receive chemotherapy, 23 (29%) relapsed. In patients with tumours >5 cm, relapse occurred in 41% (7/17) of those who received chemotherapy compared to 37% (18/49) in those that received no chemotherapy. Conclusions: Patients with SS < 5 cm have an excellent chance of cure with surgery and RT. Large tumours and those with evidence of bone invasion have a poor outlook. It is unlikely that chemotherapy contributes to an improvement in survival in SS.

No significant financial relationships to disclose.
Clinical outcomes of systemic therapy for patients with desmoids
Authors: Camargo V. P. , Maki R. G.
Published: August 2020

10585

Background: Desmoids are rare, slow growing, histologically benign tumors without metastatic potential. Methods: We examined outcomes of patients with desmoid tumors receiving systemic therapy at a single institution, to provide a basis for examination of newer agents. Retrospective chart review of 682 patients with desmoid tumors (1982–2006) from a prospectively collected sarcoma database. The activity of NSAIDs was not addressed. Patients without measurable disease, those receiving therapy we could not document, and those receiving prophylactic therapy were excluded. Results: A total of 70 patients received 163 lines of well-documented systemic therapy starting before 1/1/2007. Nine patients died, 7 of progressive disease/surgical complications, and two with Gardner syndrome-related malignancies. Demographics: 45 females (65%), median age 30 (range 15–75), 21 with Gardner syndrome (30%), median follow-up 68 months, and median of 2 lines of therapy (1–7). Intra-abdominal primary location was most common (29/70=41%). Tamoxifen, doxorubicin (including Caelyx/Doxil), imatinib, and methotrexate combinations were most commonly used. Five partial responses were observed with anthracyclines (43 courses administered), 2 with hormonal therapy (32 courses), and 1 with imatinib (35 courses), for 8 PR s. Conclusions: Anthracycline-containing regimens, hormonal therapy, and tyrosine kinase inhibitors have modest activity against desmoid tumors. The choice of therapy for these morbid and potentially fatal tumors should balance the efficacy of treatments with their short- and long-term side effects.

No significant financial relationships to disclose.