bluuebunny/crossref_metadata_2025 huggingface dataset:
Osteosarcoma of the jaw/craniofacial bones: Outcomes following multimodality treatment
Authors: Guadagnolo B. , Zagars G. K. , Raymond A. K. , Benjamin R. S. , Sturgis E. M.
Published: August 2020

10511

Purpose: To evaluate outcomes for patients with osteosarcoma of the jaw/craniofacial bones treated with surgery or combined modality therapy (CMT) consisting of surgery and radiation therapy (RT). Methods: Retrospective analysis was performed on data for 119 patients with osteosarcoma of jaw/craniofacial bones who underwent definitive resection with or without RT between 1960 and 2007. Median age was 33 years (range, 7–77 years). Ninety-two (77%) underwent surgery alone while 27 (23%) were treated with CMT. Median RT dose was 60 Gy (range, 50–66 Gy). Kaplan-Meier method was used to calculate the actuarial curves for survival (OS), disease-specific survival (DSS), local recurrence (LR), distant metastatic relapse (DM), and complication rates; and the log-rank statistic was used to test for significance of differences between curves. Results: Median follow-up was 5.8 years (range, 0.25 to 44.5 years). The OS rates at 5 and 10 years were 63% and 55%, respectively. Corresponding DSS rates were 67% and 61% respectively. Surgical margin status (positive/uncertain vs. negative) was adversely prognostic for OS (p=0.0001) and DSS (0.0001). Stratified analysis by margin status showed that CMT compared to surgery alone improved OS (80% vs. 31%, p=0.02) and DSS (80% vs. 35%, p=0.02) for patients with positive/uncertain margins. Multivariate analysis showed that CMT for patients with positive/uncertain margins improved OS (p<0.0001). Forty-four patients (40%) experience LR and 25 (21%) developed DM. There was no difference in DSS if relapse was isolated LR vs. DM (26% vs. 29%, respectively at 5 years, p=0.48) Local control (LC) rates were 59% and 57% at 5 and 10 years, respectively. The use of CMT vs. surgery alone significantly improved LC for patients with positive/uncertain margins (75% vs. 24%, p=0.006). The rate of surgical complications was 28% at 5 years. Rates of RT-associated complications were 40% and 47% at 5 and 10 years, respectively. Conclusions: RT in addition to surgery improves OS, DSS, and LC for patients with osteosarcoma of the jaw/craniofacial bones who have positive/uncertain surgical margins. Complication rates from surgery and RT are high, but LR is lethal in this disease. Morbidity risks must be weighed against the need to eradicate disease with primary local managmement.

No significant financial relationships to disclose.
Improving the detection of osteosarcoma tumor margins and metastasis using diagnostic nanoparticles
Authors: Dutour A. , Decouveleare A. , Josserand V. , Coll J. , Chotel F. , Rousseau R.
Published: August 2020

10512

Background: The aim of osteosarcoma resection is the complete removal of the primary malignant lesion with adequate margins taking into account tumor control and functional reconstruction. To date, no intraoperative method is available to assist surgeons in precisely delineating tumor extension in the adjacent normal tissues. Thus, preoperative imaging and extended surgical resection remains the gold standard. We developed fluorescent nanoparticles RAFT-cRGD4-ICG’ targeting αVβ3 integrins on tumor neovessels and demonstrated their capacity to reveal tumor and its margins when exposed to near infrared (NIR) light. Methods: We evaluated in an orthotopic metastatic osteosarcoma in rats the potential of RAFT-cRGD4-ICG’ detected intra operatively by NIR illumination to improve margin resection without compromising local tumor control. Controls consisted of pathological margin analysis of the resected tumor/metastasis comparing ICG’ fluorescence with conventional tissue coloration, and pre operative magnetic resonance imaging. Results: We showed a significantly lesser extent of healthy tissue resection after surgical excision when assessing tumor margin intra operatively using RAFT-cRGD4-ICG’ and NIR camera compared to preoperative imaging studies and post operative conventional pathology coloration (p<0.01). Importantly, intraoperative NIR illumination of lungs revealed more metastases than by intraoperative manual lung palpation (p<0.01). Conclusions: Our preclinical data confirm the potential of intraoperative imaging for improved primary tumor and lung metastasis excision. We are now generating clinical-grade RAFT-cRGD4-ICG’ to further evaluate this approach as a mean to improve functional outcome after surgical excision while maintaining tumor control in patients with relapsed/metastatic osteosarcoma.

No significant financial relationships to disclose.
Long-term follow-up (>20 years) for one of the original randomized prospective trials evaluating adjuvant chemotherapy in patients with high-grade operable osteosarcoma
Authors: Tap W. D. , Eilber F. R. , Rosen G. , Eckardt J. , Schwartz A. , Federman N. , Eilber F. C.
Published: August 2020

10514

Background: Neoadjuvant and adjuvant chemotherapy is now standard practice for patients who present with localized osteosarcoma. We present the long-term follow-up (>20years) for one of the original prospective randomized trials that compared adjuvant chemotherapy to no treatment in patients with high-grade operable osteosarcoma. Methods: The original study was performed at UCLA from 1981 to 1984. During this time, 59 patients with high-grade, operable, non-metastatic osteosarcoma were randomized to receive adjuvant chemotherapy (MSKCC T-10B protocol)(N=32; 24 men, 8 women, median age 15 yrs) vs. expectant management (N=27; 20 men, 7 women, median age 18 yrs). All patients received one neoadjuvant course of intra-arterial doxorubicin hydrochloride (90mg) and radiation (1750cGy). At a median follow-up of 2 years, there was a statistically significant improvement in both disease-free (55% vs. 20%, p<.01) and overall survival (80% vs. 48%, p<.01) for those who received immediate adjuvant chemotherapy. Upon recurrence, patients in the T-10B arm received salvage chemotherapy with doxorubicin hydrochloride and cisplatin while those in the expectant arm received the T-10B protocol. 27 years after the initiation of the trial, long-term follow-up was obtained on all patients. Results: Median follow-up time for survivors was 24 years. 18 patients in the adjuvant chemotherapy arm died of disease (DOD) while 14 have no evidence of disease (NED). 22 patients in the control arm DOD, 1 died of other causes and 4 have NED. The 5, 10, and 20 year disease specific survival (DSS) for the treatment arm (47%, 43%, 43% respectfully) was significantly better than that of the control arm (30%, 26%, 17% respectfully) (p=0.0254). Conclusions: Early administration of chemotherapy in patients with high-grade operable osteosarcoma provides a significant survival benefit that is maintained with long-term (>20 years) follow-up. These results support the idea that early systemic treatment offers the best opportunity to cure patients with this high-risk malignancy.

No significant financial relationships to disclose.
A European treatment protocol for bone sarcoma in patients older than 40 years
Authors: Ferrari S. , Smeland S. , Bielack S. , Comandone A. , Dileo P. , Picci P. , Sundby Hall K. , Eriksson M. , Honegger H. , Reichardt P.
Published: August 2020

10516

Background: EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.) is the first prospective multicenter international study for patients 41 - 65 years old with high-grade bone sarcoma. Methods: Patients with HG Osteosarcoma (OS), HG sarcoma NOS (S), Fibrosarcoma, MFH, Leiomyosarcoma, Dedifferentiated Chondrosarcoma (DCh) were included. Chemotherapy: Combinations of cisplatin/doxorubicin (CDP 100mg/m2/ADM 60mg/m2), ifosfamide/CDP(IFO 6g/m2/CDP 100mg/m2) and IFO/ADM (IFO 6g/m2/ADM 60mg/m2) were repeated three times (9 cycles). Surgery was planned after 3 cycles. Methotrexate (8g/m2) was postoperatively added in poor responders. Immediate surgery was allowed and 9 cycles with CDP, ADM, IFO were postoperatively given. Results: In December 2007, 140 patients were registered (median age 51 years). OS (51%), S (16%), and DCh (11%) were the more frequent histotypes. Synchronous metastases in 30 (21%) patients, central location of tumor in 45 (32%). Surgical complete remission (SCR) was achieved in 84% of patients, (localized 91%, metastatic 37%) without difference among the histology groups. One surgical-related and one chemotherapy-related death were reported. Grade 4 WBC and PLT incidence was 55% and 17%.Renal toxicity and peripheral neurotoxicity were reported in 16% and 20% of patients. With a median follow-up of 25 months (4–68) 3 year OS was 58% (95%CI 48–68%) [7% (95%CI 0–19%) without SCR]. In patients with SCR, 3 year OS and EFS were 46% (95%CI 9–83%) and 0% in case of synchronous metastases and 69% (95%CI58–80%) and 45% (95%CI33–57%) for localized patients; 50% (95%CI 29–71%) and 40% (95%CI 20–59%) for patients with central tumor, 73% (95%CI61–85%) and 44% (95%CI31–57%) for those with extremity tumor; 68% (95%CI 52–83%) and 46% (95%CI 32–54%) for OS, 64% (95%CI 42–85%) and 48% (95%CI 25–71%) for S, 48% (95%CI 13–82%) and 27% (95%CI 1–54%) for DCh. Conclusions: The protocol is feasible, but the chemotherapy-related toxicity is remarkable. Surgical complete remission is the main factor influencing survival. Central location and synchronous metastases are negative prognostic factors, but 50% 3-year OS can be achieved with aggressive local and systemic treatment. Osteosarcoma and high-grade sarcoma NOS benefit from chemotherapy more than patients with dedifferentiated chondrosarcoma.

No significant financial relationships to disclose.
Activity of cediranib, a highly potent and selective VEGF signaling inhibitor, in alveolar soft part sarcoma
Authors: Gardner K. , Judson I. , Leahy M. , Barquin E. , Marotti M. , Collins B. , Young H. , Scurr M.
Published: August 2020

10523

Background: Alveolar soft part sarcoma (ASPS) is a rare entity making up <1% of soft tissue sarcomas (STS). It is typically indolent but with a high incidence of metastatic disease, usually to lungs, but also to sites such as the brain. Response to conventional chemotherapy is poor (overall response rates are approximately 7% [Reichardt P et al,Eur J Cancer.2003;39:1511–1516]). This is a preliminary report of the activity of cediranib, a highly potent and selective VEGF signaling inhibitor, in this disease. Methods: Efficacy and tolerability data were collected for seven patients with ASPS. One patient was treated in a phase II randomized trial of cediranib ± prophylactic antihypertensive therapy and six were treated in a Phase II study in patients with imatinib-refractory gastrointestinal stromal tumors or other STS. Cediranib was administered orally, once daily at an initial dose of 45 mg. Response was assessed using RECIST (Response Evaluation Criteria in Solid Tumors). Results: Median age at diagnosis was 39 years (range: 26–49). All patients had pulmonary metastases and two had additional sites of disease (brain, bone, intra-abdominal) at study entry. Adverse events were generally CTC grade 1–2 and manageable. The most common adverse events were fatigue (n = 6), diarrhea (n = 5), stomatitis (n = 4), headache (n = 3), and hypertension (n = 3). Four patients had a best response of partial response, two patients had a confirmed reduction in maximum tumor diameter of ≥10% and <30% and one patient experienced stable disease. As of November 2008, three patients remain on treatment with a median (range) time on study of 61 weeks (49–74). Time to progression and progression-free survival will be calculated and available at the time of presentation. Conclusions: These data demonstrate the promising preliminary activity and safety of chronic administration of cediranib in this disease. Further investigation is warranted, particularly as there is no effective systemic treatment for patients with advanced ASPS.

[Table: see text]
A phase II study of intravenous (IV) wild-type reovirus (Reolysin) in the treatment of patients with bone and soft tissue sarcomas metastatic to the lung
Authors: Mita A. C. , Sankhala K. , Sarantopoulos J. , Carmona J. , Okuno S. , Goel S. , Chugh R. , Coffey M. C. , Mettinger K. , Mita M. M.
Published: August 2020

10524

Background: Reolysin is a Dearing strain, naturally occurring, ubiquitous human reovirus. The PKR (double stranded RNA-activated protein kinase) is inhibited and therefore the virus replicates specifically in transformed cells possessing an activated Ras pathway producing lysis. In vitro and in vivo studies with Reolysin in sarcoma cell lines revealed significant antitumor activity. Methods: This phase II open-label, single agent study was designed to characterize the efficacy and safety of Reolysin given IV every 28 days in patients (pts) with bone or soft tissue sarcoma with lung metastasis using a Simon two-stage design. 38 pts were accrued to the first stage. If 1 or more pts experience clinical benefit (prolonged SD > 6 months, partial or complete response) up to 52 pts could be accrued. The agent will be considered active if 3 or more responses or prolonged SD are observed. Results: Since July 2007, 43 pts age 19–76 (median 49) were enrolled (20 female) and received a total of 141 cycles (range 1–18). All pts had performance status 1 (29 pts) or 0 (14 pts). 38 pts received prior chemotherapy, radiotherapy, biological agents or combinations for their metastatic disease, 15 pts received more than 3 chemotherapy regimens. The sarcoma subtypes included: synovial sarcoma (13 pts), osteosarcoma (7 pts), leiomyosarcoma (7 pts), MFH (5 pts), Ewing/PNET (1 pt), chordoma (1 pt), others (9 pts). Side effects were mild to moderate (grade 1–2) and included constitutional symptoms fever, chills, fatigue. Two pts experienced respiratory side effects (cough and dyspnea) and 2 pts had diarrhea. Hematological side effects included grade 2–3 neutropenia (6 pts) and grade 2 thrombocytopenia (2 pts). One patient experienced grade 2 AST elevation. 33 pts are evaluable for response to date: 14 pts (42%) had SD for 2+ months including 5 pts having SD for more than 6 months. Conclusions: Utilization of single agent reovirus for treatment of sarcoma is a novel and unique therapeutic approach to date. Reolysin is well tolerated and shows promise for the treatment of metastatic sarcoma. Primary efficacy goals have been met. Accrual is ongoing to a total of 52 pts.

[Table: see text]
Final results of a FNCLCC French Sarcoma Group multicenter randomized phase II study of gemcitabine (G) versus gemcitabine and docetaxel (G+D) in patients with metastatic or relapsed leiomyosarcoma (LMS)
Authors: Pautier P. , Bui Nguyen B. , Penel N. , Piperno-Neumann S. , Delcambre-Lair C. , Bompas E. , Collin F. , Rey A. , Jimenez M. , Duffaud F.
Published: August 2020

10527

Background: An objective response rate (RR) of 8% and 17% with G and G+D were respectively reported in metastatic soft tissue sarcomas (Maki, J Clin Oncol. 2007). We previously reported a 5% RR in 41 evaluable patients (pts) with ‘non uterus‘ LMS randomized to each arm of this randomized phase II study (Duffaud, ASCO. 2008). We present here the results of G vs G+D in uterine and all LMS. Methods: Patients had histologically proven metastatic or unresectable LMS, one prior anthracycline- based regimen, age ≥18, measurable disease (RECIST), PS ≤ 2. Treatment was G 1,000 mg/m2(over 100 minutes, d1+d8+d15) q28 days (d) or G 900 mg/m2(over 90 min, d1+d8) and docetaxel 100 mg/m2 (over 60 min, d8) q21 days; in the G+D arm, pts received lenograstim d9–15, 25% dose reductions were employed for prior pelvic radiation. The primary endpoint was the objective RR (CR+PR), evaluated every 2 cycles. Stratification was by primary tumor location (uterus vs. non-uterus). The Simon method was used: for “uterus” study, 20 pts per arm for a 74% probability of selecting the arm with a real RR of 50%, expected baseline RR was 40%; for the “non-uterus” study, 20 pts per arm for a 92% probability of selecting the arm with a real RR of 40%, expected baseline RR was 20%. Results: From 02/06 to 12/08, 44 pts were enrolled in the “non-uterus” study, 40 pts in the “uterus” study. Currently 76/82 pts are evaluable for response (41/44 in the “non uterus” and 35/38 in the “uterus” study) and 80/84 for toxicity. In the uterus group the median age is 57 (range 41–80), 24 pts received prior pelvic radiotherapy, the median number of cycles was 5 (range 0–8) and dose received/dose planned (%) were 69% in G arm, 88% of G and 86% of D in G+D arm. No differences in toxicity were observed between both LMS locations: in the G arm, toxicity was moderate except for one pulmonary gr4; in the G+D arm one toxic death was related to gr5 thrombocytopenia and there were 2 non-haemathologic gr4 toxicities; 11 pts stopped for intolerable toxicity (3 in G and 8 in G+D arm) and 1 pt for hypersensitivity (G+D arm). Conclusions: Final tumor response for uterine LMS and updated toxicity and PFS data for all the LMS will be presented during the meeting.

[Table: see text]
Myelodysplastic syndromes developing after imatinib therapy for GIST
Authors: Spadaro P. , Ingemi M. , Pitini V. , Arrigo C. , Soto Parra H.
Published: August 2020

10532

Background: Imatinib mesylate 400 mg a day is the standard treatment for patients (pts.) who have advanced or metastatic gastrointestinal stromal tumor (GIST) even if different kit and PDGFRA mutations have a marked impact on the outcome of pts.; briefly, pts. with exon 9 mutations fared worse than those who had exon 11 mutations and both types of pts. did better than those with wild type genotype. Previously, we had detected clonal chromosomal abnormalities in the bone marrow of GIST pts. who developed a myelodysplastic syndrome during treatment with imatinib, so we performed a systematic study in a series of male and female GIST pts. during treatment with imatinib. Methods: Between January 2007 and December 2008, bone marrow samples for morphologic analysis, FISH and classical cytogenetics were obtained from 49 pts. (30 male; 19 female, mean age 62) with unresectable or metastatic GIST before and during treatment with 400 mg/d of imatinib. For pts. with progressive disease (15 pts.) or exon 9 mutant disease (5 pts.), imatinib 800 mg a day was scheduled. All pathologic material was reviewed to identify pts. with MDS or AML according to the WHO classification. Interphase and metaphase preparations were done according to the standard protocol. Results: At the time of analyses, all pts. were evaluable. Ten patients experienced anemia of grade 3–4 while five pts. developed granulocytopenia of grade 3–4. Eight pts. acquired cytogenetic chromosomal abnormalities in their bone marrow. A trisomy 8 was detectable in seven pts. even if, curiously, in four of these pts. this come and went on repeated sampling without any apparent clinical effect, three pts. developed an MDS (two refractory cytopenias with multilineage dysplasia, and one refractory cytopenia with multilineage dysplasia and ringed sideroblast). One patient developed a RAEB-1 with monosomy 7 which rapidly transformed into AML. Conclusions: During therapy with imatinib some pts. with GIST developed chromosomal abnormalities. Although, these occurrences are rare, the findings highlight the need for close monitoring of pts. with GIST treated with imatinib.

No significant financial relationships to disclose.
Efficacy of a genetically modified Salmonella typhymurium against metastatic osteosarcoma in an orthotopic mouse model
Authors: Hoffman R. M. , Zhao M. , Hayashi K.
Published: August 2020

10543

Background: We have previously developed a genetically-modified strain of S. typhimurium, selected for tumor targeting and therapy in vivo. Normal tissue is cleared of these bacteria even in immunodeficient athymic mice with no apparent side effects. Methods: In this study, the tumor-targeting strain of S. typhimurium, termed A1-R, was administered i.v. to nude mice which have primary bone tumor and lung metastasis. Primary bone tumor was obtained by orthotopic intratibial injection of 5 × 105143B-RFP (red fluorescent protein) human osteosarcoma cells. One group of mice was treated with A1-R and another group was used a as control. A1-R (5 × 107 colony-forming units) was injected in the tail vein three times on weekly basis. On day 28, lung samples were excised and observed with the Olympus OV100 Small Animal Imaging System. Results: The size of the primary tumor and RFP intensity of lung metastasis were measured. Primary bone tumor size (fluorescence area [mm2]) was 232 ± 70 in the untreated group and 95 ± 23 in the treated group (P<0.05). RFP intensity of the lung metastasis was 3 ± 1.5 × 106in the untreated group and 0.42 ± 0.33 × 106 in the treated group (P<0.05). No toxicity was observed in the treated mice. Conclusions: Therefore, bacterial treatment was effective for both primary bone tumor and lung metastasis. Treatment with the tumor-targeting but non-toxic mutant of S. typhimuriumis a promising approach to therapy of metastatic osteosarcoma.

No significant financial relationships to disclose.
A prognostic score at diagnosis for Ewing tumor patients with metastatic disease at extrapulmonary sites
Authors: Ladenstein R. , Pötschger U. , Le Deley M. , Whelan J. , Paulussen M. , Oberlin O. , van der Berg H. , Dirksen U. , Craft A. , Jürgens H.
Published: August 2020

10544

Background: To assess prognostic factors at diagnosis in prospectively treated patients with primary extra-pulmonary metastatic Ewing tumors (EPM-ET) of the EURO-E.W.I.N.G. 99 Study. Methods: From 1999 to 2005, 281 patients were enrolled. Median age was 16.2 years (0.4–49). Primary site was extremity in 84 patients and axial in 197 (115 pelvic sites), with a tumor volume >200ml in 171 patients. Treatment consisted of 6 VIDE cycles, one VAI/VAC cycle, local treatment (surgery and/or radiotherapy), and high-dose busulfan-melphalan followed by peripheral stem cell transplantation (HDT/SCT). Results: After a median follow up of 3.8 years, event-free survival (EFS) and overall survival (OS) at 3 years for all 281 patients were 27%±3% and 34%±4%. Six VIDE cycles were completed by 250 patients (89%); 169 (60%) received HDT/SCT. Cox regression analyses demonstrated increased risk for patients with more than two bone metastatic sites (hazard ratio: HR 2.0), a primary tumor volume >200ml (HR 1.8), bone marrow metastases (HR 1.6), age >14 years (HR 1.6), and additional lung metastases (HR 1.5). A risk score based on these HR identified three risk groups with EFS rates of 50% for scores <_3 (82 patients), 25% for scores >3 to <5 (102 patients), and 10% for scores >_5 (70 patients), p< 0.0001. Conclusions: A proportion of EPM-ET patients may survive with intensive multimodal therapy. Age, tumor volume, and extent of metastatic spread are relevant risk factors. A score based on these factors identifies EPMD-ET patients with a more favorable outlook at diagnosis and may facilitate risk adapted treatment approaches.

No significant financial relationships to disclose.
High-dose chemotherapy with autologous stem cell transplantation for relapsed Ewing's sarcoma
Authors: Palmerini E. , Brach Del Prever A. , Fagioli F. , Luksch R. , Prete A. , Tamburini A. , Abate M. E. , Picci P. , Ferrari S. , Tienghi A.
Published: August 2020

10545

Background: Nearly 30–40% of patients with newly diagnosed, non-metastatic Ewing's Sarcoma (EWS) relapse. Post-relapse survival (PRS) in EWS is very poor, with less than 15–20% alive 5-years after recurrence. The role of high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is under investigation in metastatic and high risk localized EWS patients. In order to improve PRS, we employed HDCT with ASCT in EWS patients at 1st relapse. Methods: All non-metastatic EWS patients treated in Italian Sarcoma Group centers who relapsed between 1999 and June 2008 were offered HDCT (busulfan 4 mg/kg × 4 days orally and melphalan 140 mg/m2) with ASCT whenever possible (no previous HDCT; stable or responding disease after standard dose chemotherapy; adequate peripheral blood stem cells harvest). Results: 72 EWS patients experienced disease recurrence. Fifty (62%) were male. Twenty-eight (39%) of patients had previously received HDCT. Median relapse free interval (RFI) was 16 months (2.8–64). Pattern of relapse was: lung metastases in 20 (28%) patients, bone metastases in 12 (16%), local recurrence in 11 (15%) and multiple sites in 29 (40%). Treatment at 1st relapse was: standard dose chemotherapy in 31 (43%) patients; HDCT followed by ASCT in 24 (33%); palliative treatment in 12 (17%) and surgery only in 5 (7%). Three patients died of treatment-related toxicity. With a median follow-up of 24 months (1–64), the 3-year post-relapse survival (PRS) was 21% (95%CI 7–35). 3-year PRS was better for patients with a lung only relapse [48%, (95%CI 21–74)] and a RFI > 2 years [51%, (95%CI 27–76)]. 3-year PRS was 33% (95%CI 13–54) for patients treated with HDCT and 22% (95%CI 6–39) for those receiving standard dose chemotherapy. A significant (P 0.02) advantage was observed in the subgroup of patients with a shorter RFI treated with HDCT [3-year PRS 29% (95%CI 5–52)] compared to those treated with standard dose chemotherapy [3-years PRS 13%, (95%CI 2–29)]. Conclusions: Pattern of recurrence and RFI are the main factors influencing PRS in EWS. The use of HDCT with ASCT in recurrent EWS is investigational. Patients with shorter RFI could more likely benefit from HDCT.

No significant financial relationships to disclose.
Long-term results with combined treatment in adult localized extraskeletal Ewing's sarcoma (ES): A retrospective analysis of 51 patients (pts) from a single referral center
Authors: Dileo P. , Bertulli R. , Piovesan C. , Marrari A. , Puma E. , Spreafico C. , Gronchi A. , Olmi P. , Gandola L. , Casali P. G.
Published: August 2020

10548

Background: After the first description in 1975, only small series of adult extraskeletal ES have been reported. In general, adulthood is claimed to be an adverse prognostic factor, while the meaning of extraskeletal origin is less established. Methods: We retrospectively reviewed adult pts with extraskeletal, localized ES, undergoing medical therapy between 1988 and 2004, who were included in the dataset of the current Adult Sarcoma Medical Unit at Istituto Nazionale Tumori, Milano, Italy, which serves as a reference center for adult soft tissue sarcoma. Fifty-one pts were treated with a combined approach, including chemotherapy, surgery when appropriate, and radiation therapy. Overall, 27/51 pts were male, and age ranged from 16 to 63 years. Site of primary lesions was: thorax 14 (27%), limbs 18 (35%), paravertebral region 5 (10%), pelvis 4 (8%), head&neck 3 (6%), superficial trunk 6 (12%), other 1 (2%). Seven pts presented with locally advanced disease. Chemotherapy regimens included: vincristine (V), ifosfamide (I), epirubicin (E)/adriamycin (A), dacarbazine (D), actinomycinD (ActD), cisplatin (C), etoposide (Et). 35/51 pts (68%) underwent preoperative chemotherapy: 30 pts received IVE × 4–7 cycles; 5 pts received VAI alternating with IEt × 9 cycles. 42/51 pts underwent surgery; 38/51 pts received radiation therapy. Results: Response rate to induction chemotherapy including antracicline, ifosfamide + etoposide was 83%. Of these pts, 9 showed a complete response (CR), 17 a partial response (PR), 3 a minor response (MR), 3 stable disease (SD), and 3 progressive disease (PD). Overall, DFS at 10 years (y) was 55%. Pts with limb, head&neck, or superficial trunk lesions had a better outcome compared to those with other primary sites (DFS at 10y is 71% vs 33%). Conclusions: In this series of adult pts with extraskeletal ES, response rate and DFS were comparable to those of ES of bone in conventional series. The primary site may identify a subset of pts with worse outcome and prognosis, for whom more intensive treatments could be investigated.

No significant financial relationships to disclose.
Outcome of patients with advanced GIST achieving a complete remission (CR) with imatinib (IM) before interruption: Pooled analysis of two consecutive prospective randomizations of the French Sarcoma Group BFR14 phase III trial
Authors: Chevreau C. , Ray-Coquart I. , Bui B. , Adenis A. , Rios M. , Duffaud F. , Darnis S. , Le Cesne A. , Moneron C. , Blay J.
Published: August 2020

10549

Background: Patients (pts) experiencing a major response under IM treatment seem to have a better outcome than others (Cioffi, ASCO 08). IM interruption in responding patients after 1 and 3 yrs of treatment results in a high risk of rapid progression after a few months. The influence of pattern of response on PFS before IM discontinuation is unknown. Methods: Since June 2002, 415 pts were included in this trial. Fifty-eight, 50 and 12 (ongoing) non progressive pts at 1, 3 and 5 yrs respectively were randomly offered to continue (C arm) or interrupt (I arm) IM. Sixty-four pts were randomized in the I arm, 32, 25 and 7 after 1, 3 and 5 yrs of IM treatment respectively. Time to progression (TTP) of pts achieving a CR or a major PR (residual tumor < 10mm) before IM interruption was compared to outcome of pts experiencing others patterns of response. Results: Twenty-three pts achieving a CR or a major PR (36%) before randomization in the I arm, 9 after 1 yr, 10 after 3 yrs and 4 after 5 yrs of IM treatment. As of December 2008, 15 relapses were observed in the CR group (65%) versus 36 in the other cohort of pts (90%). The median TTP were 10.5 months (IC95%: 9–16 months) for the CR group and 6.1 months (IC95%: 4–9.2 months) for the non CR group (p=0.058). The median TTP were 9.4 months for the CR group vs 6 months for pts randomized after 1 yr of treatment, 12.3 months versus 5.7 months for pts randomized after 3 yrs of treatment respectively. One third of pts achieving a CR before randomization in the I arm was free of disease in December 2008. Conclusions: A CR achieved under IM is not a prerequisite for a prolonged disease-free survival in advanced GIST after 1 or 3 yrs of treatment. Despite a trend for a favourable outcome, prognosis of pts with a CR or a major PR is similar to those achieving a PR or a disease stabilisation. A selected group of advanced GIST pts in CR could be cured with IM alone. New radiological assessments or response critera have to be implemented in order to define a real CR.

[Table: see text]
Neoadjuvant imatinib and organ preservation in locally advanced gastrointestinal stromal tumors (GIST)
Authors: Hohenberger P. , Oladeji O. , Licht T. , Dimitrakopoulou-Strauss A. , Jakob J. , Pink D. , Schwarzbach M. , Ströbel P. , Reichardt P. , Wardelmann E.
Published: August 2020

10550

Background: We assessed the outcome of patients with locally advanced gastrointestinal stromal tumors (GIST) undergoing preoperative therapy with imatinib. Methods: 36 patients with biopsy proven GIST (23 f, 13 m, median age 58 (27–85) yrs, 31 primary tumors, 5 local recurrences) of the esophagus/EGJ (n=5), stomach (n=17), duodenum (n=2), small bowel (n=3), or rectum (n=9) were treated with imatinib 400mg/d for 6 mos. preop. Six pts had been found unresectable at exploratory lap. and no pt. had signs of metastases on CT/MRI and/or FDG-PET. Average tumor size was 10.5 cm (4–28 cm). According to Consensus two tumors were low risk, 11 intermediate, and 23 were high risk for aggressive behaviour. 33 pts were symptomatic. Extent of surgery, local outcome, morbidity and response to therapy were analyzed; median follow-up is 22 mos. Results: Median treatment duration was 11 mos. (range 2–31 mos). Successful dose adjustment for exon 9 mutation to 800 mg imatinib/d was used in two pts. 33 pts. completed the treatment schedule, two died from unrelated disease, another one had to be operated for tumor rupture. Of the remaining 33, median tumor size shrank to 55 mm. Two elderly patients refused surgery and continued with the drug; one pt. was found still unresectable. Complete tumor removal was possible in 28 pts without operative mortality, but two pts showed previously undetected peritoneal spread (R2 resection). Histologically, one pCR and 11 near CR/good PRs were found. The extent of resection found 5 of 6 inoperable pts now resectable and in 21/25 pts a less extensive procedure could be performed in comparison to recommendations by previous tumor boards (segmental gastric resection for gastrectomy, avoidance of pancreatectomy, transanal resection instead of colo-anal anastomosis). Two local recurrences were detected at 31 and 44 mos. postop. Conclusions: Locoregionally advanced GIST can be treated successfully with upfront imatinib at 400mg/ (800 mg in exon 9 mutation). Substantial tumor shrinkage facilitates radical but conservative surgery and results in organ-preservation in the overwhelming majority of patients. PET monitoring proved very helpful and added to CT/MRI evaluation. Long-term results on survival and metastatic spread have to be awaited.

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Neoadjuvant imatinib in patients with locally advanced GIST in the prospective BFR14 trial
Authors: Cassier P. A. , Blesius A. A. , Perol D. , Ray-Coquard I. , Adenis A. , Bui B. , Bertucci F. , Rios M. , Le Cesne A. , Blay J.
Published: August 2020

10551

Background: The role of surgery in the management of patients with advanced gastrointestinal stromal tumors (GIST) in the era of imatinib mesylate (IM) remains unknown. We sought to assess the outcome of patients with locally advanced primary GIST tumors without metastases treated with IM in the neoadjuvant setting within the prospective BFR14 phase III trial. Methods: The data base of the BFR14 trial was searched for patients with locally advanced disease and no metastases. Patients with recurrent disease were excluded. Results: Twenty five patients (9 females, 16 males) met these criteria. Twenty patients were PS 0 or 1, primary tumor sites were: small intestine (n=7), peritoneum (n=7), rectum (n=4), stomach (n=4), esophagus (n=2), and pelvis (n=1). Nine of the 25 patients underwent surgical resection of the primary tumor after a median of 7.3 (range 3.4–12.1) months of treatment with IM. There was a significant improvement in progression-free survival (PFS) for patient who underwent surgical resection versus those who did not: median PFS: 28.7 month vs 12.9 months respectively (p=0.0463) this benefit did not however translate into a significant benefit in overall survival (OS), although the trend favoured the resected group: median OS median not reached vs 29.4 months (p=0.0677). Conclusions: Surgery may increase progression-free survival in patients with locally advanced GIST who become resectable following treatment with IM.

[Table: see text]
Correlation between spiral CT and PET in patients with advanced GIST refractory to high-dose imatinib: A GEIS study
Authors: Fuster D. , Sierra A. , Ayuso J. R. , Poveda A. , Cubedo R. , Casado A. , Martínez-Trufero J. , López-Pousa A. , Garcia Del Muro X. , Maurel J.
Published: August 2020

10553

Background: Small changes in tumor size or density on computed tomography (CT) are sensitive and specific methods to assess response of GISTs and correlates well with positron emission tomography with 18F-Fluorodeoxyglucose (FDG-PET) in untreated GIST patients (pts). Despite of it, there is inconsistent prospective data in imatinib (IM) refractory disease. Methods: This multicenter phase I-II study prospectively evaluated 26 pts with metastatic high-dose IM refractory GISTs treated with doxorubicin 15 - 20 mg/m2/weekly per 4 cycles, followed by IM maintanance (400mg p.o.qd). CT and FDG-PET were performed at baseline and after 2 months of therapy. Response rate was assessed by RECIST criteria by Principal Investigator (PI). CT and FDG-PET (EORTC criteria) were reviewed by two experts in abdominal CT (AR) and one expert on Nuclear Medicine in one Institution. Results: Tumor density measurements were not assessed on CT because some studies were not available in DICOM format and different tube currents were used. There were significant lower number of lesions identified by PI (n=73; median 2, range 1–6) than AR (n=122; median 5, range 1–10). Twenty-eight out of 122 lesions identified by CT did not demonstrate significant uptake in FDG-PET at baseline (upon 800mg/day of IM treatment) on FDG-PET. Mean baseline tumor size on CT was 5.9cm (ranging from 0.9 to 28cm), and mean baseline SUVmax on FDG-PET was 7.2 (ranging from 1.9 to 26.4). Nine patients responded on FDG-PET compared with 2 pts and 5 pts with RECIST or modified RECIST criteria (decrease in tumor size more than 10%), respectively. The sensitivity for RECIST or modified RECIST in identifying PET responders was 22% and 55%, showing a 100% of specificity by both methods. Good responders on FDG-PET at 2 months had significantly longer progression free survival (264 days) than non-responders (64 days) (P=0.01). Conclusions: FDG-PET is sensitive and specific to assess response of GISTs pts refractory to high-dose IM. If the prognostic value of FDG-PET can be confirmed should be employed in future studies of pts with refractory GIST.

No significant financial relationships to disclose.
The natural history of imatinib-naive GIST: A retrospective analysis of 929 cases with long-term follow-up
Authors: Dei Tos A. P. , Rossi S. , Messerini L. , Bearzi I. , Mazzoleni G. , Capella C. , Arrigoni G. , Sonzogni A. , Amore P. , Casali P. G.
Published: August 2020

10555

Background: GIST represent a rare form of malignancy and one of best paradigms of molecularly targeted therapy. While the natural history of GIST following treatment with tyrosine kinase inhibitors is relatively well known, most information on imatinib naïve GIST are drawn form either small series or larger studies with possible referral bias. Methods: 1,021 GIST diagnosed between 1980 and 2000 were retrieved from the archives of 35 Departments of Pathology throughout Italy. Pathologic and clinical data were collected. All cases were centrally reviewed and stratified according to NIH 2002 and NCCN 2008 risk classifications. The prognostic meaning of a large set of morphologic and clinical parameters were evaluated by uni- and multi-variate analysis. Informed consent was obtained from all living patients. Results: 92 cases were excluded as non-GIST. Mean and median age were 63 and 65 years. Females were 52%. Disease status at diagnosis was localized in 767 and metastatic in 111 cases. 516 cases were gastric, 229 ileal/jejunal, 26 duodenal, 22 colonic, 28 rectal, and 25 peritoneal/retroperitoneal. NIH 2002 risk classification was available in 917 cases: 121 (13%) very low, 247 (27%) low, 201 (22%) moderate and 348 (38%) high risk. NCCN 2008 risk classification was available in 892 patients. Metastatic sites included liver (5%), peritoneum (10%), lymph-node (1%), skin and soft tissue (0.5%), and lungs (0.2%). Median follow-up was 75 months (range 1–323). Median survival was 88 months. 62% patients died (ED in 46%). Mitotic activity, tumor size and anatomic site correlated with overall survival at multivariate analysis. Striking differences were observed for groups with < 5 mitoses/50HPF, 5 and 10, 10 and 30, and >30. Non gastric GIST exhibit a significant poorer outcome. R2 surgery represents a negative prognostic factor. Conclusions: Mitotic rate has a deep prognostic impact if split in more than two intervals. Setting only two categories may be a limitation of existing prognostic classifications, although the mitotic count is affected by reproducibility issues. Survival curves according to the two main prognostic classifications will be shown.

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Integrative analysis of gene expression profiling and high-resolution genomic copy number in gastrointestinal stromal tumor (GIST)
Authors: Nannini M. , Astolfi A. , Pantaleo M. A. , Di Battista M. , Formica S. , Santini D. , Saponara M. , Maleddu A. , Lolli C. , Martinelli G. , Biasco G.
Published: August 2020

10559

Background: Besides mutually exclusive cKIT or PDGFRA mutations, sequential accumulation of other genetic events may be involved in GISTs development and progression, but very few data is still available. Methods: Fresh tissues specimens of GISTs from 10 patients (9 gastric and 1 intestinal) were collected and used for RNA and DNA extraction, labeled and hybridized to HG-U133Plus 2.0 and SNP array 6.0, respectively (Affymetrix). Six patients had exon 9 or exon 11 c-KIT mutation, two PDGFRA mutation, and other two wild-type disease. Gene expression data were quantified by the RMA algorithm, filtered and analysed with supervised techniques (SAM algorithm). Genomic copy number data were analysed with Partek Genomic Suite software against a reference set of 90 Ceu HapMap individuals using a segmentation algorithm with stringent p-value cutoff. Results: Almost all patients exhibited both macroscopic cytogenetic alterations and cryptic microdeletions or amplifications by SNP-array copy number data analysis. The most frequent chromosomal alterations were: 14q complete or partial deletion (7/10), chromosome 19 monosomy (3/10), 22q and 1p deletion (2/10), chromosome 5 trisomy (2/10). The minimal overlapping region ranged from 14q22.3 to 14q32.33, covering a region including 320 genes. The integration of copy number and gene expression data showed that at least 40% of the genes inside the 14q deleted region were significantly downregulated (FDR<10%) in comparison to 14q-diploid patients. In this region several tumor suppressor genes involved in cell cycle checkpoint control (SNW1, CHES1, PPP2R5E), apoptosis induction (PPM1A, MOAP1, PPP1R13B), DNA damage response (MLH3, TDP1), WNT/Notch pathway inhibition (NUMB, DACT1, SEL1L) are located. Conclusions: A wide spectrum of genetic aberrations in GISTs may occur besides c-KIT and PDGFRA mutations. The most frequent is 14q deletion that leads to a significant downregulation of many putative tumor suppressor genes. Combining gene expression and high resolution genomic copy number analysis could identify new haploinsufficient tumor suppressor genes involved in GISTs pathogenesis and tumor progression.

No significant financial relationships to disclose.
Protein kinase C θ (PKCθ) expression as a potential diagnostic marker for KIT-negative GIST
Authors: Braggio D. A. , Romano S. , Small I. A. , Soares F. A. , Ferreira C. G. , Guimarães D. P.
Published: August 2020

10561

Background: Currently, GIST is differentiated from other mesenchymal tumors based on morphologic characteristics and immunohistochemical detection of KIT. Nevertheless, 5% of tumors with clinicopathologic features of GIST lack KIT expression (KIT-negative GIST). A precise diagnosis of GIST is crucial due to the therapeutic efficacy of tyrosine kinase inhibitors. Our goal was to characterize mutational status of tyrosine kinase receptors (KIT and PDGFRA) and to evaluate the value of PKCθ as a diagnostic marker in KIT-negative GISTs. Methods: KIT-negative GISTs (n=22) were analyzed in a retrospective manner. As controls, we included KIT-positive GISTs (n=46), mesenchymal non-GIST tumors (n=28) and KIT-positive non-GIST tumors (n=32). PKCθ and diagnostic markers including CD34, S-100 and desmin were analyzed by immunohistochemistry using a tissue microarray. The χ2test was used to compare the presence of PKCθ among the tumors included. Further, PDGFRA gene (exons 12, 14, 18) and KIT gene (exons 9, 11) were examined in KIT-negative GISTs (n=14) by sequencing. Results: PKCθ expression was detected in 63.6% (14/22) of KIT-negative GISTs and this was significantly higher than the frequency of non-GIST tumors (23.3%; 14/60) (p=0.001). PKCθ was detected in 83.7% of KIT-positive GISTs. We found no significant difference between expression rates for PKCθ in KIT-negative and KIT positive GISTs (p=0.069). However, expression rates for PKCθ was higher among all GISTs, regardless KIT expression, when compared to non-GISTs tumors (p<0.001). In addition, among KIT-negative GISTs, CD34 was detected in 59.1% and desmin in 13.6%. None expressed S-100. PDGFRA mutations were found in 5/14 (35.7%) (exon 18, 33.3%; exon 12, 33.3%; exon 14, 16.7%). KIT mutation was found in 1/14 (16.7%; exon 9) tumors analyzed. Conclusions: In contrast to previous reports, there was no predominance of PDGFRA exon 18 mutations in our KIT-negative GISTs. Further, mutation frequency was lower in these tumors than those reported for KIT-positive GISTs. The diagnostic and pathogenic relevance of both PDGFRA and KIT mutations should be better explored. In this study, PKCθ could differentiate GIST, regardless KIT expression, from non-GIST tumors and emerged as a potential diagnostic biomarker for KIT-negative GISTs.

No significant financial relationships to disclose.
The potential role of IGF1r in young adult patients with gastroinetstinal stromal tumor (GIST)
Authors: Pantaleo M. , Astolfi A. , Di Battista M. , Paterini P. , Santini D. , Catena F. , Nannini M. , Saponara M. , Lolli C. , Maleddu A. , Biasco G.
Published: August 2020

10562

Background: The insulin-like growth factor 1 receptor (IGF1r) is a tyrosine kinase receptor that plays a key role in the growth of normal tissues. The aberration of IGF system has been found in many cancers. Some interesting results about IGF1r were published on GISTs. However, until now the real role on the pathogenesis of this disease and its clinical implications still needs to be defined. Methods: We studied IGF1r in 8 patients affected by gastric GIST. Seven patients underwent surgery at diagnosis, whereas one patient was operated after imatinib and sunitinib treatment. Two patients were young (< 30 years old), and other patients ranged between 54 and 85 years. IGF1r was studied as gene expression profiling performed with Affymetrix GeneChip HG-U133 Plus 2.0 arrays, as genomic copy number with SNP array analysis Affymetrix Genome Wide Human SNP 6.0 arrays, and with western blotting (WB) usinganti-IGF-IRβ (Santa Cruz Biotechnology). Results: The unsupervised analysis of gene expression profiling of our patients merged with a data set from a gastric GIST identified two groups with different regulation of IGF1r (FDR threshold to 0.2%). In particular, IGF1r was up-regulated in the two youngest patients (28 and 30 years-old). The SNPs array analysis gene copy number showed that none of the patients bore IGF1r amplification. The quantitative analysis of protein level by WB again showed that only the two youngest patients had an over-expression of IGF1r. In all the other patients the WB analysis was negative. Conclusions: These results suggest that IGF1r seems to be a novel signalling pathway other than KIT and PDGFRA in a subset of GISTs. The young adult patients had a strongly different molecular background in comparison to the other older ones. The correlation between IGF1r and mutational status of KIT and PDGFRA, clinical outcome, treatments responsiveness as well as its role as potential target deserves to be further investigated.

No significant financial relationships to disclose.