bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant therapy for localized gastrointestinal stromal tumors (GISTs): A propensity score weighted analysis.
Authors: Marqueen Kathryn E. , Moshier Erin , Buckstein Michael , Ang Celina 
Published: May 2020

e23516 Background: Retrospective and single-arm prospective studies have reported clinical benefit associated with receipt of neoadjuvant imatinib for GISTs. In the absence of randomized phase III data, the impact of neoadjuvant systemic therapy (NAT) on survival, in comparison to upfront resection, remains unknown. Methods: We identified N = 14,402 patients with complete clinical, demographic, treatment and pathologic data within the National Cancer Database (2004-2016) who underwent resection of localized GIST of the stomach, esophagus, small bowel, and colorectum, with or without ≥3 months of NAT. Inverse probability of treatment weighting (IPTW) was used to adjust for covariable imbalance among treatment groups, with the propensity score estimated by logistic regression. The effect of NAT on overall survival was estimated with a weighted time-dependent Cox proportional hazards model. A weighted logistic regression was used to estimate the effect of NAT on 90-day postoperative mortality and R0 resection. Results: 759 (5.3%) patients received NAT followed by resection, compared to 13,643 (94.7%) who underwent upfront resection. Median length of NAT was 6.3 months. 53% of NAT patients were male vs. 49% of UR patients, 68% vs. 66% had primary gastric GIST, and 73% vs 49% were high risk. Patients receiving NAT had larger tumors (p < 0.001) and higher mitotic index (p = 0.003). There was a significant survival benefit associated with receipt of NAT (table). 90-day postoperative mortality rate was 3/759 (0.4%) among NAT patients vs. 307/13,643 (2.3%) UR patients. Receipt of NAT was significantly associated with lower odds of 90-day postoperative mortality (table). Of the 13,562 patients with information on margin status, the R0 resection rate was 635/716 (88.7%) for the neoadjuvant group vs. 11,823/12,846 (92%), with no significant difference between treatment groups (table). Conclusions: After adjustment for imbalance in prognostic and demographic factors, this analysis demonstrates that receipt of NAT for localized GIST is associated with a modest overall survival benefit. Although NAT patients had higher risk features, NAT was associated with a lower risk of 90-day postoperative mortality, with no difference in likelihood of achieving an R0 resection. [Table: see text]
High frequency of c-KIT genetic variants in exons 9, 11, 13 and 17 and PDGFRA in exon 18 in gastric GIST tumors.
Authors: Omelchuk Ekaterina P. , Gvaldin Dmitry Yu. , Timoshkina Natalya N. , Vladimirova Liubov Yu , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Kharagezov Dmitry A. , Dashkov Andrey V. , Kaymakchi Dmitry O. , Poluektov Sergey I. , Kolesnikov Vladimir E. , Dontsov Vladimir A. , Tolmakh Roman E. , Ilchenko Sergei A. , Stateshny Oleg N. , Petrov Dmitry S. , Grechkin Fedor N. , Oganyan Nairi B. , Kolesnikov Valeriy V. , Mirzoyan Ellada 
Published: May 2020

e23525 Background: Gastrointestinal stromal tumors (GIST) are rare malignant mesenchymal neoplasms of the gastrointestinal tract, the diagnosis and treatment of which is associated with the presence of mutations in the c-KIT and PDGFRA genes. Purpose of this study was molecular genetic genotyping of GIST according to clinically significant exons of the c-KIT and PDGFRA genes. Methods: The study included patients with an immunohistochemically confirmed diagnosis of GIST who underwent treatment in the RRIO, Rostov-on-Don, for the period 2018-2019 (n = 20, median age 63.5 years, men/women–10 people each, gastric tumors). DNA was isolated from FFPE tissue using the GeneJET FFPE DNA Purification Kit, USA. The presence of mutations in exons 9, 11, 13 and 17 of c-KIT and exon 18 of PDGFRA was detected by Sanger sequencing. Results: Activating mutations in exon c-KIT were detected in 10 ps, including one substitution p.V560E and 4 deletions – p.V559_E561del, p.M552_V555delMYEV, p.W557_V559 > F and p.W557_V559 > C. These mutations cause sensitivity to imatinib. Pathogenic mutations were detected in PDGFRA exon 18: an activating deletion p.I843_D846delIMHD (2 ps) and a substitution p.D842Y, which determines imatinib resistance (2 ps). Thus, 20% of GIST cases are promising for obtaining avapritinib, the first FDA approved drug in 2020 for patients with GIST with a mutation in PDGFRA exon 18. In addition, neutral genetic variants were revealed: in 17 exon c-KIT in 16 patients, benign rs1008658, in PDGFRA 18 exon – rs3830355 (3 ps) and silent mutation p.V824V (3 ps). Conclusions: Genotyping of c-KIT and PDGFRA identified 12 types of clinically significant mutations and, in 80% of cases, the carriage of benign polymorphisms and / or SNPs of unknown clinical significance. As a result, 70% of patients from the South of Russia with GIST may be sensitive to treatment with imatinib and/or avapritinib.
Clinical behavior and treatment outcomes in angiosarcoma: A 10-year retrospective review.
Authors: Espejo Freire Andrea P. , Costa Philippos , Alasfour Maryam , Akgun Yamac , Rosenberg Andrew , Diaz-Perez Julio , Kwon Deukwoo , Subhawong Ty , Arshad Junaid , Trent Jonathan C. 
Published: May 2020

e23555 Background: Angiosarcoma (AS) is a highly aggressive sarcoma. Five-year overall survival (OS) with local disease is only about 60% despite multimodality treatment. In advanced disease, responses to cytotoxic chemotherapy are common; however, median OS is only 3-12 mos. Targeted therapies (TT) have not been consistently effective. Early results for immune checkpoint inhibitors (ICI) are promising but their efficacy has not been compared to chemotherapy. Here we present the outcome of AS patients by systemic regimen and multimodality approach. Methods: We identified 39 patients with pathologically confirmed AS treated at Sylvester Comprehensive Cancer Center and Jackson Memorial Hospital from 2009 to 2019. Clinical characteristics, treatment, responses and survival were analized. We calculated OS using Kaplan-Meier method and statistical significance with Log-Rank Test and Cox regression to estimate hazard ratio (HR) and 95% confidence interval. Progression-free survival (PFS) was analyzed for different regimens in the palliative setting using same approach as for OS. Results: In our cohort, median follow-up is 2.3 years (95% CI = 2 to 3.3), 48% were women and median age at diagnosis was 63 (range 13-89). At presentation, 16 pts (41%) had local disease and 23 advanced or metastatic (59%). By location, 13 pts (33%) had primary cutaneous AS, 12 pts (31%) visceral AS, 5 pts (13%) primary breast AS, 2 (5%) extremity AS and 7 (18%) radiation associated AS. Multimodality treatment was used in 29 pts (74%). OS in the entire cohort at 3 years was 49% (95% CI = 28 to 67%). OS between local disease was (N = 16) and in advanced disease (N = 23) was not statistically significant (p = 0.485; HR = 1.1 [95% CI = 0.4 to 3.3]). In the neoadjuvant setting, objective response rates trended to favor doxorubicin-based regimen (DBR) over taxane-based regimens (TBR) (80% vs. 40%) but were not statistically different (p = 0.519). In the advanced setting, PFS for DBR was 3.9 mo (95% CI 1.1 to 4.9 mo), 5.9 mo for TBR (95% CI 2.3 to 10.9 mo), 6.1 mo for ICI (95% CI not estimable), and 2.4 mo for targeted therapy (TT) (95% CI 0.8 to 8.8 mo), most common TT agent was pazopanib (71% of TT agents). Conclusions: AS is highly aggressive and most patients with local presentation will relapse translating in similar OS to the advanced cohort. No significant activity was seen for TT. In the advanced setting, chemotherapy with TBR appears slightly superior to DBR. ICIs resulted in similar if not superior PFS despite its use in a later line setting. Studies incorporating ICIs into earlier lines of therapy are warranted.
The prognostic impact of unplanned excision in primary STS of the extremities and trunk wall: Is re-excision always mandatory?
Authors: Danieli Maria , Barretta Francesco , Fiore Marco , Radaelli Stefano , Callegaro Dario , Barisella Marta , Sangalli Claudia , Stacchiotti Silvia , Palassini Elena , Miceli Rosalba , Casali Paolo Giovanni , Gronchi Alessandro 
Published: May 2020

e23557 Background: To investigate the outcome of patients affected by soft tissue sarcomas (STS) of the extremities and trunk wall who underwent unplanned excision (UE) and the prognostic impact of microscopic residual tumor at re-excision. Methods: All consecutive patients affected by primary STS of the extremity and trunk wall operated at Fondazione IRCCS Istituto Nazionale dei Tumori from Jan 1997 to Dec 2017 were included and divided in 3 groups: patients primarily resected at our institution (group A), patients undergoing re-excision after macroscopically complete UE (group B) and patients undergoing completion resection after macroscopically incomplete UE (group C). Inverse probability treatment weighted overall survival (OS), crude cumulative incidence of local relapse (CCI-LR) and of distant metastasis (CCI-DM) were calculated and compared. Histological subgroup curves were drawn and multivariable models were performed in group B. Results: 1965 patients were identified; 1079, 679 and 189 in group A, B and C respectively. Median follow-up was 84.41 months. 7-yrs OS was 0.74, 0.84 and 0.81 (p < .001) for group A, B and C respectively; 7-yrs CCI-LR and DM were 0.05 and 0.25, 0.12 and 0.16, 0.14 and 0.29 (p < .001 for both) for group A, B and C respectively. In group B, microscopic residual tumor was present in 26.9% of the surgical specimens, but this figure varied broadly among the histologic subtypes (being the lowest in Solitary Fibrous Tumor, 7.7%, and the highest in Myxofibrosarcoma [MFS], 46.5%). At multivariable analysis, age (for OS only), grade, size and histology were associated to OS and CCI-DM; while age, presence of residual tumor (p < .001) and grade to CCI-LR. Of note, Myxoid liposarcoma (MLPS) and MFS showed the highest CCI-LR in presence of residual disease (18.6% vs 1.3% and 24.7% vs 7.2% respectively). Conclusions: Patients who underwent UE had a risk of LR twice as high as those primarily resected at a referral institution. However, this higher risk was not associated to a higher risk of DM or worse OS. In patients undergoing re-excision after macroscopic complete UE the presence of residual tumor was associated to a higher LR risk, again with no association with DM or OS. Despite the probable presence of a residual selection bias, it is possible that postponing re-excision after macroscopic complete UE doesn’t impact on the outcome. However, higher caution should be exerted for MLPS and MFS, given the higher probability of local relapse when microscopic residual tumor is found in the surgical specimen.
Analysis of signaling pathway activity in desmoid-type fibromatosis (DF) to identify druggable pathways.
Authors: Van De Stolpe Anja , Akse Martijn , den Biezen-Timmermans Eveline , Blay Jean-Yves , Penel Nicolas 
Published: May 2020

e23558 Background: DF are locally invasive soft tissue tumors of fibroblast origin, with unpredictable course. CTTNB1 mutations are a hallmark of DF. Molecular-targeted therapies are lacking. Recently developed OncoSignal (www.philips.com/oncosignal) pathway activity tests enable quantitative measurement of activity of clinically relevant oncogenic signal transduction pathways (estrogen, progesterone & androgen receptors; PI3K, MAPK-AP1, TGFβ, Notch, Hedgehog, Wnt pathways), based on computational interpretation of expression levels of direct target genes of the pathway-associated transcription factor. Methods: OncoSignal was used to measure activity of signaling pathways on Affymetrix transcriptome data from sporadic DF (n = 128), generated before in our center (GEO database: GSE58697), and from presumably healthy fibroblasts (n = 63) derived from a number of different tissue types (public dataset GSE63626). Pathway activity was expressed on a normalized scale 0-100 (min and max pathway activity score depend on the cell/tissue type analyzed). Comparisons used Mann Whitney test. Results: Mean Notch (43.2+/-7.2 vs 11.2 +/- 5.2; p < .0001), PI3K (54.6 +/- 10.0 vs 48.1 +/- 6.6, p < .0001) and androgen receptor (AR) pathway activities (32.8 +/- 3.7 vs 21.7 +/- 2.4, p < .0001) were increased in DF compared to fibroblasts. MAPK-AP1 pathway activity was lower in DF (40.8+/-6.0 vs 70.2 +/- 9.5; p < .0001). Mean Wnt (p = 0.7), HH (p = 0.8) pathway activities were not different between DF and fibroblasts, however the range in Wnt pathway activity scores was larger in DF (median score 24.1, range 5.3-41.7) than in normal fibroblasts (median 26.0, range 14.6-33.0). Conclusions: The increased activity of Notch, PI3K pathways in DF is consistent with the mesenchymal nature. We confirm here the key role of AR pathway. The wide range of Wnt pathway expression was larger, suggesting the heterogeneity in TD biology, possibly related to the type of CTTNB1 mutations. Overall, the large inter-patient variation in pathway activities is in line with variety of TD course. We identified signaling pathways which may provide novel options for targeted drug treatment.
Radiochemotherapy with gemcitabine as radiosensitizer in patients with soft tissue sarcoma.
Authors: Augustin Marinela , Wilhelm Martin , Reichert Bert , Siegler Gabriele Margareta , Dreier Juergen , Rottmann Michael , Blos Martin , Kalisch Alexander , Dressler Sabine , Stein Hubert , Koehler Jens , Papadopoulos Thomas , Meyer Christian , Hohenberger Peter , Jakob Jens , Vassos Nikolaos , Grehn Christian , Albrecht Clemens 
Published: May 2020

e23559 Background: Radiation therapy is an essential backbone of the management of patients (pts.) with soft tissue sarcoma (STS) as part of a multimodal curative or palliative treatment. Concurrent external-beam radiation therapy (EBRT) and chemotherapy with doxorubicin (doxo) and ifosfamide (ifo) may be indicated as well, but is associated with relevant toxicity. Gemcitabine (gem) is a known radiosensitizer and has shown activity in STS. The purpose of this study was to evaluate the efficacy and toxicity of concurrent EBRT and gemcitabine. Methods: A single center, retrospective analysis of 12 patients (pts) with STS treated with concurrent EBRT and gemcitabine from Nov 2017 to Dez 2019 in a neoadjuvant (6 pts) or palliative setting (6 pts). Gemcitabine (gem) was administered with 150-300mg/m2 once weekly for the duration of the EBRT (50 Gy in 25 fractions over 5 weeks). In the neoadjuvant treated group, 4 pts had undifferentiated pleomorphic sarcoma (UPS) G3, 1 leiomyosarcoma (LMS) G2 and 1 retroperitoneal G1 liposarcoma (LPS). The pts. were either not eligible for a neoadjuvant systemic treatment with doxo/ifo or received the EBRT/gem treatment in addition to it. Results: 5/6 pts. with neoadjuvant EBRT/gem had R0 resection and 1/6pt. R1. The IUCC stage was IIIB in 5/6 pts and IB in 1/6 pt. The tumor regression grade (TRG) was > 99% in 3/4 pts. with UPS G3 (75%) and 80% in 1/4 pt. with UPS G3. The TRG for the G2 LMS and for the G1 LPS was 20%. All pts treated in palliative setting had high grade sarcoma and responded to the treatment with partial remission, the 6 months’ local control rate was 83% (5/6 pts) for symptomatic fast growing lesions, 1/6 pt. being in PR at 4 months follow up. The combination treatment was well tolerated with reversible skin toxicity CTCAE grade I. As expected transient thrombocytopenia was observed without limiting effect on the planned EBRT. Conclusions: The combination therapy of EBRT and gemcitabine as sensitizer in pts. with STS is feasible und well tolerated. The treatment is an option for patients not eligible for neoadjuvant systemic treatment with doxo/ifo and in the palliative setting as well. It might be more potent than radiation only in achieving tumor regression and local control for high grade STS.
HLA genotyping in synovial sarcoma: Identifying HLA-A*02 and its association with clinical outcome.
Authors: Rosenbaum Evan , Seier Kenneth , Bandlamudi Chaitanya , Chi Ping , Dickson Mark Andrew , Gounder Mrinal M. , Kelly Ciara Marie , Keohan Mary Louise , Movva Sujana , Nacev Benjamin , Slotkin Emily Kanaya , Simeone Noemi , Donoghue Mark , Qin Li-Xuan , Antonescu Cristina R. , Tap William D. , D'Angelo Sandra P. 
Published: May 2020

e23560 Background: Patients (pts) with synovial sarcoma (SS) and an HLA-A*02 genotype whose tumors express NY-ESO-1 may be eligible for clinical trials of adoptive T cell therapy. We reasoned that a next generation tumor sequencing platform utilizing matched normal DNA (MSK-IMPACT) could accurately identify HLA genotype. Although HLA-A*02 is necessary for some adoptive T cell therapies, the prognosis of this genotype on clinical outcome has not been described in SS. Methods: Pts with metastatic SS who consented to screen for a clinical trial of engineered T cells had high-resolution HLA genotyping performed with a Clinical Laboratory Improvement Amendments (CLIA)-certified test. Where feasible, HLA genotype and loss-of-heterozygosity (LOH) of HLA alleles were determined from IMPACT samples. Overall survival (OS) was estimated in three overlapping cohorts and stratified by HLA-A*02 status: pts treated with anthracyclines or alkylators in the first line, pazopanib in the second line or beyond, and all pts from time of metastasis. Results: 66 pts with SS were screened, but not treated with T cells; 30% (n = 20) were HLA-A*02-positive on a CLIA-certified outside test. 23 pts had HLA genotyping both by IMPACT and an outside laboratory, 22 (96%) of whom had concordant results. 3 pts had LOH of at least 1 HLA allele, including one with LOH of HLA*02:01 in the primary tumor. Among pts treated chemotherapy (n = 36) or pazopanib (n = 37), OS did not significantly differ between HLA-A*02-positive or negative pts. Univariable analyses of OS from the time of metastasis in the whole cohort identified primary tumor size and time to metastasis as variables significantly associated with outcome (hazard ratio (HR) 1.2, 95% confidence interval (CI) 1.123 – 1.345 [P < 0.001] and HR 0.99, 95% CI 0.976 – 0.999 [P = 0.032], respectively). HLA-A*02-positive status and age did not reach the significance threshold (HR 1.95, 95% CI 0.995 – 3.813 [P = 0.052] and HR 1.021, 95% CI 0.999 – 1.044 [P = 0.061], respectively). Multivariable analysis found older age and larger tumor size were independently associated with significantly shorter OS (HR 1.03, 95% CI 1.002 – 1.049 [P = 0.037] and HR 1.2, 95% CI 1.127 – 1.37 [P < 0.001], respectively). Conclusions: Targeted exome panels like IMPACT that utilize matched tumor-normal DNA may accurately identify HLA genotype. Detection of LOH at HLA loci may identify a subgroup of pts who would be refractory to treatment with HLA-A*02-restricted engineered T cells. HLA-A*02 status was not associated with a statistically significant survival difference in pts with metastatic SS.
Irinotecan and temozolomide upfront and in relapsed Ewing sarcoma: A translational study on MGMT (O6-methylguanine–DNA methyltransferase) and ABCG2 (MGMTLiberati).
Authors: Palmerini Emanuela , Pasello Michela , Jones Robin Lewis , Manara Maria Cristina , Fagioli Franca , Grignani Giovanni , Longhi Alessandra , Cesari Marilena , Abate Massimo Eraldo , Paioli Anna , Setola Elisabetta , Hakim Rossella , D'Ambrosio Lorenzo , Parra Alessandro , Sebastian Asaftei Dorin , Righi Alberto , Morandi Luca , Donati Davide Maria , Ferrari Stefano , Scotlandi Katia 
Published: May 2020

e23564 Background: Activity of temozolomide (TEM) and irinotecan (IRI) in recurrent Ewing sarcoma (EWS) was demonstrated. Few data are available on TEMIRI use upfront. Biological predictive factors are lacking. Methods: This multi-institutional retrospective study (NCT03542097) included 59 patients with EWS. 8 patients with very high risk (HR) EWS (multivisceral ± bone marrow) received TEMIRI (TEM 100 mg/m2/day oral, and IRI 40 mg/m2/day intravenous, days 1-5, every 21 days) upfront, 51 patients after relapse (28% in 1st line, 72% ≥ 2nd line). Overall response rate (ORR: CR+PR), SD, and PD, progression-free (PFS) and overall survival (OS) were assessed. The relationship between pre-treatment expression of MGMT and ABCG2 (when FFPE tissue available) with ORR, PFS and OS was evaluated. Results: Median age was 27 years (range 4-62 years): 47 patients (80%) were adults (≥18 years), 35 (61%) had ECOG 0 and 42 (71%) presented with multivisceral disease (+ bone marrow in 5). MGMT was positive in 16/30 (53%), ABCG2 in 4/33 (12%). ORR for upfront TEMIRI (n = 8) was 50% (CR + PR = 1 + 3), with SD 50%, while in recurrent EWS (n = 49, 2 patients no measurable by RECIST) ORR was 31% (CR + PR = 4 + 11), SD 38%, and PD 31%. A better ORR was observed in adult (p = 0.008) & ECOG 0 (p = 0.001) patients; MGMT & ABCG2 expression did not influence ORR. 6-mos PFS was 87% after TEMIRI upfront, 43% at recurrence (p = 0.06), and 65% vs 28% (p = 0.02) for ECOG 0 vs ECOG 1-2, respectively. 6-mos PFS was 62% in MGMT+ vs 33% in MGMT- (p = 0.4) and 75% in ABCG2+ vs 50% in ABCG2- (p = 0.7). Median time to progression (TTP) with upfront TEMIRI was 9 months (range 5-28 months), with 1 patient with ongoing CR at 56 months; median TTP at relapse was 3 months (1-29 months). MGMT and ABCG2 expression did not influence 1-yr OS, whereas ECOG (0 vs 1-2) did (88% vs 31% p < 0.001). Grade 3-4 diarrhea, neutropenia, and thrombocytopenia incidence was < 5%, 1 patient with recurrent kidney EWS died of acute liver failure. Conclusions: TEMIRI showed promising activity in a very unfavorable cohort of EWS patients, with manageable toxicity. Performance status correlated with 6-month PFS & OS whereas MGMT & ABCG2 did not. Clinical trial information: NCT03542097 .