bluuebunny/crossref_metadata_2025_split huggingface dataset:
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. [Table: see text]
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.
A randomized phase II study of perifosine (P) plus imatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST)
Authors: Conley A. P. , Araujo D. , Ludwig J. , Ravi V. , Samuels B. L. , Choi H. , Thall P. F. , Patel S. , Benjamin R. , Trent J. 
Published: August 2020

10563 Background: P inhibits activation of the Akt pathway which results in apoptosis and block cancer cell proliferation. Since AKT is a molecule downstream of Kit, its inhibition may overcome Kit-dependent imatinib resistance. We performed a phase II trial to assess antitumor activity of perifosine in patients with advanced GIST who were refractory to imatinib mesylate. Methods: Pts with Kit(+) advanced GIST who have PD on IM were eligible. Pts continued their current dose of IM and were randomized to one of two dosing schedules of P (Arm A: 100 mg p.o. qd x 28 + IM or Arm B: 900 mg [300 mg p.o tid] qweekly + qd IM). A Bayesian approach was utilized to assess a target response rate or 20% with an unacceptable toxicity rate of 15% or less. Response was measured at q8 wk intervals by RECIST and Choi criteria. The primary endpoint was to determine the efficacy of P with IM in pts with advanced GIST with PD while receiving IM. Results: From 8/2005 to 7/2008, 41 pts were accrued. After 1 pt exclusion and 2 cross-overs, 22 pts were in Arm A and 18 pts in Arm B. Median age was 58 (range, 32–82), 51% were male, and median ECOG PS was 1. The most common primary site of disease and metastasis was the stomach (29%) and liver (66%), respectively. KIT genotype was available for 22 pts(54%); 5(12%) WT, 13(32%) exon 11 mutations, and 4(10%) exon 9 mutations. The median number of cycles was 2 (range, 1–24). By Choi and RECIST, 30 pts(73%) and 36 pts(87%) were available for response, respectively. No CR was identified but the PR rate was 4/36 (11%) by Choi (4 PR, 9 SD) and 0/36 (0%) by RECIST (16 SD). 4/5 (80%) of pts with WT KIT appeared to benefit (Choi: 1 PR, 3 SD; RECIST: 4 SD). Median PFS and OS for 40 pts were 2.2 months and 18.3 months. No difference in PFS was noted for the 2 schedules. Toxicity was assessed in 39 pts; 46 grade 3 events and 4 grade 4 events (ALT elevation, blurred vision, fatigue, and mood alteration) were noted. The most common grade 3 event was fatigue (20%). Three pts (7%) were removed from the study for toxicity (Arm A:1 pt, Arm B:2 pts). Conclusions: The addition of P to IM has minimal activity in IM-refractory GIST although its activity in GIST with WT KIT may be further investigated. No significant financial relationships to disclose.
Rechallenge with trabectedin in patients with responding myxoid liposarcoma
Authors: Sanfilippo R. , Grosso F. , Virdis E. , Morosi C. , Tercero J. C. , Gronchi A. , Pilotti S. , D'Incalci M. , Casali P. G. 
Published: August 2020

10575 Background: To determine the efficacy of rechallenge with trabectedin (T) in patients with myxoid liposarcoma who were responding to T at the time of discontinuation but subsequently developed progressive disease. Methods: Since September 2002, 32 patients with recurrent or advanced myxoid liposarcoma received T at our institution within an expanded access program. We report herein 8 patients who received T for a median of 10 cycles (range 5–15) prior to discontinuation. We used RECIST criteria to classify patient response to therapy. During the initial administration of T, a CR had been observed in 2 patients, a PR in 3 patients, SD in 2 patients, and one had had tumor shrinkage but did not meet RECIST definition of PR. The median PFS was 24 months from treatment start, and 14 months (range 9–27) from treatment-end. In 6 of the 8 patients, the treatment had been discontinued in the absence of any evidence of disease: 4 patients had undergone complete surgical resection (R0) of residual disease and 2 patients had achieved a radiological complete response (CR). The other two patients stopped treatment voluntarily, one with a partial response (PR) and one with stable disease (SD). All these patients resumed treatment at the time of progression. Results: Following rechallenge with T, no PD was seen at first assessment, and no patients had to discontinue or reduce the dose due to toxicity. Response rate according to RECIST was 50%. At a median follow up of 7 months (range 2.7–12), the median TTP has not yet been reached. Treatment is still ongoing in 5 patients. Conclusions: Rechallenge with T can be beneficial in some patients with myxoid liposarcoma. If further data confirm this, treatment of progressing patients previously responding to T may include this option. Furthermore, studies on optimization of treatment duration upfront may be worthwhile. [Table: see text]
Effect of metastasectomy and doxorubicin dose on the outcome of patients with metastastic leiomyosarcoma: A multicenter study
Authors: Penel N. , Italiano A. , Isambert N. , Bompas E. , Bousquet G. , Bousquet G. , Duffaud F. 
Published: August 2020

10580 Background: The role of metastasectomy and front-line chemotherapy modalities remain debated in the metastastatic soft tissue sarcoma setting. Methods: Data from 147 M-LMS patients (1988–2008) reviewed in 6 French centers were retrospectively analyzed. Prognostic factors for progression-free and overall survivals (PFS and OS) were identified using log-rank tests and Cox multivariate analysis. The respective impact of treatment modalities on PFS and OS were assessed after adjustment to prognostic factors. Results: This database included 46 (31%) uterus and 101 soft-tissues (69%) M-LMS. All patients received doxorubicin as front-line regimen associated with ifosfamide in 78 cases (53%) or dacarbazine in 56 cases (38%). The planned dose of doxorubicin was > 60 mg/m2/3 weeks in 24 patients (16%). After front-line chemotherapy, 36 patients with lung metastasis (24%) underwent subsequent complete metastasectomy. The median PFS was 6 months. The univariate analysis identified the following prognostic factors for PFS: performance status (PS), grade, presence of liver or lung metastases. But, the multivariate analysis did not retain independent prognostic factor for PFS. Only one treatment parameter was associated with better PFS: planned doxorubicin dose superior to 60 mg/m2/3 weeks (HR=7.57 [1.32–10.40], p=0.023). The median OS was 14 months (1–115). The univariate analysis identified the following prognostic factors: PS, time interval between diagnosis and metastatic relapse, local relapse and grade. Under multivariate analysis, there was only one good prognostic factor for PFS: interval time between initial diagnosis and metastasis > 12 months (p=0.006). After adjustment to this factor, multivariate analysis shown that complete metastasectomy improved the PFS (HR=0.52, [0.38–0.87], p=0.012) and addition of ifosfamide was associated with worst outcome (HR=1.42 [1.05–2.10], p=0.028). Other chemotherapy parameters did not significantly modify OS. Conclusions: Doxorubicin dose and metastasectomy remain the cornerstone of the optimal treatment of M-LMS. Addition of Ifosfamide seemed to be associated with worst outcome. Dacarbazine seemed to have no significant impact. [Table: see text]
Ifosfamide, carboplatin, and etoposide (ICE) in combination with regional hyperthermia (RHT) in chemotherapy-pretreated nonresponders with locally advanced high-risk soft tissue sarcoma (HR-STS)
Authors: Nickenig C. , Buecklein V. , Lindner L. H. , Abdel-Rahman S. , Kuhlencordt M. , Hiddemann W. , Issels R. D. 
Published: August 2020

10581 Background: Regional hyperthermia (RHT) improves outcome in combination with neoadjuvant chemotherapy as first-line therapy in locally advanced HR-STS (Issels et al., Abstract 10009, ASCO 2007). Efficacy of ICE combined with RHT as second-line treatment strategy in pts with locally advanced HR-STS pretreated with anthracycline-based chemotherapy ± RHT was evaluated. Methods: Between 9/97 and 6/08, 49 pts were treated with ICE + RHT (median age: 51 years, range: 21–74 years), with high-grade (G2 24 pts; G3 25 pts) STS histology (20 Lipo-Sa; 6 Leiomyo-Sa, 6 MPNST, 5 NOS, 2 DSRCT, 10 others). As first-line therapy 35 pts had received chemotherapy combined with RHT and 14 pts without RHT. Second-line ICE consisted of 1.5 g/m2 ifosfamide, 100 mg/m2 carboplatin, and 150 mg/m2 etoposide on days 1–4 combined with RHT on two days and was repeated on day 28 (4–6 cycles). Besides toxicity, primary and secondary endpoints were objective response (OR) (RECIST), progression free rate (PFR) at 3 and 6 months, and overall survival (OS). Results: Pts received a median of 4 ICE cycles (range 1–8) in combination with RHT. Hematological toxicity grade III (11 pts)/ IV (23 pts) occurred in 34 pts (69 %), 3 pts (6 %) suffered from therapy-related deaths due to infection during cytopenia (2 pts) or postsurgery-related complications (1 pt). In 35 of 49 pts evaluable for OR, 26% achieved objective remission (1 CR + 8 PR), 51% showed stable disease (18 SD) and 23% progressive disease (8 PD). OR rates after initial chemotherapy with or without RHT were 17 % (4 PR of 24 pts) and 45% (1 CR + 4 PR of 11 pts), respectively (p=0.13). Irrespective of pretreatment, for all pts the PFR after 3 and 6 months was 87% (CI95=96%-77%) and 76% (CI95=88%-63%) and median OS was 22 months (CI95=29–16 months). Conclusions: Second-line ICE combined with RHT is feasible and effective in pts with locally advanced HR-STS non-responding to first-line anthracycline-based chemotherapy with or without RHT. (Supported by Deutsche Krebshilfe and HelmholtzZentrum münchen - German Research Center for Environmental Health) No significant financial relationships to disclose.
Clinical features and course of brain metastases in triple-negative breast cancer: Comparison with HER2+ and other type
Authors: Jang G. , Lee S. , Ahn J. , Jung K. , Lee H. , Gong G. , Kim H. , Ahn S. , Ahn S. , Kim S. 
Published: August 2020

1064 Background: Incidences and clinical aggressiveness of intracranial metastasis in triple negative (TN) breast cancer have not been well delineated compared to HER2+ subtype. Methods: Patients (pts) who were diagnosed with primary breast cancer at Asan Medical Center from January 1990 to July 2006 were screened (Lee SS, Breast Cancer Res Treat. 2008). All pts with brain metastases, identified by CT or MRI, were included and classified into three subtypes (TN, HER2+ and other). The clinical features and course of brain metastases with TN breast cancer, defined according to immunohistochemical staining and HER2 FISH analysis, were reanalyzed and compared among three groups. Results: Of 7,872 breast cancer pts, 198 pts developed brain metastases and 61 pts with unknown ER, PR, or HER2 status were excluded. Of 137 pts, incidences of TN, HER2+ and other group were 32% (44), 50% (69), and 18% (24), respectively. The median age at the time of brain metastases was 46 years (yr) (range 29–70 yr) in TN group, 48 yr (range 27–78 yr) in HER2 group, and 37 yr (range 25–62 yr) in other group with no significant difference. Clinical parameters such as performance status, previous adjuvant chemotherapy or radiotherapy, was similarly distributed among groups except that pts with earlier stages (I, II) were more prevalent in TN group compared to other two groups (59% vs 36% vs 38%, p = 0.01). With a median follow-up duration of 99 months (m), the median time from initial diagnosis of primary breast cancer to brain metastases was significantly shorter in TN group, compared with other two groups (TN, HER2, other; 20 m vs 32 m vs 45 m, p = 0.01) and the one from diagnosis of primary cancer to the first distant metastases at any sites was also shorter (16 m vs 23 m vs 23 m, p = 0.005). The median overall survival from diagnosis of primary cancer was significantly shorter in TN group (31 m vs 39 m vs 57 m, p = 0.02) and however, the one after brain metastases was not different among 3 groups (5.9 m vs 5.2 m vs 8.8 m, p = 0.31). Conclusions: TN breast cancer showed earlier brain metastases, earlier distant metastases at any sites and shorter overall survival in spite of high proportion of early stages, compared with other phenotypes. Preventive and therapeutic strategies of brain metastases in TN breast cancer are urgently needed. No significant financial relationships to disclose.