Publications by authors named "Maria Abbondanza Pantaleo"

76 Publications

Gene Expression Landscape of SDH-Deficient Gastrointestinal Stromal Tumors.

J Clin Med 2021 Mar 4;10(5). Epub 2021 Mar 4.

Division of Oncology, IRCCS-Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy.

Background: About 20-40% of gastrointestinal stromal tumors (GISTs) lacking KIT/PDGFRA mutations show defects in succinate dehydrogenase (SDH) complex. This study uncovers the gene expression profile (GEP) of SDH-deficient GIST in order to identify new signaling pathways or molecular events actionable for a tailored therapy.

Methods: We analyzed 36 GIST tumor samples, either from formalin-fixed, paraffin-embedded by microarray or from fresh frozen tissue by RNA-seq, retrospectively collected among KIT-mutant and SDH-deficient GISTs. Pathway analysis was performed to highlight enriched and depleted transcriptional signatures. Tumor microenvironment and immune profile were also evaluated.

Results: SDH-deficient GISTs showed a distinct GEP with respect to KIT-mutant GISTs. In particular, SDH-deficient GISTs were characterized by an increased expression of neural markers and by the activation of fibroblast growth factor receptor signaling and several biological pathways related to invasion and tumor progression. Among them, hypoxia and epithelial-to-mesenchymal transition emerged as features shared with SDH-deficient pheochromocytoma/paraganglioma. In addition, the study of immune landscape revealed the depletion of tumor microenvironment and inflammation gene signatures.

Conclusions: This study provides an update of GEP in SDH-deficient GISTs, highlighting differences and similarities compared to KIT-mutant GISTs and to other neoplasm carrying the SDH loss of function. Our findings add a piece of knowledge in SDH-deficient GISTs, shedding light on their putative histology and on the dysregulated biological processes as targets of new therapeutic strategies.
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http://dx.doi.org/10.3390/jcm10051057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961685PMC
March 2021

Trabectedin for Patients with Advanced Soft Tissue Sarcoma: A Non-Interventional, Retrospective, Multicenter Study of the Italian Sarcoma Group.

Cancers (Basel) 2021 Mar 2;13(5). Epub 2021 Mar 2.

Chemotherapy Unit, IRCCS Istituto Ortopedico Rizzoli, 1 Via Pupilli, 40136 Bologna, Italy.

The Italian Sarcoma Group performed this retrospective analysis of patients with advanced soft tissue sarcoma, pretreated with ≥1 anthracycline-based treatment, and treated with trabectedin every three weeks. Primary endpoint was to describe real-life use of trabectedin across Italy. Secondary endpoints included objective response rate (ORR) and safety. Overall, 512 patients from 20 Italian centers were evaluated. Leiomyosarcoma (37.7%)/liposarcoma (30.3%) were the most prevalent histological types (abbreviated as L-sarcoma). Patients received a median of four trabectedin cycles (range: 1-40), mostly as a second-line treatment (~60% of patients). The ORR was 13.7% superior ( < 0.0001) in patients with L-sarcoma compared with patients with non-L-sarcoma (16.6% vs. 9.0%). Median progression-free survival (PFS) was 5.1 months, whereas median overall survival (OS) was 21.6 months. Significantly better PFS and OS were observed in patients with L-sarcoma, those with objective responses and/or disease stabilization, treated in an early line and treated with reduced dose. Bone marrow toxicity (61.4%) and transaminase increases (21.9%) were the most common grade 3/4 adverse events. The results of this real-life study suggest that trabectedin is an active treatment, which is mostly given as a second-line treatment to patients with a good performance status and high-grade, metastatic L-sarcoma (clinical trial information: NCT02793050).
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http://dx.doi.org/10.3390/cancers13051053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958606PMC
March 2021

The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST).

Cancers (Basel) 2021 Feb 9;13(4). Epub 2021 Feb 9.

Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.

The majority of gastrointestinal stromal tumors (GIST) carry a sensitive primary KIT mutation, but approximately 5% to 10% of cases harbor activating mutations of platelet-derived growth factor receptor (PDGFRA), mainly involving the A-loop encoded by exon 18 (~5%), or more rarely the JM domain, encoded by exon 12 (~1%), or the ATP binding domain encoded by exon 14 (<1%). The most frequent mutation is the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V) in exon 18, widely recognized as D842V. This mutation, as well known, provides primary resistance to imatinib and sunitinib. Thus, until few years ago, no active drugs were available for this subtype of GIST. Conversely, recent years have witnessed the development of a new specific inhibitor-avapritinib-that has been studied in in vitro and clinical setting with promising results. In light of this primary resistance to conventional therapies, the biological background of D842V-mutant GIST has been deeply investigated to better understand what features characterize this peculiar subset of GIST, and some promising insights have emerged. Hereinafter, we present a comprehensive overview on the clinical features and the molecular background of this rare subtype of GIST.
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http://dx.doi.org/10.3390/cancers13040705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916155PMC
February 2021

Immunobiology of Thymic Epithelial Tumors: Implications for Immunotherapy with Immune Checkpoint Inhibitors.

Int J Mol Sci 2020 Nov 28;21(23). Epub 2020 Nov 28.

Oncologia Medica, Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy.

Thymic epithelial tumors (TETs) are a group of rare thoracic malignancies, including thymic carcinomas (TC) and thymomas (Tm). Autoimmune paraneoplastic diseases are often observed in TETs, especially Tms. To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options are available for relapsed/refractory TETs. In the last few years, the deepening of knowledge on thymus' immunobiology and involved altered genetic pathways have laid the foundation for new treatment options in these rare neoplasms. Recently, the immunotherapy revolution has landed in TETs, showing both a dark and light side. Indeed, despite the survival benefit, the occurrence of severe autoimmune treatment-related adverse events has risen crescent uncertainty about the feasibility of immunotherapy in these patients, prone to autoimmunity for their cancer biology. In this review, after summarizing immunobiology and immunopathology of TETs, we discuss available data on immune-checkpoint inhibitors and future perspectives of this therapeutic strategy.
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http://dx.doi.org/10.3390/ijms21239056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730788PMC
November 2020

Gene duplication, rather than epigenetic changes, drives FGF4 overexpression in KIT/PDGFRA/SDH/RAS-P WT GIST.

Sci Rep 2020 11 16;10(1):19829. Epub 2020 Nov 16.

"Giorgio Prodi" Cancer Research Center (CIRC), University of Bologna, Bologna, Italy.

Gastrointestinal stromal tumours that are wild type for KIT and PDGFRA are referred to as WT GISTs. Of these tumours, SDH-deficient (characterized by the loss of SDHB) and quadruple WT GIST (KIT/PDGFRA/SDH/RAS-P WT) subgroups were reported to display a marked overexpression of FGF4, identifying a putative common therapeutic target for the first time. In SDH-deficient GISTs, methylation of an FGF insulator region was found to be responsible for the induction of FGF4 expression. In quadruple WT, recurrent focal duplication of FGF3/FGF4 was reported; however, how it induced FGF4 expression was not investigated. To assess whether overexpression of FGF4 in quadruple WT could be driven by similar epigenetic mechanisms as in SDH-deficient GISTs, we performed global and locus-specific (on FGF4 and FGF insulator) methylation analyses. However, no epigenetic alterations were detected. Conversely, we demonstrated that in quadruple WT GISTs, FGF4 expression and the structure of the duplication were intimately connected, with the copy of FGF4 closer to the ANO1 super-enhancer being preferentially expressed. In conclusion, we demonstrated that in quadruple WT GISTs, FGF4 overexpression is not due to an epigenetic mechanism but rather to the specific genomic structure of the duplication. Even if FGF4 overexpression is driven by different molecular mechanisms, these findings support an increasing biologic relevance of the FGFR pathway in WT GISTs, both in SDH-deficient and quadruple WT GISTs, suggesting that it may be a common therapeutic target.
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http://dx.doi.org/10.1038/s41598-020-76519-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670422PMC
November 2020

Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile.

Cancers (Basel) 2020 Jul 31;12(8). Epub 2020 Jul 31.

"Giorgio Prodi" Cancer Research Center, University of Bologna, 40138 Bologna, Italy.

Uterine Leiomyosarcoma (uLMS) is by far the most common type of uterine sarcoma, characterized by an aggressive clinical course, a heterogeneous genetic profile and a very scarce response to cytotoxic chemotherapy. The genetic make-up of uLMS is an area of active study that could provide essential cues for the development of new therapeutic approaches. A total of 216 patients with uLMS from cBioPortal and AACR-GENIE databases were included in the study. The vast majority of patients (81%) carried at least one mutation in either , , or . The most frequently mutated gene was , with 61% of the patients harboring at least one mutation, followed by at 48%. alteration was more frequent in metastases than in primary lesions, consistent with a later acquisition during tumor progression. There was a significant trend for and mutations to occur together, while both and were mutually exclusive with respect to inactivation. Overall survival did not show significant correlation with the mutational status, even if mutation emerged as a favorable prognostic factor in the -mutant subgroup. This comprehensive analysis shows that uLMS is driven almost exclusively by the inactivation of tumor suppressor genes and suggests that future therapeutic strategies should be directed at targeting the main genetic drivers of uLMS oncogenesis.
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http://dx.doi.org/10.3390/cancers12082126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464219PMC
July 2020

Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis.

Ther Adv Med Oncol 2020 7;12:1758835920936932. Epub 2020 Jul 7.

Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Background: Regorafenib (REG) is an oral multikinase inhibitor used in colorectal cancer, gastrointestinal stromal tumour and hepatocellular carcinoma. Several adverse events (AEs) are commonly reported during REG administration, and strategies for managing AEs in everyday clinical practice include supportive care, dose modifications and, when necessary, treatment withdrawal. We performed a systematic review and meta-analysis to assess the schedule treatment modifications of REG associated with AEs across randomized controlled clinical trials (RCTs).

Methods: Eligible studies included RCTs assessing standard dose REG placebo. Outcomes of interest included: AE-related permanent discontinuation, dose interruptions and dose reductions.

Results: We retrieved all the relevant RCTs through PubMed/Med, Cochrane library and EMBASE: 7 eligible studies involving a total of 2099 patients (Regorafenib: 1362; placebo: 737) were included in our analysis. The use of REG was associated with higher incidence and risk of all outcomes of interest when compared with placebo. The incidences of permanent discontinuation, dose interruptions and dose reductions in patients receiving REG were 9.7%, 57.2% and 47%, respectively, 3.3%, 16.7% and 7.7% of placebo group; compared with placebo, the summary relative risks (RRs) of permanent discontinuation, dose interruptions and dose reductions in REG arm were 2.80 (95% CI 1.85-4.22), 3.21 (95% CI 2.59-3.99) and 6.02 (95% CI 3.28-11.03), respectively.

Conclusions: Treatment with REG at the standard dose of 160 mg is associated with a significant increase in AE-related permanent discontinuation, dose interruptions and dose reductions. Prompt identification and management of AEs seem mandatory to obtain maximal benefit from REG treatment. In the current landscape, dose personalization of REG may have the potential to improve quality of life, minimize treatment discontinuation and maximize patient outcomes.
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http://dx.doi.org/10.1177/1758835920936932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343359PMC
July 2020

Impact of Chemotherapy in the Adjuvant Setting of Early Stage Uterine Leiomyosarcoma: A Systematic Review and Updated Meta-Analysis.

Cancers (Basel) 2020 Jul 14;12(7). Epub 2020 Jul 14.

Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, 40128 Bologna, Italy.

Background: Although the use of adjuvant chemotherapy (AC) appears to be increasing over the past few years, several clinical trials and previous meta-analyses failed to determine whether AC could improve clinical outcomes in uterine leiomyosarcoma (uLMS). The aim of this systematic review and meta-analysis was to compare AC (with or without radiotherapy) versus observation (obs) after primary surgery in early stage uLMS.

Materials And Methods: Randomized controlled (RCTs) and non-randomized studies (NRSs) were retrieved. Outcomes of interest were as follows: distant recurrence rate, locoregional recurrence rate and overall recurrence rate. Results about distant recurrence rate, locoregional recurrence rate and overall recurrence rate were compared by calculating odds ratios (ORs) with 95% confidence intervals (CIs); ORs were combined with Mantel-Haenszel method.

Results: Nine studies were included in the analysis, involving 545 patients (AC: 252, obs: 293). Compared with obs, AC did not reduce locoregional and distant recurrence rate, with a pooled OR of 1.36 and 0.63, respectively. Similarly, administration of AC did not decrease overall recurrence rate in comparison to obs.

Conclusion: According to our results, AC (with or without radiotherapy) did not decrease recurrence rate in early stage uLMS; thus, the role of AC in this setting remains unclear.
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http://dx.doi.org/10.3390/cancers12071899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409135PMC
July 2020

Gene Expression Profiling of PDGFRA Mutant GIST Reveals Immune Signatures as a Specific Fingerprint of D842V Exon 18 Mutation.

Front Immunol 2020 2;11:851. Epub 2020 Jun 2.

Medical Oncology Unit, S.Orsola-Malpighi University Hospital, Bologna, Italy.

Platelet Derived Growth Factor Receptor Alpha (PDGFRA) mutations occur in only about 5-7% of gastrointestinal stromal tumors (GIST), notably with alterations on exons 12/14/18. The most frequent PDGFRA mutation is the exon 18 D842V, which is correlated to specific clinico-pathological features, such as primary imatinib resistance and higher indolence. Here, we present a gene expression profile (GEP) comparison of D842V vs. PDGFRA with mutations other than D842V (non-D842V). GEP was followed by bioinformatic analysis aimed at evaluating differential expression, tumor microenvironment composition and pathway enrichment. We found a large set of oncogenes, transcription factors and nuclear receptors downregulated in the D842V mutant. Conversely, D842V showed a significant enrichment of immune- and interferon- related gene signatures. Differences in tumor microenvironment composition were also highlighted, including a higher abundance of CD8+ T-cells and an overexpression of the T cell-inflamed signature in the D842V mutant subgroup, which is predictive of immunotherapy response. PDGFRA D842V vs. non-D842V GIST display a different expression profile, with a prominent immunological signature, that could represent a proof of principle for testing immunotherapeutic strategies in this drug-orphan subset of GIST.
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http://dx.doi.org/10.3389/fimmu.2020.00851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326057PMC
March 2021

Complete radiological response to first-line regorafenib in a patient with abdominal relapse of mutated GIST.

Therap Adv Gastroenterol 2020 30;13:1756284820927305. Epub 2020 Jun 30.

Medical Oncology 1 Unit, Department of Oncology, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy.

Up to 13% of and wild-type (WT) gastrointestinal stromal tumours (GIST) harbour a BRAF mutation, mostly involving the exon 15 hot spot. Even if mutation is recognized as druggable target in other solid tumours, currently advanced -mutant GIST share the same therapeutical algorithm of mutants. We report a complete radiological response in a 51-year-old woman with V600E BRAF-mutated metastatic GIST who was treated with regorafenib (REG) as first-line therapy. REG represents the standard third-line therapy for advanced GIST patients progressing on or failing to respond to imatinib and sunitinib. However, according to its wide spectrum of action, with signalling pathway blockade at different levels, metastatic WT, including mutants, may benefit from REG upfront in first line.
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http://dx.doi.org/10.1177/1756284820927305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328213PMC
June 2020

Living Donor Liver Transplantation for Imatinib-Resistant Gastrointestinal Stromal Tumor Liver Metastases: A New Therapeutic Option in Transplant Oncology.

Liver Transpl 2020 10 13;26(10):1373-1374. Epub 2020 Aug 13.

Medical Oncology Unit, Sant'Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1002/lt.25844DOI Listing
October 2020

Skull Metastasis From Uterine Leiomyosarcoma, a Rare Presentation for a Rare Tumor: A Case Report and Review of the Literature.

Front Oncol 2020 16;10:869. Epub 2020 Jun 16.

Medical Oncology Unit, S.Orsola-Malpighi University Hospital, Bologna, Italy.

Uterine leiomyosarcoma (uLMS) is a rare and aggressive malignancy with poor clinical outcomes. Even when localized, uLMS is associated with high rates of local and distant recurrences that are usually fatal. Common sites of recurrence are lung, liver, pelvic lymph nodes, and vertebral and long bones, though atypical patterns of recurrence have been described. Among them, intracranial recurrence appears as a rare finding, almost exceptional in skull and dura. We describe the case of a solitary skull metastasis from uLMS in a 39-year-old woman, which represents the third reported case of skull recurrence in literature. After multidisciplinary discussion, the patient underwent surgery and received adjuvant radiotherapy. After 4 months, she is currently alive, without evidence of extracranial disease. This case highlights the importance of suspecting and recognizing atypical and extremely rare metastasis to this region. We encourage the need for large case series in order to provide further information about cranial recurrences of uLMS taking into account the paucity of data currently available in literature and the frequently unpredictable behavior of this rare and highly lethal disease.
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http://dx.doi.org/10.3389/fonc.2020.00869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308452PMC
June 2020

The Activity of Chemotherapy in Inflammatory Myofibroblastic Tumors: A Multicenter, European Retrospective Case Series Analysis.

Oncologist 2020 11 12;25(11):e1777-e1784. Epub 2020 Jul 12.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: This study aimed to review the activity of cytotoxic chemotherapy in patients with inflammatory myofibroblastic tumors (IMTs) treated at nine European sarcoma reference centers.

Materials And Methods: Patients of any age, with histologically proven IMT, treated with anthracycline-based methotrexate plus/minus vinorelbine/vinblastine (MTX-V) or other chemotherapeutic regimens between 1996 and 2018 were retrospectively reviewed. Diagnosis was confirmed at the local level by an expert pathologist. Response was retrospectively assessed by local investigators by RECIST v1.1. Progression-free survival (PFS), relapse-free survival (RFS), and overall survival (OS) were computed by Kaplan-Meier method.

Results: Thirty-eight patients were included. Twenty-five patients (8 localized, 17 advanced disease) received an anthracycline-based regimen; 21 were evaluable for response. Overall response rate (ORR) was 10/21 (47.6%). At a 70.8-month median follow-up (FU), median RFS and median OS were not reached (NR) in patients with localized disease; median PFS and median OS were 6.3 (interquartile range [IQR]: 1.9-13.4) and 21.2 (IQR: 7.7-40.7) months in patients with advanced disease. Thirteen patients received MTX-V (4 localized, 9 advanced disease), all evaluable for response. ORR was 7/13 (53.8%). At a 56.6-month median FU, median RFS and median OS were 42.5 (IQR: 12.9-61.2) months and NR (no death events) in patients with localized disease, and NR (IQR: 24.9 to NR) and 83.4 months (IQR: 83.4 to NR) in patients with advanced disease. In the "other-regimens group," responses were seen in 3/4 patients treated with oral cyclophosphamide and 1/2 with docetaxel/gemcitabine.

Conclusion: Anthracycline-based and MTX-V regimens are very effective in IMT, with a similar ORR in both groups. MTX-V achieved a prolonged disease control. Responses were also seen with oral cyclophosphamide and docetaxel/gemcitabine, but few patients were treated with these schedules.

Implications For Practice: Inflammatory myofibroblastic tumor (IMT) is an ultrarare sarcoma with known sensitivity to anaplastic lymphoma kinase (ALK) inhibitors in ALK-fused cases, although ALK inhibitors are not licensed in the disease. The current knowledge on the activity of cytotoxic chemotherapy is limited. This multi-institutional retrospective study on pediatric and adult patients with IMT shows that cytotoxic chemotherapy, and in particular anthracycline-based and methotrexate plus/minus vinorelbine/vinblastine regimens, represents a treatment option and can be considered in IMT patients irrespectively from ALK status. This study provides a benchmark for future studies on new medical therapies.
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http://dx.doi.org/10.1634/theoncologist.2020-0352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648357PMC
November 2020

Diagnostic Accuracy of Cardiac Computed Tomography and 18-F Fluorodeoxyglucose Positron Emission Tomography in Cardiac Masses.

JACC Cardiovasc Imaging 2020 11 17;13(11):2400-2411. Epub 2020 Jun 17.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Objectives: This study sought to assess the diagnostic accuracy of cardiac computed tomography (CT) and F-fluorodeoxyglucose (F-FDG) with positron emission tomography/computed tomography (PET/CT) in defining the nature of cardiac masses.

Background: The diagnostic accuracy of cardiac CT and F-FDG PET/CT in identifying the nature of cardiac masses has been analyzed to date only in small samples.

Methods: Of 223 patients with echocardiographically diagnosed cardiac masses, a cohort of 60 cases who underwent cardiac CT and F-FDG PET/CT was selected. All masses had histological confirmation, except for a minority of thrombotic formations. For each mass, 8 morphological CT signs, standardized uptake value (SUV, SUV), metabolic tumor volume, and total lesion glycolysis in F-FDG PET were used as diagnostic markers.

Results: Irregular tumor margins, pericardial effusion, invasion, solid nature, mass diameter, CT contrast uptake, and pre-contrast characteristics were strongly associated with the malignant nature of masses. The coexistence of at least 5 CT signs perfectly identified malignant masses, whereas the detection of 3 or 4 CT signs did not accurately discriminate the masses' nature. The mean SUV, SUV, metabolic tumor volume, and total lesion glycolysis values were significantly higher in malignant than in benign masses. The diagnostic accuracy of SUV, metabolic tumor volume, and total lesion glycolysis F-FDG PET/CT parameters was excellent in detecting malignant masses. Among patients with 3 or 4 pathological CT signs, the presence of at least 1 abnormal F-FDG PET/CT parameter significantly increased the identification of malignancies.

Conclusions: Cardiac CT is a powerful tool to diagnose cardiac masses as the number of abnormal signs was found to correlate with the lesions' nature. Similarly, F-FDG PET/CT accurately identified malignant masses and contributed with additional valuable information in diagnostic uncertainties after cardiac CT. These imaging tools should be performed in specific clinical settings such as involvement of great vessels or for disease-staging purposes.
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http://dx.doi.org/10.1016/j.jcmg.2020.03.021DOI Listing
November 2020

Genetic aberrations and molecular biology of cardiac sarcoma.

Ther Adv Med Oncol 2020 18;12:1758835920918492. Epub 2020 May 18.

Department of Specialized, Experimental and Diagnostic Medicine, Medical Oncology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti, 9, Bologna, Bologna 40138, Italy.

Cardiac tumors are rare and complex entities. Early assessment and differentiation between non-neoplastic and neoplastic masses, be they benign or malignant, is essential for guiding diagnosis, determining prognosis, and planning therapy. Cardiac sarcomas represent the most frequent primary malignant histotype. They could have manifold presentations so that the diagnosis is often belated. Moreover, considering their rarity and the limitation due to the cardiac location itself, the optimal multimodal management of patients affected by primary cardiac sarcomas still remains highly difficult and outcome dismal. Therefore, there is an urgent need to improve these results mainly focusing on more adequate tools for prompt diagnosis and exploring new and more effective therapies. Knowledge about the molecular landscape and pathogenesis of cardiac sarcoma is even more limited due to the rarity of this disease. In this sense, the molecular characterization of heart tumors could unfold potentially novel, druggable targets. In this review, we focused on genetic aberrations and molecular biology of cardiac sarcomas, collecting the scarce information available and resuming all the molecular findings discovered in each tumor subtype, with the aim to get further insights on mechanisms involved in tumor growth and to possibly highlight specific molecular profiles that can be used as diagnostic tests and unveil new clinically actionable targets in this tricky and challenging disease.
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http://dx.doi.org/10.1177/1758835920918492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238448PMC
May 2020

Letter to the editor concerning "Liver transplantation for metastatic wild-type gastrointestinal stromal tumor in the era of molecular targeted therapies: Report of a first case".

Am J Transplant 2020 12 17;20(12):3701-3702. Epub 2020 Jun 17.

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1111/ajt.16076DOI Listing
December 2020

The Emerging Role of the FGF/FGFR Pathway in Gastrointestinal Stromal Tumor.

Int J Mol Sci 2020 May 7;21(9). Epub 2020 May 7.

Medical Oncology Unit, S.Orsola-Malpighi University Hospital, 40138 Bologna, Italy.

Gastrointestinal stromal tumors (GIST) are rare neoplasms of mesenchymal origin arising in the gastrointestinal tract. The vast majority are characterized by mutually exclusive activating mutations in KIT or Platelet-derived growth factor alpha (PDGFRA) receptors, or less frequently by succinate dehydrogenase complex (SDH) or NF1 inactivation, with very rare cases harboring mutant BRAF or RAS alleles. Approximately 5% of GISTs lack any of such mutations and are called wild-type (WT) GISTs. Recently, deregulated Fibroblast Growth Factor (FGF)/FGF-receptor (FGFR) signaling emerged as a relevant pathway driving oncogenic activity in different molecular subgroups of GISTs. This review summarizes all the current evidences supporting the key role of the FGF/FGFR pathway activation in GISTs, whereby either activating mutations, oncogenic gene fusions, or autocrine/paracrine signaling have been detected in WT, SDH-, or KIT-mutant GISTs.
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http://dx.doi.org/10.3390/ijms21093313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246647PMC
May 2020

Targeted Deep Sequencing Uncovers Cryptic KIT Mutations in KIT/PDGFRA/SDH/RAS-P Wild-Type GIST.

Front Oncol 2020 22;10:504. Epub 2020 Apr 22.

"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.

Gastrointestinal stromal tumors (GIST) are known to carry oncogenic KIT or PDGFRA mutations, or less commonly SDH or NF1 gene inactivation, with very rare cases harboring mutant BRAF or RAS alleles. Approximately 10% of GISTs are devoid of any of such mutations and are characterized by very limited therapeutic opportunities and poor response to standard treatments. Twenty-six sporadic KIT/PDGFRA/SDH/RAS-pathway wild type GIST were profiled for the molecular status of genes frequently altered in GIST by a targeted next generation sequencing (NGS) approach. Molecular findings were validated by alternative amplicon-based targeted sequencing, immunohistochemistry, gene expression profiling and Sanger sequencing. Three patients harboring NF1 inactivating mutations were identified and excluded from further analysis. Intriguingly, five patients carried cryptic KIT alterations, mainly represented by low-allele-fraction mutations (12-16% allele ratio). These mutations were confirmed by another targeted NGS approaches and supported by CD117 immuno-staining, gene expression profiling, Sanger sequencing, with peak signals at the level of background noise, and by the patients' clinical course assessment. This study indicates that ~20% patients diagnosed with a KIT/PDGFRA/SDH/RAS-pathway wild-type GIST are carriers of pathogenic KIT mutations, thus expected to be eligible for and responsive to the various therapeutic lines of TK-inhibitors in use for KIT/PDGFRA-mutant GIST. The centralization for a second level molecular analysis of GIST samples diagnosed as wild-type for KIT and PDGFRA is once again strongly recommended.
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http://dx.doi.org/10.3389/fonc.2020.00504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188756PMC
April 2020

Primary malignant pericardial tumour in Lynch syndrome.

BMC Cancer 2020 Mar 6;20(1):191. Epub 2020 Mar 6.

Department of Experimental, Diagnostic and Specility Medicine - DIMES- Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Background: This case represents the first report of malignant primary cardiac tumour in a patient with Lynch Syndrome associated with MSH2 pathogenic variant.

Case Presentation: A 57-year-old woman with previous ovarian cystadenocarcinoma was admitted to the emergency room for hematic pericardial effusion. Multimodal diagnostic imaging revealed two solid pericardial vascularized masses. After pericardiectomy, the final histological diagnosis was poorly differentiated pleomorphic sarcomatoid carcinoma. During follow-up she developed an ampulla of Vater adenocarcinoma. Genetic analysis identified an MSH2 pathogenic variant.

Conclusion: This case contributes to expand the tumour spectrum of Lynch syndrome, suggesting that MSH2 pathogenic variants cause a more complex multi-tumour cancer syndrome than the classic Lynch Syndrome. In MSH2 variant carriers, symptoms such as dyspnoea and chest discomfort might alert for rare tumours and a focused cardiac evaluation should be considered.
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http://dx.doi.org/10.1186/s12885-020-6677-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059379PMC
March 2020

Recurrent Uterine Smooth-Muscle Tumors of Uncertain Malignant Potential (STUMP): State of The Art.

Anticancer Res 2020 Mar;40(3):1229-1238

Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy.

The term 'uterine STUMP' (smooth-muscle tumors of uncertain malignant potential) is currently used to define a heterogeneous group of uterine tumors distinct from leiomyomas and leiomyosarcomas. This rare entity is often characterized by a slow growth and protracted patient survival when compared to leiomyosarcomas but few data are available about its clinical management and outcome. In this review, we summarize the current state of knowledge about uterine STUMP, with a particular focus on cases of recurrence.
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http://dx.doi.org/10.21873/anticanres.14064DOI Listing
March 2020

Paratesticular Mesenchymal Malignancies: A Single-Center Case Series, Clinical Management, and Review of Literature.

Integr Cancer Ther 2020 Jan-Dec;19:1534735419900554

Sant'Orsola-Malpighi Hospital, Bologna, Italy.

Primary soft tissue sarcomas arising from the male urinary and genital tract are rare tumors, only accounting for 1% to 2% of all malignancies of the genitourinary tract. Clinical management of advanced disease is lacking in standardized recommendations due to the rarity of the disease. To date, complete and extensive surgery represents the only curative and standardized approach for localized disease, while the impact of retroperitoneal lymphadenectomy and adjuvant treatments on clinical outcomes are still unclear. Similarly, a standardized systemic treatment for advanced metastatic disease is still missing. Four out of 274 patients have been identified in our sarcoma population. The mean age was 54 years (range = 45-73). The histotypes showed liposarcoma in 2 cases and leiomyosarcoma in the remaining 2 cases. In all 4 cases, the disease was localized at presentation, patients underwent complete surgery, and no adjuvant treatments were done. Three cases presented a recurrence of disease at a mean follow-up of 86 months (range = 60-106 months), more than 7 years. Two cases were treated with a second surgery and chemotherapy and 1 case only with chemotherapy. Sharing data about clinical management of paratesticular mesenchymal tumors is a key issue due to the rarity of this tumor's subtype. In this article, we report the clinical history of 4 patients affected by paratesticular mesenchymal tumor. In particular, main issues of interest are the decision of postoperative treatment and systemic treatment at time of disease recurrence.
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http://dx.doi.org/10.1177/1534735419900554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050957PMC
March 2020

Successful multidisciplinary clinical approach and molecular characterization by whole transcriptome sequencing of a cardiac myxofibrosarcoma: A case report.

World J Clin Cases 2019 Oct;7(19):3018-3026

Department of Specialized, Experimental and Diagnostic Medicine, Medical Oncology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.

Background: Cardiac tumors are rare and complex entities. Surgery represents the cornerstone of therapy, while the role of adjuvant treatment remains unclear and, in case of relapse or metastatic disease, the prognosis is very poor. Lack of prospective, randomized clinical trials hinders the generation of high level evidence for the optimal diagnostic workup and multimodal treatment of cardiac sarcomas. Herein, we describe the multidisciplinary clinical management and molecular characterization of a rare case of cardiac myxofibrosarcoma in an elderly woman.

Case Summary: A 73-year-old woman presented signs and symptoms of acute left-sided heart failure. Imaging examination revealed a large, left atrial mass. With suspicion of a myxoma, she underwent surgery, and symptoms were promptly relieved. Histology showed a cardiac myxofibrosarcoma, a rare histotype of cardiac sarcoma. Eight months later, disease unfortunately relapsed, and after a multidisciplinary discussion, a chemotherapy with doxorubicin and then gemcitabine was started, achieving partial radiologic and complete metabolic response, which was maintained up to 2 years and is still present. This report is focused on the entire clinical path of our patient from diagnosis to follow-up, through surgery and strategies adopted at relapse. Moreover, due to their rarity, very little is known about the molecular landscape of myxofibrosarcomas. Thus, we also performed and described preliminary genome analysis of the tumor tissue to get further insight on mechanisms involved in tumor growth, and to possibly unveil new clinically actionable targets.

Conclusion: We report a case of cardiac myxofibrosarcoma that achieved a very good prognosis due to an integrated surgical, cardiac and oncologic treatment strategy.
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http://dx.doi.org/10.12998/wjcc.v7.i19.3018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795718PMC
October 2019

Current status of the adjuvant therapy in uterine sarcoma: A literature review.

World J Clin Cases 2019 Jul;7(14):1753-1763

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna 40138, Italy.

Uterine sarcomas (US) are rare mesenchymal tumours accounting approximately for 3%-7% of all uterine cancers. Histologically, US are classified into mesenchymal tumours or mixed epithelial and mesenchymal tumours. The group of mesenchymal tumours includes uterine leiomyosarcoma (uLMS, 65% of cases), endometrial stromal sarcoma (ESS, 21%) - traditionally divided into low grade (LG-ESS) and high grade-undifferentiated uterine sarcoma (5%) and other rare subtypes such as alveolar or embryonal rhabdomyosarcoma. Despite the fact that several drugs demonstrated clinical activity in advanced or metastatic settings, the role of postoperative therapy in US remains controversial. In this review, we have summarised the current state of the art, including the chief trials on adjuvant treatment modalities in US, especially focusing on uLMS, LG-ESS and other rare histotypes.
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http://dx.doi.org/10.12998/wjcc.v7.i14.1753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692269PMC
July 2019

Gain of FGF4 is a frequent event in KIT/PDGFRA/SDH/RAS-P WT GIST.

Genes Chromosomes Cancer 2019 09 16;58(9):636-642. Epub 2019 Apr 16.

Department of Specialized, Experimental and Diagnostic Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Gastrointestinal stromal tumors (GIST) lacking mutations in KIT/PDGFRA or RAS pathways and retaining an intact SDH complex are usually referred to as KIT/PDGFRA/SDH/RAS-P WT GIST or more simply quadruple WT GIST (~5% of all GIST). Despite efforts made, no recurrent genetic event in quadruple WT GIST has been identified so far. To further investigate this disease, we performed high throughput copy number analysis on quadruple WT GIST specimens identifying a recurrent focal gain in band 11q13.3 (involving FGF3/FGF4) in 6/8 cases. This event was not found in the other molecular GIST subgroups. FGF3/FGF4 duplication was associated with high expression of FGF4, both at mRNA and protein level, a growth factor normally not expressed in adult tissues or in KIT/PDGFRA-mutated GIST. FGFR1 was found to be the predominant FGF receptor expressed and phosphorylation of AKT was detected, suggesting that a FGF4-FGFR1 autocrine loop could stimulate downstream signaling in quadruple WT GIST. Together with the recent reports of quadruple WT cases carrying FGFR1 activating alterations, these findings strengthen the hypothesis of a potential involvement of FGFR pathway deregulation in quadruple WT GIST, which may represent a rationale for novel therapeutic approaches.
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http://dx.doi.org/10.1002/gcc.22753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619263PMC
September 2019

Molecular modelling evaluation of exon 18 His845_Asn848delinsPro PDGFRα mutation in a metastatic GIST patient responding to imatinib.

Sci Rep 2019 02 18;9(1):2172. Epub 2019 Feb 18.

Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.

Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) mutations occur in approximately 5-7% of gastrointestinal stromal tumours (GIST). Over half of all PDGFRA mutations are represented by the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V), recognized as D842V, conferring primary resistance to imatinib in vitro and in clinical observations due to the conformation of the kinase domain, which negatively affects imatinib binding. The lack of interaction between imatinib and the D842V PDGFRA mutated model has been established and widely confirmed in vivo. However, for the other PDGFRA mutations, the correlation between pre-clinical and clinical data is still unclear. An in silico evaluation of the p.His845_Asn848delinsPro mutation involving exon 18 of PDGFRA in a metastatic GIST patient responding to first-line imatinib has been provided. Docking analyses were performed, and the ligand-receptor interactions were evaluated with the jCE algorithm for structural alignment. The docking simulation and structural superimposition analysis show that PDGFRA p.His845_Asn848delinsPro stabilizes the imatinib binding site with the residues that are conserved in KIT. The in vivo evidence that PDGFRA p.His845_Asn848delinsPro is sensitive to imatinib was confirmed by the molecular modelling, which may represent a reliable tool for the prediction of clinical outcomes and treatment selection in GIST, especially for rare mutations.
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http://dx.doi.org/10.1038/s41598-018-38028-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379366PMC
February 2019

Treatment Outcomes and Sensitivity to Hormone Therapy of Aggressive Angiomyxoma: A Multicenter, International, Retrospective Study.

Oncologist 2019 07 5;24(7):e536-e541. Epub 2018 Dec 5.

Medical Oncology Unit 2, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

Background: Aggressive angiomyxoma (AA) is a rare, locally aggressive tumor usually arising from pelvis or perineum, with a high local-recurrence rate after complete surgery. Anecdotal responses to hormone therapy have been reported. In the present study we aimed at studying surgical treatment outcomes and sensitivity to hormone therapy of AA.

Materials And Methods: We conducted a multicenter, international retrospective effort including patients with AA treated at three European referral centers (Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and the Italian Rare Cancer Network; Centre Léon Bérard, Lyon, France; and Hospital Universitario Virgen del Rocio, Seville, Spain).

Results: A total of 36 patients were included. Median follow-up was 51.3 months. Thirty-three patients (92%) underwent complete (R0 + R1) surgery, with a local relapse rate of 50% and a median relapse-free survival of 39 months (95% confidence interval [CI], 27-68.1). Thirteen patients received a first-line systemic treatment with hormone therapy for locally advanced disease, with an overall response rate of 62% and a median progression-free survival of 24.6 months (95% CI, 11.0-39.7). In two patients, adding an aromatase inhibitor (AI) on progression to first-line GnRH agonist (GnRHa) resulted in a new tumor response.

Conclusion: Our findings confirm that in AA, surgical local control may be challenging, with a significant rate of local relapse despite complete surgery. Hormone therapy is an active treatment option, with a potential of disease control and of being combined with surgery. The addition of an AI to first-line GnRHa could be an effective second-line systemic therapy in premenopausal female patients with AA.

Implications For Practice: In this retrospective effort including 36 patients with aggressive angiomyxoma, local relapse rate after complete surgery was 50%, with a median relapse-free survival of 39 months, confirming that local control is challenging. Overall response rate to first-line hormone therapy was 62%, with a median progression-free survival of 24.6 months. Thus, hormone therapy has a potential of disease control and of being combined with surgery.
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http://dx.doi.org/10.1634/theoncologist.2018-0338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656447PMC
July 2019

F-FDG-PET/CT imaging in cardiac tumors: illustrative clinical cases and review of the literature.

Ther Adv Med Oncol 2018 30;10:1758835918793569. Epub 2018 Aug 30.

Division of Medical Oncology, University of Bologna, Bologna, Italy.

Cardiac tumors are a very rare condition. Mostly, they are benign tumors (75%), with myxomas being the most frequent. The remaining 25% are malignant; either primary malignant sarcoma or secondary metastases. Given the small number of cases reported and the lack of prospective and randomized clinical trials, the level of evidence for the optimal multimodal treatment of primary cardiac sarcomas is very low and the optimal imaging diagnostic workup is not well established. In particular, F-FDG-PET/CT is not yet included in routine diagnosis of cardiac masses. Here, we report four illustrative clinical cases and a review of the literature on the current available data on the role of F-fluorodeoxyglucose PET/CT imaging in cardiac tumors.
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http://dx.doi.org/10.1177/1758835918793569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188102PMC
August 2018

Biliary stone disease in patients receiving somatostatin analogs for neuroendocrine neoplasms. A retrospective observational study.

Dig Liver Dis 2019 05 24;51(5):689-694. Epub 2018 Sep 24.

NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy.

Background: Somatostatin analogs are the backbone of neuroendocrine neoplasms treatment. Biliary stone disease is a potentially severe adverse event of somatostatin analogs: an increased incidence has been reported in somatostatin analogs-treated acromegalic patients, but studies on patients with neuroendocrine neoplasms are lacking.

Aims: To evaluate biliary stone disease incidence and associated factors in a large series of patients treated with somatostatin analogs for neuroendocrine neoplasms.

Methods: A prospectively-collected database of patients with a diagnosis of neuroendocrine neoplasms of any grade and site, treated with somatostatin analogs at our Institution between 1995 and 2017, was retrospectively analyzed. Patients' demographics and disease characteristics were analyzed to evaluate the incidence and the factors related to biliary stone disease.

Results: Three-hundred patients were included; 101 (33.7%) patients underwent cholecystectomy before starting somatostatin analogs. Among 164 patients with gallbladder in situ and no history of stone disease, 60 (36.6%) developed gallstones after a mean of 36.7 months (range 1-239) from treatment start with a mean yearly incidence of 8.73%. Previous cholecystectomy was associated with a lower rate of development of gallstones (p < 0.001) or related complications (p = 0.017).

Conclusion: We observed a high incidence of biliary stone disease in patients treated with somatostatin analogs-treated for neuroendocrine neoplams. Previous cholecystectomy was the only factor associated with a lower occurrence of biliary stone disease.
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http://dx.doi.org/10.1016/j.dld.2018.09.013DOI Listing
May 2019

Imatinib rechallenge in patients with advanced gastrointestinal stromal tumors following progression with imatinib, sunitinib and regorafenib.

Ther Adv Med Oncol 2018 29;10:1758835918794623. Epub 2018 Aug 29.

Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna.

Background: Rechallenge with imatinib is an option in advanced gastrointestinal stromal tumor (GIST) patients following progression with standard tyrosine-kinase inhibitors (TKIs), imatinib, sunitinib and regorafenib. We retrospectively collected data from metastatic Italian GIST patients treated with imatinib resumption after progression to conventional TKIs.

Methods: A total of 104 eligible advanced GIST patients, previously treated with imatinib, sunitinib and regorafenib, were collected from six referral Italian institutions. Mutational analysis was recorded and correlated with survival and response according to RECIST 1.1 or CHOI criteria.

Results: Overall, 71 patients treated with imatinib 400 mg as rechallenge were included. Mutational status was available in all patients. The median follow up was 13 months. In patients who received a rechallenge therapy, the median time to progression (TTP) was 5.4 months [95% confidence interval (CI) 1.9-13.5] and overall survival (OS) was 10.6 months (95% CI 2.8-26.9). A correlation between mutational status, response rate, TTP and OS was not found but comparing deleted nondeleted exon 11 patients, a significant difference was identified in terms of TTP and OS ( = 0.04 and  = 0.02, respectively).

Conclusions: Our retrospective data confirm that imatinib rechallenge is a reasonable option in advanced GIST. The prognostic value of the specific mutations was confirmed in our series.
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http://dx.doi.org/10.1177/1758835918794623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116078PMC
August 2018

A Single-Centre Experience on the Management of Adenosarcoma: A Successful Report of an Integrated Medical and Surgical Approach.

Clin Med Insights Oncol 2018 18;12:1179554918782477. Epub 2018 Jun 18.

Department of Specialized, Experimental and Diagnostic Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Adenosarcomas are the rarest form of uterine sarcomas, and clinical experience with their management is still limited. Here, we reported 7 patients with uterine adenosarcoma referred to our institution, focusing on main pathologic features, their medical history, and long-term follow-up. Among these patients, we provided a detailed description of the medical history of a 49-year-old woman with advanced uterine adenosarcoma with sarcomatous overgrowth who presented a brilliant radiologic and pathologic response after 3 cycles of epirubicin and ifosfamide, ultimately achieving an extraordinary long-term outcome through an integrated surgical and medical approach. Our single-centre experience would suggest that aggressive uterine adenosarcomas with sarcomatous overgrowth are sensitive to standard epirubicin and ifosfamide and that an integrated approach, both medical and surgical, could be considered in clinical practice, again emphasizing the relevant role of multidisciplinary management for this extremely rare disease.
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http://dx.doi.org/10.1177/1179554918782477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024524PMC
June 2018