Publications by authors named "Margherita Nannini"

101 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

Case Report: The Complete Remission of a Mixed Germ Cell Tumor With Somatic Type Malignancy of Sarcoma Type With a GCT-Oriented Therapy: Clinical Findings and Genomic Profiling.

Front Oncol 2021 16;11:633543. Epub 2021 Mar 16.

Department of Translational Medicine, University of Ferrara, Ferrara, Italy.

Somatic malignant transformation in a germ cell tumor (GCT) is the development of non-germ malignancies; much of available literature refers to teratoma with malignant transformation (TMT). There are various transformation histologies such as sarcoma, adenocarcinoma, primitive neuroectodermal tumors, and more rarely carcinoid tumors, hemangioendothelioma, lymphoma, or nephroblastoma. The treatments of these entities include surgery and/or chemotherapy. A standard approach in choosing chemotherapy in TMT cases has not yet been established. Many authors suggest using chemotherapeutic agents based on the transformed histology, while others recommend GCT-oriented therapy combined with surgery as the primary treatment, reserving histology-driven chemotherapies for metastatic relapse. We report the clinical findings and the genomic profile of a mixed GCT case with somatic-type malignancy of sarcoma type. We achieved a complete radiological response with GCT-oriented chemotherapy performed as salvage therapy after sarcoma-histology therapy. In addition, molecular profiles with RNA-sequencing and exome sequencing analyses of the primary tumor and the tumor with somatic-type malignancy of sarcoma type were explored.
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http://dx.doi.org/10.3389/fonc.2021.633543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008106PMC
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

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

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

Genetics and treatment of gastrointestinal stromal tumors with immune checkpoint inhibitors: what do we know?

Pharmacogenomics 2020 03 24;21(4):231-234. Epub 2020 Jan 24.

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

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http://dx.doi.org/10.2217/pgs-2019-0173DOI Listing
March 2020

Familial adenomatosis polyposis-related desmoid tumours treated with low-dose chemotherapy: results from an international, multi-institutional, retrospective analysis.

ESMO Open 2020 01;5(1)

Medical Oncology, Universita Campus Bio-Medico di Roma, Roma, Lazio, Italy

Introduction: Desmoid tumour (DT) is a locally aggressive fibroblastic proliferative disease representing the most common extraintestinal manifestation of familial adenomatosis polyposis (FAP). As data on the activity of chemotherapy in these patients are limited, we examined the outcomes of patients treated with low-dose methotrexate (MTX)+vinca alkaloids (vinorelbine or vinblastine).

Patients And Methods: We retrospectively reviewed clinical and outcome data from all patients with confirmed FAP-associated DTs treated with weekly MTX+vinca alkaloids in seven European sarcoma reference centres between January 2000 and December 2018. Radiological responses were assessed using RECIST V.1.0 and V.1.1. The Kaplan-Meier method associated to the log-rank test was used to estimate and compare survival curves.

Results: We identified 37 patients (median age 29 years, range 7-44). According to RECIST, 20/37 (54.1%) patients achieved partial response (PR), 15/37 (40.5%) patients had stable disease and 2/37 (5.4%) had progressive disease as best response. Overall, the median progression-free survival (PFS) was 6.5 years (range, 0.3-12.1 years). In the subset of patients achieving PR as best response, the median PFS was not reached. In a subset of 11 patients with progressive disease offered MTX+vinca alkaloids rechallenge (after chemotherapy withdrawal following prolonged disease control), the disease control rate was 100%, resulting in a median PFS after rechallenge of 5.8 years.

Conclusions: This is the largest series on the activity of low-dose chemotherapy in patients with FAP-related DT. In this population, MTX+vinca alkaloids is an active combination, as already reported in patients with sporadic DT.
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http://dx.doi.org/10.1136/esmoopen-2019-000604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003390PMC
January 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

Immune microenvironment profiling of gastrointestinal stromal tumors (GIST) shows gene expression patterns associated to immune checkpoint inhibitors response.

Oncoimmunology 2019;8(9):e1617588. Epub 2019 Jun 4.

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

Few studies were conducted investigating the immunological profiles in gastrointestinal stromal tumors (GIST). Adaptive and innate immune cells are present in the tumor microenvironment, indicating GIST as inflamed tumors. In addition, murine models suggested a potential interaction between immune components and imatinib. In this retrospective study, the GIST immunological profile was investigated through analysis and immunohistochemistry (IHC), exploring the basis for immunotherapy approaches. Gene expression profiles (GEP) from 31 KIT/PDGFRA-mutant GIST were analyzed to evaluate the tumor microenvironment and immunotherapy predictive signatures such as the expanded IFN-γ-induced immune signature (EIIS) and the T-cell-inflamed signature (TIS). GEP and IHC supported the presence of immune infiltrate in GIST, with dominance of CD4+ and CD8+ T cells and M2 macrophages showing a remarkable similarity with melanoma microenvironment. The EIIS genes were expressed in most of GIST samples and positively correlated with PD-L1 abundance ( < .0001). Co-expression was also found between PD-L1 and CD8A ( < .0001) or CD8B ( = .0003). Moreover, the median TIS score for GIST was between the 65th and 70th percentile of the Cancer Genome Atlas dataset, in the same range of tumors responding to anti-PD-1/PD-L1. Analysis of the Gene Expression Omnibus database GIST samples pre- and post-treatment confirmed that imatinib downregulates PD-L1 and IRF1 expression through the inhibition of KIT and PDGFRA, thus contributing to counteract the suppressed adaptive immune response against GIST. The presence of a rich immune infiltrate in GIST along with the presence of TIS and EIIS suggests that GIST may benefit from immunotherapy along with tyrosine kinase inhibitors.
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http://dx.doi.org/10.1080/2162402X.2019.1617588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685519PMC
February 2021

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

The rs17084733 variant in the 3' UTR disrupts a miR-221/222 binding site in gastrointestinal stromal tumour: a sponge-like mechanism conferring disease susceptibility.

Epigenetics 2019 06 13;14(6):545-557. Epub 2019 Apr 13.

a Department of Pharmacy and Biotechnology , University of Bologna , Bologna , Italy.

Several miRNAs are dysregulated in gastrointestinal stromal tumours (GIST), and miR-221/222 appear to have a prominent role in GIST biology. Therefore, we investigated the role of DNA variants located in miR-221/222 precursor sequences and their target 3'UTR. Ninety-five polymorphisms were analysed in 115 GIST cases and 88 healthy controls. 3'UTR rs17084733 and pri-miR-222 rs75246947 were found significantly associated with GIST susceptibility. Specifically, rs17084733 A allele was more common in GIST, particularly in KIT wild-type (WT) patients (Padj = 0.017). rs17084733 variant is located within one of the three miR-221/222 binding sites in the 3'UTR, resulting in a mismatch in this seed region. Conversely, KIT mRNA levels were lower in patients carrying the variant allele, except for mutant GIST. Luciferase assay data in GIST cells, generated using a construct containing all the three miR-221/222 binding sites, are consistent with KIT mRNA levels in GIST patients. Reporter assay data, generated using a construct containing only the site encompassing rs17084733, confirmed that this is a functional variant disrupting the miR-221/222 binding site. In conclusion, this is the first study investigating the role of SNPs on miR-221/222 precursor sequences and their binding region on 3'UTR in GIST. We identified the variant rs17084733 as a possible novel genetic biomarker for risk of developing -WT GIST. Moreover, our findings suggest the role of one of the three miR-221/222 binding sites on 3'UTR as endogenous sponge, soaking up and subtracting miR-221/222 to the other two sites characterized by a higher affinity.
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http://dx.doi.org/10.1080/15592294.2019.1595997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557610PMC
June 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

Clinical relevance of circulating molecules in cancer: focus on gastrointestinal stromal tumors.

Ther Adv Med Oncol 2019 1;11:1758835919831902. Epub 2019 Mar 1.

Department of Pharmacy and Biotechnology, Via Irnerio 48, 40126 Bologna, Italy.

In recent years, growing research interest has focused on the so-called liquid biopsy. A simple blood test offers access to a plethora of information, which might be extremely helpful in understanding or characterizing specific diseases. Blood contains different molecules, of which circulating free DNA (cfDNA), circulating tumor DNA (ctDNA), circulating tumor cells (CTCs) and extracellular vesicles (EVs) are the most relevant. Conceivably, these molecules have the potential for tumor diagnosis, monitoring tumor evolution, and evaluating treatment response and pharmacological resistance. This review aims to present a state-of-the-art of recent advances in circulating DNA and circulating RNA in gastrointestinal stromal tumors (GISTs). To date, progress in liquid biopsy has been scarce in GISTs due to several issues correlated with the nature of the pathology. Namely, heterogeneity in primary and secondary mutations in key driver genes has greatly slowed the development and application in GISTs, unlike in other tumor types in which liquid biopsy has already been translated into clinical practice. However, meaningful novel data have shown in recent years a significant clinical potential of ctDNA, CTCs, EVs and circulating RNA in GISTs.
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http://dx.doi.org/10.1177/1758835919831902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399766PMC
March 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

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

An exploratory study by DMET array identifies a germline signature associated with imatinib response in gastrointestinal stromal tumor.

Pharmacogenomics J 2019 08 20;19(4):390-400. Epub 2018 Sep 20.

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

Imatinib represents the standard therapy for gastrointestinal stromal tumor (GIST) patients with metastatic/unresectable disease. Despite  the excellent results achieved with its introduction, the majority of patients quite invariably experience disease progression. The aim of this study was to understand the contribution of germline DNA polymorphisms in discriminating between imatinib clinical response [evaluated as progression free survival (PFS)] and toxicity. In particular, a discovery cohort (34 GIST with a KIT exon 11 primary mutation, and no toxicity) was analyzed through DMET array that interrogates 1936 variants in 231 genes of the ADME process. We further confirmed the genotype of selected variants in an extended cohort of 49 patients (the original cohort and 15 new cases, all with exon 11 primary mutation), identifying 6 SNPs- ABCB4 rs1202283, ABCC2 rs2273697, ABCG1 rs1541290, CYP11B1 rs7003319, CYP7B1 rs6987861, and NQO1 rs10517-significantly associated with response to imatinib. Three SNPs, ABCB4 rs1202283, ABCC2 rs2273697, and NQO1 rs10517, which had a significant association after adjusted multivariate analysis, were included in a genetic prediction model. We confirmed that these SNPs could stratify the cohort of 49 patients according to the risk of developing progression under imatinib treatment. In conclusion, we identified a genetic signature of response to imatinib therapy in GIST patients able to stratify patients at low and high risk to progress, according to their genotype.
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http://dx.doi.org/10.1038/s41397-018-0050-4DOI Listing
August 2019

Whole Exome Sequencing Uncovers Germline Variants of Cancer-Related Genes in Sporadic Pheochromocytoma.

Int J Genomics 2018 19;2018:6582014. Epub 2018 Aug 19.

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

Background: Pheochromocytomas (PCCs) show the highest degree of heritability in human neoplasms. However, despite the wide number of alterations until now reported in PCCs, it is likely that other susceptibility genes remain still unknown, especially for those PCCs not clearly syndromic.

Methods: Whole exome sequencing of tumor DNA was performed on a set of twelve PCCs clinically defined as sporadic.

Results: About 50% of PCCs examined had somatic mutations on the known susceptibility , , and genes. In addition to these driver events, mutations on , , and genes were also detected. Moreover, extremely rare germline variants were present in half of the sporadic PCC samples analyzed, in particular variants of and were detected in the germline of cases wild-type for mutations in the known susceptibility genes.

Conclusions: Additional somatic passenger mutations can be associated with known susceptibility , , and genes in PCCs, and a wide number of germline variants with still unknown clinical significance can be detected in these patients. Therefore, many efforts should be aimed to better define the pathogenetic role of all these germline variants for discovering novel potential therapeutic targets for this disease still orphan of effective treatments.
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http://dx.doi.org/10.1155/2018/6582014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120303PMC
August 2018