Publications by authors named "Angelo P Dei Tos"

82 Publications

Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities.

Cancer 2021 Apr 28. Epub 2021 Apr 28.

Department of Epidemiology, Regional Health Council, Biomedical Research Institute of Murcia-Arrixaca, Murcia University, Murcia, Spain.

Background: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies.

Methods: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan.

Results: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types.

Conclusions: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients.
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http://dx.doi.org/10.1002/cncr.33618DOI Listing
April 2021

Solid Pseudopapillary Neoplasm of the Pancreas and Abdominal Desmoid Tumor in a Patient Carrying Two Different Germline Mutations: New Horizons from Tumor Molecular Profiling.

Genes (Basel) 2021 Mar 26;12(4). Epub 2021 Mar 26.

Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy.

This case report describes the history of a 41 year-old woman with a solid pseudopapillary neoplasm (SPN) of the pancreas and a metachronous abdominal desmoid tumor (DT) that occurred two years after the SPN surgical resection. At next-generation sequencing of 174 cancer-related genes, both neoplasms harbored a somatic mutation which was different in each tumor. Moreover, two pathogenic mutations were found in both tumors, confirmed as germline by the sequencing of normal tissue. The mutations were c.631G>A, resulting in the amino-acid change p.V211I, and c.7008-2A>T, causing a splice acceptor site loss. However, as the two neoplasms showed neither loss of heterozygosity nor somatic mutation in the second allele, they cannot be considered as -dependent tumors. Nevertheless, this study highlights the important opportunities opened by extensive tumor molecular profiling. In this particular case, it permitted the detection of -germline mutations, essential for addressing the necessary -related genetic counseling, surveillance, and screening for the patient and her family.
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http://dx.doi.org/10.3390/genes12040481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065547PMC
March 2021

Synaptophysin expression in mutated advanced colorectal cancers identifies a new subgroup of tumours with worse prognosis.

Eur J Cancer 2021 Mar 16;146:145-154. Epub 2021 Feb 16.

Department of Oncology, University of Turin at Umberto I "Ordine Mauriziano" Hospital, Turin, Italy.

Background: Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting.

Methods: We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests.

Results: Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001).

Conclusions: Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.
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http://dx.doi.org/10.1016/j.ejca.2021.01.016DOI Listing
March 2021

Primary sclerosing epithelioid fibrosarcoma of the spine: a single-institution experience.

Histopathology 2021 Jan 11. Epub 2021 Jan 11.

Department of Oncological and Degenerative Spine Surgery, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Aims: To present our experience on spinal sclerosing epithelioid fibrosarcoma (SEF) and review the existing literature pertaining to SEF of the spine.

Methods And Results: Six cases of spinal SEF were reviewed, and a literature search of all primary SEFs of the spine was performed. All tumours occurred in adults (median age, 41 years) and were located all along the spine, the lumbar vertebrae being the most commonly involved. All patients presented with pain that they had experienced for months. The mean tumour size at diagnosis was 52 mm. Five tumours showed a spectrum of microscopic features consistent with pure SEF, and one showed a hybrid morphology with areas of low-grade fibromyxoid sarcoma. All were diffusely and strongly positive for mucin 4. Two cases were initially misdiagnosed as epithelioid haemangioendothelioma and aggressive chondroblastoma. Fluorescence in-situ hybridisation showed rearrangements of either FUS or EWSR1 in four cases. Reverse transcription polymerase chain reaction showed the presence of FUS-CREB3L1 and EWSR1-CREB3L1 fusion transcripts in two cases and one case, respectively. Of five patients with follow-up data available, two developed one or more local recurrences and three patients had metastatic disease. Distant metastases were mainly to other osseous locations, followed by lungs and lymph nodes. At last follow-up, three patients had died of disease and one was alive with multiple metastases.

Conclusions: SEF is an aggressive sarcoma that can involve the spine. It is important to recognise the spine as the primary location of SEF, in order to avoid misdiagnosis as more common primary spinal neoplasms, which can impact on therapeutic approaches.
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http://dx.doi.org/10.1111/his.14332DOI Listing
January 2021

The 2020 WHO Classification of Soft Tissue Tumours: news and perspectives.

Pathologica 2020 Nov 3. Epub 2020 Nov 3.

Department of Pathology, Azienda Ospedale Università Padova, Padova, Italy.

Mesenchymal tumours represent one of the most challenging field of diagnostic pathology and refinement of classification schemes plays a key role in improving the quality of pathologic diagnosis and, as a consequence, of therapeutic options. The recent publication of the new WHO classification of Soft Tissue Tumours and Bone represents a major step toward improved standardization of diagnosis. Importantly, the 2020 WHO classification has been opened to expert clinicians that have further contributed to underline the key value of pathologic diagnosis as a rationale for proper treatment. Several relevant advances have been introduced. In the attempt to improve the prediction of clinical behaviour of solitary fibrous tumour, a risk assessment scheme has been implemented. NTRK-rearranged soft tissue tumours are now listed as an "emerging entity" also in consideration of the recent therapeutic developments in terms of NTRK inhibition. This decision has been source of a passionate debate regarding the definition of "tumour entity" as well as the consequences of a "pathology agnostic" approach to precision oncology. In consideration of their distinct clinicopathologic features, undifferentiated round cell sarcomas are now kept separate from Ewing sarcoma and subclassified, according to the underlying gene rearrangements, into three main subgroups (CIC, BCLR and not ETS fused sarcomas) Importantly, In order to avoid potential confusion, tumour entities such as gastrointestinal stroma tumours are addressed homogenously across the different WHO fascicles. Pathologic diagnosis represents the integration of morphologic, immunohistochemical and molecular characteristics and is a key element of clinical decision making. The WHO classification is as a key instrument to promote multidisciplinarity, stimulating pathologists, geneticists and clinicians to join efforts aimed to translate novel pathologic findings into more effective treatments.
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http://dx.doi.org/10.32074/1591-951X-213DOI Listing
November 2020

Primary malignant ossifying fibromyxoid tumour of the bone. A clinicopathologic and molecular report of two cases.

Pathologica 2020 Dec 3;112(4):184-190. Epub 2020 Nov 3.

Department of Pathology, Azienda Ospedale Università Padova, Padova, Italy.

Objective: To report the exceptional occurrence of ossifying fibromyxoid tumour (OFMT) as a primary bone lesion. OFMT is a rare soft tissue tumour of uncertain differentiation and variable malignant potential, that occurs in adults with a slight male predominance. It is typically located in the subcutis or in the skeletal muscles of the extremities, followed by trunk or head and neck.

Methods: Two cases of OFMT proven to arise from bone are presented. The first is a 65-year old female with a history of rib "osteosarcoma", presenting with an inferior lobe left lung mass. The second is a man with a lytic lesion of the 5th cervical vertebra that recurred shortly after resection. Following H&E and immunohistochemical examination, tumour samples were analysed by NGS and by break-apart FISH to detect rearrangement of the and genes.

Results: gene-rearrangement was identified by FISH on both the primary and the metastatic lesion of first patient. NGS identified a (intron1) and (exon 10) fusion transcript later confirmed by positive rearrangement on FISH in the second case.

Conclusions: The demonstration of gene rearrangements represents a fundamental ancillary diagnostic test when presented with challenging examples of OFMT.
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http://dx.doi.org/10.32074/1591-951X-207DOI Listing
December 2020

Activity of sirolimus in patients with progressive epithelioid hemangioendothelioma: A case-series analysis within the Italian Rare Cancer Network.

Cancer 2021 Feb 27;127(4):569-576. Epub 2020 Oct 27.

Department of Medical Oncology, IRCCS Foundation National Cancer Institute, Milan, Italy.

Background: The objective of this study was to report on a retrospective series of patients with epithelioid hemangioendothelioma (EHE) who received treatment with sirolimus within the Italian Rare Cancer Network.

Methods: From January 2005, 38 adult patients with advanced EHE received continuous-dosing sirolimus, 5 mg daily, until they developed either toxicity or disease progression. Disease progression in the 6 months before the start of treatment was required. Each pathologic diagnosis was reviewed. The daily dose of sirolimus was adjusted based on plasma levels. Response was retrospectively assessed by local investigators using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST). Survival was estimated using the Kaplan-Meier method.

Results: All 38 patients (WW Domain Containing Transcription Regulator 1 [WWTR1]-positive, n = 37; transcription factor E3 [TFE3]-positive, n = 1) had disease progression before starting sirolimus (at baseline, 13 of 38 patients had the presence of serosal effusions and systemic symptoms). Thirty-seven patients were evaluable for response (there was 1 early interruption). The best RECIST responses were a partial response in 4 patients (10.8%), stable disease in 28 patients (75.7%), and disease progression in 5 patients (13.5%). At a 41.5-month median follow-up (interquartile range [IQR], 23.9-56.8 months), the median PFS was 13 months (95% CI, 3.7 months to not estimated [NE]), and the median OS was 18.8 months (95% CI, 10.6 months to NE). In patients who had serosal effusions at baseline, the median PFS was 4.8 months (IQR, 3.5-11.7 months), and the median OS was 10.6 months (IQR, 5.1-13.0 months), compared with 47.8 months (IQR, 11.4 months to NE) and 47.8 months (IQR, 15.7 months to NE), respectively, in patients without serosal effusions. Overall, sirolimus was fairly well tolerated, with 10 patients reporting irregular menstruation/ovary disfunction.

Conclusions: The current results confirm that sirolimus is active in EHE, leading to prolonged stabilization in most patients who present without serosal effusions. Serosal effusions are confirmed as an unfavorable prognostic sign associated with short survival, and sirolimus displays limited activity in this subgroup.
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http://dx.doi.org/10.1002/cncr.33247DOI Listing
February 2021

Detection of HPV16/18 E6 Oncoproteins in Head and Neck Squamous Cell Carcinoma Using a Protein Immunochromatographic Assay.

Laryngoscope 2021 05 26;131(5):1042-1048. Epub 2020 Oct 26.

Department of Neurosciences, Regional Center for Head and Neck Cancer, University of Padova, Treviso, Italy.

Objectives/hypothesis: The accurate diagnostic assessment of clinically relevant human papillomavirus (HPV) infections in patients with head and neck squamous cell carcinoma represents an urgent unmet medical need. The aim of this study was to determine feasibility, accuracy, and clinical significance of HPV16/18 E6 oncoprotein detection on cytological specimens from oropharyngeal squamous cell carcinoma (OPSCC) and neck lymph node metastasis of SCC from unknown primary tumor (CUP) via a protein immunochromatographic assay.

Study Design: Cross-sectional study.

Methods: Cytological specimens from primary tumor and neck metastases were collected from 34 patients with OPSCC or CUP and applied to a lateral flow format test that detects HPV16 and HPV18 E6 oncoproteins. E6 oncoprotein positivity or negativity in these specimens was compared to the specimens' "HPV-driven" reference status, defined by presence of HPV-DNA in combination with p16 overexpression and/or HPV E6 seropositivity.

Results: Eighteen of 29 OPSCC (62%) and three of five CUP (60%) were HPV-driven according to our reference method. The E6 oncoprotein lateral flow test had a sensitivity of 94% (95% CI: 70%-100%) and a specificity of 100% (95% CI: 66%-100%) on primary tumor, and a sensitivity of 88% (95% CI: 64%-99%) and a specificity of 100% (95% CI: 74%-100%) on neck metastases. Test agreement between the E6 lateral flow test and the clinical reference method, HPV-DNA plus p16 was excellent, both for primary lesion and neck metastases.

Conclusions: We found the detection of HPV16/18 E6 oncoproteins to be a feasible, highly reliable, and low-invasive method to assess "HPV-driven" status in OPSCC and CUP.

Level Of Evidence: II Laryngoscope, 131:1042-1048, 2021.
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http://dx.doi.org/10.1002/lary.29184DOI Listing
May 2021

Clear cell sarcoma-like/malignant gastrointestinal neuroectodermal tumor of the tongue: a clinicopathologic and molecular case report.

Virchows Arch 2020 Oct 2. Epub 2020 Oct 2.

Department of Pathology, Azienda Ospedale Università Padova, Padua, Italy.

Malignant gastrointestinal neuroectodermal tumor (M-GNET) and clear cell sarcoma (CCS) of soft tissue represent closely related, extremely rare, malignant mesenchymal neoplasm of uncertain differentiation. Both entities are characterized genetically by the same molecular alterations represented by the presence of EWSR1-ATF1 and, more rarely, EWSR1-CREB1 fusion genes. The latter translocation seems to be more represented in M-GNET that, despite significant morphologic overlap with CCS, tends to lack overt features of melanocytic differentiation. Most M-GNET occur in the lower gastrointestinal tract, whereas occurrence in the upper tract has been reported only exceptionally. The differential diagnosis represents a major challenge, and accurate diagnosis impact significantly on therapeutic planning. We herein report the clinicopathologic features of a molecularly confirmed M-GNET that arose at the base of the tongue and review the pertinent literature.
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http://dx.doi.org/10.1007/s00428-020-02933-2DOI Listing
October 2020

Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial.

Lancet Oncol 2020 10 14;21(10):1366-1377. Epub 2020 Sep 14.

Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: Unlike for extremity sarcomas, the efficacy of radiotherapy for retroperitoneal sarcoma is not established. The aim of this study was to evaluate the impact of preoperative radiotherapy plus surgery versus surgery alone on abdominal recurrence-free survival.

Methods: EORTC-62092 is an open-label, randomised, phase 3 study done in 31 research institutions, hospitals, and cancer centres in 13 countries in Europe and North America. Adults (aged ≥18 years) with histologically documented, localised, primary retroperitoneal sarcoma that was operable and suitable for radiotherapy, who had not been previously treated and had a WHO performance status and American Society of Anesthesiologists score of 2 or lower, were centrally randomly assigned (1:1), using an interactive web response system and a minimisation algorithm, to receive either surgery alone or preoperative radiotherapy followed by surgery. Randomisation was stratified by hospital and performance status. Radiotherapy was delivered as 50·4 Gy (in 28 daily fractions of 1·8 Gy) in either 3D conformal radiotherapy or intensity modulated radiotherapy, and the objective of surgery was a macroscopically complete resection of the tumour mass with en-bloc organ resection as necessary. The primary endpoint was abdominal recurrence-free survival, as assessed by the investigator, and was analysed in the intention-to-treat population. Safety was analysed in all patients who started their allocated treatment. This trial is registered with ClinicalTrials.gov, NCT01344018.

Findings: Between Jan 18, 2012 and April 10, 2017, 266 patients were enrolled, of whom 133 were randomly assigned to each group. The median follow-up was 43·1 months (IQR 28·8-59·2). 128 (96%) patients from the surgery alone group had surgery, and 119 (89%) patients in the radiotherapy and surgery group had both radiotherapy and surgery. Median abdominal recurrence-free survival was 4·5 years (95% CI 3·9 to not estimable) in the radiotherapy plus surgery group and 5·0 years (3·4 to not estimable) in the surgery only group (hazard ratio 1·01, 95% CI 0·71-1·44; log rank p=0·95). The most common grade 3-4 adverse events were lymphopenia (98 [77%] of 127 patients in the radiotherapy plus surgery group vs one [1%] of 128 patients in the surgery alone group), anaemia (15 [12%] vs ten [8%]), and hypoalbuminaemia (15 [12%] vs five [4%]). Serious adverse events were reported in 30 (24%) of 127 patients in the radiotherapy plus surgery group, and in 13 (10%) of 128 patients in the surgery alone group. One (1%) of 127 patients in the radiotherapy plus surgery group died due to treatment-related serious adverse events (gastropleural fistula), and no patients in the surgery alone group died due to treatment-related serious adverse events.

Interpretation: Preoperative radiotherapy should not be considered as standard of care treatment for retroperitoneal sarcoma.

Funding: European Organisation for Research and Treatment of Cancer, and European Clinical Trials in Rare Sarcomas.
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http://dx.doi.org/10.1016/S1470-2045(20)30446-0DOI Listing
October 2020

Lipoblastoma-like tumor of the spermatic cord: case report and review of the literature.

Virchows Arch 2021 May 2;478(5):1013-1017. Epub 2020 Jul 2.

Department of Pathology, IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, 40136, Bologna, Italy.

Lipoblastoma-like tumor is a very rare mesenchymal tumor believed to be restricted to female patients and only recently reported in the spermatic cord of a male patient. We describe herein an additional case of lipoblastoma-like tumor occurring in the spermatic cord, describing its histopathological, immunohistochemical, and molecular features.
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http://dx.doi.org/10.1007/s00428-020-02883-9DOI Listing
May 2021

Addition of Antiestrogen Treatment in Patients with Malignant PEComa Progressing to mTOR Inhibitors.

Clin Cancer Res 2020 Oct 30;26(20):5534-5538. Epub 2020 Jun 30.

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

Purpose: Perivascular epithelioid cell tumors (PEComa) are rare mesenchymal neoplasms. mTOR inhibitors are the most active agents in PEComa and in patients progressing to mTOR inhibitors, other available therapies have limited benefit. Preclinical evidences showed a cross-talk between the mTOR pathway and estrogen receptor signaling. This provided a rationale for adding an antiestrogen treatment in female patients becoming resistant to mTOR inhibitors.

Experimental Design: Since April 2018, female patients with advanced/metastatic PEComa progressing to mTOR inhibitors were treated with a combination of sirolimus and exemestane with or without LHRH analogue (based on menopausal status). This case series was retrospectively reviewed. Survival analyses were performed using the Kaplan-Meier method.

Results: A total of seven consecutive patients treated with the combination of sirolimus and antiestrogen treatment were retrospectively reviewed. Six (86%) received a combination of sirolimus and exemestane, whereas one patient (14%) received a combination of sirolimus, exemestane, and triptorelin since in premenopausal status. After a median follow-up of 13.1 months, three patients (43%) experienced a partial response, three patients (43%) experienced a stabilization of disease, and one patient (14%) had disease progression with an overall response rate of 43% and a disease control rate of 86%.

Conclusions: In this small retrospective case series, the addition of antiestrogen treatment in female patients with advanced PEComa progressing to mTOR inhibitors resulted in a remarkable clinical benefit in a setting where no other options are available.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1191DOI Listing
October 2020

Synovial chondrosarcoma: a single-institution experience with molecular investigations and review of the literature.

Histopathology 2020 Sep 28;77(3):391-401. Epub 2020 Jul 28.

Department of Pathology, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy.

Aims: To evaluate the available diagnostic histological criteria for synovial chondrosarcoma and to screen for the presence of IDH1/IDH2 mutations in a series of cases of this malignant cartilaginous neoplasm.

Methods And Results: Ten cases of synovial chondrosarcoma diagnosed at our institute were reviewed. At presentation, all tumours occurred in adults (median age, 62 years). The most common location was the knee joint (five cases), and the size at diagnosis ranged from 30 mm to 170 mm. Eight patients had secondary synovial chondrosarcomas associated with pre-existing/recurrent or concomitant synovial chondromatosis. Five patients had local recurrences and three had lung metastases. All patients with intralesional excisions developed local recurrences, whereas those who underwent wide resections did not. At last follow-up (mean, 91 months), available for nine patients, seven patients were alive and disease-free, one patient had died of disease, and one was alive with paravertebral metastases. Frequent histological features observed included loss of clustering of chondrocytes (nine cases), the presence of variable amounts of myxoid matrix (eight cases), peripheral hypercellularity (eight cases), tumour necrosis (six cases), and spindling of chondrocytes (four cases). Of the seven cases for which it was possible to evaluate bone permeation, six showed infiltration of bone marrow. All seven cases screened for mutations of exon 4 of IDH1 and IDH2 were found to be wild-type.

Conclusions: Histological criteria in correlation with clinical and radiological features allow the recognition of synovial chondrosarcoma. IDH1/IDH2 mutations were not present in synovial chondrosarcoma. Adequate surgical margins are important for disease control.
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http://dx.doi.org/10.1111/his.14170DOI Listing
September 2020

Primary Vascular Tumors of Bone: A Monoinstitutional Morphologic and Molecular Analysis of 427 Cases With Emphasis on Epithelioid Variants.

Am J Surg Pathol 2020 09;44(9):1192-1203

Department of Pathology.

Recent molecular discoveries have refined vascular bone tumor classification. To investigate the clinical relevance of these refinements, we reviewed all cases of primary vascular bone tumors treated at our Institute. On the basis of morphology, cases were assessed immunohistochemically and molecularly. A total of 427 cases of primary vascular tumor of bone with available follow-up and histologic material were retrieved and reclassified according to the most recent diagnostic criteria as follows: 289 hemangiomas, 38 epithelioid hemangiomas, 21 epithelioid hemangioendotheliomas, 2 retiform hemangioendotheliomas, 1 intraosseous papillary intralymphatic angioendothelioma, 24 pseudomyogenic hemangioendotheliomas, and 52 angiosarcomas (of these, 45 were epithelioid angiosarcomas and 7 spindle cell secondary angiosarcoma). Both epithelioid and classic hemangiomas behave as benign tumors with excellent prognosis. The distinction between cellular and conventional type of epithelioid hemangioma was not associated with a different clinical course. Conversely, epithelioid hemangioendothelioma exhibited a more aggressive clinical behavior than hemangioma, with higher rates of multifocality and distant spread. Immunohistochemical positivity for CAMTA1 or TFE3 did not have a prognostic implication. In epithelioid hemangioendothelioma, the presence of morphologic malignant features was associated with reduced disease-free (P=0.064) and overall survival (P=0.055). Pseudomyogenic hemangioendothelioma featured local aggressiveness in 5/24 patients exhibiting a clinical behavior closer to epithelioid hemangioma than epithelioid hemangioendothelioma. Last, 32/45 patients with epithelioid angiosarcoma died of disease with a median survival time of 10 months from diagnosis. In conclusion, the integration of morphologic, immunohistochemical, and molecular features allows a better stratification of primary vascular tumors of bone with significant prognostic and therapeutic implications.
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http://dx.doi.org/10.1097/PAS.0000000000001487DOI Listing
September 2020

Assessment of Safety and Efficacy of Combined Trabectedin and Low-Dose Radiotherapy for Patients With Metastatic Soft-Tissue Sarcomas: A Nonrandomized Phase 1/2 Clinical Trial.

JAMA Oncol 2020 04;6(4):535-541

TERABIS Group, IBiS (Instituto de Biomedicina de Sevilla), Sevilla, Spain.

Importance: Active therapeutic combinations, such as trabectedin and radiotherapy, offer potentially higher dimensional response in second-line treatment of advanced soft-tissue sarcomas. Dimensional response can be relevant both for symptom relief and for survival.

Objective: To assess the combined use of trabectedin and radiotherapy in treating patients with progressing metastatic soft-tissue sarcomas.

Design, Setting, And Participants: Phase 1 of this nonrandomized clinical trial followed the classic 3 + 3 design, with planned radiotherapy at a fixed dose of 30 Gy (3 Gy/d for 10 days) and infusion of trabectedin at 1.3 mg/m2 as the starting dose, 1.5 mg/m2 as dose level +1, and 1.1 mg/m2 as dose level -1. Phase 2 followed the Simon optimal 2-stage design. Allowing for type I and II errors of 10%, treatment success was defined as an overall response rate of 35%. This study was conducted in 9 sarcoma referral centers in Spain, France, and Italy from April 13, 2015, to November 20, 2018. Adult patients with progressing metastatic soft-tissue sarcoma and having undergone at least 1 previous line of systemic therapy were enrolled. In phase 2, patients fitting inclusion criteria and receiving at least 1 cycle of trabectedin and the radiotherapy regimen constituted the per-protocol population; those receiving at least 1 cycle of trabectedin, the safety population.

Interventions: Trabectedin was administered every 3 weeks in a 24-hour infusion. Radiotherapy was required to start within 1 hour after completion of the first trabectedin infusion (cycle 1, day 2).

Main Outcomes And Measures: The dose-limiting toxic effects of trabectedin (phase 1) and the overall response rate (phase 2) with use of trabectedin plus irradiation in metastatic soft-tissue sarcomas.

Results: Eighteen patients (11 of whom were male) were enrolled in phase 1, and 27 other patients (14 of whom were female) were enrolled in phase 2. The median ages of those enrolled in phases 1 and 2 were 42 (range, 23-74) years and 51 (range, 27-73) years, respectively. In phase 1, dose-limiting toxic effects included grade 4 neutropenia lasting more than 5 days in 1 patient at the starting dose level and a grade 4 alanine aminotransferase level increase in 1 of 6 patients at the +1 dose level. In phase 2, among 25 patients with evaluable data, the overall response rate was 72% (95% CI, 53%-91%) for local assessment and 60% (95% CI, 39%-81%) for central assessment.

Conclusions And Relevance: The findings of this study suggest that the recommended dose of trabectedin for use in combination with this irradiation regimen is 1.5 mg/m2. The trial met its primary end point, with a high overall response rate that indicates the potential of this combination therapy for achieving substantial tumor shrinkage beyond first-line systemic therapy in patients with metastatic, progressing soft-tissue sarcomas.

Trial Registration: ClinicalTrials.gov Identifier: NCT02275286.
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http://dx.doi.org/10.1001/jamaoncol.2019.6584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042948PMC
April 2020

Ewing sarcoma and Ewing-like tumors.

Virchows Arch 2020 Jan 4;476(1):109-119. Epub 2019 Dec 4.

Department of Pathology, Azienda Ospedaliera Universitaria di Padova, Padova, Italy.

Ewing sarcoma (ES) and Ewing-like sarcomas are highly aggressive round cell mesenchymal neoplasms, most often occurring in children and young adults. The identification of novel molecular alterations has greatly contributed to a profound reappraisal of classification, to the extent that the category of undifferentiated round cell sarcoma has significantly shrunk. In fact, in addition to Ewing sarcoma, we currently recognize three main categories: round cell sarcomas with EWSR1 gene fusion with non-ETS family members, CIC-rearranged sarcomas, and BCOR-rearranged sarcomas. Interestingly, despite significant morphologic overlap, most of these entities tend to exhibit morphologic features predictive of the underlying molecular alteration. Ewing sarcoma is the prototype of round cell sarcoma whereas in CIC sarcomas, focal pleomorphism and epithelioid morphology can predominate. BCOR sarcomas often exhibit a spindled neoplastic cell population. NFATC2 sarcoma may exhibit remarkable epithelioid features, and PATZ1 sarcomas often feature a sclerotic background. The differential diagnosis for these tumors is rather broad, and among round cell sarcomas includes alveolar rhabdomyosarcoma, desmoplastic small round cell tumor, poorly differentiated round cell synovial sarcoma, small cell osteosarcoma, and mesenchymal chondrosarcoma. A combination of morphologic, immunohistochemical, and molecular findings allows accurate classification in most cases. A granular diagnostic approach to Ewing sarcoma and Ewing-like sarcomas is justified by significant differences in terms of both response to chemotherapy and overall survival. As all these entities are in part defined by specific fusion genes, a molecular diagnostic approach based on NGS technology should be considered. In consideration of the extreme rarity of many of these tumor entities, referral to expert rare cancer centers or to rare cancer networks represents the best strategy in order to minimize diagnostic inaccuracy, and allow proper patient management.
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http://dx.doi.org/10.1007/s00428-019-02720-8DOI Listing
January 2020

Interferon-Gamma and Tumor Necrosis Factor-Related Weak Inducer of Apoptosis Expression in Neoangiogenesis in Colorectal Polypoid Lesions.

Eur Surg Res 2019 9;60(5-6):186-195. Epub 2019 Oct 9.

General Surgery Unit, University Hospital of Padova, Padova, Italy,

Background: Interferon gamma (IFNγ) and tumor necrosis factor-related weak inducer of apoptosis (TWEAK) molecules seem to have a potential effect on angiogenic factors such as vascular endothelial growth factor (VEGF). The aim of this study was to assess a possible interplay between IFNγ and TWEAK cytokines and VEGF machinery in the different steps of colorectal carcinogenesis.

Methods: A total of 92 subjects with colonic adenoma or cancer who underwent screening colonoscopy or surgery were prospectively enrolled. Polypoid lesion tissue samples were collected and frozen. Real-time reverse transcription polymerase chain reaction for IFNγ, TWEAK, and VEGF-A mRNA expression was performed. Immunoassays for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were also performed. Nonparametric statistics, receiver operating characteristic curve analysis, and logistic multiple regression analysis were used.

Results: IFNγ and TWEAK mRNA expression was higher in patients with T2 or more advanced colorectal cancer than in those with adenomas or T1 cancer (p < 0.001 and p = 0.01, respectively). IFNγ and TWEAK mRNA expression levels directly correlated with VEGF-A mRNA expression levels (rho = 0.44, p < 0.001 and rho = 0.29, p = 0.004, respectively). On the contrary, IFNγ and TWEAK mRNA expression levels inversely correlated with VEGF-C protein levels (rho = -0.29, p = 0.04 and rho = -0.31, p = 0.03, respectively). Similarly, IFNγ and TWEAK mRNA expression levels inversely correlated with VEGFR2 protein levels (rho = -0.38, p = 0.033 and rho = -0.40, p = 0.025, respectively).

Conclusion: This study showed that in colorectal polypoid lesions, IFNγ and TWEAK expressions are directly correlated to VEGF-A expression but inversely correlated with VEGFR2 levels, suggesting a possible feedback mechanism in the regulation of VEGF-A expression.
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http://dx.doi.org/10.1159/000502786DOI Listing
June 2020

Role of Chemotherapy, VEGFR Inhibitors, and mTOR Inhibitors in Advanced Perivascular Epithelioid Cell Tumors (PEComas).

Clin Cancer Res 2019 09 19;25(17):5295-5300. Epub 2019 Jun 19.

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

Purpose: Perivascular epitheliod cell tumors (PEComas) are rare mesenchymal neoplasms for which the role of systemic treatments is not established as there are no published prospective clinical trials or sufficiently large retrospective case series. The aim of this study is to clarify the activity of conventional chemotherapy and biological agents in advanced/metastatic PEComas.

Experimental Design: This was an observational, retrospective, international study that included patients with advanced/metastatic PEComa treated with systemic therapy at 5 European sarcoma reference centers and within the Italian Rare Cancer Network. Survival analyses were performed using the Kaplan-Meier method and the Cox hazards regression models.

Results: A total of 53 patients were included. Cytotoxic chemotherapy regimens were active only in a small proportion of PEComas. Gemcitabine-based regimens [objective response rate (ORR): 20%, median progression-free survival (PFS): 3.4 months] seemed to have the same activity of anthracycline-based regimens (ORR: 13%, median PFS: 3.2 months). Antiangiogenic agents resulted in disease stabilization in some patients, with a number having density changes/tissue response on imaging, with an ORR of 8.3% and a median PFS of 5.4 months. mTOR inhibitors were the most active agents, with an ORR of 41% and a median PFS of 9 months.

Conclusions: Our study provides data for the selection of systemic therapy in patients with advanced/metastatic PEComa: mTOR inhibitors are the most active agents. Antiangiogenics and chemotherapy with gemcitabine-based regimens or anthracycline-based regimens are options in further line, but with a lower response rate and PFS.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0288DOI Listing
September 2019

Trabectedin and RAdiotherapy in Soft Tissue Sarcoma (TRASTS): Results of a Phase I Study in Myxoid Liposarcoma from Spanish (GEIS), Italian (ISG), French (FSG) Sarcoma Groups.

EClinicalMedicine 2019 Mar 11;9:35-43. Epub 2019 Mar 11.

Biomedicine Institute of Seville (IBIS), Spain.

Background: Myxoid liposarcoma (ML) exhibits a special sensitivity to trabectedin (T) and radiation therapy (RT). Preclinical data suggest a synergistic effect. We aimed to study safety, feasibility and activity of the administration of pre-operative concurrent T and RT in patients affected by localized resectable ML.

Methods: Patients received 3 cycles (C) of T in combination with RT (45 Gy) in 25 fractions (1.8 Gy/fraction). Dose Levels for T were: - 1 (1.1 mg/m2), 0 (1.3 mg/m2) and 1 (1.5 mg/m2). Primary endpoint was safety; antitumor activity was assessed by RECIST and Choi criteria. This study is registered at ClinicalTrials.gov, number NCT02275286. The phase 1 part of the study is complete and phase 2 is ongoing.

Findings: From February 2015 to May 2016, 14 patients (M/F 7/7), median age 36 years (range 24-70) and median tumor size 12.5 cm (range 7-17 cm), were enrolled. One dose limiting toxicity (G3 transaminitis) occurred at Level 0 and one (sepsis due to catheter infection) at Level 1. All patients completed RT. Five patients achieved PR (36%), 8 SD (57%), 1 distant PD (7%) by RECIST, while 12 achieved PR (86%), 1 SD (7%) and 1 distant PD (7%) by Choi criteria. Twelve patients underwent surgery. Median viable residual tumor was 5% (0-60).

Interpretation: T in combination with RT showed a favorable safety profile and antitumor activity in localized ML. T dose of 1.5 mg/m2 is the recommended dose for the phase 2 study, which is ongoing.

Funding: This study was partially supported by Pharmamar.
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http://dx.doi.org/10.1016/j.eclinm.2019.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510725PMC
March 2019

NR4A3 fusion proteins trigger an axon guidance switch that marks the difference between EWSR1 and TAF15 translocated extraskeletal myxoid chondrosarcomas.

J Pathol 2019 09 14;249(1):90-101. Epub 2019 May 14.

Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma histotype with uncertain differentiation. EMC is hallmarked by the rearrangement of the NR4A3 gene, which in most cases fuses with EWSR1 or TAF15. TAF15-translocated EMC seem to feature a more aggressive course compared to EWSR1-positive EMCs, but whether the type of NR4A3 chimera impinges upon EMC biology is still largely undefined. To gain insights on this issue, a series of EMC samples (7 EWSR1-NR4A3 and 5 TAF15-NR4A3) were transcriptionally profiled. Our study unveiled that the two EMC variants display a distinct transcriptional profile and that the axon guidance pathway is a major discriminant. In particular, class 4-6 semaphorins and axonal guidance cues endowed with pro-tumorigenic activity were more expressed in TAF15-NR4A3 tumors; vice versa, class 3 semaphorins, considered to convey growth inhibitory signals, were more abundant in EWSR1-NR4A3 EMC. Intriguingly, the dichotomy in axon guidance signaling observed in the two tumor variants was recapitulated in in vitro cell models engineered to ectopically express EWSR1-NR4A3 or TAF15-NR4A3. Moreover, TAF15-NR4A3 cells displayed a more pronounced tumorigenic potential, as assessed by anchorage-independent growth. Overall, our results indicate that the type of NR4A3 chimera dictates an axon guidance switch and impacts on tumor cell biology. These findings may provide a framework for interpretation of the different clinical-pathological features of the two EMC variants and lay down the bases for the development of novel patient stratification criteria and therapeutic approaches. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766969PMC
September 2019

The impact of chemotherapy on survival of patients with extremity and trunk wall soft tissue sarcoma: revisiting the results of the EORTC-STBSG 62931 randomised trial.

Eur J Cancer 2019 03 25;109:51-60. Epub 2019 Jan 25.

Sarcoma Service, Department of Surgery, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy. Electronic address:

Background: This study was aimed at determining whether patients with high-risk soft tissue sarcoma (STS), as identified using the nomogram Sarculator, benefitted from adjuvant chemotherapy in the EORTC-STBSG 62931 randomised controlled trial (RCT), which failed to detect an impact for adjuvant doxorubicin plus ifosfamide (Adj) over observation (Obs).

Methods: Patients with extremity and trunk wall STS in the EORTC-STBSG 62931 RCT were analysed (N = 290/351). Ten-year predicted probability of overall survival (pr-OS) was calculated using the prognostic nomogram Sarculator. Patients were grouped into three categories of predicted pr-OS: high (pr-OS>66%), intermediate (51
Results: Nomogram pr-OS was dispersed (median 72%, interquartile range 57-83%) and had prognostic value for OS and DFS (log-rank test: P < 0.001). One hundred seventy, 68 and 52 patients had high (58.6%, 90 Obs/80 Adj), intermediate (23.5%, 34 Obs/34 Adj) and low pr-OS (17.9%, 24 Obs/28 Adj), respectively. Adjuvant chemotherapy halved the risk of recurrence (hazard ratio [HR] = 0.46, 95% confidence interval [CI] 0.24-0.89) and death (HR = 0.46, 95% CI 0.23-0.94) in the low pr-OS category, while no effect was detected in intermediate and high pr-OS categories. To strengthen these findings, study participants with pr-OS<60% were combined (N = 80, 27.6%, 39 Obs/41 Adj), and a significant DFS (HR = 0.49, 95% CI 0.28-0.85) and OS (HR = 0.50, 95% CI 0.30-0.90) benefit was detected.

Conclusion: Patients of the EORTC-STBSG 62931 RCT with extremity and trunk wall STS and a low predicted pr-OS (high-risk patients) had better outcomes when treated with adjuvant chemotherapy. This may help reconcile the disparate results of clinical studies on adjuvant/neoadjuvant chemotherapy in STS.
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http://dx.doi.org/10.1016/j.ejca.2018.12.009DOI Listing
March 2019

Chordoma: update on disease, epidemiology, biology and medical therapies.

Curr Opin Oncol 2019 03;31(2):114-120

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori.

Purpose Of Review: Chordoma is an exceedingly rare subtype of bone sarcoma. This review aims to provide a comprehensive insight into chordoma epidemiology, and an update on the recent advances in disease, biology and medical therapies.

Recent Findings: The incidence of chordoma is approximately 0.08/100 000 and the 5-year overall age-adjusted relative survival is 72% in the United States and 61% in Europe. Over the last years, significant steps forwards have been done in the comprehension of chordoma complexity, with insights gained into the biology and morphology of this disease. New entities have been described and potentially druggable molecular targets identified. This is becoming all the more relevant today, as new potentially active agents are under development.

Summary: Chordoma is a complex disease because of its rarity, biological heterogeneity and peculiar clinical behaviour. Despite the progress done, the outcome in this disease remains unsatisfactory and the identification of active systemic treatments remains an urgent, unmet medical need.
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http://dx.doi.org/10.1097/CCO.0000000000000502DOI Listing
March 2019

Osteoblastoma-like osteosarcoma: high-grade or low-grade osteosarcoma?

Histopathology 2019 Feb 4;74(3):494-503. Epub 2018 Nov 4.

Department of Pathology, IRCCS Rizzoli Orthopaedic Institute, Bologna, Italy.

Aims: Osteoblastoma-like osteosarcoma is a rare variant of osteosarcoma (1% of all osteosarcomas), histologically similar to osteoblastoma. In the current World Health Organisation (WHO) classification, osteoblastoma-like osteosarcoma is classified within the group of conventional (high-grade) osteosarcomas. However, several published cases have been actually regarded as low-grade malignant tumours. As strict morphological criteria to distinguish between low- and high-grade lesions are not available, we reviewed our series of osteoblastoma-like osteosarcomas in the attempt to identify clinical and morphological features predictive of aggressiveness.

Methods And Results: We retrieved 15 cases of osteoblastoma-like osteosarcoma from the files of the Istituto Ortopedico Rizzoli. Patients received various treatments. Five patients developed metastasis and five patients developed local recurrences (all after incomplete surgery). Eleven patients were alive without disease, while four patients died of their disease. Statistical analysis revealed a statistically significant (P = 0.048) lower disease-free survival in patients with areas of conventional (high-grade) osteosarcoma.

Conclusions: With the important limitation of a small cohort of patients, the presence of areas of conventional (high-grade) osteosarcoma is the only parameter to predict the aggressiveness of osteoblastoma-like osteosarcoma.
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http://dx.doi.org/10.1111/his.13746DOI Listing
February 2019

The pathology of soft tissue sarcomas.

Radiol Med 2019 Apr 12;124(4):266-281. Epub 2018 Jun 12.

Department of Pathology, Azienda ULSS 2 "Marca Trevigiana", Piazza Ospedale, 1, 31100, Treviso, Italy.

Soft tissue sarcomas represent a heterogeneous group of rare malignancies exhibiting mesenchymal differentiation with an overall incidence of around 5/100,000/year. Rarity and morphologic heterogeneity significantly affect diagnostic accuracy; therefore, expertise can be achieved only through access to large number of cases. Soft tissue sarcomas are currently classified on the basis of the 2013 WHO classification of soft tissue tumors that integrate conventional morphology with immunohistochemistry and molecular genetics. The morphologic diagnosis of sarcoma relies on the evaluation as well as the integration of four main features: the shape of the neoplastic cells; the pattern of growth; the quality of the background; the architecture of the vascular network. Immunohistochemical characterization plays a key role in the diagnostic workup of soft tissue sarcomas. The majority of classic differentiation markers tend to show good sensitivity, however, associated with rather limited specificity, making interpretation in context with morphology mandatory. Molecular genetics is increasingly used for diagnostic purposes to distinguish specific subtypes of sarcomas, to support diagnosis in non-canonical clinical presentations and also to distinguish true sarcomas from benign mimickers. With many exceptions, histologic typing does not provide sufficient information for predicting the clinical course of the disease and, therefore, grading systems based on histological parameters were introduced to provide a more accurate estimation of the degree of malignancy of tumors. The three-tiered system devised by the French Federation of Cancer Centers Sarcoma Group (FNCLCC) systems is widely adopted; however, several limitations exist that have led to the development of prognostic nomograms that incorporate the specific histotype as one of the relevant parameters.
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http://dx.doi.org/10.1007/s11547-018-0882-7DOI Listing
April 2019

Anthracycline, Gemcitabine, and Pazopanib in Epithelioid Sarcoma: A Multi-institutional Case Series.

JAMA Oncol 2018 09 13;4(9):e180219. Epub 2018 Sep 13.

Department of Pathology, Radboud University Medical Centre, Nijmegen, the Netherlands.

Importance: Epithelioid sarcoma (ES) is an exceedingly rare malignant neoplasm with distinctive pathologic, molecular, and clinical features as well as the potential to respond to new targeted drugs. Little is known on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in this disease.

Objective: To report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with advanced ES.

Design, Setting, And Participants: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis of patients with locally advanced/metastatic ES diagnosed between 1990 and 2016. Local pathological review was performed in all cases to confirm diagnosis according to most recent criteria.

Exposures: All patients included in the study received anthracycline-based regimens, gemcitabine-based regimens, or pazopanib.

Main Outcome And Measures: Response was assessed by RECIST. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Classic and proximal subtypes were defined based on morphology (according to 2013 World Health Organization guidelines).

Results: Overall, 115 patients were included, 80 (70%) were men and 35 (30%) were women, with a median age of 32 years (range, 15-77 years). Of the 115 patients with ES, 85 were treated with anthracycline-based regimens, 41 with gemcitabine-based regimens, and 18 with pazopanib. Twenty-four received more than 1 treatment. Median follow-up was 34 months. Response rate for anthracycline-based regimens was 22%, with a median PFS of 6 months. One complete response (CR) was reported. A trend toward a higher response rate was noticed in morphological proximal type (26%) vs classic type (19%) and in proximal vs distal primary site (26% vs 18%). The response rate for gemcitabine-based regimens was 27%, with 2 CR and a median PFS of 4 months. In this group, a trend toward a higher response rate was reported in classic vs proximal morphological type (30% vs 22%) and in distal vs proximal primary site (40% vs 14%). In the pazopanib group, no objective responses were seen, and median PFS was 3 months.

Conclusions And Relevance: This is the largest retrospective series of systemic therapy in ES. We confirm a moderate activity of anthracycline-based and gemcitabine-based regimens in ES, with a similar response rate and PFS in both groups. The value of pazopanib was low. These data may serve as a benchmark for trials of novel agents in ES.
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http://dx.doi.org/10.1001/jamaoncol.2018.0219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143006PMC
September 2018

Prolonged activity and toxicity of sirolimus in a patient with metastatic renal perivascular epithelioid cell tumor: a case report and literature review.

Anticancer Drugs 2018 07;29(6):589-595

Departments of Medicine, Adult Mesenchymal and Rare Tumor Medical Oncology Unit.

Perivascular epithelioid cell tumor (PEComa) is a family of mesenchymal tumors. Conventional chemotherapy has little activity in this disease, but case reports are available on the activity of mammalian target of rapamycin inhibitors (e.g. sirolimus and temsirolimus). Pharmacokinetic assays of sirolimus are available as this drug has a precise therapeutic window and blood levels might be influenced by CYP3A4 polymorphisms and drug interactions. We report on a case of a patient with metastatic, progressive PEComa who started sirolimus at a dose of 5 mg/day with evidence of grade (G) 3 mucositis, G2 thrombocytopenia, and G1 leucopenia 10 days after the treatment started, in absence of concomitant medications or prohibited food assumption. Elevated sirolimus blood levels were detected (156.8 ng/ml). Sirolimus was stopped, and toxicity resolved in 5 weeks. Computed tomography scan 2 months after the treatment started showed a partial response (RECIST). After toxicity resolution, the patient restarted sirolimus at a dose of 1 mg/day, with blood levels in the range of 10-20 ng/ml. Tumor response was confirmed and maintained, and the patient is still under treatment 18 months later, with no additional adverse effects. Genetic analysis of five selected polymorphisms (rs2740574, rs776746, rs1128503, rs2032582, and rs1045642) in drug metabolism enzymes and transporters did not provide a clear explanation of the observed unusual pharmacokinetic. This case confirms the activity of mammalian target of rapamycin inhibitors in PEComa and strengthens the importance of pharmacokinetic drug blood levels monitoring in patients treated with sirolimus. In our patient, after dose adjustment, sirolimus could be restarted with a prolonged clinical benefit and no additional toxicity.
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http://dx.doi.org/10.1097/CAD.0000000000000634DOI Listing
July 2018

Activity of anthracycline- and ifosfamide-based chemotherapy in a series of patients affected by advanced myxofibrosarcoma.

Clin Sarcoma Res 2017 22;7:16. Epub 2017 Aug 22.

Medical Oncology Unit 2, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.

Background: We report on the activity of anthracycline-based and high-dose prolonged-infusion ifosfamide chemotherapy in a retrospective series of patients affected by advanced myxofibrosarcoma treated at Istituto Nazionale Tumori in Milan, Italy, and within the Italian Rare Cancer Network (RTR).

Methods: Advanced myxofibrosarcoma patients treated with anthracycline + ifosfamide and high-dose prolonged-infusion ifosfamide as a single agent from November 2001 to December 2016 were retrospectively reviewed. All pathological diagnosis were centrally reviewed by at least two expert pathologists. Response was evaluated by RECIST, and survival functions were computed.

Results: Among 34 advanced myxofibrosarcoma patients, 13 were treated with front-line anthracycline + ifosfamide chemotherapy (male/female = 6/7, median age 54 years, range 33-72). Overall best response was: 4 partial responses, 3 stable diseases and 6 progressive diseases, with a median progression-free survival of 4 months. Twenty-eight patients received second/further line high-dose prolonged-infusion ifosfamide (male/female = 17/11, median age 55 years, range 27-75 years). We observed 10 partial responses, 4 stable diseases and 14 progressive diseases, with a median progression-free survival of 4 months. Median overall survival was 12 months.

Conclusions: This retrospective analysis suggests that the combination of anthracyclines and ifosfamide is active in myxofibrosarcoma. In patients already treated with a combination of anthracyclines and ifosfamide, high-dose prolonged-infusion ifosfamide showed activity as well.
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http://dx.doi.org/10.1186/s13569-017-0082-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568720PMC
August 2017

Soft Tissue Tumors Rarely Presenting Primary in Bone; Diagnostic Pitfalls.

Surg Pathol Clin 2017 Sep 29;10(3):705-730. Epub 2017 Jun 29.

Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy; Department of Medicine, University of Padua School of Medicine, Padua, Italy. Electronic address:

Primary bone sarcomas represent extremely rare entities. The use of now abolished labels, such as malignant fibrous histiocytoma and hemangiopericytoma, has significantly hampered the chance of identifying specific entities. It is now accepted that a broad variety of mesenchymal malignancies most often arising on the soft tissue may actually present as primary bone lesions. A more accurate morphologic partition is justified based on availability of distinct therapeutic options. An integrated diagnostic approach represents the only way to achieve a correct classification. In consideration of the significant complexity, primary bone sarcomas should ideally be handled in the context of expert centers.
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http://dx.doi.org/10.1016/j.path.2017.04.013DOI Listing
September 2017

Rare Neoplasm Mimicking Neuoroendocrine Pancreatic Tumor: A Case Report of Solitary Fibrous Tumor with Review of the Literature.

Anticancer Res 2017 06;37(6):3093-3097

Department of Surgery (IV unit), Regional Hospital "Ca' Foncello", Treviso, Italy.

Background: Solitary fibrous tumors (SFTs) are rare biological entities described mainly in the pleura. To date, in the pancreas, only 14 cases have been reported in the English literature.

Case Report: A 52-year-old male was diagnosed incidentally with a suspected neuroendocrine tumor (NET) of the pancreas. He underwent pancreatic enucleation of the mass, which, at final pathology, showed spindle cell proliferation set in a collagenous background and featuring the presence of hemangiopericytoma-like blood. Immunohistochemistry showed cytoplasmic expression of CD34 and nuclear expression of STAT6. As mitotic activity was of 1 mitoses/10 high-power fields (HPFs) a diagnosis of conventional SFT was made. The patient was discharged without major complications and is alive and free of disease after 24 months.

Conclusion: SFTs of pancreas are rare tumors, often mimicking pancreatic NET.
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http://dx.doi.org/10.21873/anticanres.11665DOI Listing
June 2017