Establishment of an Academic Tissue Microarray Platform as a Tool for Soft Tissue Sarcoma Research.

Soft tissue sarcoma (STS) is a heterogeneous family of rare mesenchymal tumors, characterized by histopathological and molecular diversity. Tissue microarray (TMA) is a tool that allows performing research in orphan diseases in a more efficient and cost-effective way. TMAs are paraffin blocks consisting of multiple small representative tissue cores from biological samples, for example, from multiple donors, diverse sites of disease, or multiple different diseases. In 2015, we began constructing TMAs using archival tumor material from STS patients. Specimens were well annotated in terms of histopathological diagnosis, treatment, and clinical follow-up of the tissue donors. Each TMA block contains duplicate or triplicate 1.0-1.5 mm tissue cores from representative tumor areas selected by sarcoma pathologists. The construction of TMAs was performed with TMA Grand Master (3DHistech). So far, we have established disease-specific TMAs from 7 STS subtypes: gastrointestinal stromal tumor (72 cases included in the array), alveolar soft part sarcoma (n = 12 + 47), clear cell sarcoma (n = 22 + 32), leiomyosarcoma (n = 55), liposarcoma (n = 42), inflammatory myofibroblastic tumor (n = 12 + 21), and alveolar rhabdomyosarcoma (n = 24). We also constructed a multisarcoma TMA covering a representative number of important histopathological subtypes on arrays for screening purposes, namely, angiosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, and myxoid liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, myxofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma, with 7-11 individual cases per subtype. We are currently expanding the list of TMAs with additional sarcoma entities, considering the heterogeneity of this family of tumors. Our extensive STS TMA platform is suitable for rapid and cost-effective morphological, immunohistochemical, and molecular characterization of the tumor as well as for the identification of potential novel diagnostic markers and drug targets. It is readily available for collaborative projects with research partners.

Retrospective Analysis of Patients with Advanced Liposarcoma in a Tertiary Referral Center.

BACKGROUND: Liposarcoma (LPS) is a common subtype of soft tissue sarcoma. We describe the clinical outcome of patients with advanced LPS treated in a tertiary referral center and explore potential prognostic factors. PATIENTS AND METHODS: We retrospectively reviewed the records of patients with inoperable or metastatic dedifferentiated liposarcoma (DDLPS), myxoid/round cell liposarcoma (MLPS), and pleomorphic liposarcoma (PLPS) diagnosed and/or treated at the University Hospitals Leuven, Leuven, Belgium, between 2000 and 2014. RESULTS: We identified 100 patients with LPS (67 DDLPS, 25 MLPS, and 8 PLPS). Median overall survival from diagnosis of inoperable or metastatic disease was 13.0 months, without substantial variation between histological subtypes. Sixty-seven patients were treated with systemic chemotherapy. The most common first-line chemotherapeutic agents used were doxorubicin (n = 32), doxorubicin + alkylating agent (n = 16), and trabectedin (n = 5). Best response upon first-line treatment was partial/complete response, stable disease, or progressive disease in 17, 25, and 46% of patients, respectively. On multivariate analysis, metastasectomy and objective response or stable disease achieved with first-line chemotherapy were indicators for better overall survival. CONCLUSION: The LPS subtypes analyzed have a poor prognosis and low response rates to chemotherapy. The prognostic factors identified support the concept of offering systemic chemotherapy to patients with inoperable, advanced disease and of considering metastasectomy in eligible patients.

Crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumours with and without anaplastic lymphoma kinase gene alterations (European Organisation for Research and Treatment of Cancer 90101 CREATE): a multicentre, single-drug, prospective, non-randomised phase 2 trial.

BACKGROUND: An inflammatory myofibroblastic tumour (IMFT) is a rare mesenchymal neoplasm characterised by anaplastic lymphoma kinase (ALK) gene rearrangements. We assessed the activity and safety of crizotinib, a tyrosine kinase inhibitor, targeting ALK in patients with advanced IMFT either with or without ALK alterations. METHODS: We did a multicentre, biomarker-driven, single-drug, non-randomised, open-label, two-stage phase 2 trial (European Organisation for Research and Treatment of Cancer 90101 CREATE) at 13 study sites (five university hospitals and eight specialty clinics) in eight European countries (Belgium, France, Germany, Italy, Netherlands, Poland, Slovakia, and the UK). Eligible participants were patients aged at least 15 years with a local diagnosis of advanced or metastatic IMFT deemed incurable with surgery, radiotherapy, or systemic therapy; measurable disease; an Eastern Cooperative Oncology Group performance status of 0-2; and adequate haematological, renal, and liver function. Central reference pathology was done for confirmation of the diagnosis, and ALK positivity or negativity was assessed centrally using immunohistochemistry and fluorescence in-situ hybridisation based on archival tumour tissue and defined as ALK immunopositivity or rearrangements in at least 15% of tumour cells. Eligible ALK-positive and ALK-negative patients received oral crizotinib 250 mg twice per day administered on a continuous daily dosing schedule (the duration of each treatment cycle was 21 days) until documented disease progression, unacceptable toxicity, or patient refusal. If at least two of the first 12 eligible and assessable ALK-positive patients achieved a confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, a maximum of 35 patients were to be enrolled. If at least six ALK-positive patients achieved a confirmed response, the trial would be deemed successful. The primary endpoint was the proportion of patients who achieved an objective response (ie, a complete or partial response) as per RECIST 1.1, with response confirmation assessed by the local investigator every other cycle. Activity and safety endpoints were analysed in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01524926. FINDINGS: Between Oct 3, 2012, and April 12, 2017, we recruited and treated 20 eligible participants, 19 of whom were assessable for the primary endpoint. Median follow-up was 863 days (IQR 358-1304). Six of 12 ALK-positive patients (50%, 95% CI 21·1-78·9) and one of seven ALK-negative patients (14%, 0·0-57·9) achieved an objective response. The most common treatment-related adverse events in the 20 participants were nausea (11 [55%]), fatigue (9 [45%]), blurred vision (nine [45%]), vomiting (seven [35%]), and diarrhoea (seven [35%]). Eight serious adverse events occurred in five patients: pneumonia, fever of unknown cause, a heart attack with increased creatinine and possible sepsis, an abdominal abscess with acute renal insufficiency, and a QT prolongation. INTERPRETATION: With 50% of participants with ALK-positive tumours achieving an objective response, crizotinib met the prespecified criteria for success in this trial. The results presented here support the rationale for inhibiting ALK in patients with IMFT. Crizotinib could be considered as the standard of care for patients with locally advanced or metastatic ALK-positive IMFT who do not qualify for curative surgery. FUNDING: The European Organisation for Research and Treatment of Cancer and Pfizer.

Incidence of osteonecrosis of the jaw in patients with bone metastases treated sequentially with bisphosphonates and denosumab.

OBJECTIVES: Osteonecrosis of the jaw (ONJ) is a serious adverse event of bone resorption inhibitors (BRIs), such as bisphosphonates and denosumab. Bisphosphonates and denosumab inhibit osteoclast function through different pharmacological effects and bisphosphonates are retained in bone for several months to years. Sequential treatment with bisphosphonates and denosumab might lead to an overlapping treatment effect, due to the addition of the effect of denosumab on the residual bisphosphonate effect. Therefore, the aim of our study was to investigate if switching from denosumab to bisphosphonates is associated with a higher incidence of ONJ. METHODS: We retrospectively reviewed records of patients with solid tumors and bone metastases treated with denosumab after prior treatment with bisphosphonates at the University Hospitals Leuven (sequential group). Patients treated with denosumab or bisphosphonates alone were used as control groups. RESULTS: We identified 110 patients sequentially treated with bisphosphonates and denosumab with a median total BRI exposure of 36 months (sequential group). Median bisphosphonates exposure was 16 months and median denosumab exposure was 13 months. About 299 patients were included in the bisphosphonates control group with a median bisphosphonate exposure 19 months. About 6.7% (20/299) of patients developed ONJ. About 240 patients were included in the denosumab control group with a median denosumab exposure 17.5 months. About 10.0% of patients (24/240) developed ONJ. In the sequential group, 15.5% of patients (17/110) developed ONJ. The incidence of ONJ was 1.8% (2/110), 6.3% (6/99), 4.9% (4/82), 5.6% (3/54), and 3.4% (1/29), respectively in the first, second, third, fourth, and fifth year of BRI exposure, an ONJ-incidence similar to ONJ-incidence in the denosumab control group. In a time-to-ONJ-analysis, the curves of the sequential group and the denosumab control group were overlapping. In the sequential group, most of the ONJs occurred in the first year of denosumab exposure and in a matched control group analysis, with correction for median BRI-exposure, ONJ cases tend to occur earlier in the sequential group compared to ONJ cases in the bisphosphonates group. CONCLUSION: Cancer patients with bone metastases treated with BRIs seem to have a slightly higher risk of ONJ early after switching from bisphosphonates to denosumab compared to patients remaining on bisphosphonates. Nevertheless, based on the global ONJ-incidence, the switch from bisphosphonates to denosumab can be considered as safe as an equivalent exposure to denosumab from the start on.

Single-Center Experience with Intimal Sarcoma, an Ultra-Orphan, Commonly Fatal Mesenchymal Malignancy.

BACKGROUND: Intimal sarcoma is a rare malignancy that, clinically and radiographically, often mimics pulmonary embolism. The intravascular tumor tends to disseminate rapidly and metastases can be present at first diagnosis. METHODS: We reviewed all cases of intimal sarcoma that were diagnosed, treated and followed at the University Hospitals Leuven between April 2006 and April 2016. RESULTS: We identified 13 patients with a median age of 51 years. In 6 patients initial findings were suggestive of thromboembolic disease. Platelet-derived growth factor receptor α (PDGFRA) amplification was the most prevalent molecular finding, present in 11 patients. The MDM2 gene was amplified in 9 cases, and the EGFR gene in 3 patients. The median overall survival was 13 months. 11 patients underwent surgery. In 5 cases with inoperable and/or metastatic disease chemotherapy was given. Treatment with imatinib was initiated in 4 patients. CONCLUSIONS: Intimal sarcoma is an extremely rare and aggressive malignancy that has a very poor prognosis. Mimicking thromboembolic disease, diagnosis and treatment can be delayed. Surgery is the mainstay of treatment but is seldom curative. The disease is highly resistant to cytotoxic and targeted treatment. Given the fact that intimal sarcoma commonly expresses more than 1 molecular target, combination therapy might be an option, although toxicity may be a limitation.

Biology and management of clear cell sarcoma: state of the art and future perspectives.

INTRODUCTION: Clear cell sarcoma (CCS) is an aggressive tumor, typically developing in tendons or aponeuroses. The outcome of this orphan disease is poor, with 5-year and 10-year survival rates of localized CCS around 60-70% and 40-50%. Once the disease has metastasized, it is usually fatal due to its chemotherapy-resistant nature. Systemic treatment options are poorly standardized and the use of chemotherapy is based on weak scientific evidence. AREAS COVERED: In this review, we systematically discuss the current scientific evidence for the systemic treatment of CCS, including tyrosine kinase inhibitors, immunotherapy and MET inhibitors. Expert commentary: Recent insights in the biology of CCS have identified new potential therapeutic targets, which should be tested in prospective clinical trials. Whenever possible, patients with metastatic CCS should be included in clinical trials with good biological rationale. Innovative trial methodology and new regulatory mechanisms are required to provide patients with uncommon cancers with active drugs.

Renal infarctions caused by dissections of surnumerary renal arteries.

Renal infarction is an uncommon and underdiagnosed cause of acute flank pain. We describe a 48-year-old male patient, previously diagnosed with a bicuspid aortic valve, who presented with multiple renal infarctions, secondary to multiple dissections of the aberrant renal vascular anatomy.