Markus Schuler

Late onset Li-Fraumeni Syndrome with bilateral breast cancer and other malignancies: case report and review of the literature

BackgroundLi-Fraumeni-Syndrome (LFS) is an autosomal-dominant, inherited tumour predisposition syndrome associated with heterozygous germline mutations in the TP53 gene. Patients with LFS are at a high risk to develop early-onset breast cancer and multiple malignancies, among which sarcomas are the most common. A high incidence of childhood tumours and close to 100% penetrance has been described. Knowledge of the genetic status of the TP53 gene in these patients is critical not only due to the increased risk of malignancies, but also because of the therapeutic implications, since a higher rate of radiation-induced secondary tumours in these patients has been observed.Case reportWe report a patient with LFS harbouring heterozygous, pathogenic TP53 germline mutation, who was affected by four synchronous malignancies at the age of 40: a myxofibrosarcoma of the right upper arm, bilateral breast cancer and a periadrenal liposarcoma. Radiological treatments and a surveillance program were adjusted according to recommendations for LFS patients.ConclusionManagement of tumour treatment of patients with LFS is different to the general population because of their risk for secondary cancers in the radiation field. Screening procedures should take a possibly elevated risk for radiation induced cancer into account.

Burden of soft-tissue and bone sarcoma in routine care: Estimation of incidence, prevalence and survival for health services research.

BACKGROUND Sarcomas constitute a rare group of malignant tumors which can originate from any organ, tissue, bone or cartilage. Due to their heterogeneity, estimates of sarcoma incidence, prevalence and survival are rare. We estimated the burden of sarcoma in Germany from a large unselected cohort of patients from routine healthcare. METHODS We utilized the AOK PLUS health services research database covering complete medical information on 2,615,865 individuals from the German federal state of Saxony from 2005 to 2012. Persons were defined as sarcoma cases if they had ≥4 medical accounts with respective ICD-10 code C49 (soft-tissue sarcoma) or C40/C41 (bone sarcoma). We assessed sarcoma burden by calculating five-year prevalences, cumulative incidences, and one- and five-year relative survival rates. RESULTS Overall 1,468 persons with soft-tissue sarcoma and 671 persons with bone sarcoma were identified. Age-standardized cumulative incidence was 4.5/100,000 persons for soft-tissue and 2.1/100,000 persons for bone sarcoma (European Standard). One- and five-year relative survival was 87.8% and 66.4% for soft-tissue and 91.8% and 52.9% for bone sarcoma, respectively. CONCLUSION This is the first estimation of the burden of sarcoma based on an unselected sample of routine care data and the first estimation of the burden of sarcoma in Germany. We believe that the proposed methods offer a valuable approach for further outcomes research on cancer.

18F-FDG PET/MRI for therapy response assessment in sarcoma: comparison of PET and MR imaging results

BACKGROUND (18)F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) has proven to be of substantial benefit in imaging of sarcoma patients. We therefore investigated the feasibility and benefit of combined PET/magnetic resonance imaging (MRI). METHODS Twelve patients with sarcoma who underwent FDG PET/MRI for staging and response assessment after chemotherapy were included. RESULTS Based on contrast-enhanced MRI and application of Choi criteria, therapy response was classified as stable disease in 6/12 patients (50%) and as partial remission in 6/12 patients (50%). CONCLUSION In sarcoma patients, response assessment using Choi criteria based on contrast-enhanced MRI in comparison to FDG PET imaging only demonstrates slight correlation.

PET/MRI Imaging in High-Risk Sarcoma: First Findings and Solving Clinical Problems

Simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) is a new whole-body hybrid PET/MR imaging technique that combines metabolic and cross-sectional diagnostic imaging. Since the use of MRI in imaging of soft-tissue sarcoma is extremely beneficial, investigation of the combined PET/MRI is of great interest. In this paper, we present three cases and first data. Combined PET/MRI technique can support the process of clinical decision-making and give answers to some meaningful questions when treating patients with STS. Therefore, the combined modality of simultaneous PET/MRI offers new pieces to the puzzle of sarcoma treatment.

FDG PET/MR in initial staging of sarcoma: Initial experience and comparison with conventional imaging

OBJECTIVE To assess the feasibility of positron emission tomography/magnetic resonance imaging (PET/MR) with 18F-fluordeoxyglucose (FDG) for initial staging of sarcoma. MATERIALS AND METHODS Twenty-nine patients with sarcoma were included in this study. Weighted kappa (κ) was used to assess the agreement between PET/MR and conventional imaging (CT and MR). The accuracy of PET/MR and conventional imaging for distant metastases was compared using receiver operating characteristic (ROC) analysis. RESULTS T and M stage were identical for PET/MR and conventional modalities in all patients (κ=1). N stage was identical for 28/29 patients (κ=0.65). CONCLUSIONS FDG PET/MR shows excellent agreement with the currently preferred imaging methods (CT and MR) in initial staging of sarcoma.

Histological response assessment following neoadjuvant isolated limb perfusion in patients with primary, localised, high-grade soft tissue sarcoma

Abstract Purpose: Histological response assessment following neoadjuvant treatment can help identify patients at a higher risk for systemic disease progression. Our goal was to evaluate whether mitotic count and the amount of viable tumour following neoadjuvant isolated limb perfusion (ILP) for primary, locally advanced, non-metastatic, high-grade extremity soft tissue sarcoma correlate with prognosis. Patients and methods: This study is a retrospective analysis of 61 patients who underwent neoadjuvant ILP followed by surgical resection with curative intent between 2001 and 2011. Non-parametric analyses were carried out with the Mann-Whitney U and the Wilcoxon signed-rank test. Survival curves were calculated with the Kaplan-Meier method and compared with the log-rank test. Results: The median follow-up was 44 months for all patients and 55 months for survivors. The amount of viable tumour after ILP had no correlation with overall (OS) (P = 0.227) or event-free (EFS) (P = 0.238) survival probability. Patients with a low mitotic count after ILP had a significantly higher OS (P < 0.001), EFS (P = 0.002) and post-relapse survival probability (P = 0.030) compared to patients with an intermediate or high mitotic count. Conclusions: The mitotic count following ILP for primary, high-grade, locally advanced, non-metastatic soft tissue sarcoma appears to significantly correlate with prognosis. If these results are validated in a prospective setting, they could provide a rationale for the design of adjuvant systemic chemotherapy trials with the goal of improving the prognosis of patients with an intermediate or high mitotic count after ILP.

Trabectedin clinical cases: use according to indication in diverse clinical scenarios

BACKGROUND Key distinguishing characteristics of trabectedin in the treatment of advanced soft tissue sarcoma are its prolonged tumor control activity in multiple histological subtypes, positive outcomes in translocation-related sarcomas, maintenance of response, option to rechallenge after treatment interruption and lack of cumulative toxicity. Trabectedin is indicated for use in advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, or as front-line treatment in patients unsuited to receive these agents. METHODS In this review, cases studies are presented in which trabectedin was used according to its indication but in diverse clinical settings. RESULTS As second-line treatment of uterine leiomyosarcoma, trabectedin produced prolonged tumor control with good quality of life. In treatment of recurrent synovial sarcoma, the best objective response (partial response) and longest disease control (37 months) was achieved under treatment with trabectedin. As neoadjuvant treatment of undifferentiated pleomorphic sarcoma in a patient unsuited to receive doxorubicin-based chemotherapy, trabectedin induced a pathological response with 85% of necrosis. CONCLUSION These cases illustrate the broad range of indications for trabectedin in advanced soft tissue sarcoma and highlight how its unique characteristics can be optimized to achieve maximum clinical benefit.

Trabectedin in the Neoadjuvant Treatment of High-Grade Pleomorphic Sarcoma: Report of a Rare Case and Literature Review

Background. Pleomorphic sarcoma is an aggressive soft tissue sarcoma. In patients with high-risk extremity sarcomas, the significant survival benefits conferred by an intense regimen of neoadjuvant chemoradiotherapy and surgery were reported. To our knowledge, this is the first report in the literature of the neoadjuvant use of trabectedin in a patient with high-grade pleomorphic sarcoma, ineligible for standard neoadjuvant combination therapy with an anthracycline-based regimen. Case Presentation. Here we present a 58-year-old White male with a large tumor in the left thigh, but with no signs of metastases. Owing to the history of severe heart attack, three cycles of neoadjuvant trabectedin were administrated to achieve surgically wide margins. After two cycles, an 18F-FDG-PET showed a large proportion of the central tumor area was without metabolic activity. According to RECIST and Choi criteria, the tumor was stable. After the third cycle of trabectedin, the patient underwent a complete resection, which revealed completely necrotic high-grade pleomorphic sarcoma (stage pT2b), with only a small vital area. Conclusion. The present paper on a promising treatment with neoadjuvant trabectedin of patients with high-grade pleomorphic sarcoma might suggest that such treatment approach may provide a greater chance of cure and survival of such patients.

Pulmonary adverse events in unrelated donors of peripheral blood stem cells

Short-term treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF) followed by leukapheresis (LPH) is the common procedure for obtaining CD34+ peripheral blood progenitor cells from allogeneic donors. Bone pain, headache and flu-like symptoms are well-known G-CSFassociated side effects that occur for a short duration. In addition, fatigue and gastrointestinal or cardiovascular symptoms may also be observed, but these are rare complications. D’Souza et al. (2008) reported on the different adverse events experienced by healthy donors after stimulation with rhG-CSF, of which pulmonary toxicity was a prominent finding. Here, we report two cases of healthy donors with lung injury and interstitial pneumonia, respectively, and haemoptysis. A 31-year-old woman, who was an unrelated donor, received G-CSF (lenograstim, 8·5 μg kg−1 day−1) over 5 days, without unexpected adverse events, for peripheral blood stem cell mobilisation. The white blood cell (WBC) count at the time of LPH (day 0) was 39·9 × 109 L−1. Three days after LPH (day 3), she experienced symptoms of common cold. Unilateral otitis media was diagnosed, and she was treated with oral amoxicillin for 2 days. Forty-eight hours later (day 5), she was admitted to the hospital because of fever (38·3 ◦C), thoracic pain and dyspnoea. Massively increased levels of C-reactive protein (CRP; maximum 290 mg L−1) and procalcitonin (17 μg L−1) were detected. At this time, the WBC count was 41·0 × 109 L−1. Computed tomography (CT) of the chest indicated patchy consolidations in the middle and lower lung fields of both lungs. In addition, papular skin lesions, muscle pain and impairment of renal function (creatinine 1·7 mg dL−1) was noted. Due to worsened respiratory distress (SO2 92% on 8 L O2 min−1) and bilateral pleural effusions, the donor was temporarily monitored in the intensive care unit (days 7 and 8). As the symptoms likely appeared to be associated with a disseminated overwhelming inflammatory reaction after G-CSF administration, high-dose steroid treatment (prednisone, 3·5 mg kg−1) was initiated. Bronchoscopy on day 7 demonstrated normal respiratory mucosa. Transbronchial biopsy of lung tissue and open biopsy of skin lesions showed infiltration by neutrophils. Microbiologic analyses failed to detect any microbes. All tests for autoantibodies and virus-specific polymerase chain reactions (PCRs) remained negative (rheumatoid factor; antinuclear antibodies; extractable nuclear antigen

Association of Oesophageal Varices and Splanchnic Vein Thromboses in Patients with JAK2-Positive Myeloproliferative Neoplasms: Presentation of Two Cases and Data from a Retrospective Analysis

Background: Oesophageal varices and gastrointestinal bleeding are common complications of liver cirrhosis. More rarely, oesophageal varices occur in patients with non-cirrhotic portal hypertension that results from thromboses of portal or splanchnic veins. Case Report: We describe 2 young men who initially presented with varices as a result of portal vein thromboses. In the clinical follow-up, both were tested positive for a JAK2 mutation and consequently diagnosed with myeloproliferative neoplasms (MPNs). In an attempt to characterise the frequency of gastrointestinal complications in patients with JAK2-positive MPNs, we retrospectively analysed all known affected patients from our clinic for the diagnosis of portal vein thromboses and oesophageal varices. Strikingly, 48% of those who had received an oesophagogastroduodenoscopy had detectable oesophageal or gastric varices, and 82% of those suffered from portal or splanchnic vein thromboses. Conclusion: While the association between JAK2, myeloproliferative disease and thrombotic events is well established, patients with idiopathic oesophageal varices are not regularly tested for JAK2 mutations. However, the occurrence of oesophageal varices may be the first presenting symptom of a MPN with a JAK2 mutation, and affected patients may profit from a close haematological monitoring to assure the early detection of developing MPN.