A European project on incidence, treatment, and outcome of sarcoma

Abstract BACKGROUND: Sarcomas are rare tumors (1-2% of all cancers) of mesenchymal origin that may develop in soft tissues and viscera. Since the International Classification of Disease (ICD) attributes visceral sarcomas (VS) to the organ of origin, the incidence of sarcoma is grossly underestimated. The rarity of the disease and the variety of histological types (more than 70) or locations account for the difficulty in acquiring sufficient personal experience. In view of the above the European Commission funded the project called Connective Tissues Cancers Network (CONTICANET), to improve the prognosis of sarcoma patients by increasing the level of standardization of diagnostic and therapeutic procedures through a multicentre collaboration. METHODS/DESIGN: Two protocols of epidemiological researches are here presented. The first investigation aims to build the population-based incidence of sarcoma in a two-year period, using the new 2002 WHO classification and the "second opinion" given by an expert regional pathologist on the initial diagnosis by a local pathologist. A three to five year survival rate will also be determined. Pathology reports and clinical records will be the sources of information.The second study aims to compare the effects on survival or relapse-free period - allowing for histological subtypes, clinical stage, primary site, age and gender - when the disease was treated or not according to the clinical practice guidelines (CPGs). DISCUSSION: Within CONTICANET, each group was asked to design a particular study on a specific objective, the partners of the network being free to accept or not the proposed protocol. The first protocol was accepted by the other researchers, therefore the incidence of sarcoma will be assessed in three European regions, Rhone-Alpes and Aquitaine (France) and Veneto (Italy), where the geographic distribution of sarcoma will be compared after taking into account age and gender. The conformity of the clinical practice with the recommended guidelines will be investigated in a French (Rhone Alps) and Italian (Veneto) region since the CPGs were similar in both areas

Diagnosis and management of anaemia and iron deficiency in patients with haematological malignancies or solid tumours in France in 2009-2010: the AnemOnHe study

OBJECTIVE: To describe the management of anaemia in 2009-2010 in France in patients with haematological malignancies (HM) or solid tumours (ST). METHODS: Retrospective observational study in 57 centres, enrolling adult patients with HM or ST treated for an episode of anaemia (duration of the episode >/= 3 months occurring in the last 12 months). RESULTS: 220 patients with ST (breast, 18%; lung, 18%) and 56 with HM (lymphoma, 60%) were included (median age, 68 years; female, 53%). Mean haemoglobin level at anaemia diagnosis was 9.3 +/- 1.4 g/dL (<8 g/dL for 16%) and 9.8 +/- 1.1g/dL (<8 g/dL for 6%) in HM and ST patients, respectively. At least one parameter of iron deficiency (ferritin, transferrin saturation) was assessed in 26% of HM and 19% of ST patients. Treatment of anaemia included erythropoiesis-stimulating agents (ESA) for 98% of HM and 89% of ST patients. Iron was prescribed to 14% (oral, 12%; intravenous, 2%) of HM patients and to 42% (oral, 17%; intravenous, 25%) of ST patients. The rates of blood transfusions were high: 70% in HM and 46% in ST patients; transfusions alone or administrated with ESA were more frequent in patients with Hb <8 g/dL. CONCLUSION: Although recent guidelines recommend evaluating iron deficiency and correcting anaemia by using intravenous iron, our study in cancer patients evidenced that ESA and blood transfusions are still frequently used as the treatment of anaemia in cancer patients. Iron deficiency is insufficiently assessed (only one patient among five) and as a consequence iron deficiency is most likely insufficiently treated

Spectroimmunohistochemistry: A Novel Form of MALDI Mass Spectrometry Imaging Coupled to Immunohistochemistry for Tracking Antibodies.

Peer reviewe

Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study

BACKGROUND: Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer. METHODS: JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02580058. The trial is no longer enrolling patients and this is the final analysis of both primary endpoints. FINDINGS: Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6-21·9) for the combination group, 17·4 months (15·2-21·3) for the PLD group, and 18·2 months (15·8-21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3-5·1) in the combination group, 3·5 months (2·1-4·0) in the PLD group, and 1·9 months (1·8-1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 [repeated 93·1% CI 0·59-1·24], one-sided p=0·030; avelumab vs PLD: 1·68 [1·32-2·60], one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7-18·7) in the combination group, 13·1 months (11·8-15·5) in the PLD group, and 11·8 months (8·9-14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 [repeated 88·85% CI 0·74-1·24], one-sided p=0·21; avelumab vs PLD: 1·14 [0·95-1·58], one-sided p=0·83]). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 [10%] in the combination group vs nine [5%] in the PLD group vs none in the avelumab group), rash (11 [6%] vs three [2%] vs none), fatigue (ten [5%] vs three [2%] vs none), stomatitis (ten [5%] vs five [3%] vs none), anaemia (six [3%] vs nine [5%] vs three [2%]), neutropenia (nine [5%] vs nine [5%] vs none), and neutrophil count decreased (eight [5%] vs seven [4%] vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction). INTERPRETATION: Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany

Identification of patients at risk for early death after conventional chemotherapy in solid tumours and lymphomas

1–5% of cancer patients treated with cytotoxic chemotherapy die within a month after the administration of chemotherapy. Risk factors for these early deaths (ED) are not well known. The purpose of this study was to establish a risk model for ED after chemotherapy applicable to all tumour types. The model was delineated in a series of 1051 cancer patients receiving a first course of chemotherapy in the Department of Medicine of the Centre Léon Bérard (CLB) in 1996 (CLB-1996 cohort), and then validated in a series of patients treated in the same department in 1997 (CLB-1997), in a prospective cohort of patients with aggressive non-Hodgkin's lymphoma (NHL) (CLB-NHL), and in a prospective cohort of patients with metastatic breast cancer (MBC series) receiving first-line chemotherapy. In the CLB-1996 series, 43 patients (4.1%) experienced early. In univariate analysis, age > 60, PS > 1, lymphocyte (ly) count ≤ 700 μl−1 immediately prior to chemotherapy (d1), d1-platelet count ≤ 150 Gl−1, and the type of chemotherapy were significantly correlated to the risk of early death (P ≤ 0.01). Using logistic regression, PS > 1 (hazard ratio 3.9 (95% Cl 2.0–7.5)) and d1-ly count ≤ 700 μl−1 (3.1 (95% Cl 1.6–5.8)) were identified as independent risk factors for ED. The calculated probability of ED was 20% (95% Cl 10–31) in patients with both risk factors, 6% (95% Cl 4–9) for patients with only 1 risk factor, and 1.7% (95% Cl 0.9–3) for patients with none of these 2 risk factors. In the CLB-97, CLB-NHL and MBC validation series, the observed incidences of early death in patients with both risk factors were 19%, 25% and 40% respectively and did not differ significantly from those calculated in the model. In conclusion, poor performance status and lymphopenia identify a subgroup of patients at high risk for early death after chemotherapy. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity

MDM2–MDMX complexes bind the p53 tumor-suppressor protein, inhibiting p53's transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response, but their use in the treatment of cancers that retain wild-type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2–MDMX–E2(UbcH5B)–ubiquitin complex, we designed MDM2 mutants that prevent E2–ubiquitin binding without altering the RING-domain structure. These mutants lack MDM2's E3 activity but retain the ability to limit p53′s transcriptional activity and allow cell proliferation. Cells expressing these mutants respond more quickly to cellular stress than cells expressing wild-type MDM2, but basal p53 control is maintained. Targeting the MDM2 E3-ligase activity could therefore widen the therapeutic window of p53 activation in tumors