Cost Study of the PlasmaJet Surgical Device Versus Conventional Cytoreductive Surgery in Patients With Advanced-Stage Ovarian Cancer.

PURPOSE: Adjuvant use of Neutral Argon Plasma (PlasmaJet Surgical Device) during cytoreductive surgery (CRS) for advanced-stage epithelial ovarian cancer improves surgical outcomes. The aim of this study is to examine the costs of adjuvant use of the PlasmaJet during surgery compared with conventional CRS in advanced-stage epithelial ovarian cancer. MATERIALS AND METHODS: The patients were randomly assigned to surgery with or without the PlasmaJet. Analysis of the intra- and extramural health care costs was performed. Costs were divided into three categories: costs of the diagnostic phase (T1), inpatient care up to discharge including costs of surgery (T2), and outpatient care including chemotherapy until 6 weeks after the last cycle of chemotherapy (T3). RESULTS: Overall, 327 patients underwent CRS (surgery with PlasmaJet: n = 157; conventional surgery: n = 170). The mean total health costs were significantly higher for CRS with adjuvant use of PlasmaJet compared with conventional CRS (€19,414 v €18,165, P = .017). Costs are divided into costs of the diagnostic phase (€2,034 v €1,974, P = .890), costs of inpatient care (€10,956 v €9,556, P = .003), and costs of outpatient care (€6,417 v €6,628, P = .147). CONCLUSION: Mean total health care costs of the use of PlasmaJet in CRS were significantly higher than those for conventional CRS. This difference is fully explained by the additional surgery costs of the use of PlasmaJet. However, surgery with the use of the PlasmaJet leads to a significantly higher percentage of complete CRS and a halving of stomas. A cost-effectiveness analysis will be performed once survival data are available (funded by ZonMw, Trial Register NL62035.078.17).

Identification of genes transcriptionally responsive to the loss of MLL fusions in MLL-rearranged acute lymphoblastic leukemia.

INTRODUCTION: MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is characterized by high relapse rates and a dismal prognosis. To facilitate the discovery of novel therapeutic targets, we here searched for genes directly influenced by the repression of various MLL fusions. METHODS: For this, we performed gene expression profiling after siRNA-mediated repression of MLL-AF4, MLL-ENL, and AF4-MLL in MLL-rearranged ALL cell line models. The obtained results were compared with various already established gene signatures including those consisting of known MLL-AF4 target genes, or those associated with primary MLL-rearranged infant ALL samples. RESULTS: Genes that were down-regulated in response to the repression of MLL-AF4 and MLL-ENL appeared characteristically expressed in primary MLL-rearranged infant ALL samples, and often represented known MLL-AF4 targets genes. Genes that were up-regulated in response to the repression of MLL-AF4 and MLL-ENL often represented genes typically silenced by promoter hypermethylation in MLL-rearranged infant ALL. Genes that were affected in response to the repression of AF4-MLL showed significant enrichment in gene expression profiles associated with AF4-MLL expressing t(4;11)+ infant ALL patient samples. CONCLUSION: We conclude that the here identified genes readily responsive to the loss of MLL fusion expression potentially represent attractive therapeutic targets and may provide additional insights in MLL-rearranged acute leukemias.

MLL fusion-driven activation of CDK6 potentiates proliferation in MLL-rearranged infant ALL.

Acute lymphoblastic leukemia in infants (< 1 year-of-age) is characterized by a high incidence of MLL rearrangements. Recently, direct targets of the MLL fusion protein have been identified. However, functional validation of the identified targets remained unacknowledged. In this study, we identify CDK6 as a direct target of the MLL fusion protein and an important player in the proliferation advantage of MLL-rearranged leukemia. CDK6 mRNA was significantly higher expressed in MLL-rearranged infant ALL patients compared with MLL wild-type ALL patients (P < 0.001). Decrease of MLL-AF4 and MLL-ENL fusion mRNA expression by siRNAs resulted in downregulation of CDK6, affirming a direct relationship between the presence of the MLL fusion and CDK6 expression. Knockdown of CDK6 itself significantly inhibited proliferation in the MLL-AF4-positive cell line SEM, whereas knockdown of the highly homologous gene CDK4 had virtually no effect on the cell cycle. Furthermore, we show in vitro sensitivity of MLL-rearranged leukemia cell lines to the CDK4/6-inhibitor PD0332991, inducing a remarkable G 1 arrest, and downregulation of its downstream targets pRB1 and EZH2. We therefore conclude that CDK6 is indeed a direct target of MLL fusion proteins, playing an important role in the proliferation advantage of MLL-rearranged ALL cells.

Diagnosis and management of neonatal leukaemia.

Leukaemia in neonates (infants <1 month) is rare, whereby neonatal acute myeloid leukaemia (AML) is more frequent than neonatal acute lymphoblastic leukaemia (ALL). High mortality rates are observed, though AML has a better prognosis than ALL. Neonatal leukaemia is typically presented with hepatosplenomegaly, leukaemia cutis and/or hyperleucocytosis. Congenital infections should be ruled out before diagnosis. Rearrangement of the MLL gene is the most frequently occurring genetic aberration. Treatment includes intensive multi-agent chemotherapy, usually with age-related dose adjustments next to supportive care. Treatment intensification for ALL could be indicated in the future as the dismal prognosis is subject to high relapse rates in ALL.

Gene expression profiling-based dissection of MLL translocated and MLL germline acute lymphoblastic leukemia in infants.

Acute lymphoblastic leukemia (ALL) in infants (< 1 year) is characterized by a poor prognosis and a high incidence of MLL translocations. Several studies demonstrated the unique gene expression profile associated with MLL-rearranged ALL, but generally small cohorts were analyzed as uniform patient groups regardless of the type of MLL translocation, whereas the analysis of translocation-negative infant ALL remained unacknowledged. Here we generated and analyzed primary infant ALL expression profiles (n = 73) typified by translocations t(4;11), t(11;19), and t(9;11), or the absence of MLL translocations. Our data show that MLL germline infant ALL specifies a gene expression pattern that is different from both MLL-rearranged infant ALL and pediatric precursor B-ALL. Moreover, we demonstrate that, apart from a fundamental signature shared by all MLL-rearranged infant ALL samples, each type of MLL translocation is associated with a translocation-specific gene expression signature. Finally, we show the existence of 2 distinct subgroups among t(4;11)-positive infant ALL cases characterized by the absence or presence of HOXA expression, and that patients lacking HOXA expression are at extreme high risk of disease relapse. These gene expression profiles should provide important novel insights in the complex biology of MLL-rearranged infant ALL and boost our progress in finding novel therapeutic solutions.

Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol.

Acute lymphoblastic leukemia (ALL) diagnosed in the first month of life (congenital ALL) is very rare. Although congenital ALL is often assumed to be fatal, no studies have been published on outcome except for case reports. The present study reports the outcome of 30 patients with congenital ALL treated with the uniform Interfant-99 protocol, a hybrid regimen combining ALL treatment with elements designed for treatment of acute myeloid leukemia. Congenital ALL was characterized by a higher white blood cell count and a strong trend for higher incidence of MLL rearrangements and CD10-negative B-lineage ALL compared with older infants. Induction failure rate was 13% and not significantly different from that in older infants (7%, P = .14), but relapse rate was significantly higher in congenital ALL patients (2-year cumulative incidence [SE] was 60.0 [9.3] vs 34.2 [2.3], P < .001). Two-year event-free survival and survival of congenital ALL patients treated with this protocol was 20% (SE 9.1%). Early death in complete remission and treatment delays resulting from toxicity were not different. The survival of 17% after last follow-up, combined with a toxicity profile comparable with that in older infants, justifies treating congenital ALL with curative intent. This trial was registered at www.clinicaltrials.gov as no. NCT 00015873, and at www.controlled-trials.com as no. ISRCTN24251487.