Sodium accumulation in breast cancer predicts malignancy and treatment response.

BACKGROUND: Breast cancer remains a leading cause of death in women and novel imaging biomarkers are urgently required. Here, we demonstrate the diagnostic and treatment-monitoring potential of non-invasive sodium (23Na) MRI in preclinical models of breast cancer. METHODS: Female Rag2-/- Il2rg-/- and Balb/c mice bearing orthotopic breast tumours (MDA-MB-231, EMT6 and 4T1) underwent MRI as part of a randomised, controlled, interventional study. Tumour biology was probed using ex vivo fluorescence microscopy and electrophysiology. RESULTS: 23Na MRI revealed elevated sodium concentration ([Na+]) in tumours vs non-tumour regions. Complementary proton-based diffusion-weighted imaging (DWI) linked elevated tumour [Na+] to increased cellularity. Combining 23Na MRI and DWI measurements enabled superior classification accuracy of tumour vs non-tumour regions compared with either parameter alone. Ex vivo assessment of isolated tumour slices confirmed elevated intracellular [Na+] ([Na+]i); extracellular [Na+] ([Na+]e) remained unchanged. Treatment with specific inward Na+ conductance inhibitors (cariporide, eslicarbazepine acetate) did not affect tumour [Na+]. Nonetheless, effective treatment with docetaxel reduced tumour [Na+], whereas DWI measures were unchanged. CONCLUSIONS: Orthotopic breast cancer models exhibit elevated tumour [Na+] that is driven by aberrantly elevated [Na+]i. Moreover, 23Na MRI enhances the diagnostic capability of DWI and represents a novel, non-invasive biomarker of treatment response with superior sensitivity compared to DWI alone.

Volatile compounds in human breath: critical review and meta-analysis.

Volatile compounds contained in human breath reflect the inner workings of the body. A large number of studies have been published that link individual components of breath to disease, but diagnostic applications remain limited, in part due to inconsistent and conflicting identification of breath biomarkers. New approaches are therefore required to identify effective biomarker targets. Here, volatile organic compounds have been identified in the literature from four metabolically and physiologically distinct diseases and grouped into chemical functional groups (e.g. methylated hydrocarbons or aldehydes; based on known metabolic and enzymatic pathways) to support biomarker discovery and provide new insight on existing data. Using this functional grouping approach, principal component analysis doubled explanatory capacity from 19.1% to 38% relative to single individual compound approaches. Random forest and linear discriminant analysis reveal 93% classification accuracy for cancer. This review and meta-analysis provides insight for future research design by identifying volatile functional groups associated with disease. By incorporating our understanding of the complexities of the human body, along with accounting for variability in methodological and analytical approaches, this work demonstrates that a suite of targeted, functional volatile biomarkers, rather than individual biomarker compounds, will improve accuracy and success in diagnostic research and application.

Pharmacokinetic and clinical outcomes when ideal body weight is used to dose busulfan in obese hematopoietic stem cell transplant recipients.

Weight-based dosing of intravenous busulfan is widely used in hematopoietic cell transplantation. However, a variety of dosing weights have been described. The objective of this retrospective study was to determine the pharmacokinetic impact of using ideal body weight as the initial dosing weight in obese as compared to non-obese transplant recipients. The secondary objectives were to describe the use of alternative dosing weights, the impact on survival, and the rates of toxicities. The mean steady-state concentration was 779.3 ng/mL (n = 82) in the non-obese cohort and 673.7 ng/mL (n = 63) in the obese cohort (p < 0.001). A smaller proportion of concentrations were below goal in the non-obese cohort (10% vs. 41%, p < 0.001). Ideal body weight and adjusted body weights with a 25 and 40% correction factor are appropriate in non-obese patients; adjusted body weights with a 25 and 40% correction factor are appropriate in obese patients. There was no difference in overall survival (p = 0.18); there was a difference in median progression-free survival (1078 vs. 500 days, p = 0.045) in the non-obese compared to obese cohorts. The use of ideal body weight to dose busulfan resulted in lower steady-state concentrations, a larger proportion of subtherapeutic concentrations, and worse progression-free survival in obese patients.

Tandem Autologous Stem Cell Transplantation for Multiple Myeloma Patients Based on Response to Their First Transplant-A Prospective Phase II Study.

In this prospective phase II clinical trial, multiple myeloma (MM) patients were randomized to receive a second (tandem) autologous stem cell transplantation (ASCT) based on whether they achieved a partial response or worse (≤PR) following initial ASCT (ASCT1). Patients who achieved a very good partial response or better (≥VGPR) had salvage ASCT at relapse. Seventy-five patients received conditioning therapy and ASCT1. A total of 44 patients (59%) achieved ≥VGPR, whereas 31 patients entered ≤PR and were offered tandem ASCT. In all, 20 patients agreed to tandem ASCT. Demographic and clinical characteristics were similar between the two cohorts except for median lactate dehydrogenase (LDH) (P = 0.0141) and percentage of marrow plasma cells before ASCT1 (P = 0.0047), both lower in the ≥VGPR group. Intent to treat analysis showed that patients who achieved ≥VGPR to ASCT1 had a trend toward improved progression-free survival (PFS) (37 vs. 26 months, P = 0.078) and superior overall survival (OS) (not reached vs. 50 months, P = 0.0073). Patients with ≤PR who declined tandem transplantation had shortened PFS (20 vs. 28 months, P = 0.05) but similar OS (53 vs. 57.5 months, P = 0.29) compared to those who received it. Thus, a favorable clinical response to ASCT1 identifies a low-risk group with superior long-term prognosis despite similar PFS.

Hematopoietic cell transplantation in 2020: summary of year 2 recommendations of the National Marrow Donor Program's System Capacity Initiative.

The National Marrow Donor Program, in partnership with the American Society for Blood and Marrow Transplantation, sponsored and organized a series of symposia to identify complex issues affecting the delivery of hematopoietic cell transplantation (HCT) and to collaboratively develop options for solutions. "Hematopoietic Cell Transplantation in 2020: A System Capacity Initiative" used a deliberative process model to engage professional organizations, experts, transplant centers, and stakeholders in a national collaborative effort. Year 2 efforts emphasized data analysis and identification of innovative ideas to increase HCT system efficiency, address future capacity requirements, and ensure adequate reimbursement for HCT programs to meet the projected need for HCT. This report highlights the deliberations and recommendations of Year 2 and the associated symposium held in September 2011.

African American adult apheresis donors respond to granulocyte-colony-stimulating factor with neutrophil and progenitor cell yields comparable to those of Caucasian and Hispanic donors.

BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPCs) are the most common source of cells used for hematopoietic transplantation. Benign ethnic neutropenia has been found in persons of African descent, affecting circulating white blood cells (WBCs), but not WBC production within marrow. Persons of African descent have reduced neutrophil mobilization after steroid administration, and newborns have fewer nucleated and progenitor cells in their cord blood. STUDY DESIGN AND METHODS: Twenty-two African American (AA) and 12 Hispanic PBPC donors were age, sex, and weight matched with 34 Caucasian donors. Groups were compared based on WBC and neutrophil counts after mobilization and numbers of CD34+ cells collected on Day 5 of G-CSF mobilization. RESULTS: AA donors had significantly lower baseline WBC (6.1±1.1 vs. 7.1±1.7, p=0.04) and neutrophil (3.4±1.1 vs. 4.5±1.3, p=0.01) counts compared to matched Caucasian donors. G-CSF-stimulated AAs had a significantly greater increase in WBC and neutrophil counts compared to matched Caucasians (889±293% vs. 665±230% neutrophils, p=0.02). There was no significant difference in product cell counts when comparing total nucleated, CD3+, CD34+, and mononuclear cells or colony-forming units (CFUs) between Caucasians and Hispanics or AAs and trends to greater numbers of neutrophils in products from AA donors. CONCLUSION: When stimulated by G-CSF, AAs are able to increase WBC and neutrophil counts to a higher degree than Caucasians, achieving similar numbers of neutrophil and progenitor cells in apheresis products despite starting from lower baseline blood counts.

Hypomethylating agent induction therapy followed by hematopoietic cell transplantation is feasible in patients with myelodysplastic syndromes.

Disease remission in patients with myelodysplastic syndromes can be achieved with azanucleosides, which act as pyrimidine analogs and hypomethylating agents. However, despite treatment with azanucleoside induction, patients with myelodysplastic syndromes nearly always relapse. Allogeneic hematopoietic cell transplantation (HCT) can be curative, but it is risky. Given that azanucleosides affect human leukocyte antigen expression and lymphocyte reactivity, we conducted a retrospective study to define the impact of pre-HCT azanucleoside therapy on post-HCT donor chimerism. Patients receiving azanucleoside induction therapy achieved rapid and high levels of donor chimerism post-transplant. Lineage analysis also found rapid donor chimerism of lymphocyte and granulocyte subsets. These data indicate the feasibility of pretransplant azanucleoside therapy in patients who subsequently receive an HCT.

Phase 1 study of TLK286 (Telcyta) administered weekly in advanced malignancies.

PURPOSE: To determine the dose-limiting toxicities, maximum tolerated dose, and pharmacokinetics of TLK286, a novel cancer prodrug, administered weekly. PATIENTS AND METHODS: Patients with advanced malignancies were treated with TLK286 administered weekly by i.v. infusion over 30 min in escalating doses 60-960 mg/m(2). A treatment cycle was defined as 3 weekly treatments. Patients underwent tumor assessments on day 43, and those patients receiving clinical benefit continued on treatment until disease progression or unacceptable toxicity. Safety was assessed by the WHO criteria. RESULTS: Thirty-seven patients received 111 cycles of TLK286 at eight dose levels (median, 3 cycles; range, 1-16 cycles). In this study, TLK286 given weekly at 960 mg/m(2) was well tolerated without dose-limiting toxicities. TLK286-related toxicities included grade 1-2 nausea and vomiting, fatigue and anemia. Nine of 31 evaluable patients continued therapy beyond day 43 and received a median of 5 cycles (range of 3-16 cycles) and experienced durable stable disease or minor tumor regression. Pharmacokinetic characteristics of TLK286 are described by an optimized two-compartment model. Mild to moderate renal or hepatic organ dysfunction did not impact the elimination of TLK286. CONCLUSIONS: TLK286 administered weekly at doses up to 960 mg/m(2) were well tolerated. The safety and antitumor activity observed in a broad range of cancer types supports Phase 2 disease-specific investigations of TLK286 given weekly at 960 mg/m(2).