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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.

With phenotypic heterogeneity in whole cell populations widely recognised, the demand for quantitative and temporal analysis approaches to characterise single cell morphology and dynamics has increased. We present CellPhe, a pattern recognition toolkit for the characterisation of cellular phenotypes within time-lapse videos. To maximise data quality for downstream analysis, our toolkit includes automated recognition and removal of erroneous cell boundaries induced by inaccurate tracking and segmentation. We provide an extensive list of features extracted from individual cell time series, with custom feature selection to identify variables that provide greatest discrimination for the analysis in question. We demonstrate the use of ensemble classification for accurate prediction of cellular phenotype and clustering algorithms for the characterisation of heterogeneous subsets. We validate and prove adaptability using different cell types and experimental conditions. Our methods could be extended to other imaging modalities, such as fluorescence, and would be suitable for all time-lapse studies including clinical applications.

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.

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 (Female Rag2Orthotopic breast cancer models exhibit elevated tumour [Na

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

BACKGROUND Beta-lactam antibiotics are the mainstay of empiric therapy for febrile neutropenia. Aztreonam may benefit certain patients because of a lack of cross-hypersensitivity to penicillins and cephalosporins. This is the first study, to our knowledge, to evaluate the efficacy of aztreonam as monotherapy for febrile neutropenia (FN). METHODS Our study was a single-center retrospective chart review of patients ≥18 years of age receiving aztreonam for the treatment of FN. Primary outcome was treatment success of aztreonam monotherapy. Secondary analyses included need for modification to antimicrobial therapy, patients transitioned to aztreonam from another empiric regimen, and patients receiving aztreonam in combination with other antibacterial agents. RESULTS In patients prescribed aztreonam for first fever, 11 of 27 (40.7%) patients who received aztreonam alone and 19 of 40 (47.5%) given aztreonam plus another antibiotic responded within 96 h (P = 0.62). Twenty-four (89%) patients prescribed aztreonam monotherapy were alive when FN resolved or treatment ended. Infectious mortality was low (1 patient, 3.7%). In patients prescribed aztreonam monotherapy following an adverse reaction to cefepime, 6 of 11 (54.5%) responded within 96 h of initiating aztreonam; 10 (91%) were alive when FN resolved or treatment ended. CONCLUSION Aztreonam monotherapy may be acceptable for use in patients with a history of beta-lactam hypersensitivity or following an adverse reaction with another beta-lactam. Further studies are needed to compare efficacy of aztreonam monotherapy with other therapies for the treatment of FN.

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.

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.

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.

Background: Among the ambulant population of children with spastic cerebral palsy CP, dynamic equinus is one of the most common form of gait deviation that is encountered. Objective: To investigate the combined effects of Functional Electrical Stimulation FES and Botulinum Toxin A BTXA therapy in children with spastic CP, and to demonstrate the feasibility of this combination therapy. Methods: A single-subject design with repeated measures was adopted. Eight children six males, two females; mean age 7 y 9 mo, SD 1 y 5 mo; range 7 y to 11 y diagnosed with hemiplegic n=6 or diplegic n=2 spastic CP completed the study. Each subject participated in the study for twenty weeks. This period consisted of baseline one week, BTXA phase three weeks, first FES phase four weeks, first control phase four weeks, second FES phase four weeks and second control phase four weeks. Subjects were assessed at the end of each phase. The ankle angle at the end of swing phase was selected as the primary outcome measure. The secondary outcome measure recorded was the foot contact pattern. Results: There was an increase in ankle dorsiflexion at the end of the combined intervention in most subjects n=6, accompanied by an improvement in foot contact pattern. Conclusions: This pilot study demonstrated that it is feasible to combine BTXA therapy with FES in ambulant children with spastic CP.

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.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.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.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.

Abstract 2023 Background: The role of tandem and salvage autologous stem cell transplant (ASCT) in multiple myeloma (MM) has been a subject of interest for many myeloma investigators. Further, the role of tandem ASCT in patients achieving very good partial remission (VGPR) or complete remission (CR) has not been studied prospectively. Methods: We conducted a prospective phase II clinical trial in which enrolled MM patients are assessed after the first ASCT. Patients achieving ≤ partial remission (PR) were offered 2nd tandem ASCT followed by maintenance therapy. Patients that were found to be ≥VGPR were offered maintenance therapy followed by salvage ASCT at the time of relapse. Busulfan 0.75 mg/kg PO q 6 hr days -8 through -5, Cyclophosphamide (Cy) 60 mg/kg IV days -3 and -2, and Etoposide 10 mg/kg IV days -4 to -2 were used as the conditioning regimen for the first ASCT. Patients receiving a second ASCT received 96-hour (days -6 to -3) continuous IV Cy 6 gr/m2 and low dose total body irradiation (loTBI) 600 cGy (days -2 and -1). Etoposide was omitted if patients were ≥65 years. Melphalan 140 mg/m2 was used in lieu of TBI if prior irradiation did not allow for TBI. Results: Between the years 2001–2009, 76 patients were enrolled into the study. 54 patients achieved ≥VGPR. 31 patients had ≤ PR and were offered ASCT. Of these patients, 21 patients ultimately received tandem ASCT and 1 patient had tandem autologous-allogeneic transplants. Reasons for not receiving the planned tandem ASCT were lack of socioeconomic resources, physical co-morbidities, and patient refusal. There were no treatment related mortalities in the ASCT patients. Progression-free (PFS) and overall (OS) were compared between the single ASCT (n=54) and tandem ASCT (n=21) groups. The median PFS for the single ASCT group was 27 months (range, 3–107) and 21 months (range, 7–101) in the tandem group (P=0.814). OS was 76 months (range, 5–144) vs. 38 months (range, 12–128), respectively (P=0.121). At the time of submission, a total of 26 (48%) patients in the single ASCT group and 6 (30%) patients in the tandem group are still alive. Among the tandem patients, 2 later underwent salvage ASCT and 3 went on to receive non-myeloablative allogeneic transplants. In the single ASCT group, 6 had salvage ASCT and 7 had allogeneic SCT. All salvage transplants were done at a median of 30 months (range, 8–90) from the last ASCT. Patients who declined tandem transplant had a median PFS of 20 months (range 4–38). Patients who did not quality for tandem ASCT had a median PFS of 28 months (range 3–107) (p–0.08). Median OS between the two groups was 53 months (range 5–95) and 57.5 months (12–144), respectively (p–0.67). Conclusions: Patients who achieve ≥VGPR after 1st ASCT have similar PFS and a trend toward better OS than patients who had tandem ASCT. Thus, the use of such response criteria may identify a group of lower risk patients that will do well without upfront tandem ASCT. Disclosures: No relevant conflicts of interest to declare.

The role of tandem transplants as well as a later salvage second transplant has been in the center of interest for many myeloma investigators. Also, the need for tandem ASCT in patients (pts) achieving very good partial remission (VGPR) or complete remission has not been studied prospectively. We conducted a prospective phase II clinical trial in which enrolled myeloma pts are assessed after the first ASCT and offered either 2nd tandem ASCT if they achieve ≤ PR or maintenance if they achieve ≤ VGPR. These latter pts received 2nd salvage transplant after relapse. The conditioning regimens used were different for the two ASCT: Busulfan 0.75 mg/kg PO q 6 hr days –8 through –5, Cyclophosphamide (CP) 60 mg/kg IV days –3 and –2, and Etoposide 10 mg/kg IV days –4 to –2 for the first ASCT, and 96 hr (days –6 to –3) continuous IV CP 6 gr/m2 and total body irradiation (TBI) 600 cGy (days –2 and –1) for the second ASCT. Etoposide was omitted if pts were ≤ 65 year old, and TBI was substituted by melphalan 140 mg/m2 if prior radiation did not allow TBI. Between the years 2001-2009, 76 pts were enrolled. Of the 31 pts planned to have tandem ASCT, 20 received tandem ASCT, 2 additional pts had tandem auto-allo transplants and one patient had progressive disease. The primary reasons for not receiving the planned tandem ASCT were lack of socioeconomic resources and physical co-morbidities. Maintenance treatment was offered to both groups of pts. There were no treatment related mortalities in the ASCT pts. We compared the progression-free (PFS) and overall (OS) survival following the first ASCT between pts who received tandem ASCT (n=20) and pts who received single ASCT (n=54). The median PFS for tandem pts was 27 mo (range, 10-93) versus 28 mo for single ASCT (range, 4-99) (P=0.889); the OS was 38 mo (range, 11-120) versus 72 mo (range, 5-136), respectively (P=0.293). At the present time, a total of 7 (35%) and 30 (55%) pts are still alive in the tandem and single ASCT groups, respectively. Among the tandem pts, 2 underwent salvage ASCT and one non-myeloablative allogeneic transplant (allo-SCT); while in the single ASCT group 6 had salvage ASCT and 6 had allo-SCT. All salvage transplants were done at a median of 37 mo (range, 8-91) from 1st ASCT. In conclusion, pts who achieve ≤ VGPR after 1st ASCT have similar PFS and may be better OS than pts who had tandem ASCT. Thus, the use of such response criteria may identify a group of lower risk pts that will do well without the upfront tandem ASCT. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4618. doi:1538-7445.AM2012-4618

Graft-versus-host-disease (GVHD) is a life threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). The calcineurin inhibitor tacrolimus is commonly used in combination with other immunosuppressants to prevent GVHD; however the optimal serum target concentration for tacrolimus in this population remains unknown. A retrospective review was conducted to determine whether an association exists between tacrolimus concentrations and transplant-related outcomes, specifically acute GVHD, as well as the rate of renal toxicity and mortality. Data from 203 patients who underwent an allogeneic HSCT from a related (n1⁄495) or unrelated (n1⁄4108) donor between January 1, 2003 and December 31, 2011 at a large academic hospital was analyzed. Sixty-two (31%) patients developed acute GVHD within the first 30 days following allogeneic stem cell transplant. Median tacrolimus concentrations at day 0, 7, 14, and 28 were 11.2, 13.8, 13.5 and 10.2 ng/mL, respectively among those who developed acute GVHD. Patients who did not develop acute GVHD had similar tacrolimus concentrations of 10.4,13.1,12.3 and 9.9 ng/mL for the same respective time points. Serum tacrolimus concentrationswere similar across all grades of GVHD and therewas no correlation between drug concentrations with respect to renal toxicity. Patients who developed renal dysfunction (n1⁄418) had tacrolimus concentrations similar to the median concentration of the entire cohort, including those who did not experience renal toxicity. Overall mortality among the 203 included patients was 49%. Mortality was higher among patients who developed acute GVHD (55%) than in patients who did not experience the disease (47%). The results of this analysis support previous conclusions that tacrolimus blood concentrations are not associated with acute GVHD within the first 30 days post allogeneic HSCT.