Complexity complicates lean: lessons from seven emergency services.

PURPOSE: The purpose of this paper is to explain how different emergency services adopt and adapt the same hospital-wide lean-inspired intervention and how this is reflected in hospital process performance data. DESIGN/METHODOLOGY/APPROACH: A multiple case study based on a realistic evaluation approach to identify mechanisms for how lean impacts process performance and services' capability to learn and continually improve. Four years of process performance data were collected from seven emergency services at a Swedish University Hospital: ear, nose and throat (ENT) (two), pediatrics (two), gynecology, internal medicine, and surgery. Performance patterns were linked with qualitative data collected through realist interviews. FINDINGS: The complexity of the care process influenced how improvement in access to care was achieved. For less complex care processes (ENT and gynecology), large and sustained improvement was mainly the result of a better match between capacity and demand. For medicine, surgery, and pediatrics, which exhibit greater care process complexity, sustainable, or continual improvement were constrained because the changes implemented were insufficient in addressing the higher degree of complexity. ORIGINALITY/VALUE: The variation in process performance and sustainability of results indicate that lean efforts should be carefully adapted to the complexity of the care process and to the educational commitment of healthcare organizations. Ultimately, the ability to adapt lean to a particular context of application depends on the development of routines that effectively support learning from daily practices.

The bisphosphonate, zoledronic acid reduces experimental neuroblastoma growth by interfering with tumor angiogenesis.

BACKGROUND: Zoledronic acid is a new member of the bisphosphonate (BP) class of compounds, a family of closely related synthetic molecules originally derived from the naturally occurring pyrophosphate. These compounds that are potent inhibitors of bone resorption, have been shown to reduce the growth of several cancer cell lines in vitro, and can act as inhibitors of angiogenesis. The angiogenesis inhibitor TNP-470, a synthetic analogue of the fungal antibiotic fumagillin, has been shown to inhibit the growth of multiple tumors in vivo, and is currently in Phase II clinical trials for cancer. MATERIALS AND METHODS: The effects of daily subcutaneous (s.c.) administration of zoledronic acid (0.1 mg/kg) were compared with those of TNP-470 (15 mg/kg/day and 30 mg/kg every other day, s.c.) in a nude mouse xenograft model for the childhood cancer, neuroblastoma (NB). RESULTS: Zoledronic acid reduced the tumor growth by 33% whereas TNP-470 was less effective and reduced the tumor growth by 26% and 11% for animals treated with 15 mg/kg/day and 30 mg/kg every other day, respectively. Analysis of angiogenesis showed a significant reduction of the number of vessels per grid and in vessel length in all the treatment groups. CONCLUSION: Zoledronic acid shows tumoristatic and angiostatic properties that might be beneficial in the treatment of solid tumors such as neuroblastoma.

Angiogenesis can be reduced without significant reduction of tumor growth.

BACKGROUND: High risk neuroblastoma (NB) patients have an overall five-year survival of approximately 50%, indicating the need for new treatment strategies, such as angiogenesis inhibition. MATERIALS AND METHODS: The angiogenesis inhibitor TNP-470 (30 mg/kg, every other day, subcutaneously) was given to nude mice with subcutaneous human neuroblastoma xenografts. The plasma concentrations of the angiogenesis stimulators, i.e. vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2) and hepatocyte growth factor (HGF), were assayed longitudinally. Angiogenesis, proliferation and apoptosis were quantified on tumor tissue slides. RESULTS: Upon treatment with TNP-470, angiogenesis was significantly inhibited by the reduction of length and surface area of vessels per tumor volume, without having significant effect on tumor growth, tumor cell proliferation or apoptosis. Plasma concentrations of VEGF-A per tumor volume were significantly increased upon treatment. CONCLUSION: Angiogenesis inhibition must reach a threshold before significant tumor cell apoptosis and a reduction of the tumor growth rate occur.

The anti-VEGF antibody bevacizumab potently reduces the growth rate of high-risk neuroblastoma xenografts.

Neuroblastoma (NB) is a rapidly growing, well-vascularized childhood cancer that often presents with metastases. The overall five-year survival in NB is approximately 45% despite multimodality treatment, and therefore there is a clinical need for new therapeutic strategies. NB frequently overexpresses the angiogenic factor VEGF (vascular endothelial growth factor). The aim of this study was to investigate the effect of bevacizumab (Avastin, Genentech/Roche), a humanized anti-VEGF-A antibody, on NB growth in three different xenograft models, chosen to resemble high-risk NB. The human NB cell lines SK-N-AS, IMR-32 and SH-SY5Y, which are poorly differentiated and overexpress VEGF-A, were injected s.c. in immunodeficient mice. Bevacizumab was given intraperitoneally twice weekly at 5 mg/kg body weight, starting at a tumor volume of 0.3 mL. Bevacizumab significantly (p < 0.01-0.05) reduced NB growth in vivo without toxicity by causing a 30-63% reduction of angiogenesis, but had no effect on NB cell survival in vitro. Serum concentrations of VEGF-A increased two- to six-fold during bevacizumab therapy which did not result in faster tumor growth compared with control animals. Based on our experimental data we suggest consideration of bevacizumab in treatment of high-risk NB that does not respond to conventional therapy and that overexpresses VEGF.

Digoxin inhibits neuroblastoma tumor growth in mice.

BACKGROUND: Epidemiological data suggest a more favorable outcome of breast carcinoma in women taking cardiac glycosides. This study investigated whether digoxin could inhibit tumor growth in mice. MATERIALS AND METHODS: Tumor growth experiments were done in mice grafted with the neuroblastoma cell lines SH-SY5Y, Neuro-2a, colonic cancer cells (LS174T) or Lewis lung cancer cells (LLC). Angiogenesis inhibition was investigated in vitro on fibroblast growth factor-2 (FGF-2)-stimulated bovine endothelial cell (BCE) growth and in vivo in the chick chorioallantoic membrane (CAM) assay. RESULTS: SH-SY5Y and Neuro-2a grafts were inhibited by 44% (p=0.008) and 19% (p=0.007), respectively, whereas the colonic cancer xenografts and LLC syngrafts were less responsive. The neuroblastoma specificity was confirmed in vitro. Digoxin also inhibited angiogenesis in the CAM assay and the BCE cell survival in vitro was 50% at 53 ng/ml. CONCLUSION: Our data suggest that digoxin may be a specific neuroblastoma growth inhibitor and an unspecific inhibitor of angiogenesis.

The selective class III/V receptor tyrosine kinase inhibitor SU11657 inhibits tumor growth and angiogenesis in experimental neuroblastomas grown in mice.

Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their cognate receptor tyrosine kinases are strongly implicated in angiogenesis associated with solid tumors. SU11657 (SUGEN) is a selective multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity exerted by targeting PDGF receptors (PDGFR), VEGF receptors (VEGFR), stem cell factor receptor (c-KIT), and FMS-related tyrosine kinase 3. Oral administration of SU11657 at 40 mg x kg(-1) x d(-1) to athymic mice resulted in significant growth inhibition of a panel of s.c. human neuroblastoma xenografts, namely, fast-growing SK-N-AS, MYCN- amplified IMR-32, and SH-SY5Y, by 90, 93.8, and 88%, respectively, and was well tolerated. All of the cell lines expressed VEGFR-2, PDGFR-beta, and c-KIT protein in the tumor cell and endothelial cell compartment by immunohistochemistry, and the expression decreased during therapy. Plasma concentrations of VEGF-A, PDGF-BB, and stem cell factor increased per milliliter of tumor volume at days 10, 18, and 20 of therapy. Furthermore, SU11657 reduced tumor angiogenesis by 63-96%. Our experimental data suggest that the angiogenesis inhibitor SU11657 may be beneficial in the treatment of rapidly growing and highly vascularized solid tumors of childhood, such as neuroblastoma. In summary, the class III/V receptor tyrosine kinases and their ligands are implicated in angiogenesis, tumor cell proliferation, and cell survival, and it seems reasonable to determine whether interference with these pathways can suppress neuroblastoma growth or not.

CHS 828 inhibits neuroblastoma growth in mice alone and in combination with antiangiogenic drugs.

CHS 828 is a new chemotherapeutic drug, a pyridyl cyanoguanidine. CHS 828 has low toxicity and lacks known patterns of multidrug resistance. Here we report that oral, daily treatment with CHS 828 reduced the growth of SH-SY5Y human neuroblastoma tumors in male NMRI nu/nu mice by 82% without apparent toxicity. CHS 828 induced complete tumor regression for at least 5 weeks in four of nine animals (44%). Combination therapy with CHS 828 and the antiangiogenic drugs TNP-470 or SU5416 decreased neuroblastoma growth by a further 10 and 3%, respectively. Combination therapy induced tumor regression at d 4 with CHS plus TNP and d 6 with CHS plus SU5416, compared with d 14 with CHS 828 alone (p < 0.05), and complete tumor regression was seen in nine of 19 animals (47%). Combination treatment of CHS 828 and TNP-470 decreased the total viable tumor volume by 71% compared with treatment with CHS 828 alone. Our findings support CHS 828 as a promising new drug in treatment of childhood cancers. Furthermore, they imply efficiency of daily administration of nontoxic doses of chemotherapy, and a possible additive effect when chemotherapy is combined with angiogenesis inhibitors.

Importance of vascular endothelial growth factor A in the progression of experimental neuroblastoma.

Vascular endothelial growth factor A (VEGF-A) and its receptor tyrosine kinases located on endothelial cells seem to play an important role in the multistep pathway of angiogenesis. SU5416 is a small molecule which inhibits angiogenesis by acting as an inhibitor of VEGF receptor-2 tyrosine kinase. We have developed a reproducible murine model for neuroblastoma, a childhood cancer, based on s.c. xenotransplantation of SH-SY5Y neuroblastoma cells. We found that SH-SY5Y cells expressed VEGF-A on both the mRNA and protein levels, that plasma concentrations of VEGF-A were significantly elevated in animals with neuroblastoma with a volume > 1.4 ml, and that there was a correlation between VEGF-A levels in plasma and tumor size in untreated tumor-bearing animals. Treatment with SU5416 reduced the growth of neuroblastoma tumors by 65% without apparent toxicity. SU5416 treatment also suppressed tumor angiogenesis, despite an increase in plasma VEGF-A levels per ml tumor volume during therapy. Our experimental data suggest that the angiogenesis inhibitor SU5416 may be beneficial in the treatment of solid tumors of childhood such as neuroblastoma.