[A Case of Microangiopathic Hemolytic Anemia with Bone Marrow Carcinomatosis from Breast Cancer].

We report a case of microangiopathic hemolytic anemia(MHA)caused by metastatic breast cancer treated with weekly paclitaxel. A 58-year-old woman was diagnosed with metastatic breast cancer 2 years earlier. She was treated with various chemotherapy regimens and hormonal therapy, before being switched to fulvestrant 3 months earlier. She presented with severe anemia, and was diagnosed with MHA with bone marrow carcinomatosis following bone marrow biopsy. She was treated with weekly paclitaxel and recovered successfully. A subsequent biopsy showed that the bone marrow carcinomatosis had decreased. MHA due to breast cancer is rare and is associated with poor prognosis; however, rapid initiation of chemotherapy may be effective.

The perivascular niche regulates breast tumour dormancy.

In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-ß1 and periostin as tumour-promoting factors derived from endothelial tip cells. Our work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth.

P-450-dependent epoxygenase pathway of arachidonic acid is involved in myeloma-induced angiogenesis of endothelial cells.

P-450-dependent epoxygenase pathway of arachidonic acid and the products of epoxyeicosatrienoic acids (EETs) have been demonstrated to be involved in angiogenesis and tumor progression. This study examined the expression of EETs and the role of the pathway in the angiogenesis of multiple myeloma (MM). MM cell lines of U266 and RPMI8226 were cultured, and the EETs levels (11, 12-EET and 14, 15-EET) in the supernatant were determined by ELISA. Human umbilical vein endothelial cells (HUVECs) were cultured and used for analysis of the angiogenesis activity of the two MM cell lines, which was examined both in vitro and in vivo by employing MTT, chemotaxis, tube formation and matrigel plug assays. 11, 12-EET and 14, 15-EET were found in the supernatant of the cultured MM cells. The levels of the two EETs in the supernatant of U266 cells were significantly higher than those in the RPMI8226 cell supernatant (P<0.05), and the levels paralleled the respective angiogenesis activity of the two different MM cell lines. 17-octadecynoic acid (17-ODYA), as a specific inhibitor of P450 enzyme, suppressed HUVECs proliferation and tube formation induced by MM cells. Furthermore, 17-ODYA decreased the EET levels in the supernatant of MM cells. These results suggest that EETs may play an important role in the angiogenesis of MM, and the inhibitor 17-ODYA suppresses this effect.

Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer pain.

Early, preemptive blockade of nerve growth factor (NGF)/tropomyosin receptor kinase A (TrkA) attenuates tumor-induced nerve sprouting and bone cancer pain. A critical unanswered question is whether late blockade of NGF/TrkA can attenuate cancer pain once NGF-induced nerve sprouting and neuroma formation has occurred. By means of a mouse model of prostate cancer-induced bone pain, anti-NGF was either administered preemptively at day 14 after tumor injection when nerve sprouting had yet to occur, or late at day 35, when extensive nerve sprouting had occurred. Animals were humanely killed at day 70 when, in vehicle-treated animals, significant nerve sprouting and neuroma formation was present in the tumor-bearing bone. Although preemptive and sustained administration (days 14-70) of anti-NGF more rapidly attenuated bone cancer nociceptive behaviors than late and sustained administration (days 35-70), by day 70 after tumor injection, both preemptive and late administration of anti-NGF significantly reduced nociceptive behaviors, sensory and sympathetic nerve sprouting, and neuroma formation. In this model, as in most cancers, the individual cancer cell colonies have a limited half-life because they are constantly proliferating, metastasizing, and undergoing necrosis as the parent cancer cell colony outgrows its blood supply. Similarly, the sensory and sympathetic nerve fibers that innervate the tumor undergo sprouting at the viable/leading edge of the parent tumor, degenerate as the parent cancer cell colony becomes necrotic, and resprout in the viable, newly formed daughter cell colonies. These results suggest that preemptive or late-stage blockade of NGF/TrkA can attenuate nerve sprouting and cancer pain.

Assessment of bone marrow angiogenesis in patients with acute myeloid leukemia by using contrast-enhanced MR imaging with clinically approved iron oxides: initial experience.

PURPOSE: To prospectively assess bone marrow (BM) angiogenesis in patients with acute myeloid leukemia (AML) by using iron oxide-enhanced magnetic resonance (MR) imaging. MATERIALS AND METHODS: The study was institutional ethics committee approved. Informed signed consent was obtained from each study participant. The requirement for informed consent for use of data from a reference database was waived. Eleven patients (seven women, four men; mean age, 53 years+/-4.40 [standard deviation]) with an initial diagnosis of AML were enrolled in the study and underwent T2*-weighted two-echo echo-planar MR imaging of the pelvis before and after intravenous injection of a clinically approved iron oxide blood-pool contrast agent. Six healthy control subjects (one woman, five men; mean age, 35 years+/-2.31) were examined with the same MR protocol. The iron oxide-induced change in R2* relaxation rate (DeltaR2*) was calculated, and the vascular volume fraction (VVF) of the BM was derived by dividing the DeltaR2* of the BM by the DeltaR2* of the muscle. Parametric DeltaR2* maps were calculated to visualize vessel distribution. Patients underwent BM biopsy for correlative determination of microvessel density (MVD) and vascular endothelial growth factor (VEGF). Differences in DeltaR2*, VVF, VEGF, and MVD were compared by using the Wilcoxon rank sum test. RESULTS: DeltaR2* maps showed prominent areas of highly vascularized BM in the patients with AML, whereas the control subjects had moderately vascularized BM with homogeneous vessel distribution. Quantitative analysis revealed VVF values to be significantly higher in patients with AML than in control subjects: The mean VVF in the pelvis was 9.18%+/-1.54 for patients versus 3.91%+/-0.61 for control subjects (P=.010). In accordance with MR results, MVD (P=.009) and VEGF expression (P=.017) were significantly elevated in the AML group compared with values in the control group. CONCLUSION: Iron oxide-enhanced MR imaging enables assessment of BM angiogenesis in patients with AML.

Neovascularization of bone marrow in patients with diffuse multiple myeloma: a correlative study of magnetic resonance imaging and histopathologic findings.

BACKGROUND: The goal of the current study was to assess the correlation between bone marrow histology and contrast enhancement in infiltrative diffuse myeloma. METHODS: Forty-four patients with homogeneous diffuse infiltration of bone marrow by multiple myeloma were examined using magnetic resonance imaging of the spine. The sequence protocol included T1-weighted spin-echo (pre- and post-gadolinium dimeglumine administration) and short-inversion time inversion recovery sequences. The percent increase in signal after intravenous gadolinium administration was calculated in bone marrow from patients with myeloma and from a control group of 86 patients who did not have bone marrow disease. Grade of infiltration with plasma cells, fat cell content, and hematopoietic marrow content were evaluated via histologic assessment of bone marrow, and microvessel density was evaluated via anti-CD34-positive immunostaining. RESULTS: Increased microvessel density was observed in association with increasing plasma cell content (Kruskall-Wallis test: P < 0.0001). Contrast enhancement increased in a stepwise manner according to grade of microvessel density (Mann-Whitney U test: P < 0.05 and P < 0.001 for increases from low to intermediate and intermediate to high grade) and was significantly higher in patients with myeloma compared with control patients (Mann-Whitney U test: P < 0.001). A significant correlation also was found between histologic extent of tumor infiltration and contrast enhancement (Mann-Whitney U test: P < 0.0001). The mean level of contrast enhancement was 18% in the control group, 26% in patients with low-grade infiltration, 49% in patients with intermediate-grade infiltration, and 90% in patients with high-grade infiltration. In addition, fat cell content was found to be inversely correlated with contrast enhancement (chi-square test: P < 0.01). CONCLUSIONS: As a consequence of increased microvessel density, decreased fat cell content, and increased cellularity, the presence of diffuse bone marrow infiltration in patients with multiple myeloma can be verified using gadolinium-enhanced magnetic resonance imaging.

Tumour micrometastases: the influence of angiogenesis.

INTRODUCTION: Many cancer patients have undetected micrometastatic disease at first presentation which ultimately progresses. Angiogenesis-the development of an independent blood supply-is a key event in the growth of metastases. Improved understanding of the influence of angiogenesis on micrometastatic growth may lead to new therapeutic intervention. METHODS: This study examines current concepts of the significance of micrometastases and the role of angiogenesis in their development and destruction. A comprehensive review of the literature on micrometastasis and angiogenesis was performed using the Medline database between 1966 and 1999. CONCLUSIONS: Advances in technology have improved our ability to diagnose metastatic disease, but micrometastases in loco-regional lymph nodes and at distant sites can only be detected by sophisticated histological techniques. While the significance of micrometastases remains controversial, there is increasing evidence that micrometastatic status provides useful prognostic information and should be part of standard staging techniques. Anti-angiogenic therapy has the potential to favourably influence management of certain cancers by manipulating a number of key events in the metastatic process.

Evaluation of angiogenesis and perfusion of bone marrow lesions: role of semiquantitative and quantitative dynamic MRI.

Magnetic resonance imaging (MRI) is a noninvasive technique that complements computed tomography (CT), conventional X-ray, and bone marrow biopsies by sampling a large volume of musculoskeletal bone and providing information that aids the diagnosis, staging, and follow-up of various lesions. Although less sensitive to the mineral components of bones, the MRI appearance of physiologic bone marrow is mainly a reflection of the relative amounts of red marrow, yellow marrow, and trabecular bone. Therefore, use of T1-and T2-weighted MR sequences with or without fat suppression currently remains the most common approach to musculoskeletal bone lesion imaging. An additional imaging strategy to characterize various bone lesions is the application of contrast-enhanced dynamic MRI. This article examines semiquantitative and quantitative dynamic imaging, evaluation, and postprocessing techniques in various benign and malignant musculoskeletal lesions. Practical guidelines for performing a dynamic contrast-enhanced MR examination are proposed.