Capsule endoscopy in adult celiac disease: a potential role in equivocal cases of celiac disease?

BACKGROUND: There have been limited studies evaluating capsule endoscopy (CE) in equivocal celiac disease (CD). OBJECTIVE: To determine the role CE may have in equivocal CD cases, compared with patients with biopsy-proven and serology-proven CD who have persisting symptoms. DESIGN: Prospective cohort study. SETTING: University hospital. PATIENTS: A total of 62 patients with equivocal CD and 69 patients with nonresponsive CD. INTERVENTION: CE. MAIN OUTCOME MEASUREMENTS: Diagnostic yield of CE in equivocal cases and accuracy of mucosal abnormality detection in patients with nonresponsive CD. RESULTS: Equivocal cases (n = 62) were divided into two subgroups: group A (antibody-negative villous atrophy, n = 32) and group B (Marsh 1-2 changes, n = 30). In group A, CE secured a diagnosis of CD or Crohn's disease in 28% (9/32), significantly higher than the diagnostic yield in group B (7%; P = .044). In patients with CD with persisting symptoms, significant CE findings were identified in 12% (8/69), including 2 cases of enteropathy-associated lymphoma, 4 type 1 refractory disease cases, 1 polypoidal mass histologically confirmed to be a fibroepithelial polyp, and 1 case of ulcerative jejunitis. This outcome was significantly lower than the diagnostic yield of CE in antibody-negative villous atrophy (P = .048). LIMITATIONS: Single center. CONCLUSION: There have been no previous reports systematically evaluating equivocal CD by using CE. The diagnostic yield of CE in patients with antibody-negative villous atrophy is better than that of CE in patients with CD with persisting symptoms. We advocate the use of CE in equivocal cases, particularly in patients with antibody-negative villous atrophy.

Combination therapy inhibits development and progression of mammary tumours in immunocompetent mice.

We have determined the effect of combining the chemotherapy agent doxorubicin and the anti-resorptive drug zoledronic acid on the early stages of spontaneous mammary tumour development using the immunocompetent PyMT mouse model that closely mimics human breast cancer development. 6-week-old PyMT mice were treated weekly for 6 weeks with PBS, 2 mg/kg doxorubicin, 100 µg/kg zoledronic acid or doxorubicin followed 24 h later by zoledronic acid (n = 15/group). Untreated, 6-week-old animals were used for comparison of tumour development. Tumour volume, apoptosis and angiogenesis were analysed on H&E, caspase 3, CD31 and CD34 stained histological sections. Proliferation was measured by BrdU incorporation and Ki67 staining and tumour macrophage infiltration assessed by F4/80 immunohistochemistry. Animals treated with doxorubicin followed by zoledronic acid did not develop palpable mammary tumours, whereas in all other treatment groups tumours progressed to late stage adenocarcinomas. Tumours from the combination treatment group were of comparable size to those in 6-week-old untreated animals, remaining pre-malignant with well-differentiated acinar arrangements and with tumour volume only reaching on average 26% of that in the PBS control group. Tumour cell apoptosis and proliferation was significantly reduced compared to control, single agent or untreated 6-week-old mice. Significantly fewer circulating tumour cells were present in animals following sequential treatment compared to all other groups. Combination treatment with doxorubicin followed by zoledronic acid inhibits development and progression of spontaneously occurring mammary tumours.

Tumour macrophages as potential targets of bisphosphonates.

Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use.Bisphosphonates (BPs), such as zoledronic acid, are anti-resorptive agents approved for treatment of skeletal complication associated with metastatic breast cancer and prostate cancer. These agents act on osteoclasts, key cells in the bone microenvironment, to inhibit bone resorption. Over the past 30 years this has led to a great reduction in skeletal-related events (SRE's) in patients with advanced cancer and improved the morbidity associated with cancer-induced bone disease. However, there is now a growing body of evidence, both from in vitro and in vivo models, showing that zoledronic acid can also target tumour cells to increase apoptotic cell death and decrease proliferation, migration and invasion, and that this effect is significantly enhanced in combination with chemotherapy agents. Whether macrophages in the peripheral tumour microenvironment are exposed to sufficient levels of bisphosphonate to be affected is currently unknown. Macrophages belong to the same cell lineage as osteoclasts, the major target of BPs, and are highly phagocytic cells shown to be sensitive to bisphosphonates in model studies; In vitro, zoledronic acid causes increased apoptotic cell death; in vivo the drug has been shown to inhibit the production of pro-angiogenic factor MMP-9, as well as most recent evidence showing it can trigger the reversal of the TAMs phenotype from pro-tumoral M2 to tumoricidal M1. There is thus accumulating evidence supporting the hypothesis that effects on TAMs may contribute to the anti-tumour effect of bisphosphonates. This review will focus in detail on the role of tumour associated macrophages in breast cancer progression, the actions of bisphosphonates on macrophages in vitro and in tumour models in vivo and summarise the evidence supporting the potential for the targeting of tumour macrophages with bisphosphonates.