Tacrolimus Suppositories in Therapy-Resistant Ulcerative Proctitis.

BACKGROUND: Ulcerative proctitis may often be managed with topical salicylates or steroids alone, but in some patients, symptoms are persistent and severe. We analyzed the efficacy of tacrolimus suppositories in patients who had proven refractory to combined topical and systemic treatment. METHODS: In this retrospective analysis, ulcerative colitis activity index (CAI), side effects, co-medication and drug levels were assessed in 43 patients with distal ulcerative colitis who received suppositories containing 2 mg of tacrolimus b.i.d. as add-on medication. RESULTS: A total of 23 patients with ulcerative proctitis presented to follow-up within ≤50 days (mean 27.0 days) after suppositories were started. A decrease in CAI (from 8.0 to 5.5 points) was observed and 52.3% reached clinical remission (CAI ≤4). In total, 43 patients were available for analysis, of whom 9 had inflammation of the sigmoid colon as well. For the entire cohort, the median treatment duration was 76 days; 60% were in remission on the last documented visit. Serum measurements revealed a substantial tacrolimus level with a mean of 5.5 ng/mL. We observed one case of mild reversible acute kidney injury. CONCLUSIONS: In ulcerative proctitis, adding tacrolimus suppositories can be an effective and safe option when topical mesalazine, corticoid formulations and concomitant oral or parenteral medications have failed.

A subgroup of pleural mesothelioma expresses ALK protein and may be targetable by combined rapamycin and crizotinib therapy.

Malignant pleural mesothelioma (MPM) is a neoplasm with inferior prognosis and notorious chemotherapeutic resistance. Targeting aberrantly overexpressed kinases to cure MPM is a promising therapeutic strategy. Here, we examined ALK, MET and mTOR as potential therapeutic targets and determined the combinatorial efficacy of ALK and mTOR targeting on tumor cell growth in vivo. First, ALK overexpression, rearrangement and mutation were studied in primary MPM by qRT-PCR, FISH, immunohistochemistry and sequence analysis; mTOR and MET expression by qRT-PCR and immunohistochemistry. Overexpression of full-length ALK transcripts was observed in 25 (19.5%) of 128 primary MPM, of which ten expressed ALK protein. ALK overexpression was not associated with gene rearrangement, amplification or kinase-domain mutation. mTOR protein was detected in 28.7% MPM, co-expressed with ALK or MET in 5% and 15% MPM, respectively. The ALK/MET inhibitor crizotinib enhanced the anti-tumor effect of the mTOR-inhibitor rapamycin in a patient-derived MPM xenograft with co-activated ALK/mTOR: combined therapy achieved tumor shrinkage in 4/5 tumors and growth stagnation in one tumor. Treatment effects on proliferation, apoptosis, autophagy and pathway signaling were assessed using Ki-67 immunohistochemistry, TUNEL assay, LC3B immunofluorescence, and immunoblotting. Co-treatment significantly suppressed cell proliferation and induced autophagy and caspase-independent, necrotic cell death. Rapamycin/crizotinib simultaneously inhibited mTORC1 (evidenced by S6 kinase and RPS6 dephosphorylation) and ALK signaling (ALK, AKT, STAT3 dephosphorylation), and crizotinib suppressed the adverse AKT activation induced by rapamycin. In conclusion, co-treatment with rapamycin and crizotinib is effective in suppressing MPM tumor growth and should be further explored as a therapeutic alternative in mesothelioma.

Positive effect of intravenous iron-oxide administration on left ventricular remodelling in patients with acute ST-elevation myocardial infarction - a cardiovascular magnetic resonance (CMR) study.

OBJECTIVES: This study investigated the safety profile and potential "therapeutic" effect of intravenous ultrasmall superparamagnetic iron-oxide (USPIO)-based iron administration regarding infarct healing in patients with ST-elevation myocardial infarction (STEMI). USPIO-administration was recently shown to enable an improved characterization of myocardial infarct pathology in acute STEMI patients. MATERIALS AND METHODS: Seventeen study patients (IRON, 54 ± 9 yrs, 88% male) and 22 matched controls (CONTROL, 57 ± 9 yrs, 77% male) both with primary reperfused STEMI underwent multi-parametric CMR studies in the first week and three months after acute MI. Only IRON patients received a single intravenous bolus of 510 mg elemental iron as ferumoxytol (Feraheme(TM)) within four days following acute MI. RESULTS: Three months later, all patients were alive and there were no adverse cardiac events. Significant improvement in left ventricular (LV) ejection fraction (IRON: 53 ± 10% to 59 ± 9%, p=0.002; CONTROL: 54 ± 6% to 57 ± 10%, p=0.005) as well as shrinkage of infarct size were seen in both groups at follow-up. There was a more pronounced decrease in infarct size in the IRON group (IRON: -10.3 ± 5.4% vs. CONTROL: -7.0 ± 8.4%, p=0.050) in addition to a significant decrease in both endocardial extent and prevalence of transmural infarctions in IRON but not in CONTROL patients. A significant decrease in LV end systolic volume was only seen in the IRON group (71 ± 25 mL to 59 ± 25 mL, p=0.002). CONCLUSIONS: Intravenous iron administration in acute STEMI patients seems to be associated with an improved infarct healing and a beneficial global left ventricular remodelling. These findings together with the good safety profile make USPIO-based iron administration a promising future candidate as a "diagnostic" and "therapeutic" adjunctive solution in acute MI management.

Imaging of myocardial infarction using ultrasmall superparamagnetic iron oxide nanoparticles: a human study using a multi-parametric cardiovascular magnetic resonance imaging approach.

AIMS: The purpose of this clinical trial was to investigate whether cardiovascular magnetic resonance imaging (CMR) using ferumoxytol (Feraheme™, FH), an ultrasmall superparamagnetic iron oxide nanoparticle (USPIO), allows more detailed characterization of infarct pathology compared with conventional gadolinium-based necrosis/fibrosis imaging in patients with acute myocardial infarction. METHODS AND RESULTS: Fourteen patients who had experienced an acute ST-elevation myocardial infarction were included in this study. Following coronary angiography, a first baseline study (pre-FH) was performed followed by subsequent CMR studies (post-FH) 48 h after intravenous ferumoxytol administration. The CMR studies comprised cine-CMR, T(2)-weighted short tau inversion recovery spin echo imaging, T(2)-mapping, and T(1)-weighted late gadolinium enhancement (LGE) imaging. The median extent of short-axis in-plane LGE was 30% [inter-quartile range (IQR) 26-40%]. The median in-plane extent of T(2)-weighted 'hypoenhancement' in the region of myocardial infarction, which was not present prior to ferumoxytol administration in any patient, was 19% (IQR 14-22%; P < 0.001 compared with the extent of LGE). The median in-plane extent of areas showing signal void in T(2)-mapping images post-FH in the region of myocardial infarction was 16% (IQR 12-18%; P < 0.001 compared with the extent of LGE; P = 0.34 compared with the extent of T(2)-weighted hypoenhancement). A substantial drop in absolute T(2)-values was observed not only in the infarct core and peri-infarct zone, but also in the remote 'healthy' myocardium, although there was only a minor change in the skeletal muscle. Substantial ferumoxytol uptake was detected only in cultured macrophages, but not in peripheral blood monocytes from study patients. CONCLUSION: We could demonstrate in humans that USPIO-based contrast agents enable a more detailed characterization of myocardial infarct pathology mainly by detecting infiltrating macrophages. Considering the multi-functionality of USPIO-based particles and their superior safety profile compared with gadolinium-based compounds, these observations open up new vistas for the clinical application of USPIO.