TAFRO Syndrome: A Case of Significant Endocrinopathy in a Caucasian Patient.

Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disorder that manifests as multiorgan dysfunction secondary to widespread inflammation. The underlying pathogenesis is driven by an excessive and inappropriate cytokine storm. TAFRO syndrome is a rare subtype of iMCD, characterized by thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly. Multiorgan dysfunction is a known consequence of this syndrome, although endocrine involvement has yet to be reported. We present a case of TAFRO in a previously healthy Caucasian male who presented with abdominal pain, dysuria, diffuse anasarca, and ascites. On presentation, the patient was found to have acute kidney injury, thrombocytopenia, elevated inflammatory markers, elevated interleukin-6 (IL-6), and endocrinopathy. Following an extensive infectious and autoimmune workup, lymph node biopsy confirmed the diagnosis of TAFRO. The patient was started on prednisone, rituximab, and anti-IL-6 therapy with siltuximab. He achieved clinical remission after 4 months of treatment, with normalization of renal function, thrombocytopenia, inflammatory markers, and endocrinopathy. He has continued on siltuximab for maintenance therapy. It is our hope that this unique case of TAFRO syndrome with significant endocrinopathy will add to the growing literature surrounding iMCD, and help clinicians better understand the pathogenesis and treatment of this rare disease.

Geminin overexpression promotes imatinib sensitive breast cancer: a novel treatment approach for aggressive breast cancers, including a subset of triple negative.

Breast cancer is the second leading cause of cancer-related deaths in women. Triple negative breast cancer (TNBC) is an aggressive subtype that affects 10-25% mostly African American women. TNBC has the poorest prognosis of all subtypes with rapid progression leading to mortality in younger patients. So far, there is no targeted treatment for TNBC. To that end, here we show that c-Abl is one of several tyrosine kinases that phosphorylate and activate geminin's ability to promote TNBC. Analysis of >800 breast tumor samples showed that geminin is overexpressed in ∼50% of all tumors. Although c-Abl is overexpressed in ∼90% of all tumors, it is only nuclear in geminin overexpressing tumors. In geminin-negative tumors, c-Abl is only cytoplasmic. Inhibiting c-Abl expression or activity (using imatinib or nilotinib) prevented geminin Y150 phosphorylation, inactivated the protein, and most importantly converted overexpressed geminin from an oncogene to an apoptosis inducer. In pre-clinical orthotopic breast tumor models, geminin-overexpressing cells developed aneuploid and invasive tumors, which were suppressed when c-Abl expression was blocked. Moreover, established geminin overexpressing orthotopic tumors regressed when treated with imatinib or nilotinib. Our studies support imatinib/nilotonib as a novel treatment option for patients with aggressive breast cancer (including a subset of TNBCs)-overexpressing geminin and nuclear c-Abl.

Usefulness of three posterior chest leads for the detection of posterior wall acute myocardial infarction.

A significant proportion of patients with myocardial infarction are missed upon initial presentation to the emergency department. The 12-lead electrocardiogram (ECG) has a low sensitivity for the detection of acute myocardial infarction, especially if the culprit lesion is in the left circumflex artery (LCA). This study was designed to evaluate the benefit of adding 3 posterior chest leads on top of the 12-lead ECG to detect ischemia resulting from LC disease, using a model of temporary balloon occlusion to produce ischemia. We studied 53 consecutive patients who underwent clinically indicated coronary interventions. At the time of coronary angiography, the balloon was inflated to produce complete occlusion of the proximal LCA. We recorded and analyzed the changes noted on the 15-lead ECG, which included 3 posterior leads in addition to the standard 12 leads. In response to acute occlusion of the LCA, the posterior chest leads showed more ST elevation than the other leads, and more patients had ST elevation in the posterior leads than in any other lead. The 15-lead ECG was able to detect>or=0.5 mm (74% vs 38%, p<0.0001) and >or=1 mm (62% vs 34%, p<0.0001) ST elevation in any 2 contiguous leads more frequently than the 12-lead ECG. In conclusion, the 15-lead ECG identified more patients with posterior myocardial wall ischemia because of temporary balloon occlusion of the LC than the 12-lead ECG. This information may enhance the detection of posterior MI in the emergency department and potentially facilitate early institution of reperfusion therapy.