A Rare Case of Squamous Cell Carcinoma of the Bladder Presenting as a Metastatic Right Ventricular Mass

A 74-year-old woman presented with bilateral lower extremity swelling, worsening dyspnea on exertion, and mild hemoptysis. An echocardiogram at time of admission showed a mass in the right ventricle. The pathology of a sample obtained via transvenous biopsy was consistent with squamous cell carcinoma; no primary source could initially be identified. Severe thrombocytopenia, likely consumptive, precluded surgical intervention, so the patient underwent palliative radiation. Unfortunately, she developed fatal respiratory failure. Upon autopsy, the bladder was found to contain polyps of invasive squamous cell carcinoma, similar in morphology to the tumor mass in the heart. Her lungs contained multiple tumor emboli at different stages, which was likely the final cause of her death. Squamous cell carcinoma metastases to the endocardium are extremely rare and without defined treatment. Surgery can improve prognosis in those with primary tumors that are benign or without metastases. In those with symptomatic metastatic tumors, palliative debulking can done although generally will not improve prognosis. It is currently unknown whether radiation improves survival. In this case, irradiation did destroy a portion of the tumor as the final pathology showed extensive necrosis of the tumor; unfortunately, it did not change her symptoms and did not change the final outcome

Inhibition of Progenitor Dendritic Cell Maturation by Plasma from Patients with Peripartum Cardiomyopathy: Role in Pregnancy-associated Heart Disease

Dendritic cells (DCs) play dual roles in innate and adaptive immunity based on their functional maturity, and both innate and adaptive immune responses have been implicated in myocardial tissue remodeling associated with cardiomyopathies. Peripartum cardiomyopathy (PPCM) is a rare disorder which affects women within one month antepartum to five months postpartum. A high occurrence of PPCM in central Haiti (1 in 300 live births) provided the unique opportunity to study the relationship of immune activation and DC maturation to the etiology of this disorder. Plasma samples from two groups (n = 12) of age- and parity-matched Haitian women with or without evidence of PPCM were tested for levels of biomarkers of cardiac tissue remodeling and immune activation. Significantly elevated levels of GM-CSF, endothelin-1, proBNP and CRP and decreased levels of TGF- were measured in PPCM subjects relative to controls. Yet despite these findings, in vitro maturation of normal human cord blood derived progenitor dendritic cells (CBDCs) was significantly reduced (p < 0.001) in the presence of plasma from PPCM patients relative to plasma from post-partum control subjects as determined by expression of CD80, CD86, CD83, CCR7, MHC class II and the ability of these matured CBDCs to induce allo-responses in PBMCs. These results represent the first findings linking inhibition of DC maturation to the dysregulation of normal physiologic cardiac tissue remodeling during pregnancy and the pathogenesis of PPCM

Unusual Presentation of Anaplastic Large Cell Lymphoma with Clinical Course Mimicking Fever of Unknown Origin and Sepsis: Autopsy Study of Five Cases

Aim To describe a subset of cases with the unusual clinical and histomorphological presentation of anaplastic large cell lymphoma (ALCL) mimicking fever of unknown origin (FUO) and sepsis. Methods A pathology database was searched using full term Systematized Nomenclature of Medicine codes for ALCL to identify 23ALCL cases from the period 1999-2006. Of those, five cases that did not have a correct premortem diagnosis were further analyzed to elucidate the reasons for delayed and incorrect pre-mortem diagnosis. The analyzed data included clinical presentation, duration of symptoms, duration of hospital stay, premortem presumed cause of death, white blood cell count, platelet count, anion gap and blood pH, liver enzymes (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase), lactate, coagulation tests (prothrombin time, partial thromboplastin time, fibrinogen, D-dimers), microbiology cultures, and radiology and surgical pathology reports. Autopsy reports were reviewed for description of major gross findings, initial clinical diagnosis, and cause of death. Results Five fatal and pre-mortem unrecognized ALCL cases were characterized by rapid decline, with histologic findings showing predominantly extranodal involvement, intravascular lymphomatosis, and hemophagocytosis. The cases were also characterized by unusual clinical manifestations including a FUO, sepsis, and disseminated intravascular coagulation-like picture, lactic acidosis, hepatosplenomegaly, and absence of significant peripheral adenopathy. Conclusions There is a distinct group of ALCLs with unique and specific clinical, gross autopsy, and histopathologic findings. Recognition of this clinical variant may facilitate early detection and potentially timely diagnosis and therap

Global gene expression profiling of endothelium exposed to heme reveals an organ-specific induction of cytoprotective enzymes in sickle cell disease.

Sickle cell disease (SCD) is characterized by hemolysis, vaso-occlusion and ischemia reperfusion injury. These events cause endothelial dysfunction and vasculopathies in multiple systems. However, the lack of atherosclerotic lesions has led to the idea that there are adaptive mechanisms that protect the endothelium from major vascular insults in SCD patients. The molecular bases for this phenomenon are poorly defined. This study was designed to identify the global profile of genes induced by heme in the endothelium, and assess expression of the heme-inducible cytoprotective enzymes in major organs impacted by SCD.Total RNA isolated from heme-treated endothelial monolayers was screened with the Affymetrix U133 Plus 2.0 chip, and the microarray data analyzed using multiple bioinformatics software. Hierarchical cluster analysis of significantly differentially expressed genes successfully segregated heme and vehicle-treated endothelium. Validation studies showed that the induction of cytoprotective enzymes by heme was influenced by the origin of endothelial cells, the duration of treatment, as well as the magnitude of induction of individual enzymes. In agreement with these heterogeneities, we found that induction of two major Nrf2-regulated cytoprotective enzymes, heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1 is organ-specific in two transgenic mouse models of SCD. This data was confirmed in the endothelium of post-mortem lung tissues of SCD patients.Individual organ systems induce unique profiles of cytoprotective enzymes to neutralize heme in SCD. Understanding this heterogeneity may help to develop effective therapies to manage vasculopathies of individual systems

Concentration- and time-dependent induction of HO-1 and NQO1 by hemin in endothelial cells.

<p>(A) Western blot analysis confirming concentration dependent induction of HO-1 and NQO1 in PMVECs and PAECs treated with hemin for 7 days. Blots were probed for EF-1αto control protein loading. (B, C) Quantification of HO-1 and NQO1 protein expression in PAECs, PMVECs, BMVECs and DMVECs treated with hemin and vehicle, assayed by western blot analysis. Data shown is mean fold change in protein level as arbitrary units relative to the EF-1α-normalized expression in vehicle treated cells (n = 9). (D) Quantification of western blot showing variable timing of HO-1 and NQO1 induction by hemin (5 µM) in PAECs (n = 9).</p

Organ-specific induction of HO-1 and NQO1 in SS mice.

<p>Total RNA was isolated from the indicated organs from transgenic mice of the Townes model, expressing normal human hemoglobin (Hb AA n = 4), or with sickle trait (Hb AS n = 7) or SCD (Hb SS, n = 6). Expression of HO-1 (A) and NQO1 (B) was determined by relative quantitative real-time PCR. Data shown are the mean ± SD. *p<0.05.</p

Enhanced expression of NQO1 in SS mice.

<p>(A) Western blot analysis for NQO1 expression in snap-frozen organs from Townes SS, AS and AA mice. (B) Quantitative data of western blot experiments. Data shown are mean arbitrary units of β-actin-normalized NQO1 expression in the indicated organs and genotypes (n = 6). (C) Western blot analysis of NQO1 in whole lungs of Berkeley sickle mice and control hemizygotes. (D) Quantitative data for NQO1 protein in the Berkeley mice lungs showing arbitrary units of β-actin-normalized expression (n = 4). *p<0.05, **p<0.01.</p

Induction of Nrf-2 regulated genes by hemin.

<p>(A) Central role of Nrf2 in the response of the endothelium to heme. Genes whose expression was altered by hemin in both PAECs and PMVECs are shown. ROS =  reactive oxygen species. (B) Microarray data of differentially expressed genes regulated by Nrf2 in PAECs and PMVECs treated with hemin. Data shown is mean fold change in gene expression as arbitrary units relative to the level of expression by control cells (n = 5).</p