Fatal acute cardiac vasculopathy during cisplatin-gemcitabine-bevacizumab (CGB) chemotherapy for advanced urothelial carcinoma.

BACKGROUND: Bladder cancer (BC) accounts for ∼14,680 deaths annually in the U.S. The prognosis of advanced disease remains dismal with current therapies. A phase III intergroup trial for metastatic BC adding bevacizumab to first-line cisplatin-gemcitabine chemotherapy (GCB regimen) is currently ongoing. We report the clinical-pathologic findings of a patient who developed fatal acute cardiac microvascular toxicity while receiving this regimen. CASE REPORT: A 66 year old man consulted for epigastric pain, nausea, intermittent diarrhea and lightheadedness two weeks after receiving the first cycle of GCB chemotherapy for metastatic BC. Physical evaluation, laboratory studies and electrocardiogram (EKG) were within normal limits except for marked thrombocytopenia that was attributed to his recent chemotherapy. The patient was admitted for observation, rehydrated and started on a proton pump inhibitor. The following day, however, he experienced sudden severe chest and right upper quadrant pain. EKG showed tachycardia, ST elevations in leads V2 and V3, laboratory analyses revealed marked elevation of cardiac troponin I, and an echocardiogram showed a markedly reduced ejection fraction of 10-20%, consistent with rapidly progressive cardiogenic shock. Emergent cardiac catheterization showed no significant coronary artery disease. Sepsis work-up was negative. He became progressively hypotensive, developed multi-organ failure, and died 48 h after admission. Postmortem examination showed diffuse microvasculopathy and changes due to global hypoperfusion of 12-48 h evolution. CONCLUSIONS: We present the first case of acute, fatal cardiac failure due to microvasculopathy most consistent with bevacizumab-associated toxicity. The findings are discussed in light of the existing literature.

Morphometric measurement of submucosal thickness in areas of fat deposition in the terminal ileum and colonic sections, with correlation with body mass index, weight and age: a male autopsy study.

AIMS: An increased amount of submucosal (SM) fat in the colon on imaging is considered to be characteristic of inflammatory bowel disease (IBD); however, a recent study in patients without IBD reported a correlation between colonic SM fat deposition and body weight (BW). The aim of this study was to perform a morphometric investigation of SM thickness in areas of fat deposition in the terminal ileum (TI), ileocaecal valve (ICV), and colonic sections, to determine whether there are variations by site, and whether it shows a correlation with BW, body mass index (BMI), or age. METHODS AND RESULTS: Representative samples of TI, ICV and colonic sections were collected prospectively from 115 autopsy cases without IBD. All of the study subjects were male (Veterans Hospital). SM thickness was measured in areas of fat deposition. Correlation analysis was performed between SM thickness and BW, BMI, and age. Fat deposition was common; however, with the exception of the ICV, it was neither consistent nor prominent, and it did not show a statistical correlation with BW, BMI, or age. CONCLUSIONS: SM fat deposition is common but not uniform or conspicuous in the TI or colon. In contrast to extravisceral intra-abdominal fat, it does not show a correlation with BW or BMI, and is not associated with ageing. As all study subjects were male, gender-dependent variability cannot be excluded.

[Chronic transvenous pacemaker/implantable cardioverter defibrillator leads implantation induced pathological changes].

OBJECTIVE: Widely pacemaker/implantable cardioverter defibrillator (ICD) implantation is also related to an increasing need for transvenous lead extraction. Understanding the location and extent of pathological changes, including adhesions and fibrous tissue formation along the course of chronic pacemaker/ICD leads, are essential for operators performing lead extraction operations in order to reduce the potential life threatening complications. METHODS: Three parts are included in the research, pathological examination on 83 extracted pacemaker/ICD leads using excimer laser technique from March 2008 to March 2011, autopsy examination of one died patient during lead extraction for lead-related infective endocarditis, and anatomical analysis on pacemaker/ICD leads from 10 patients died of other non-cardiac causes. RESULTS: Extensive encapsulated fibrous tissue around the leads and extensive adhesion/fibrosis along the course of the leads from venous entry site to the lead/myocardial interface could be detected on transvenous pacemaker/ICD leads. Since the tissue at the junction between superior vena cava (SVC) and right atrium (RA) is very thin, free of pericardium, thus, this is a common place for extensive adhesion/fibrosis and myocardial perforation/tear during lead extraction, which accounted for one death during extraction in our cohort. Extensive adhesion and fibrosis were also observed at the tricuspid valve and subvalvular structures. Leads implanted to the right ventricular apex were close to the epicardial surface and prone to perforation through myocardium. It is common to observe thrombus on the leads or at the interface between leads and myocardial tissue, especially at right atrial appendage (RAA) at the site of lead insertion. CONCLUSION: Extensive adhesions and fibrosis can be commonly seen along the course of pacemaker/ICD leads, and at SVC to RA junction, the tricuspid valve/subvalvular structures, and RA/RV lead interface. The tissue at SVC to RA junction is very thin, making it vulnerable for myocardial perforation/tear during lead extraction. Thrombus is commonly seen along the leads or at the lead-tissue interface.

A monoclonal antibody against synthetic Aß dimer assemblies neutralizes brain-derived synaptic plasticity-disrupting Aß.

Diverse lines of evidence indicate that pre-fibrillar, diffusible assemblies of the amyloid ß-protein (Aß) play an important role in Alzheimer's disease pathogenesis. Although the precise molecular identity of these soluble toxins remains unsettled, recent experiments suggest that sodium dodecyl sulfate (SDS)-stable Aß dimers may be the basic building blocks of Alzheimer's disease-associated synaptotoxic assemblies and as such present an attractive target for therapeutic intervention. In the absence of sufficient amounts of highly pure cerebral Aß dimers, we have used synthetic disulfide cross-linked dimers (free of Aß monomer or fibrils) to generate conformation-specific monoclonal antibodies. These dimers aggregate to form kinetically trapped protofibrils, but do not readily form fibrils. We identified two antibodies, 3C6 and 4B5, which preferentially bind assemblies formed from covalent Aß dimers, but do not bind to Aß monomer, amyloid precursor protein, or aggregates formed by other amyloidogenic proteins. Monoclonal antibody 3C6, but not an IgM isotype-matched control antibody, ameliorated the plasticity-disrupting effects of Aß extracted from the aqueous phase of Alzheimer's disease brain, thus suggesting that 3C6 targets pathogenically relevant Aß assemblies. These data prove the usefulness of covalent dimers and their assemblies as immunogens and recommend further investigation of the therapeutic and diagnostic utility of monoclonal antibodies raised to such assemblies.

Proximity of right coronary artery to cavotricuspid isthmus as determined by computed tomography.

BACKGROUND: Radiofrequency ablation of atrial flutter is a commonly performed procedure. Ablation success depends upon complete transmural atrial tissue injury to achieve bidirectional cavotricuspid isthmus (CTI) block. Transmural ablation increases risk of injury to the adjacent right coronary artery (RCA). Distance between the RCA and the endocardium within the CTI area is not well described. We aimed to perform in vivo measurements of the distance between the CTI area and adjacent RCA. METHODS: Thirty-three consecutive patients underwent electrocardiogram-gated contrast-enhanced computed tomography. CTI area was divided into nine segments based on three common catheter locations (paraseptal, central, and lateral or 5, 6, and 7 o'clock) and ventricular to atrial ablation line. RESULTS: Mean age was 64 ± 11 years and 97% of the participants were male. Paraseptal, central, and lateral measurements at the tricuspid annulus ridge showed endocardial to RCA distance 9 ± 3, 6 ± 2, and 5 ± 3 mm, respectively (range 2-17 mm). Corresponding measurements for the ventricular side were 5 ± 3, 4 ± 2, and 4 ± 2 mm and atrial side measurements were 3 ± 2, 3 ± 2, and 3 ± 3 mm. Distance was ≤2 mm in 14% of segments on the ventricular side and 39% of segments on the atrial side. Paired t-test showed significant difference (P < 0.001) between tricuspid annulus ridge measurements and adjacent atrial or ventricular measurements. CONCLUSIONS: Distance between endocardium and RCA lumen is reduced in areas adjacent to the tricuspid annulus ridge.

Atrial Fibrillation in the Elderly: The Role of Sub-Clinical Isolated Cardiac Amyloidosis.

Amyloid infiltration of the atrium is described in patients with valvular heart disease and is associated with an increased risk for atrial fibrillation(AF) while amyloid deposits in the ventricles is increasingly being diagnosed in patients with HFpEF. The role of amyloid deposits in patients with AF without valvular heart disease, which represents the most common form of AF globally, is undefined. In this study, we sought to assess the prevalence of sub-clinical isolated cardiac amyloidosis (ICA) at autopsy and the odds of AF in these patients. A total of 1083 patients were included in the study and 3.1% of patients were found to have asymptomatic ICA. Patients with ICA were older and had a higher odds of AF independent of age and CHA2DS2VASc score. Amongst patients with AF, those with ICA were more likely to have persistent forms of AF and had a lower sinus rhythm P-wave amplitude. Further studies are required to further define this entity, identify imaging modalities to aid in antemortem diagnosis of ICA and to establish the optimal management strategies in these patients.

Intra-Atrial Right Coronary Artery and its Ablation Implications.

OBJECTIVES: The study examined the frequency in which a right coronary artery (RCA) anomaly resulting in intra-atrialization of the vessel might increase risk of RCA damage during routine radiofrequency ablation in the right atrium even with low power or temperature. BACKGROUND: Right coronary artery (RCA) injury with endocardial RF ablation of the right atrium is a rare complication. METHODS: This prospective observational study comprised an analysis of coronary artery anatomies in 331 patients who underwent autopsies at our institution from 2005 to 2014. The presence of intra-atrial RCA including the number and length of intra-atrial RCA segments with accompanying atherosclerosis and coronary anomalies were evaluated. RESULTS: The authors report a case series of 6 of 331 (1.8%) patients in whom autopsies showed evidence of an intra-atrial RCA. The patients were all men (average 69 ± 12 years of age). They observed 3 variations of the intra-atrial RCA course. In 2 similar variations, the RCA entered the anterolateral aspect of the right atrium, returning to its normal distribution to supply the distal RCA (case 4 of 6) and the atrioventricular nodal artery (case 1 of 6). In the sixth case, the atrialized artery was an anterior branch of the RCA, in which the artery similarly coursed across the pectinate muscles, extending to the region of the anterior crista terminalis, before diving into the muscle. CONCLUSIONS: The prevalence and variants of the intra-atrial RCA have not been reported before. In the presence of an intra-atrial artery, RCA damage may occur due to direct injury rather than collateral injury due to transmural extension of an ablation lesion.

Atrial flutter ablation and risk of right coronary artery injury.

Radiofrequency ablation (RFA) of atrial flutter (AFL) is a commonly performed procedure with low risk of complications. Several case reports and animal studies cautioned about the risk of right coronary artery (RCA) injury following AFL ablation. This risk is due to the anatomic proximity of the RCA to the cavo-tricuspid isthmus where ablation is performed. We present a case report that demonstrates postmortem evidence of RCA injury following RFA of AFL.

Staphylococcus aureus and Clostridium difficile cause distinct pseudomembranous intestinal diseases.

We report simultaneous infections with Clostridium difficile and methicillin-resistant Staphylococcus aureus (MRSA) in a patient with discrete colonic pseudomembranes typical of C. difficile infection, as well as confluent, loosely adherent pseudomembranes in the small bowel. Identification of MRSA in the small bowel pseudomembrane by polymerase chain reaction supports S. aureus as an enteric pathogen.

Critical stenosis of aortic and mitral valves after mediastinal irradiation.

Radiotherapy is used widely in cancer treatment. Mediastinal irradiation is associated with valvular regurgitation; however, stenosis is rare. We present a patient with critical aortic and mitral valve stenosis after mediastinal irradiation and discuss the natural history, treatment, and prognosis of radiation-associated valvular heart disease.