Michael A. Seidman

The value of re-exploration in patients with inadvertently morcellated uterine sarcoma

OBJECTIVE To describe the role of immediate re-exploration in patients with inadvertently morcellated uterine leiomyosarcoma (ULMS) and smooth muscle tumors of uncertain malignant potential (STUMP). METHODS All patients with ULMS/STUMP who were managed or referred to the participating institutions from January 2005 to January 2012 following minimally invasive gynecology surgery with morcellation were detected through the pathology database. The diagnosis was confirmed by gynecologic-pathologists following post-surgery pathology review. RESULTS Twenty-one patients with the diagnosis of ULMS (N = 15) and STUMP (N = 6) after morcellation were identified. The median age of occurrence was 46 years (range, 25-58 years). Median follow-up duration was 27 months (range, 1.8-93.1 months). None of the 21 patients had documented evidence of extra-uterine disease at the time of original surgery. Ultimately 12 patients were immediately re-explored to complete staging. The median time to the staging surgery was 33 days (range 15-118 days). Two (28.5%) out of seven patients with presumed stage I ULMS and one (25%) out of four patients with presumed stage I STUMP had significant findings of disseminated intraperitoneal disease detected at immediate surgical re-exploration. One of the 8 patients with confined early ULMS and STUMP at the second surgery had intraperitoneal recurrence, while the remaining 7 patients have had no recurrence and remain disease free. CONCLUSION Surgical re-exploration is likely to show findings of disseminated peritoneal sarcomatosis in a significant number of patients diagnosed with ULMS after a morcellation procedure. Findings from re-exploration can contribute to the knowledge of natural history of morcellated ULMS/STUMP and allow for accurate prognostication.

Generation of Effector Memory T Cell–Based Mucosal and Systemic Immunity with Pulmonary Nanoparticle Vaccination

A lipid nanocapsule vaccine promotes cross-presentation of antigen with enhanced draining lymph node delivery to elicit an effector memory CD8+ T cell response. Nanoparticle Vaccine Delivered to Lungs Delivering vaccines to the lungs has been shown to protect against not only respiratory infections but also pathogens that enter in other organs, including the gastrointestinal and reproductive tracts. To capitalize on this phenomenon, Li and colleagues designed a pulmonary vaccination strategy that uses nanoparticle carriers to deliver antigen and adjuvant to the mucosal surface lining the lungs. Nanosized particles called interbilayer-crosslinked multilamellar vesicles (ICMVs) were engineered to contain antigen along with two Toll-like receptor agonists, which served as adjuvants to stimulate airway epithelial cells and promote dendritic cell uptake and cross-presentation. Mice that received ICMVs containing the model antigen ovalbumin (OVA) showed a greater T cell response than did those that received soluble OVA vaccine, with more OVA-specific T cells in the lungs after 11 weeks. ICMV-based vaccines were next put to the test in therapeutic tumor and prophylactic viral challenge models. As a therapeutic vaccine, all mice that received OVA-ICMVs after an injection of OVA-expressing melanoma cells resisted tumor formation and had prolonged survival. In the challenge model, animals were first given ICMV vaccines loaded with the peptide antigen AL11 [from simian immunodeficiency virus (SIV) gag], then exposed to vaccinia virus expressing SIV gag. Only animals that received pulmonary vaccination—not subcutaneous or soluble vaccine—were protected from viral challenge, showing a reduction of viral titers in the lungs and other organs. The nanoparticle vaccine demonstrated systemic protection when delivered locally to the lung mucosa. The authors suggest that ICMV vaccines stimulated the generation of a large population of effector memory T cells in the lungs and circulation, thus conferring such high protection in mice. Although the ICMVs were determined to be safe and well tolerated in small animals, additional safety and efficacy studies will be needed in larger animals before translation. Many pathogens infiltrate the body and initiate infection via mucosal surfaces. Hence, eliciting cellular immune responses at mucosal portals of entry is of great interest for vaccine development against mucosal pathogens. We describe a pulmonary vaccination strategy combining Toll-like receptor (TLR) agonists with antigen-carrying lipid nanocapsules [interbilayer-crosslinked multilamellar vesicles (ICMVs)], which elicit high-frequency, long-lived, antigen-specific effector memory T cell responses at multiple mucosal sites. Pulmonary immunization using protein- or peptide-loaded ICMVs combined with two TLR agonists, polyinosinic-polycytidylic acid (polyI:C) and monophosphoryl lipid A, was safe and well tolerated in mice, and led to increased antigen transport to draining lymph nodes compared to equivalent subcutaneous vaccination. This response was mediated by the vast number of antigen-presenting cells (APCs) in the lungs. Nanocapsules primed 13-fold more T cells than did equivalent soluble vaccines, elicited increased expression of mucosal homing integrin α4β7+, and generated long-lived T cells in both the lungs and distal (for example, vaginal) mucosa strongly biased toward an effector memory (TEM) phenotype. These TEM responses were highly protective in both therapeutic tumor and prophylactic viral vaccine settings. Together, these data suggest that targeting cross-presentation–promoting particulate vaccines to the APC-rich pulmonary mucosa can promote robust T cell responses for protection of mucosal surfaces.

Attenuated adiposopathy in perivascular adipose tissue compared with subcutaneous human adipose tissue.

BACKGROUND We hypothesized that human perivascular and subcutaneous adipose tissues hold distinct phenotypic signatures. We also evaluated the impact of clinical parameters on the adipose phenotype. Our overall goal is to understand the determinants of adipose biology so that this tissue can be manipulated therapeutically to lessen peripheral vascular disease. METHODS Perivascular and subcutaneous adipose tissues were collected from patients undergoing lower-extremity amputation (n = 27) and protein assayed for proinflammatory mediators (ie, interleukin 6, interleukin 8, leptin, tumor necrosis factor α, monocyte chemoattractant protein-1, and resistin), atheroprotective adiponectin, and the fibrinolysis inhibitor plasminogen activator inhibitor-1. RESULTS Leptin (2.7-fold, P = .015), TNF-α (2.2-fold, P = .013), MCP-1 (1.5-fold, P = .047), and adiponectin (1.8-fold, P = .004) were more abundant in subcutaneous vs perivascular adipose tissue. Age positively correlated with perivascular adipose tissue PAI-1 expression (β = .64, P = .042), and hyperlipidemia negatively correlated with perivascular adiponectin (β = -1.18, P = .039). CONCLUSIONS Human perivascular and subcutaneous adipose tissues hold distinct phenotypic signatures. In amputation patients, the subcutaneous adipose tissue proinflammatory phenotype was relatively attenuated in perivascular adipose tissue.

Preoperative diet impacts the adipose tissue response to surgical trauma

BACKGROUND Short-term changes in preoperative nutrition can have profound effects on surgery-related outcomes such as ischemia/reperfusion injury in preclinical models. Dietary interventions that lend protection against stress in animal models (eg, fasting, dietary restriction [DR]) impact adipose tissue quality/quantity. Adipose tissue holds high surgical relevance because of its anatomic location and large tissue volume, and it is ubiquitously traumatized during surgery. Yet the response of adipose tissue to trauma under clinically relevant circumstances including dietary status remains poorly defined. We hypothesized that preoperative diet alters the adipose tissue response to surgical trauma. METHODS A novel mouse model of adipose tissue surgical trauma was employed. Dietary conditions (diet-induced obesity [DIO], preoperative DR) were modulated before application of surgical adipose tissue trauma in the context of clinically common scenarios (different ages, simulated bacterial wound contamination). Local/distant adipose tissue phenotypic responses were measured as represented by gene expression of inflammatory, tissue remodeling/growth, and metabolic markers. RESULTS Surgical trauma had a profound effect on adipose tissue phenotype at the site of trauma. Milder but significant distal effects on non-traumatized adipose tissue were also observed. DIO exacerbated the inflammatory aspects of this response, and preoperative DR tended to reverse these changes. Age and lipopolysaccharide (LPS)-simulated bacterial contamination also impacted the adipose tissue response to trauma, with young adult animals and LPS treatment exacerbating the proinflammatory response. CONCLUSION Surgical trauma dramatically impacts both local and distal adipose tissue biology. Short-term preoperative DR may offer a strategy to attenuate this response.

Surgical Pathology of Small- and Medium-Sized Vessels.

Surgical pathologists encounter blood vessels in virtually every specimen they receive, but pathologies intrinsic to the vessels themselves are distinctly less common. Nevertheless, there are a variety of specific diagnoses and procedures involving vascular specimens that merit the attention of the anatomic pathologist. Etiologically, such pathologies can be broadly grouped into traumatic, degenerative, congenital, inflammatory, infectious, and neoplastic lesions. Major examples of most of these are discussed, including anuerysms, vasculitis, thrombosis/embolism, and atherosclerosis.

Genes in the Basement, Postmortem Genetic Testing…and 3 (New) Realities

We all have a treasure trove of things—squirreled away in knick-knack drawers or long-forgotten boxes in the basement, storage lockers, and parents’ homes. Things we tell ourselves will someday have value if we just wait long enough. Every pathology department has things too—the glass slides and paraffin blocks of specimens long since diagnosed and discarded, all tucked away in the far recesses of hospitals and storage warehouses, waiting for a time to reach their full potential. A select few of these even manage to be resurrected each year, some for a retrospective analysis of one marker or another, others to settle a diagnostic or medicolegal matter. Most, however, sit idly in file cabinets and storage facilities, out of sight and largely forgotten, reminiscent of the final scene in Raiders of the Lost Ark. See Article by Baudhuin et al Those materials, however, still have great value. Among pathologists, this is not exactly a secret—archived slides and blocks have long been appropriated for developing new stains, defining diagnoses, and understanding disease pathogenesis. And when modern genetic testing methods arrived, many had visions of Jurassic Park-style moments, unlocking the secrets embedded not in amber but in paraffin. Unfortunately, most of the promise of such materials has languished. Genetic testing methods to date have largely focused on peripheral blood and carefully preserved tissues gathered from living patients. Applying the same techniques to the stuff …

A mimic of hypertrophic cardiomyopathy.

A 52-year-old man with atrial fibrillation, chronic kidney disease (status-post renal transplant), and a presumed diagnosis of hypertrophic cardiomyopathy (HCM) underwent cardiac magnetic resonance (CMR) prior to catheter ablation for refractory atrial fibrillation. An electrocardiogram during sinus rhythm suggested an accessory pathway ( Panel 1 ). The CMR revealed normal ejection fraction ( Panel 2A , Supplementary material online, Movie S1 ), concentric left ventricular hypertrophy with wall …

Pathophysiology of Atherosclerosis

Complications resulting from advanced atherosclerosis are the most common indication for vascular reconstructive surgery. Atherosclerosis is a systemic disease affecting the entire arterial tree, but lesions involving the coronary, extracranial cerebral, and lower extremity circulations have the most clinical significance for surgeons. The pathogenesis of atherosclerosis involves a complex series of events, similar to a chronic inflammatory process, with the formation of atherosclerotic plaque as the end result. Injury to the endothelial cell of the artery, resulting in endothelial cell dysfunction, is the first step in the process. Activated endothelial cells attract leukocytes and vascular smooth muscle cells (VSMC), which accumulate and proliferate in the arterial wall. These cellular components produce an excessive amount of connective tissue matrix. The ultimate end point is the formation of a mature fibrous plaque. Symptoms occur when advanced lesions are complicated by plaque rupture, hemorrhage into the plaque, emboli, or thrombosis. A thorough understanding of the pathogenesis of atherosclerosis is essential for the development of strategies for the prevention of the disease, and for the development of new and effective treatments.