Report of the 2022 Banff Heart Concurrent: Focus on non-human leukocyte antigen antibodies in rejection and the pathology of "mixed" rejection.

The Banff Heart Concurrent Session, held as part of the 16th Banff Foundation for Allograft Pathology Conference at Banff, Alberta, Canada, on September 21, 2022, focused on 2 major topics: non-human leukocyte antigen (HLA) antibodies and mixed rejection. Each topic was addressed in a multidisciplinary fashion with clinical, immunological, and pathology perspectives and future developments and prospectives. Following the Banff organization model and principles, the collective aim of the speakers on each topic was to • Determine current knowledge gaps in heart transplant pathology • Identify limitations of current pathology classification systems • Discuss next steps in addressing gaps and refining classification system.

Magee Equations™ and response to neoadjuvant chemotherapy in ER+/HER2-negative breast cancer: a multi-institutional study.

Magee Equations™ (ME) are multivariable models that can estimate oncotype DX® recurrence score. One of the equations, Magee Equation 3 (ME3) which utilizes only semi-quantitative receptor results has been shown to provide chemopredictive value in the neoadjuvant setting in a single institutional study. This multi-institutional study (seven institutions contributed cases) was undertaken to examine the validity of ME3 in predicting response to neoadjuvant chemotherapy in estrogen receptor positive, HER2-negative breast cancers. Stage IV cases were excluded. The primary endpoint was the pathologic complete response (pCR) rate in different categories of ME3 scores calculated based on receptor results in the pre-therapy core biopsy. A total of 166 cases met the inclusion criteria. The patient age ranged from 24 to 83 years (median 53 years). The average pre-therapy tumor size was 3.9 cm, and axillary lymph nodes were confirmed positive by pre-therapy core biopsy in 85 of 166 cases (51%). The pCR rate according to ME3 scores was 0% (0 of 64) in ME3 < 18, 0% (0 of 46) in ME3 18-25, 14% (3 of 21) in ME3 > 25 to <31, and 40% (14 of 35) in ME3 score 31 or higher (p value: <0.0001). There were no distant recurrences and no deaths in the 17 patients with pCR. In the remaining 149 cases with residual disease, ME3 score of >25 was significantly associated with shorter distant recurrence-free survival and showed a trend for shorter breast cancer-specific survival. The results of this multi-institutional study are similar to previously published data from a single institution (PMID: 28548119) and confirm the chemo-predictive value of ME3 in the neoadjuvant setting. In addition, ME3 may provide prognostic information in patients with residual disease which should be further evaluated.

Sensitization in Heart Transplantation: Emerging Knowledge: A Scientific Statement From the American Heart Association.

Sensitization, defined as the presence of circulating antibodies, presents challenges for heart transplant recipients and physicians. When present, sensitization can limit a transplantation candidate's access to organs, prolong wait time, and, in some cases, exclude the candidate from heart transplantation altogether. The management of sensitization is not yet standardized, and current therapies have not yielded consistent results. Although current strategies involve antibody suppression and removal with intravenous immunoglobulin, plasmapheresis, and antibody therapy, newer strategies with more specific targets are being investigated.

The XVth Banff Conference on Allograft Pathology the Banff Workshop Heart Report: Improving the diagnostic yield from endomyocardial biopsies and Quilty effect revisited.

The XVth Banff Conference on Allograft Pathology meeting was held on September 23-27, 2019, in Pittsburgh, Pennsylvania, USA. During this meeting, two main topics in cardiac transplant pathology were addressed: (a) Improvement of endomyocardial biopsy (EMB) accuracy for the diagnosis of rejection and other significant injury patterns, and (b) the orphaned lesion known as Quilty effect or nodular endocardial infiltrates. Molecular technologies have evolved in recent years, deciphering pathophysiology of cardiac rejection. Diagnostically, it is time to integrate the histopathology of EMBs and molecular data. The goal is to incorporate molecular pathology, performed on the same paraffin block as a companion test for histopathology, to yield more accurate and objective EMB interpretation. Application of digital image analysis from hematoxylin and eosin (H&E) stain to multiplex labeling is another means of extracting additional information from EMBs. New concepts have emerged exploring the multifaceted significance of myocardial injury, minimal rejection patterns supported by molecular profiles, and lesions of arteriolitis/vasculitis in the setting of T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR). The orphaned lesion known as Quilty effect or nodular endocardial infiltrates. A state-of-the-art session with historical aspects and current dilemmas was reviewed, and possible pathogenesis proposed, based on advances in immunology to explain conflicting data. The Quilty effect will be the subject of a multicenter project to explore whether it functions as a tertiary lymphoid organ.

The impact of asymptomatic antibody-mediated rejection on outcome after heart transplantation.

PURPOSE OF REVIEW: Defining criteria for antibody-mediated rejection (AMR) in heart transplantation were standardized a few years ago, but very little is known about asymptomatic cardiac AMR. We will start the review with a background summarizing the timeline of cardiac AMR. Then we will cover past and current knowledge about asymptomatic cardiac AMR and its impact on outcome after transplantation, with added insight from experience with other solid-organ transplants. RECENT FINDINGS: The incidence of asymptomatic cardiac AMR had likely been under-estimated because biopsy surveillance for it in the absence of clinical manifestation was not the norm. Recent data indicate that it may be more common especially when counting concomitant acute cellular rejection (mixed rejection). Also a higher risk of cardiac allograft vasculopathy (CAV) and cardiovascular mortality have been linked to it. The primary implication of these findings is whether therapeutic intervention is warranted, but the appropriate target patient population likely to benefit from treatment is yet to be determined. SUMMARY: Asymptomatic cardiac AMR is not uncommon and it negatively impacts outcome after heart transplantation.

Alteration of Cardiac Deformation in Acute Rejection in Pediatric Heart Transplant Recipients.

The objective of this study is to assess changes in cardiac deformation during acute cellular- and antibody-mediated rejection in pediatric HT recipients. Pediatric HT recipients aged ≤18 years with at least one episode of biopsy-diagnosed rejection from 2006 to 2013 were included. Left ventricular systolic S (SS) and SR (SSr) data were acquired using 2D speckle tracking on echocardiograms obtained within 12 h of right ventricular endomyocardial biopsy. A mixed effect model was used to compare cardiac deformation during CR (Grade ≥ 1R), AMR (pAMR ≥ 2), and mixed rejection (CR and AMR positive) versus no rejection (Grade 0R and pAMR 0 or 1). A total of 20 subjects (10 males, 50%) with 71 rejection events (CR 35, 49%; AMR 21, 30% and mixed 15, 21%) met inclusion criteria. The median time from HT to first biopsy used for analysis was 5 months (IQR 0.25-192 months). Average LV longitudinal SS and SSr were reduced significantly during rejection (SS: -17.2 ± 3.4% vs. -10.7 ± 4.5%, p < 0.001 and SSr: -1.2 ± 0.2 s- 1 vs. -0.9 ± 0.3 s- 1; p < 0.001) and in all rejection types. Average LV short-axis radial SS was reduced only in CR compared to no rejection (p = 0.04), while average LV circumferential SS and SSr were reduced significantly in AMR compared to CR (SS: 18.9 ± 4.2% vs. 20.8 ± 8.8%, p = 0.03 and SSr: 1.35 ± 0.8 s- 1 vs. 1.54 ± 0.9 s- 1; p = 0.03). In pediatric HT recipients, LV longitudinal SS and SSr were reduced in all rejection types, while LV radial SS was reduced only in CR. LV circumferential SS and SSr further differentiated between CR and AMR with a significant reduction seen in AMR as compared to CR. This novel finding suggests mechanistic differences between AMR- and CR-induced myocardial injury which may be useful in non-invasively predicting the type of rejection in pediatric HT recipients.

Effect of ventriculotomy on right-ventricular remodeling in hypoplastic left heart syndrome: a histopathological and echocardiography correlation study.

The objective of this study was to compare histopathological changes in hypoplastic left heart syndrome right ventricles (RV) of patients undergoing Sano and modified Blalock-Taussig (MBT) shunt and correlate them with echocardiographic findings. Myocardial tissue samples were obtained from hearts with Sano or MBT shunts after transplantation or at autopsy. Histologic sections were reviewed manually and by automated digital image analysis. Velocity vector imaging was performed on echocardiogram images obtained before transplant or death. All of these parameters were compared between the Sano and MBT shunt cohorts. A total of 14 specimens (7 Sano and 7 MBT shunt) were studied. Median age at transplant/death of Sano and MBT shunt cohorts was 11 (range 2-41) and 8 months (range 2-200), respectively. All Sano specimens had a scar at ventriculotomy site, and the mean scar area was 6.2 ± 3.3 cm(2). Compared with remote RV free wall, myocardium bordering the scar showed increased fibrosis (34 ± 16 % vs. 28 ± 14 %, p = 0.04) and thinning (0.8 ± 0.9 vs. 5.3 ± 0.8 mm; p < 0.001), which did not regress with time. The Sano ventriculotomy site showed significantly decreased velocity, strain, and strain rate compared with the corresponding contralateral segment. No focal scarring or regional hypokinesia was seen in the MBT shunt cohort. This is the first study to demonstrate histopathological features of ventriculotomy-associated RV myocardial scarring and myocardial thinning. The scarred ventriculotomy site showed decreased segmental myocardial deformation after Norwood with Sano shunt.

Impact of high-dose inotropic donor support on early myocardial necrosis and outcomes in cardiac transplantation.

BACKGROUND: Cardiac donors routinely require vasoactive agents for circulatory stability after brain death. Nevertheless, inotropes have been associated with direct cardiac toxicity. Our study evaluated whether the use of high-dose inotropic support in potential donors was associated with increased early myocardial necrosis (MN) and worse clinical outcomes after cardiac transplantation. METHODS: The UTAH Cardiac Transplant Program (UCTP) and Intermountain Donor Services databases were queried for records between 1996 and 2009. The high-dose donor inotropic support (HDIS) group was defined as patients on dopamine >10 µg/kg/min. The incidence of early MN, intensive care unit (ICU) length of stay, length of ventilator support, and mortality was evaluated. RESULTS: Two hundred and forty-four recipients undergoing transplant met study criteria. The average donor age was 27 yr. The incidence of MN in the HDIS (n=29) and non-HDIS (n=204) groups was 14.8% and 6.7%, respectively, OR 2.67. Total ischemic time, ventilator support time, ICU stay, and actuarial survival were similar between both groups. CONCLUSION: The use of high-dose inotropic support to maintain donor stability appears to have a higher trend for early post-transplant MN without an impact on clinical outcomes. With the current growing shortage of organ donors, it appears reasonable to use donors on high-dose inotropic support.

Primary central nervous system vasculitis presenting with intracranial hemorrhage.

OBJECTIVE: To describe a subset of cases in a large retrospectively identified cohort of patients with primary central nervous system vasculitis (PCNSV) who present with intracranial hemorrhage. METHODS: The study consisted of a cohort of 131 consecutive patients with PCNSV who were seen at the Mayo Clinic over a 25-year period from 1983 to 2007. The diagnosis of PCNSV was based on findings of brain or spinal cord biopsy, cerebral angiography, or both. Intracranial hemorrhage at presentation was defined as the presence of intracerebral or subarachnoid hemorrhage on computed tomography or magnetic resonance imaging (MRI) of the brain within 3 months of the date of PCNSV diagnosis. The clinical, laboratory, radiologic, and pathologic findings, therapy, and outcomes in patients presenting with intracranial hemorrhage were compared with those without intracranial hemorrhage. RESULTS: Sixteen patients (12.2%) had evidence of intracranial hemorrhage at or near the time of diagnosis. Twelve patients had intracerebral hemorrhage, and 4 had subarachnoid hemorrhage. Twelve patients were diagnosed by findings on angiography and 4 by findings on CNS biopsy. Compared with the 115 patients without intracranial hemorrhage, the 16 patients presenting with intracranial hemorrhage were more frequently women, less frequently had altered cognition, a persistent neurologic deficit, or stroke at presentation, less frequently had MRI evidence of cerebral infarctions, and less frequently needed therapy at last followup. A necrotizing histopathologic pattern of vasculitis was observed in 3 of the 4 patients with positive biopsy findings (75%). CONCLUSION: Our findings suggest that intracranial hemorrhage may not be an infrequent occurrence in early PCNSV. Necrotizing vasculitis may be a predominant histopathologic pattern.

Rapidly progressive primary central nervous system vasculitis.

OBJECTIVE: To describe a subset of cases in a large cohort of patients with primary CNS vasculitis (PCNSV) who appear to have a rapidly progressive clinical course. METHOD: In the present study, we use our updated cohort of 131 consecutive patients with PCNSV seen over the 25-year period of 1983-2007 at Mayo Clinic, Rochester, MN, USA. The diagnosis of PCNSV was based on brain/spinal cord biopsy or cerebral angiography. The modified Rankin scale was used to identify rapidly progressive disease and included patients with Rankin scores indicating severe disability or death at diagnosis or within 6 months after the diagnosis. We compared patients with rapidly progressive disease to those without. RESULTS: Compared with the 120 patients without rapidly progressive vasculitis, the 11 patients with rapidly progressive vasculitis more frequently had paraparesis/quadriparesis at presentation, angiographic presence of bilateral, large-vessel vasculitis and MRI evidence of cerebral infarctions; those infarctions were more frequently multiple and bilateral, and more frequently involved both the cortex and subcortical regions on initial MRI. Granulomatous and/or necrotizing histopathological patterns of vasculitis were observed in patients with positive biopsies. CONCLUSION: Rapidly progressive PCNSV appears to form a subset of PCNSV at the worst end of the clinical spectrum of this vasculitis, characterized by bilateral, multiple, large cerebral vessel lesions and multiple CNS infarctions.

The pathology of large-vessel vasculitides.

Vasculitis affecting large elastic arteries, including the aorta and major proximal branches, encompasses various diseases including Takayasu arteritis, giant cell (or temporal) arteritis, and tertiary syphilis, but also may occur as a rare complication of Behçet's disease, rheumatoid arthritis, sarcoidosis, Cogan syndrome, Kawasaki disease, ankylosing spondylitis, systemic lupus erythematosus and Wegener's granulomatosis. Recent reports have also established a link between inflammatory abdominal aortic aneurysm as well as lymphoplasmacytic thoracic aortitis with an overabundance of IgG4-producing plasma cells and the burgeoning constellation of 'Hyper-IgG4' syndromes. This review focuses on morphologic aspects of large-vessel vasculitis pathology associated with giant cell arteritis, Takayasu arteritis, idiopathic or isolated aortitis, lymphoplasmacytic thoracic and ascending aortitis, and the inflammatory aneurysm/retroperitoneal fibrosis syndrome.

Fungal prosthetic valve endocarditis: Mayo Clinic experience with a clinicopathological analysis.

Fungal prosthetic valve endocarditis is a rare but devastating disease. To better characterise this syndrome, we retrospectively reviewed 21 cases of fungal prosthetic valve endocarditis seen at Mayo Clinic over the past 40 years. The average patient age was 65 years with a 2 : 1 male predominance. Twelve of 21 cases (57%) occurred within 1 year of prosthetic valve placement. The aortic valve was most commonly affected, and the most common aetiological agent was Candida species, followed by Histoplasma capsulatum. Although 20 of 21 patients (95%) were immunocompetent, they had other risk factors for fungal infection. Patients typically presented with systemic signs and symptoms of infection, and cardiac imaging was abnormal in 68% of cases. Pathological evaluation of valve material was of high yield, with organisms identified in 92% of cases who underwent valve replacement surgery or had an autopsy performed. Prosthetic valve fungal endocarditis was associated with a high morbidity and mortality, with 67% of patients experiencing complications and 57% of patients dying of infection-related disease. Hopefully, with the prompt institution of early medical therapy, surgical intervention and lifelong oral antifungal suppressive therapy, cure rates will continue to improve.

Dense deposit disease associated with monoclonal gammopathy of undetermined significance.

Dense deposit disease (DDD) is a rare glomerular disease that typically affects children, young adults, and much less commonly, older patients. The pathophysiologic process underlying DDD is uncontrolled activation of the alternative pathway (AP) of complement cascade, most frequently secondary to an autoantibody to C3 convertase called C3 nephritic factor, although mutations in factor H and autoantibodies to this protein can impair its function and also cause DDD. Since 1995, we have diagnosed DDD in 14 patients aged 49 years or older; 10 of these patients (71.4%) carry a concomitant diagnosis of monoclonal gammopathy of undetermined significance (MGUS). In 1 of these 10 patients, the index case described here, we evaluated the AP and showed low serum AP protein levels consistent with complement activity, heterozygosity for the H402 allele of factor H, and low levels of factor H autoantibodies, which can affect the ability of factor H to regulate AP activity. In aggregate, these findings suggest that in some adults with MGUS, DDD may develop as a result of autoantibodies to factor H (or other complement proteins) that on a permissive genetic background (the H402 allele of factor H) lead to dysregulation of the AP with subsequent glomerular damage. Thus, DDD in some older patients may be a distinct clinicopathologic entity that represents an uncommon complication of MGUS.

Localized vasculitis of the gastrointestinal tract: a case series.

OBJECTIVE: To describe the clinical features and outcomes of patients with localized vasculitis of the gastrointestinal tract (LVGT). METHODS: Medical records of 608 patients diagnosed with vasculitis involving the intra-abdominal vasculature and/or abdominal viscera between January 1996 and December 2007 were reviewed. Only patients with histopathological confirmation or typical angiographic findings of vasculitis localized to the abdomen were included. RESULTS: We identified 18 cases with LVGT over the 12-year study period. The patients were predominantly Caucasian (89%) and female (67%) with a median age at diagnosis of 53.5 (range 17.4-83.3) years. Most of the patients presented with abdominal pain and 12 (66.6%) patients presented with an acute abdomen requiring surgical intervention. At diagnosis, the median ESR was 30.5 (range 4-77) mm/h. Autoantibody screening was generally unrevealing. Abdominal CT scan findings included: bowel wall thickening, bowel infarction and solid organ infarcts. In 14 patients, the diagnosis of vasculitis was established by abdominal angiography. Histological evidence of vasculitis was recorded in 5 (28%) patients, most commonly from gall bladder or small intestine specimens. Corticosteroid therapy was administered to 10 (56%) patients, 5 of whom also received other immunosuppressive agents. Median duration of follow-up was 10.5 (range 2-156) months. No evidence of vasculitis outside the abdomen was observed during follow-up. Seven (39%) patients died during the follow-up period. Survival of the patient cohort (compared with an age-matched US white population) was significantly reduced (P < 0.001). CONCLUSION: LVGT is an uncommon form of vasculitis that can be associated with significant morbidity and mortality.

Interventions for mesenteric vasculitis.

OBJECTIVE: This study reviewed the outcomes of open and endovascular revascularization for mesenteric vasculitis (MV). METHODS: We reviewed the clinical data of all patients who underwent revascularization for occlusive MV from 1984 to 2008. Patients treated for aneurysms or mucosal bleeding without ischemic symptoms were excluded. End points were early mortality and morbidity, survival, freedom from mesenteric symptoms, and patency. Outcomes of open reconstructions were compared with the results of 163 patients who underwent open operations for atherosclerotic disease. RESULTS: There were 15 patients (13 females, 2 males) with a mean age of 38 years (range, 15-66 years). Etiologies were Takayasu's arteritis in 7, polyarteritis nodosa in 4, indeterminate in 3, and giant cell arteritis in 1. The celiac axis was affected in 13, superior mesenteric artery (SMA) in 13, renal arteries in 8, and the aorta in 4. Seven patients had active disease, and eight were in remission. Nine (60%) presented with symptomatic chronic (n = 8) and acute (n = 1) mesenteric ischemia. Six patients with asymptomatic disease underwent mesenteric revascularization during other aortic-based operations. Fourteen patients (93%) had 10 mesenteric bypasses (8 aortic based; 2 iliac), three had aortoplasties, of which two had mesenteric patch angioplasties, and one underwent arcuate ligament release with patch angioplasty. One patient (7%) underwent percutaneous transluminal angioplasty of SMA stenosis. There were no early deaths. Early complications occurred in three patients (20%) after open reconstruction, including gastrointestinal hemorrhage, ileus with re-exploration, and superior mesenteric vein thrombosis. Median follow-up was 22 months. One graft thrombosis in a patient with active disease was treated with redo bypass 74 months after aorta-celiac-SMA bypass. All patients were alive at 10 years, with similar expected survival compared with the general population (P = .69). Compared with patients with atherosclerotic disease, open reconstructions for MV had similar freedom from mesenteric symptoms (83% vs 75%, P = .80) and similar primary graft patency (83% vs 84%, P = .9). CONCLUSION: Mesenteric vasculitis is a rare manifestation of Takayasu arteritis, polyarteritis nodosa, indeterminate, or giant cell arteritis. Open revascularization is durable and effective when needed.

A novel, rapid, and low cost method for preparing tissues with metallic stents for routine histology.

BACKGROUND: Coronary artery stenting has become a common procedure and cardiovascular pathology specimens containing these metallic stents are accordingly becoming common. Histologic examination of stented vessels is imperative, but special techniques are needed due to the presence of metal within the tissue. We describe a rapid and inexpensive method for preparing stented vascular specimens for routine histology suitable for use in almost any histology laboratory. DESIGN: After formalin fixation and decalcification, stented vascular segments were freeze-embedded and sectioned using a handheld power micro cutoff wheel tool into ~1 mm slices. Sections were allowed to thaw and the strut shards removed with fine forceps. No longer containing metal, the sections were processed for routine paraffin embedding, microtomy and staining. RESULTS: Histologic sections showed only minor tissue disruption around the stent struts. In our experience with 25 stented arteries (mean interval from implantation 5.6 years), the mean subjective section quality score was 4.1 out of 5. The position of each strut could easily be determined, along with neointimal in-stent restenosis and thrombosis. Local reaction to each strut could be surmised even if minor tissue disruption occurred. The entire process was completed in 2-3 days. The incremental cost over that of routine histology is nominal. CONCLUSION: This method for examining stented vascular segments histologically could readily be applied in most pathology laboratories and serves as a highly practical solution to dilemma of examining stents histologically.

Precise Identification of Cell and Tissue Features Important for Histopathologic Diagnosis by a Whole Slide Imaging System.

BACKGROUND: Previous studies have demonstrated the noninferiority of pathologists' interpretation of whole slide images (WSIs) compared to microscopic slides in diagnostic surgical pathology; however, to our knowledge, no published studies have tested analytical precision of an entire WSI system. METHODS: In this study, five pathologists at three locations tested intra-system, inter-system/site, and intra- and inter-pathologist precision of the Aperio AT2 DX System (Leica Biosystems, Vista, CA, USA). Sixty-nine microscopic slides containing 23 different morphologic features suggested by the Digital Pathology Association as important to diagnostic pathology were identified and scanned. Each of 202 unique fields of view (FOVs) had 1-3 defined morphologic features, and each feature was represented in three different tissues. For intra-system precision, each site scanned 23 slides at three different times and one pathologist interpreted all FOVs. For inter-system/site precision, all 69 slides were scanned once at each of three sites, and FOVs from each site were read by one pathologist. To test intra- and inter-pathologist precision, all 69 slides were scanned at one site, FOVs were saved in three different orientations, and the FOVs were transferred to a different site. Three different pathologists then interpreted FOVs from all 69 slides. Wildcard (unscored) slides and washout intervals were included in each study. Agreement estimates with 95% confidence intervals were calculated. RESULTS: Combined precision from all three studies, representing 606 FOVs in each of the three studies, showed overall intra-system agreement of 97.9%; inter-system/site agreement was 96%, intra-pathologist agreement was 95%, and inter-pathologist agreement was 94.2%. CONCLUSIONS: Pathologists using the Aperio AT2 DX System identified histopathological features with high precision, providing increased confidence in using WSI for primary diagnosis in surgical pathology.

Digital Whole Slide Imaging Compared With Light Microscopy for Primary Diagnosis in Surgical Pathology.

CONTEXT.­: The adoption of digital capture of pathology slides as whole slide images (WSI) for educational and research applications has proven utility. OBJECTIVE.­: To compare pathologists' primary diagnoses derived from WSI versus the standard microscope. Because WSIs differ in format and method of observation compared with the current standard glass slide microscopy, this study is critical to potential clinical adoption of digital pathology. DESIGN.­: The study enrolled a total of 2045 cases enriched for more difficult diagnostic categories and represented as 5849 slides were curated and provided for diagnosis by a team of 19 reading pathologists separately as WSI or as glass slides viewed by light microscope. Cases were reviewed by each pathologist in both modalities in randomized order with a minimum 31-day washout between modality reads for each case. Each diagnosis was compared with the original clinical reference diagnosis by an independent central adjudication review. RESULTS.­: The overall major discrepancy rates were 3.64% for WSI review and 3.20% for manual slide review diagnosis methods, a difference of 0.44% (95% CI, -0.15 to 1.03). The time to review a case averaged 5.20 minutes for WSI and 4.95 minutes for glass slides. There was no specific subset of diagnostic category that showed higher rates of modality-specific discrepancy, though some categories showed greater discrepancy than others in both modalities. CONCLUSIONS.­: WSIs are noninferior to traditional glass slides for primary diagnosis in anatomic pathology.

Ultrastructural analysis of amyloidoma.

Amyloidomas are localized mass-forming deposits of amyloid that occur with or without association with systemic amyloidosis. The ultrastructural findings in 3 amyloidomas from 2 autopsy patients with primary systemic AL amyloidosis are described. By transmission electron microscopy, there were randomly oriented nonbranching fibrils showing some unusual curvilinear forms and considerable variability in fibril diameter (two subsets of fibrils, one 12-14 nm and another 28-30 nm in diameter). The larger fibrils showed features of microtubule formation. Scanning electron microscopy demonstrated complex 3-dimensional tangles of fibrils. These findings add to the current ultrastructural and morphologic spectrum of paraprotein deposition disease.

Mechanism of tissue heating during high intensity focused ultrasound pulmonary vein isolation: implications for atrial fibrillation ablation efficacy and phrenic nerve protection.

INTRODUCTION: The purpose of this study was to examine tissue temperatures around pulmonary veins (PVs) during high intensity focused ultrasound (HIFU) balloon ablation for atrial fibrillation. The thermodynamics and extent of PV and phrenic nerve (PN) heating during HIFU ablation have not been established. METHODS AND RESULTS: Tissue temperatures were recorded from epicardial thermocouples at right superior (RS) PV orifice and PN in eight dogs undergoing 51 RSPV HIFU ablations (40 seconds, 40 W). Maximum tissue temperatures, reflected by 288 recording profiles, were negatively correlated with distance from balloon surface (r =-0.79, P < 0.001). Average maximum RSPV temperature was 56.8 +/- 16.8 degrees C (distance: 6.6 +/- 4.1 mm), resulting in full-thickness, circumferential PV isolation in 7 of 8 animals. Direct local mechanical heating restricted to the focused ultrasound zone showed temperature rise to > or =50 degrees C within 10 seconds to a maximum temperature of 82.6 +/- 8.9 degrees C (n = 31). Apparent conductive heating showed gradual heating patterns (<50 degrees C within 10 seconds) at greater distance. PN temperature at all recording sites was 45.0 +/- 11.3 degrees C (distance: 9.2 +/- 5.0 mm). Intentional PN injury (10 of 51 [19.6%] ablations), occurred at 63.7 +/- 16.0 degrees C with closest distance of 4.4 +/- 2.5 mm, which was closer than in PNs without injury (7.3 +/- 4.3 mm, P = 0.005). CONCLUSIONS: HIFU ablation is highly effective in generating temperatures needed for full-thickness, circumferential ablation through rapid direct mechanical heating. Gradual heating of surrounding tissue supports the presence of conductive heating. This study also discloses direct HIFU effects as the mechanism of PN injury occurring within 4-7 mm from balloon surface.