Stanley J. Radio

Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis

The clinical suspicion of myocarditis relies strongly on endomyocardial biopsy for confirmation, yet the sensitivity of the procedure in this setting has not been clearly defined. Biopsy sensitivity was determined in 14 hearts with histologically proved myocarditis studied ex vivo, including 12 autopsy hearts and 2 native hearts explanted at cardiac transplantation. With use of the Stanford and Cordis bioptomes, endoymocardial biopsy was performed near the apex on the right side of the ventricular septum (four to five samples/bioptome per patient) and repeated in the nonapical portion of the septum from the moderator band to the subpulmonary infundibulum (additional three to five samples/bioptome per patient). In a casewise assessment, 43% to 57% of the endomyocardial samples were diagnostic for myocarditis, as calculated separately for each bioptome in each region of sampling (apical/nonapical). Both apical and nonapical sensitivity improved to 64% when the findings of the two bioptomes were combined (eight to nine samples/patient in each region). By collectively analyzing all available samples for each patient, 11 (79%) of 14 cases could be diagnosed, but this required a mean of 17.2 samples/patient, a number clinically unrealistic. The exclusion of four cases of fungal myocarditis from analysis did not significantly alter the results. In transmural ventricular sections, none of four patients with sudden death had inflammatory disease confined to the conduction system. In conclusion, despite six to eight negative biopsy samples/patient with suspected myocarditis, repeat biopsy may still be warranted.

Isolated intestinal transplantation for intestinal failure

OBJECTIVE:Parenteral nutrition sustains life in patients with intestinal failure. However, some experience life-threatening complications from parenteral nutrition, and in these individuals intestinal transplantation may be lifesaving.METHODS:This is a retrospective review of 28 consecutive isolated small bowel transplants performed in eight adults and 20 children between December 1993 and June 1998 at the University of Nebraska Medical Center.RESULTS:The 1-yr patient and graft survivals were 93% and 71%, respectively. The causes of graft loss were hyperacute rejection (n = 1), acute rejection (n = 5), vascular thrombosis (n = 1), and patient death (n = 1). The median length of time required until full enteral nutrition was 27 days. All 28 patients have experienced acute rejection of their small bowel grafts and rejection led to graft failure in five. Jaundice and/or hepatic fibrosis was present preoperatively in 17 of the 28 recipients and hyperbilirubinemia was completely reversed in all patients with functional grafts within 4 months of transplantation. Three patients developed posttransplant lymphoproliferative disease (11%). Three recipients developed cytomegalovirus enteritis and all were successfully treated.CONCLUSIONS:Patient survival after intestinal transplantation is comparable to parenteral nutrition for patients with intestinal failure. Better immunosuppressive regimens are needed to decrease the risk of graft loss from acute rejection. The incidence of posttransplant lymphoproliferative disorder is higher after intestinal transplantation than after other solid organ transplants and the risk of cytomegalovirus enteritis is low with the use of cytomegalovirus seronegative donors. Liver dysfunction in the absence of established cirrhosis can be reversed.

Frozen section evaluation of donor livers before transplantation

Frozen section examination was performed on 385 donor livers before transplantation. Exclusion criteria were applied to the donor livers examined to exclude potentially dysfunctional livers. The exclusion criteria included the following: severe macrovesicular steatosis, ischemic necrosis, prominent chronic portal inflammation, prominent periductular fibrosis, granulomatous inflammation, bridging fibrosis, and malignancy. Twenty-seven of the 385 donor livers examined were excluded before transplantation. The following histologic features were present in the excluded livers: severe steatosis (22), ischemic necrosis (2), portal inflammation (1), and periductular fibrosis (2). Steatosis was present in 51 of the 385 (13.25%) organs examined, including 22 of the donor organs excluded before transplantation. Twenty-nine livers with mild to moderate steatosis were implanted into size and blood type-matched recipients. Indicators of allograft function (prothrombin time and bilirubin) and damage (aspartate aminotransferase and alanine aminotransferase) were measured daily for the first 10 days after transplant. There was no statistically significant difference between the group of nonfat livers and donor livers containing mild steatosis. Statistically significant higher posttransplant serum alanine aminotransferase and prothrombin time levels were present in the patients with livers implanted with mild versus moderate steatosis. The 1-year survival rate for patients receiving fatty versus nonfatty donor livers was not statistically different (Kaplan-Meier, P=0.592). No significant differences were found in the clinical and laboratory characteristics of donors whose organs were implanted compared with the clinical and laboratory characteristics of donors whose organs were excluded. The primary non-function rate after applying the exclusion criteria was 1.4%, which is a significant decrease compared with our primary nonfunction rate of 8.5% before using frozen section examination. Frozen section examination is useful in excluding donor organs which may become dysfunctional after transplantation.

Tacrolimus and sirolimus cause insulin resistance in normal sprague dawley rats

Background. Tacrolimus-sirolimus immunosuppression has improved islet graft survival but may affect islet function. Methods. We studied the effects of tacrolimus, sirolimus, or both in normal adult male Sprague Dawley rats. Glucose and insulin response to oral glucose load and pancreas pathology were evaluated after two weeks of daily tacrolimus (1–8 mg/kg/day), sirolimus (0.08–8 mg/kg/day), or low-dose sirolimus (0.08 mg/kg/day) plus tacrolimus (1 mg/kg/day) treatment compared to controls. Results. Tacrolimus and sirolimus each caused dose-dependent hyperglycemia with hyperinsulinemia in response to oral glucose compared to controls, suggesting insulin resistance. At the highest doses of sirolimus, fasting insulin concentrations were high and did not increase with oral glucose suggesting loss of first phase insulin release. The combination of low doses of tacrolimus and sirolimus, at concentrations used in clinical transplantation, resulted in hyperglycemia without hyperinsulinemia after oral glucose administration. The combination of tacrolimus and sirolimus decreased islet size, and increased islet apoptosis more than either medication alone, or controls. Conclusions. In summary, short-term therapy with either tacrolimus or sirolimus causes insulin resistance in normal rats. Combination tacrolimus-sirolimus causes greater islet changes suggesting early islet failure.

Recommendations for processing cardiovascular surgical pathology specimens: a consensus statement from the Standards and Definitions Committee of the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology

With the advent of molecular subclassification of diseases, much consideration should be given to the proper processing of cardiovascular surgical pathology specimens to maximize patient care. Such specimens include endomyocardial biopsies, cardiac myectomy specimens, cardiac apical core segments, resected cardiac valves, pericardial biopsies, resected segments of aorta, cardiac tumors, vascular stents, vascular grafts, cardiac devices, resected veins, arterial biopsies including temporal artery biopsies and hearts removed during cardiac transplantation. In this report, the Standards and Definitions Committee of the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology present consensus guidelines for the gross description, sectioning, processing, and staining of these specimens. This report is presented to aid pathologists, pathology assistants, and clinicians in maximizing the diagnostic utility of cardiovascular surgical pathology specimens for enhanced patient care.

Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: I. Inflammatory diseases

Inflammatory diseases of the aorta include routine atherosclerosis, aortitis, periaortitis, and atherosclerosis with excessive inflammatory responses, such as inflammatory atherosclerotic aneurysms. The nomenclature and histologic features of these disorders are reviewed and discussed. In addition, diagnostic criteria are provided to distinguish between these disorders in surgical pathology specimens. An initial classification scheme is provided for aortitis and periaortitis based on the pattern of the inflammatory infiltrate: granulomatous/giant cell pattern, lymphoplasmacytic pattern, mixed inflammatory pattern, and the suppurative pattern. These inflammatory patterns are discussed in relation to specific systemic diseases including giant cell arteritis, Takayasu arteritis, granulomatosis with polyangiitis (Wegeners), rheumatoid arthritis, sarcoidosis, ankylosing spondylitis, Cogan syndrome, Behçets disease, relapsing polychondritis, syphilitic aortitis, and bacterial and fungal infections.

Flow cytometric DNA analysis of malignant fibrous histiocytoma and related fibrohistiocytic tumors

Fibrohistiocytic neoplasms with similar histologic characteristics may have vastly different biologic behaviors. We studied 23 fibrohistiocytic tumors to determine if cellular DNA content was correlated with clinical outcome. Archival paraffin blocks of 9 malignant fibrous histiocytomas (MFH), 3 dermatofibrosarcoma protuberans, 9 dermatofibromas, 1 juvenile xanthogranuloma, and 1 nodular fasciitis were processed, stained with propidium iodide, and analyzed by flow cytometry. Five of 9 (56%) MFH and 1 of 3 (33%) dermatofibrosarcoma protuberans were aneuploid. All 11 benign fibrohistiocytic tumors were diploid. Local recurrence occurred in 3 of 5 (60%) cases of aneuploid MFH, but in none with a diploid MFH tumor. No cases of dermatofibrosarcoma protuberans or benign tumors recurred. Aneuploidy was associated with decreased survival, as 2 of 5 patients with aneuploid MFH died within 1 year of diagnosis whereas all 4 patients with diploid MFH tumors are alive after an average follow-up of 4 years (range, 1 to 11). The diploid and aneuploid groups did not differ in clinical stage at the time of diagnosis. Our results indicate that retrospective DNA analysis can detect aneuploidy in both MFH as well as other fibrohistiocytic tumors, and that aneuploidy in MFH may place the patient at increased risk for local recurrence and mortality.

Inhibition of carotid artery neointimal formation with intravenous microbubbles

Because therapeutic gene products such as synthetic antisense oligodeoxynucleotides (ODN) bind to albumin-coated microbubbles, we sought to determine whether IV perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles could target their delivery to the carotid artery following balloon injury. In 5 pigs, the concentration of ODN taken up within the carotid vascular wall was found to be significantly increased when the IV antisense (ODN) was administered bound to PESDA (ODN-PESDA), and while transcutaneous low-frequency (20 kHz) ultrasound was applied over the carotid artery. Based on these results, a chronic model was then developed, in which 21 pigs received either IV ODN-PESDA, ODN alone, or control, following carotid balloon injury. At 30 days following balloon injury, percent area stenosis was only 8 +/- 2% in the ODN-PESDA groups compared to 19 +/- 8% and 28 +/- 3% in the other groups (p < 0.01). IV PESDA may be a method of noninvasively targeting the delivery of therapeutic genes.

Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: II. Noninflammatory degenerative diseases - Nomenclature and diagnostic criteria

Surgical aortic specimens are usually examined in Pathology Departments as a result of treatment of aneurysms or dissections. A number of diseases, genetic syndromes (Marfan syndrome, Loeys-Dietz syndrome, etc.), and vasculopathic aging processes involved in vascular injury can cause both distinct and nonspecific histopathologic changes with degeneration of the media as a common denominator. Terminology for these changes has varied over time leading to confusion and inconsistencies. This consensus document has established a revised, unified nomenclature for the variety of noninflammatory degenerative aortic histopathologies seen in such specimens. Older terms such as cystic medial necrosis and medionecrosis are replaced by more technically accurate terms such as mucoid extracellular matrix accumulation (MEMA), elastic fiber fragmentation and/or loss, and smooth muscle cell nuclei loss. A straightforward system of grading is presented to gauge the extent of medial degeneration and synoptic reporting tables are provided. Herein we present a standardized nomenclature that is accessible to general pathologists and useful for future publications describing these entities.

Experience with protocol biopsies after solitary pancreas transplantation

The early detection of allograft rejection remains elusive after solitary pancreas transplantation (PTX). We have previously described a modified technique of cystoscopic transduodenal PTX biopsy using the Biopty gun under ultrasound guidance. During the last 2 years, we performed 24 solitary PTXs with prospective protocol biopsy monitoring as well as biopsies performed whenever clinically indicated. The study group included 17 pancreas transplants alone, 6 sequential pancreas after kidney transplants, and 1 sequential pancreas after liver transplant. Five patients received pancreas retransplants. A total of 92 cystoscopically directed core PTX biopsies were performed, including 50 protocol biopsies (mean 2.1 per patient). Protocol biopsies were performed at 1 month (19), 2 months (3), 3 months (20), 6 months (7), and 12 months (1) after PTX. Adequate PTX tissue for histopathologic examination was obtained in 49 cases (98%). Biopsy findings included no rejection (34), mild rejection (13), pancreatitis (1), and cytomegalovirus infection (1). Overall, 15 of the 49 evaluable biopsies (31%) had significant histopathologic findings. All but 1 of the cases of mild rejection were treated with bolus steroids. Eight of these patients subsequently developed recurrent biopsy-proven rejection within 2 months; 5 grafts were subsequently lost to rejection between 3 and 13 months after PTX. Three biopsy complications occurred: 1 hematoma, 1 pancreatitis, and 1 ileus. Patient survival is 96% and PTX graft survival (complete insulin independence) is 75% after a mean follow-up of 15 months. In the remaining 42 clinically indicated biopsies, 3 were insufficient, 8 showed no rejection, and 31 (79%) had rejection. In half of these cases, the rejection was graded as moderate to severe. In conclusion, prospective monitoring with protocol PTX biopsies may result in the earlier detection of allograft rejection and have a direct effect on improving results after solitary PTX.