Eculizumab and recurrent C3 glomerulonephritis.

BACKGROUND: Hyperactivity of the alternative complement pathway is the principle defect in C3 glomerulopathies (C3G). Eculizumab, a monoclonal antibody that binds C5 to prevent formation of the membrane attack complex, has been shown to be beneficial in some patients with this disease. METHODS: In this open-label, proof-of-concept efficacy-and-safety study, a patient with the initial diagnosis of dense deposit disease (DDD) and allograft recurrence of C3 glomerulonephritis (C3GN) was treated with eculizumab every other week for 1 year. The patient had pathological evidence of C3GN and proteinuria >1 g/day at enrollment. He underwent graft biopsy before enrollment and repeat biopsy at 6 and 12 months. RESULTS: Although no mutations were identified in complement genes, functional studies were positive for C3 nephritic factors and elevated levels of soluble membrane attack complex (sMAC). On therapy, sMAC levels normalized and although proteinuria initially decreased, it increased reaching pre-treatment levels at 12 months. Although serum creatinine remained stable, repeat allograft biopsies showed progression of disease. CONCLUSIONS: Clinical and histopathologic data suggest a partial response to eculizumab in this patient. While eculizumab blocked activation of the terminal complement cascade, persistent dysregulation of the alternative pathway remained, indicating eculizumab alone cannot control disease in this patient. Additional research is required to identify effective anticomplement therapy for this group of C3G patients.

Pulmonary tumor thrombotic microangiopathy with cor pulmonale due to desmoplastic small round cell tumor.

A 12-year-old boy presented acutely after an episode of syncope with perioral cyanosis. He died 19 hours after admission due to cor pulmonale as a complication of metastatic desmoplastic small round cell tumor in the lungs with associated tumor thrombotic microangiopathy.

Clinically occult amyloidosis derived from leukocyte chemotactic factor 2 (ALECT 2) with cardiac involvement complicating renal transplantation: case report and literature review.

INTRODUCTION: Amyloidosis derived from leukocyte chemotactic factor 2 (ALECT2) may be associated with slowly progressive renal failure that is clinically unsuspected at the time of transplantation. While this is typically clinically insignificant, we report a case with extensive systemic ALECT2 amyloidosis that also involved the myocardium, contributing to perioperative death post renal transplantation. CASE DESCRIPTION: A 72-year-old Hispanic woman presented for renal transplantation due to end-stage renal disease secondary to hypertension. She was bradycardic on admission. Cardiac workup prior to transplantation had not identified an infiltrative process. Post-transplant hypotensive bradycardic arrests lead to multiorgan failure, anoxic brain injury, and death. Autopsy revealed massive amyloid deposition in the native kidneys, adrenals, spleen, and less extensive infiltration of liver and myocardium. Cardiac intramural vasculature from venules to capillaries, arterioles, and arteries showed amyloid deposition. Mass spectrometry revealed ALECT2 as the amyloidogenic protein. DISCUSSION: ALECT2 is a systemic amyloidosis that typically involves kidneys, adrenals, spleen, and liver. It may be clinically unsuspected at the time of renal transplantation and should be considered in older patients, especially from higher ALECT2 amyloid prevalence populations. Complications related to systemic disease may add to morbidity or mortality post-transplantation. Cardiac involvement in ALECT2 amyloidosis has not been previously identified as a significant clinical or autopsy finding, but our case demonstrates that the cardiovascular system may indeed rarely be involved by ALECT2 amyloidosis in cases with extensive systemic disease, and it may be associated with significant clinical sequelae.

Case report: surgical resection of right ventricular cardiac fibroma in an adult patient.

BACKGROUND: Cardiac fibromas are rare benign cardiac neoplasms, most frequently occurring in the pediatric population; with very rare cases identified in adults. The tumors are comprised of spindled cells with myofibroblastic ultrastructural features embedded in generally collagenous and elastic stroma. The tumors are intramural in the ventricles, most commonly the left ventricle. Clinical symptoms vary by location and size of tumor and some are asymptomatic. Surgical resection is curative, but rare cases require cardiac transplantation. CASE PRESENTATION: We report an asymptomatic, large, right ventricular fibroma in a 64-year-old woman. The patient underwent open incisional tumor biopsy via lower hemi-sternotomy, followed by complete tumor resection via full sternotomy a week later after confirming the tumor is benign. The tumor was resected using cardiopulmonary bypass, and the defect of right ventricular free wall was repaired using a prosthetic double-patch technique. The postoperative course was uneventful. The patient was discharged to home on day 4 post-complete tumor resection. CONCLUSION: This report expands the existing literature for better comprehension and detection of cardiac fibroma patients and also highlights the various imaging modalities, surgical management, and histological analysis.

The Many Faces of Cardiac Sarcoidosis.

OBJECTIVES: The objective of this study was to review and illustrate the sometimes diagnostically challenging features of cardiac sarcoidosis. We emphasize variable phenotypes presented at explant and biopsy evaluation and review literature regarding ancillary clinical and pathologic studies to enhance diagnostic accuracy. METHODS: A literature review was performed and two cardiac sarcoidosis cases were illustrated. RESULTS: Our cases and literature review demonstrate the pathologic spectrum of cardiac sarcoidosis. Irregular left ventricular free wall involvement is most common, followed by the interventricular septum and right ventricle. Although granulomas are often composed of tight epithelioid macrophage aggregates, early granulomas comprise loosely associated macrophages with lymphocyte predominance. Chronic disease leads to fibrosis and end-stage heart failure. Sampling errors and variable histology cause low endomyocardial biopsy sensitivity. CONCLUSIONS: Current guidelines use clinical, radiologic, and immunohistologic criteria for diagnosing cardiac sarcoidosis. Knowledge of these guidelines will assist pathologists in making accurate diagnosis of this disease.

Thymolipoma: clues to pathogenesis revealed by cytogenetics.

The pathogenesis of thymolipoma is controversial and unclear despite numerous reports. A case report of thymolipoma with cytogenetic analysis is herein presented. The lesion demonstrated a translocation involving the HMGA2 gene on chromosome 12q15, which is seen in two thirds of solitary lipomas. This finding supports the theory that this case of thymolipoma is a neoplasm of thymic fat.

Hepatic Silicone Granulomas Secondary to Ruptured Breast Implants: A Report of Two Cases.

The differential diagnosis of hepatic granulomas is vast and includes infections, drugs, immunologic diseases, foreign material exposure, and neoplasia. Silicone, whether directly injected into tissues or used as a filler in breast implants, is known to cause localized granulomatous reactions. It can also migrate to other anatomic locations resulting in granulomatous inflammation at a distance. We report two cases of unsuspected hepatic silicone granulomas in patients undergoing liver biopsy for isolated elevated alkaline phosphatase levels, both with a history of ruptured breast implants. These cases highlight the need for awareness of hepatic silicone granulomas as an etiology of elevated liver enzymes in patients with a history of surgical interventions utilizing silica, such as cosmetic surgery.

Analysis and Comparison of Tissue-Marking Dye Detection via Light Microscopy, Telemicroscopy, and Virtual Microscopy.

Objectives: To examine the fidelity of ink color identification using light microscopy (LM), telemicroscopy (TM), and virtual microscopy (VM). Methods: Twenty H&E-stained frozen section slides, prepared after tissue inking with five stain combinations, were assessed by three pathologists using LM, TM, and VM. TM was performed using Mikroscan D2 slide scanner/LiveQ software with various objectives. VM was performed using Mikroscan D2 scanner/Qumulus software, specimens digitized at20×. Results: Sensitivity/specificity by LM was 100%/100% for all colors. TM showed high overall specificity but poor sensitivity, particularly red (54%). VM showed high specificity for all colors except black (69%) and, consequently, poor sensitivity for all colors except black (96%). Conclusions: TMD identification via telepathology showed loss of sensitivity/specificity vs LM and highlighted the need for caution when interpreting TMDs with digital technologies and the need for validation protocols.

The Pathology of Acute Liver Failure.

Varied injuries may manifest clinically as acute liver failure. The pathologic features include variable amounts of necrosis and regeneration. This article reviews pathologic classification of patterns of necrosis and associated inflammatory and regenerative responses in specimens from patients with acute liver failure. Detailed pathologic examination of these specimens with clinical pathologic correlation can give the multidisciplinary team vital information regarding etiology and timing as well as extent of injury, and regenerative response. Pathologists are a vital component of the health care team for patients with acute liver failure.

Vanishing Bile Duct Syndrome in a Patient with Uterine Cancer and Paraneoplastic Systemic Sclerosis.

Vanishing bile duct syndrome (VBDS) is a rare entity of acquired disorders resulting in cholestasis secondary to progressive destruction of intrahepatic bile ducts. The syndrome has been described in the setting of autoimmune disorders, medication toxicities, genetic disorders, infectious etiologies, and in rare cases, neoplastic processes. There are no known case reports of VBDS in the setting of uterine malignancy. We present a case of VBDS in a patient with underlying uterine cancer complicated by paraneoplastic systemic sclerosis.

A case report of mesenteric heterotopic ossification: Histopathologic and genetic findings.

Mesenteric heterotopic ossification (MHO) is very rare and occurs in mid- to late-adulthood, usually in the context of prior abdominal surgery. The mechanisms of MHO are unknown. Here we describe the case of a 72-year-old man with MHO. Standard histological staining revealed that MHO occurred through an endochondral process. By comparison to known mutations in genetic conditions of HO such as fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH), DNA sequencing analysis demonstrated the presence of a commonly occurring heterozygous synonymous polymorphism (c.690G>A; E230E) in the causative gene for FOP (ACVR1/ALK2). However, no frameshift, missense, or nonsense mutations in ACVR1, or in the causative gene for POH (GNAS), were found. Although genetic predisposition may play a role in MHO, our data suggest that mutations which occur in known hereditary conditions of HO are not the primary cause.

Report and Recommendations of the Association of Pathology Chairs' Autopsy Working Group.

Autopsy has been a foundation of pathology training for many years, but hospital autopsy rates are notoriously low. At the 2014 meeting of the Association of Pathology Chairs, some pathologists suggested removing autopsy from the training curriculum of pathology residents to provide additional months for training in newer disciplines, such as molecular genetics and informatics. At the same time, the American Board of Pathology received complaints that newly hired pathologists recently certified in anatomic pathology are unable to perform an autopsy when called upon to do so. In response to a call to abolish autopsy from pathology training on the one hand and for more rigorous autopsy training on the other, the Association of Pathology Chairs formed the Autopsy Working Group to examine the role of autopsy in pathology residency training. After 2 years of research and deliberation, the Autopsy Working Group recommends the following:Autopsy should remain a component of anatomic pathology training.A training program must have an autopsy service director with defined responsibilities, including accountability to the program director to record every autopsy performed by every resident.Specific entrustable activities should be defined that a resident must master in order to be deemed competent in autopsy practice, as well as criteria for gaining the trust to perform the tasks without direct supervision.Technical standardization of autopsy performance and reporting must be improved.The current minimum number of 50 autopsies should not be reduced until the changes recommended above have been implemented.

Safety and efficacy of steroid withdrawal two days after kidney transplantation: analysis of results at three years.

BACKGROUND: Chronic steroid therapy in spite of myriad side effects is widely used in kidney transplantation. This prospective controlled study evaluated safety and efficacy of steroid withdrawal at 2 days in kidney recipients monitored by surveillance biopsy. METHODS: In all, 300 kidney recipients were studied; 150 in second-day steroid withdrawal group and 150 in steroid treated group (control group). Immunosuppression was basiliximab induction and maintenance was a calcineurin inhibitor and mycophenolate mofetil or sirolimus. Biopsy-proven acute rejection (BPAR) was treated by methylpredisolone. Surveillance biopsies were completed to evaluate subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Primary end point was acute rejection. Three-year patient and graft survival, new onset diabetes mellitus (NODM), serum creatinine and creatinine clearance were evaluated. RESULTS: Acute rejection was diagnosed in 14% in control group and 16% in steroid withdrawal group. Three-year patient and graft survival was 89% and 79% in control and 91% and 78% in steroid withdrawal group. Serum creatinine and creatinine clearance was 1.9+/-0.8 and 59+/-11 in control group and 1.8+/-0.9 mg/dl and 61+/-10 mls/minute in steroid withdrawal group. Incidence of SCAR and progression of CAN were comparable in the 2 groups. At 3-years NODM was diagnosed in 21% in control group and 4% in steroid withdrawal group (P<0.01). CONCLUSIONS: Two-day steroid withdrawal in kidney transplant recipients did not affect BPAR, SCAR, CAN, graft function and patient and graft survival compared to control group up to 3 years. NODM was significantly less in steroid withdrawal group. Two-day steroid withdrawal is safe and beneficial in kidney transplant recipients.

Successful transplantation of kidneys from deceased donors with acute renal failure: Three-year results.

BACKGROUND: Kidneys from deceased donors with acute renal failure (ARF) are generally not accepted for transplantation because of the expected poor outcome. This prospective study examined the utilization of kidneys from donors with ARF for transplantation and the outcomes. METHODS: Fifty-five kidneys from donors with ARF were transplanted. The outcome was compared with concurrent and matched 55 recipients of standard criteria donor (SCD) kidneys and 55 expanded criteria donor (ECD) kidneys. ARF kidneys were accepted from donors aged <50 years, a negative history for kidney disease, and a negative pretransplant biopsy for chronic structural changes. The immunosuppression was similar in all three groups. The outcome measurements included three-year patient and graft survival, biopsy-proven acute rejection (BPAR), subclinical acute rejection (SCAR), and chronic allograft nephropathy (CAN), serum creatinine, and creatinine clearance. RESULTS: Three-year patient and graft survival was 90% and 90% in ARF group, 100% and 89% in SCD group and 83% and 66% in ECD group. BPAR and SCAR were comparable in the groups but CAN was significantly higher in ECD group. Mean serum creatinine levels were 1.9+/-1.1, 1.9+/-0.9, and 2.2+/-1.3 mg/dl and mean creatinine clearances were 66+/-15, 68+/-14, and 58+/-10 mls/minute in ARF, SCD, and ECD groups, respectively (SCD and ARF vs. ECD P = 0.04). CONCLUSIONS: Transplantation of kidneys from selected deceased donors with ARF provides comparable survival and function compared to kidneys from non-ARF donors and may be considered for transplantation to expand the donor pool to overcome the current acute shortage of kidneys.

Impact of BMI on clinically significant unsuspected findings as determined at postmortem examination.

We conducted a retrospective cohort study based on autopsy reports of 311 patients who underwent full postmortem examinations from January 1, 1999, to December 31, 2002. Clinically unsuspected diagnoses were categorized as follows: class I, major clinically unsuspected diagnoses that were responsible for death; class II, major clinically unsuspected diagnoses that were not directly responsible for death but if left undiagnosed may have resulted in patient death; and class V, no clinically unsuspected diagnoses. Two multivariate analyses were performed using 4 variables to predict class I diagnoses. Both analyses included the variables sex, race, and age; the fourth variable included umbilicus pannus size or body mass index (BMI). Only BMI (P = .006) and umbilicus pannus size (P = .037) were independent predictors of class I diagnoses. Obese patients were 1.65 times more likely (relative risk, 1.65) to have a class I diagnosis than the normal weight and underweight groups combined (confidence interval, 1.04-2.64). Patients with obese-level BMIs seem to be at increased risk for clinically significant unsuspected diagnoses compared with underweight and normal weight populations.

Virtual microscopy improves sharing of deceased donor kidneys.

BACKGROUND: Donor kidney biopsies used for offer evaluation may lengthen cold ischemia time. Our organ procurement organization began processing wedge biopsies and having them read using virtual microscopy (VM), as opposed to its prior routine of processing/reading at local hospitals. We hypothesized that VM would decrease time to biopsy results and kidney acceptance. METHODS: All donor kidneys biopsied over 1 year were compared with those biopsied during the previous year (n = 43, 40). RESULTS: Time to biopsy result was shortened using VM (5:04 vs 6:30, P = .04), and especially for those cases with cross-clamp between 5 pm and 5 am (4:49 vs 8:12, P < .01). Time to local acceptance was also significantly improved using VM for both the entire group (7:01 vs 9:52, P < .01) and the overnight subset (7:25 vs 11:10, P < .01). CONCLUSIONS: Use of VM decreased time to biopsy result, with the most prominent effects seen during the overnight hours, resulting in shortened time to local acceptance of organs.

Comparison of steroid avoidance in tacrolimus/mycophenolate mofetil and tacrolimus/sirolimus combination in kidney transplantation monitored by surveillance biopsy.

BACKGROUND: Chronic steroid therapy in kidney transplantation has myriad side effects and steroid avoidance has become feasible. This prospective study compared the safety and efficacy of steroid avoidance in tacrolimus (TAC)/mycophenolate mofetil (MMF) and TAC/sirolimus (SRL) combinations in kidney transplantation. METHODS: In all, 150 kidney recipients were analyzed: 75 each in TAC/MMF and TAC/SRL groups. The primary endpoint was acute rejection. Surveillance biopsies were completed to analyze subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Acute rejection and SCAR were treated by methylprednisolone. Two-year patient and graft survival, renal function, and adverse effects were monitored. RESULTS: Acute rejection was seen in 12% of TAC/MMF and 8% of TAC/SRL patients. Two-year actuarial patient survival was 95% and 97%, and graft survival 90% and 90% in TAC/MMF and TAC/SRL groups, respectively. Surveillance biopsy showed cumulative incidence of SCAR was 27 % in TAC/MMF and 16 % in TAC/SRL groups at 2 years (P = 0.04). Overall, 33% of recipients in TAC/MMF and 20% in TAC/SRL received methylprednisolone for acute rejection/SCAR. Moderate/severe CAN was 10% in TAC/SRL group and 22% in TAC/MMF group(P = 0.06). New-onset diabetes mellitus (NODM) was 4% each in both groups. All recipients remain free of maintenance steroid therapy. CONCLUSIONS: Steroid avoidance in tacrolimus-based immunosuppression with MMF or SRL provides equivalent 2-year patient and graft survival with a low incidence of acute rejection and NODM. SCAR and CAN are lower in TAC/SRL compared to TAC/MMF group. The impact of decreased SCAR and CAN in TAC/SRL group on longer-term graft survival and function is to be evaluated.

Right ventricular hemangioma causing right ventricular inflow obstruction and right heart failure.

We report a patient who presented with symptoms of right heart failure. Transesophageal echocardiography revealed a right ventricular mass, causing right ventricular inflow obstruction. Coronary angiography revealed a characteristic tumor blush. After successful surgical resection, histologic findings were consistent with a right ventricular hemangioma.

Novel uses of intracardiac echocardiography with a phased-array imaging catheter.

A newer phased-array ultrasound imaging catheter (AcuNav, Siemens, Moutainview, Calif) provides comprehensive anatomic and physiologic data during cardiac interventions. The role of this catheter in percutaneous closure procedures, transseptal ablative procedures, and valvular interventions has been reported. We describe an expanded role of intracardiac echocardiography using AcuNav imaging catheter (Siemens) in 2 clinical situations.