Noninvasive vascular imaging in abdominal solid organ transplantation.

OBJECTIVE: In this article, we focus on the vascular complications related to liver, pancreas, and kidney transplantation. CONCLUSION: Long term allograft survival of solid organ transplantation depends on early intervention of complications. Noninvasive imaging with ultrasound, CT, and MRI allows accurate diagnosis of complications and aids in treatment planning.

Molecular transplantation pathology: the interface between molecules and histopathology.

PURPOSE OF REVIEW: In the last decade, high-throughput molecular screening methods have revolutionized the transplantation research. This article reviews the new knowledge that has emerged from transplant patient sample-derived 'omics data by examining the interface between molecular signals and allograft pathology. RECENT FINDINGS: State-of-the-art molecular studies have shed light on the biology of organ transplant diseases and provided several potential molecular tests with diagnostic, prognostic, and theranostic applications for the implementation of personalized medicine in transplantation. By comprehensive molecular profiling of patient samples, we have learned numerous new insights into the effector mechanisms and parenchymal response during allograft diseases. It has become evident that molecular profiles are coordinated and move in patterns similar to histopathology lesions, and therefore lack qualitative specificity. However, molecular tests can empower precision diagnosis and prognostication through their objective and quantitative manner when they are integrated in a holistic approach with histopathology and clinical factors of patients. SUMMARY: Despite clever science and large amounts of public money invested in transplant 'omics studies, multiparametric molecular testing has not yet been translated to patient care. There are serious challenges in the implementation of transplant molecular diagnostics that have increased frustration in transplant community. We appeal for a full collaboration between pathologists and researchers to accelerate transition from research to clinical practice in transplantation.

Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial.

BACKGROUND: Post-transplantation lymphoproliferative disorder (PTLD) develops in 1-10% of transplant recipients and can be Epstein-Barr virus (EBV) associated. To improve long-term efficacy after rituximab monotherapy and to avoid the toxic effects of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy seen in first-line treatment, we initiated a phase 2 trial to test whether the subsequent use of rituximab and CHOP would improve the outcome of patients with PTLD. METHODS: In this international multicentre open-label phase 2 trial, treatment-naive adult solid-organ transplant recipients diagnosed with CD20-positive PTLD who had failed to respond to upfront immunosuppression reduction received four courses of rituximab (375 mg/m(2) intravenously) once a week followed by 4 weeks without treatment and four cycles of CHOP every 3 weeks. In case of disease progression during rituximab monotherapy, CHOP was started immediately. Supportive therapy with granulocyte-colony stimulating factor after chemotherapy was mandatory and antibiotic prophylaxis was recommended. The primary endpoint was treatment efficacy measured as response rates in all patients who completed treatment with rituximab and CHOP, per protocol, and response duration, in all patients who completed all planned therapy and responded. Secondary endpoints were frequency of infections, treatment-related mortality, and overall survival. This study is registered at ClinicalTrials.gov, number NCT01458548. FINDINGS: 74 patients were enrolled between Dec 12, 2002 and May 5, 2008, of whom 70 patients were eligible to receive treatment. PTLD was of late type in 53 (76%) of 70 patients, monomorphic in 67 (96%) of 70, and histologically EBV associated in 29 (44%) of 66 cases. Four of 70 patients did not receive CHOP. 53 of 59 patients had a complete or partial response (90%, 95% CI 79-96), of which 40 (68%, 55-78) were complete responses. At data cutoff (June 1, 2011) median response duration in the 53 patients who had responded to treatment had not yet been reached (>79·1 months). The main adverse events were grade 3-4 leucopenia in 42 of 62 patients (68%, 55-78) and infections of grade 3-4 in 26 of 64 patients (41%, 29-53). Seven of 66 patients (11%, 5-21) had CHOP-associated treatment-related mortality. Median overall survival was 6·6 years (95% CI 2·8-10·4; n=70). INTERPRETATION: Our results support the use of sequential immunochemotherapy with rituximab and CHOP in PTLD. FUNDING: F Hoffmann-La Roche, Amgen Germany, Chugaï France.

Posterior reversible encephalopathy syndrome.

Posterior reversible encephalopathy syndrome (PRES) is characterized by headache, altered mental status, visual disturbances, and seizures. Radiological features typically include edema of the posterior cerebral regions, especially of the parietooccipital lobes. Atypical imaging features, such as involvement of anterior cerebral regions, deep white matter, and the brain stem are also frequently seen. Vasoconstriction is common in vascular imaging. Different conditions have been associated with PRES, but toxemia of pregnancy, solid organ or bone marrow transplantation, immunosuppressive treatment, cancer chemotherapy, autoimmune diseases, and hypertension are most commonly described. The pathophysiology of PRES is unclear and different hypotheses are being discussed. Posterior reversible encephalopathy syndrome is best managed by monitoring and treatment in the setting of a neurointensive care unit. The prognosis is usually benign with complete reversal of clinical symptoms within several days, when adequate treatment is immediately initiated. Treatment of severe hypertension, seizures, and withdrawal of causative agents represent the hallmarks of specific therapy in PRES. Delay in diagnosis and treatment may lead to permanent neurological sequelae. Therefore, awareness of PRES is of crucial importance for the intensivist.

An important role for autoimmunity in the immunopathogenesis of chronic allograft rejection.

Organ transplantation is the treatment of choice for patients with end-stage organ dysfunction. In spite of advances in understanding of donor and recipient physiology, organ preservation, operative techniques and immunosuppression, long-term graft survival still remains a major problem primarily due to chronic rejection. Alloimmune responses to mismatched major histocompatibility antigens have been implicated as an important factor leading to rejection. However, there is increasing evidence pointing towards cross-talk between the alloimmune and autoimmune responses creating a local inflammatory milieu, which eventually leads to fibrosis and occlusion of the lumen in the transplanted organ i.e. chronic rejection. In this review, we will discuss recent studies and emerging concepts for the interdependence of alloimmune and autoimmune responses in the immunopathogenesis of chronic allograft rejection. The role of autoimmunity in the development of chronic rejection is an intriguing and exciting area of research in the field of solid-organ transplantation with a significant potential to develop novel therapeutic strategies towards preventing chronic allograft rejection.

[Infections in organ transplantations]. / Infektionen bei Organtransplantationen.

Infections play a crucial role in organ transplantations as possible complications. Viruses, bacteria, fungi and parasites are potential agents. The relevance of individual diseases depends on the organ transplanted. Morphology of the inflammatory reaction is given by the agent involved, but often several reactions can be caused by the same agent and different agents can also lead to the same reaction. Histology therefore provides concrete identification of the causal agent only in some cases, such that additional microbiological diagnostics are necessary. Results from these investigations should be transferred to the pathologist to distinguish between infection-associated changes and transplant rejection.

[Transplant-associated lymphoproliferation]. / Transplantations-assoziierte Lymphoproliferationen.

Transplantation of solid organs and haematopoietic stem cells requires immunosuppressive drug therapy in order to prevent rejection or graft-versus-host disease. Depending on dosage and type of drug, the risk of developing an Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is increased. The lesion spectrum ranges from hyperplastic lesions to manifest lymphomas, the latter being classified as monomorphic PTLD. Hyperplastic changes, which are not distinguishable from viral reactions, comprise early or mononucleosis-like lesions. Those with effaced lymph node architecture or extranodal manifestation without a lymphoma-like phenotype are designated polymorphic PTLD. Monomorphic PTLD are either high grade B cell lymphomas, plasma cell neoplasms or Hodgkin lymphomas and only very rarely T cell lymphomas. Low grade B cell lymphomas do not occur. In a subfraction of cases, including even monomorphic PTLD, reduction of immunosuppression alone is sufficient to induce remission of the pathological process.

[Objective intraoperative estimation of state of the intestinal transplant prepared for placing into the perineum in experiment].

The work is devoted to experimental investigation and practical application of the objective intraoperative diagnosis method for the intestinal transplant state estimation, which is prepared for descendence to perineum, using modified pulsoximetric data analyser in environment of experimental modelling of abdominoanal rectal resection, resulting in determination of objective indices of the intestinal transplant vital capacity. The method of operative intervention in experiment on laboratory animals is adduced. The expediency of application of modified pulsoximetric data analyser in colorectal surgery was established.

Detrimental consequences of brain injury on peripheral cells.

Acute brain injury and brain death exert detrimental effects on peripheral host cells. Brain-induced impairment of immune function makes patients more vulnerable to infections that are a major cause of morbidity and mortality after stroke, trauma, or subarachnoid hemorrhage (SAH). Systemic inflammation and organ dysfunction are other harmful consequences of CNS injury. Brain death, the most severe consequence of brain injury, causes inflammatory changes in peripheral organs that can contribute to the inferior outcome of organs transplanted from brain-dead donors. Understanding of the mechanisms underlying the detrimental effects of brain injury on peripheral organs remains incomplete. However, it appears that sympathetic nervous system (SNS)-activation contributes to elicit both inflammation and immunodepression. Indeed, norepinephrine (NE)-induced production of chemokines in liver and other organs likely participates in local and systemic inflammatory changes. Conversely, catecholamine-stimulated interleukin-10 (IL-10) production by blood monocytes exerts immunosuppressive effects. Activation of the hypothalamic-pituitary-adrenal axis (HPA) by increased inflammatory cytokines within the brain is a significant component in the CNS-induced immune function inhibition. Non-neurologic consequences of brain injury show impressive similarities regardless of the brain insult and appear to depend on altered neuroimmune circuits. Modulation of these circuits could reduce extra-brain damage and improve patient outcome in both vascular and traumatic brain injury.

Analysis of acute and chronic rejection in multiple organ allografts from retransplantation and autopsy cases of multivisceral transplantation.

BACKGROUND: Small intestinal allografts in multivisceral transplantation are felt to be more susceptible to acute cellular rejection (ACR) and chronic rejection (CR) when compared with other allografts although there is little direct evidence for this impression. METHODS: A total of 48 cases of multiple allograft specimens (37 autopsy and 11 explanted allograft cases) from 41 patients were evaluated in this study. Histopathologic assessments were performed with special concern to ACR and CR in allografts. The numbers of allografts available for evaluation were liver 37, small intestine 47, stomach 41, pancreas 45, and large intestine 25. RESULTS: Among 48 cases, 15 cases showed ACR (ACR case) and 12 showed CR (CR case) in at least one organ. In ACR cases, there was a statistically significant difference of organ-specific susceptibility to ACR among multivisceral allografts with the small intestinal allograft being the most susceptible (P<0.05). Severe ACR were observed only in small and large intestinal allografts. In CR cases, there was no statistically significant difference of organ-specific susceptibility to CR among multivisceral allografts with a tendency for the pancreas allograft to be the most susceptible (P=0.35). CONCLUSIONS: Our study clearly indicated variation in organ susceptibility to ACR and CR. Small intestinal allografts were the most susceptible organ to ACR in frequency and severity. Pancreatic allografts may be more susceptible to CR in comparison with ACR.

[Organ transplants in Israel under the anatomy and pathology law].

The Anatomy and Pathology Law, as amended in 1980, granted some considerations of the deceased's family's feelings regarding transplants of cadavers. However, the law granted a special standing to the deceased's wishes. When the deceased left a written consent or objection, his/her wish overrides the family's feelings or wishes. Had he/she left a written consent, the transplant is permitted despite any objection raised by the family, and when he left a written objection, his objection overrides any consent signed by a family member, except in emergency situations as prescribed in the law. When the deceased has not left any written document regarding his wishes, the law distinguishes between transplants to save life or healing only. In most cases the law refers to "saving life" in a very broad meaning, including use of kidneys, corneas, any other parts of the corpse in order to prevent a defect in sight or hearing, and skin tissues. In these cases, a notice of intention for removal of a cadaver for transplant, should be given to a member of the family, and the removal is permitted as long as there is no written objection signed by a parent, a spouse or a child, submitted during a limited period. There is no need for a written consent of the family and any demand for such consent is against the law. To abstain from removing an organ for transplant in case of "saving life" when permitted by law, may create a breach of duty to save life and professional negligence.

Metabolic, coagulative, and hemodynamic changes during intestinal transplant: good predictors of postoperative damage?

BACKGROUND: Analysis of intraoperative changes of metabolic, hemodynamic, and coagulative parameters is useful to detect early ischemia-reperfusion damage after intestinal transplant. METHODS: The objective of our study is to correlate the histological damage at the end of transplant in relation to the intraoperative changes after reperfusion. The histological aspect was graded according to Park's classification at the end of the surgical procedure with biopsies of the graft. Patients were divided into two groups according to the presence or absence of histological damage of the small bowel wall: group A (normal mucosa/minimal damage: Park's grades 0-1) and group B (mucosal damage: Park's grades 2-8). RESULTS: Significant hemodynamic, metabolic, and coagulative disorders were observed in group B. Consequently, these disorders are thought to be early indicators of graft damage. CONCLUSIONS: Actual monitoring procedures used for postoperative graft surveillance remain paramount in detecting postoperative intestinal dysfunction, but the indicators described in this paper could represent a further help in intraoperative and postoperative management.

Culture of keratinocytes for transplantation without the need of feeder layer cells.

Patients with large burn wounds have a limited amount of healthy donor skin. An alternative for the autologous skin graft is transplantation with autologous keratinocytes. Conventionally, the keratinocytes are cultured with mouse feeder layer cells in medium containing fetal calf serum (FCS) to obtain sufficient numbers of cells. These xenobiotic materials can be a potential risk for the patient. The aim of the present study was to investigate if keratinocytes could be expanded in culture without the need of a feeder layer and FCS. Keratinocytes were cultured on tissue culture plastic with or without collagen type IV coating in medium containing Ultroser G (serum substitute) and keratinocyte growth factor (KGF). An in vitro skin equivalent model was used to examine the capacity of these cells to form an epidermis. Keratinocytes in different passages (P2, P4, and P6) and freshly isolated cells were studied. Keratinocytes grown on collagen type IV were able to form an epidermis at higher passage numbers than cells grown in the absence of collagen type IV (P4 and P2, respectively). In both cases the reconstructed epidermis showed an increased expression of Ki-67, SKALP, involucrin, and keratin 17 compared to normal skin. Only 50,000 keratinocytes grown on collagen type IV in P4 were needed to form 1 cm2 epidermis, whereas 150,000 of freshly isolated keratinocytes were necessary. Using this culture technique sufficient numbers of keratinocytes, isolated from 1 cm2 skin, were obtained to cover 400 cm2 of wound surface in 2 weeks. The results show that keratinocytes can be cultured without the need of a fibroblast feeder layer and FCS and that these cells are still able to create a fully differentiated epidermis. This culture technique can be a valuable tool for the treatment of burn wounds and further development of tissue engineered skin.

Role of the pathologist in organ transplantation: the North Italy Transplant program experience.

The North Italy Transplant program (NITp) is one of the three organ exchange organizations in Italy together with AIRT and OCST, supervised by the Centro Nazionale Trapianti. It started its activity on June 18, 1972 and serves an area of about 18 million inhabitants in northern Italy. From June 18, 1972 to December 31, 2004, 5761 cadaveric donors have been used and 18,390 transplants performed in the NITp. At December 31, 2004, the NITp waiting list included 3407 patients (2261 kidney, 425 heart, 387 liver, 153 pancreas, 181 lung). From January 1 to August 31, 2005, 13 donors with cancer were used, namely, 4.2% of the overall number of procured donors. The yearly projection of this figure is more than twofold above that in the previous year. Pathologists play a crucial role in NITp activity, by assessing donor suitability and organ quality, by performing the autopsy control of donors, and by participating in transplant follow-up. In addition the pathologist responsible for the Veneto-centralized pathology unit plays the role of expert for second opinion for the NITp area. Pathologists are involved in expanding the pool of donors by analyzing organ biopsies in specific programs. Eight HBV(+) and/or HCV(+) liver biopsies have been evaluated during 2003 and 18 during 2004 and 12 livers, according to the protocol, were suitable for transplantation, and 14 double kidney transplantations were performed in 2003 and 35 in 2004.

Composite tissue allotransplantation: classification of clinical acute skin rejection.

BACKGROUND: Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of other nonreconstructible tissue defects. As with recipients of other allotransplants, CTA recipients can experience rejection episodes that are presumed to be mediated by immune mechanisms similar to those affecting solid organ grafts. However, a systematic examination of this process has not been performed, and there are no standardized criteria for the description of severity or type of rejection METHODS: We collected biopsies from human limb allografts and abdominal walls in various stages of rejection for histological and immunohistochemical analysis to formulate a CTA rejection scheme. Biopsies were ranked by severity and reproducibility of the system was tested using a second set of biopsies. Tissue slides were examined blindly by three pathologists and the nonparametric Kendall coefficient of concordance (W) was used to assess the amount of agreement among the pathologists in their classification grades. RESULTS: Rejection initially appeared as a perivascular infiltrate progressing to involve the dermis. Arteritis was observed only in the medium to large size arteries of the subcutis. Myositis was seen occasionally. Perineural involvement without frank neuritis was present in advanced rejection. The infiltrate was predominantly CD4+ in milder cases and CD8+ in advanced cases. HLA-DR was minimally expressed in keratinocytes even in severe rejection. Kendall's W was 0.9375 (p

Genitourinary malignancies in solid organ transplant recipients.

Malignancy is a recognized complication of transplantation. Genitourinary cancers are the second most common tumors in transplant recipients with prostate cancer and renal cell carcinoma the most common. Unlike the more common skin malignancies, genitourinary tumors have a significant impact on both graft and patient survival. Surgical and radiation treatments need to consider the location of heterotopic transplants and administration of chemotherapy may need alteration in light of immunosuppression being used. The major genitourinary malignancies and their management will be reviewed in this article with emphasis on the concerns that arise in a transplant recipient.