Therapeutic drug monitoring is a well-established approach in transplantation medicine to guide immunosuppressive therapy. However, it cannot always predict the effects of immunosuppressive drugs on immune cells, because it does not reflect any aspect of an individual patient's immune system. Pharmacodynamic monitoring is a more recent strategy to provide information about the biologic effect of a specific drug or drug combination on the individual transplant patient. Currently, there is a large number of different biomarkers that either directly (specific markers) or indirectly (global markers) relate to the pharmacodynamic effects of immunosuppressive drugs and are under investigation as potential candidates to be introduced in clinical practice. Such biomarkers may be useful to identify patients at risk of developing acute rejection, infection, or cancer as well as patients who are suitable for minimization of immunosuppressant therapy and may be helpful to manage the timing and rate of immunosuppressant weaning. Serial longitudinal monitoring may allow maintenance of an individualized immunosuppressive regimen. Thus, biomarker monitoring is a potential complementary tool to therapeutic drug monitoring. This review summarizes the current state of knowledge about the use of a number of global or drug-specific pharmacodynamic biomarkers. It is not a comprehensive overview of the literature available, but rather an evidence-based reflection by experts who are intensively involved in scientific work in this field.

Biomarkers as a tool for management of immunosuppression in transplant patients.

Purpose of review In immunodeficiency, an increased sarcoma risk is confirmed for Kaposi's sarcoma. Whether rates of other sarcoma subtypes are elevated in the setting of immunodeficiency is not known. We therefore reviewed published case reports on HIV and AIDS patients and organ transplant recipients with sarcomas. For comparison, we assessed sarcomas in the U.S. general population using Surveillance Epidemiology End Results (SEER) data. Recent findings A total of 176 non-Kaposi sarcoma were identified, 75 in people with HIV and AIDS and 101 in transplant recipients. Leiomyosarcomas (n = 101) were the most frequently reported sarcomas, followed by angiosarcomas (n = 23) and fibrohistiocytic tumors (n = 17). Leiomyosarcomas were reported with two age peaks, in children and young adults. Epstein-Barr virus (EBV) was detected in the tumor cells in 85 and 88% of leiomyosarcomas in HIV-infected people and transplant recipients, respectively. Angiosarcomas and fibrohistiocytic tumors were most frequently reported in men. Among kidney transplant recipients, 20% of sarcomas arose at the site of an arteriovenous fistula. In comparison, leiomyoscarcomas, angiosarcomas, and fibrohistiocytic tumors comprised 16.9, 3.8, and 18.7% of sarcomas in the U.S. general population. Summary Leiomyosarcoma and angiosarcoma may occur disproportionately in immunodeficiency. Leiomyosarcomas appear causatively linked to EBV, whereas angiosarcomas might be correlated with an arteriovenous fistula. Additional studies are necessary to understand the contribution of immunodeficiency to the cause of these sarcomas.

/pdf/sarcomas-other-than-kaposi-sarcoma-occurring-in-25wfcaclko.pdf

Sarcomas other than Kaposi sarcoma occurring in immunodeficiency: interpretations from a systematic literature review

Background The purpose of these studies was to determine the incidence and survival of patients with specific malignancies with respect to age and transplant year and to compare the data with the normal non-transplant population Methods Data from 6,211 primary cardiac transplants between July 31, 1993, and December 30, 2008, were collected by 35 institutions participating in the Cardiac Transplant Research Database Data were compared with information collected by the Surveillance Epidemiology and End Results (SEER) Cancer Statistics Review 1975–2006 Results Multivariable analysis showed older age (relative risk [RR], 21; p p p = 0006) and lymphoma (actual/expected ratio, 43, p Conclusions The risk of malignancy has markedly declined during a 15-year period such that the aggregate rate of malignancy approached that of the general population in the United States However, the distribution of malignancies was not the same, with a greater prominence of lung cancer and lymphoproliferative disease

A multi-institutional study of malignancies after heart transplantation and a comparison with the general United States population

Problemstellung In einem prospektiven Forschungsansatz wurde ein Patientenkollektiv nach Herztransplantation nachuntersucht. Der besondere Schwerpunkt wurde auf Morbiditat, Befindlichkeit und Lebensqualitat der 10 Jahre uberlebenden Patienten gelegt. Methodik 60 Patienten (47,9±10,9 Jahre, 57 Manner, 3 Frauen), die sich innerhalb zweier Kalenderjahre an der Herz- und Thoraxchirurgie der Universitat Wien einer orthotopen Herztransplantation unterzogen hatten, wurden zum Zeitpunkt der Aufnahme auf die Warteliste, die uberlebenden Patienten genau 1, 5 und 10 Jahre postoperativ nachuntersucht. Dokumentiert wurden korperliche und psychische Beschwerden, Befindlichkeit, Mortalitat und fur die Stichprobe der 10 Jahre uberlebenden Patienten (n=23) Morbiditat (Infektionen, Malignome, Graft Arteriosklerose, Abstosungsreaktionen) und Lebensqualitat. Ergebnisse Das aktuarische Uberleben betrug in unserer Stichprobe fur 1 Jahr 83,3%, fur 5 Jahre 66,7% und fur 10 Jahre 48,3%. Innerhalb des ersten postoperativen Jahres waren vor allem Infektionen fur die Mortalitat verantwortlich, im 1.–5. postoperativen Jahr Karzinomerkrankungen, gefolgt von Graft Arteriosklerose nach dem 5. postoperativen Jahr. Die Zahl der korperlichen Beschwerden hatte sich bis zum 5.Jahr vermindert, aber anschliesend wiederum zugenommen (p<0,001). Zittern (p<0,05) und Parasthesien (p<0,01) dagegen hatten kontinuierlich abgenommen. Die psychischen Beschwerden Depression und Dysphorie (beide p<0,05) nahmen bereits nach dem ersten Jahr wieder kontinuierlich zu. Drei Malignome (der Lunge, der Haut, der Schilddruse) wurden 6–9 Jahre postoperativ diagnostiziert. Drei Patienten (13%) zeigten 10 Jahre postoperativ eine Graft Arteriosklerose, 9 Patienten (40%) hatten innerhalb der 10 Jahre Abstosungsreaktionen erlebt. Gravierende, hamodynamisch relevante Abstosungsreaktionen traten im Gesamtverlauf nicht auf. Zehn Jahre nach Herztransplantation ist die Lebensqualitat der Langzeitpatienten als durchaus gut zu bezeichnen. Schlussfolgerung Die Herztransplantation ist eine erfolgreiche Therapieform fur Patienten mit terminaler Herzerkrankung. Die 10 Jahre uberlebenden transplantierten Patienten befinden sich in gutem korperlichen und psychischen Zustand und berichten uber eine befriedigende subjektive Lebensqualitat.

Überleben, klinische Daten und Lebensqualität 10 Jahre nach Herztransplantation: Eine prospektive Studie

We compared the efficacy of histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) solution with Celsior solution using hypothermically-preserved porcine carotid arteries and studied the importance of different components of these solutions by preserving carotid arteries in modified HTK solutions. Excised carotid arteries were stored at 4 degrees C in 0.9% (w/v) NaCl, UW, HTK, Celsior, or a modified HTK solution for up to 14 days. Preservation-induced changes in smooth muscle cell and endothelial cell function were determined using an organ bath for isometric tension recording. Short-term preservation (1-3 days) in UW, HTK and Celsior did not significantly alter contractile and relaxation responses of arterial segments when compared to freshly-excised segments, but significantly impaired these responses in arterial segments stored in 0.9% (w/v) NaCl solution. Long-term hypothermic preservation of arterial segments (7 and 14 days) in 0.9% (w/v) NaCl and HTK solution almost completely abolished all responses, but only slightly reduced the responses of arterial segments stored in UW solution. Intermediate results were obtained for Celsior. Modifying HTK by replacement of chloride for sulfate and phosphate resulted in improved contractile and relaxation responses after long-term preservation. With respect to smooth muscle and endothelial function, UW is superior to HTK and Celsior and the absence of chloride or presence of sulfate and phosphate plays a relevant role in this in vitro model of hypothermic preservation of porcine carotid arteries.

In vitro function of porcine carotid arteries preserved in UW, HTK and Celsior solutions.

OBJECTIVES AND METHODS 219 heart transplant recipients with survival over 3 months were retro- and prospectively analysed for the incidence of primary neoplasms. Patients received immunosuppressive drugs (cyclosporine A, azathioprine, steroids) with a 4-5 days induction course of Rabbit Anti-Thymocyte Immunoglobulin (RATG) or monoclonal antibodies induction /OKT3/ in some cases. Anti-rejection treatment consisted of pulse doses of methyloprednisolon or RATG. RESULTS 9 cases of malignancy (4.1%) with one case of pre-malignant liver condition (dysplasia gigantocellulare, 0.45%) were found (8M; 1F; age: 45-67 y.o., x57.7). Symptoms of neoplasms occurred 7-79 months (x31.4) postoperatively. Skin carcinomas: planoepitheliale, spinocellulare, soft tissue neoplasms/mesenchymal sarcoma, larynx Ca planoepitheliale, lung: adenocarcinoma and Ca microcellulare, kidney Ca clarocellulare and post transplant non-Hodgkin lymphoma were diagnosed. Chemo- and radiotherapy, surgery and reduction of immunosuppression did not change the outcome of malignancy in 6 pts.; (regression-1 pt was., remission-2 pts). Patients died 7-86 months after Htx (x41), 4-25 mos. (x12.5) after suffering from first symptoms and 0-10 months (x4.9) after pathology-based diagnosis of neoplasm. CONCLUSIONS Heart transplant recipients have an increased risk of carcinogenesis. The incidence of malignancies in the studied group is similar or even lower than in other reports.

The incidence of malignancy in heart transplant recipients.

Correlation between heart rate variability and hypothermic storage in human cardiac transplant recipients.

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The incidence of malignancy in heart transplant recipients.

Correlation between heart rate variability and hypothermic storage in human cardiac transplant recipients.