Atypical malignancies after intestinal transplantation in children: A European single-centre experience.

BACKGROUND: Post-transplant malignancies, that is, lymphomas, are a recognized complication in intestinal transplant recipients but are mostly secondary to EBV infection. There is an increased risk for malignancies in unusual sites in intestinal transplant recipients as compared to other solid organ transplants and the general population. OBJECTIVE: To evaluate the incidence, course, and outcome of unusual malignancies in children after ITx. METHODS: Retrospective analysis of children who underwent ITx for primary digestive disorders at Birmingham Children's Hospital between January 1989 and December 2017. RESULTS: Ninety-eight intestinal transplants were performed in 90 children (49 males and 41 females) with an underlying primary digestive disorder. Median age was 2.7 years (0.6-16.2), and median weight was 14.5 kg (5.7-53.2) at the time of transplant. Within this cohort, we identified four cases of unusual malignancies at rare sites of presentation. One patient developed cerebral PTLD, two patients were diagnosed with SMT, located at the stomal orifice and in cervicothoracic paravertebral area, respectively, and the last patient developed a retroperitoneal angiosarcoma. Unfortunately, the overall patient outcome was poor in all but one child with SMT, who currently survives with cytotoxic T-cell therapy. CONCLUSION: Unusual malignancies can occur in approximately 5% of children following ITx. A high index of suspicion is required for a timely diagnosis and adequate treatment.

Management of Kaposi sarcoma after solid organ transplantation: A European retrospective study.

BACKGROUND: Systemic therapeutic management of post-transplant Kaposi sarcoma (KS) is mainly based on 3 axes: reduction of immunosuppression, conversion to mammalian target of rapamycin (mTOR) inhibitors, chemotherapy, or a combination of these. OBJECTIVE: To obtain an overview of clinical strategies about the current treatment of KS. METHODS: We conducted a multicenter retrospective cohort study including 145 solid organ transplant recipients diagnosed with KS between 1985 and 2011 to collect data regarding first-line treatment and response at 6 months. RESULTS: Overall, 95%, 28%, and 16% of patients had reduction of immunosuppression, conversion to mTOR inhibitor, and chemotherapy, respectively. Patients treated with chemotherapy or mTOR inhibitor conversion were more likely to have visceral KS. At 6 months, 83% of patients had response, including 40% complete responses. LIMITATIONS: The retrospective design of the study. CONCLUSION: Currently available therapeutic options seem to be effective to control KS in most patients. Tapering down the immunosuppressive regimen remains the cornerstone of KS management.

Solid Organ Transplantation Is Associated with an Increased Rate of Mismatch Repair Deficiency and PIK3CA Mutations in Colorectal Cancer.

Solid organ transplants are associated with a modestly increased risk of colorectal cancers (CRC). However, the molecular profile of these cancers has not been described. We hypothesized that transplant-related immunosuppression may promote development of more immunogenic tumors as suggested by a high tumor mutation burden or mismatch repair deficiency. We performed an electronic medical record search for patients seen in the Johns Hopkins University Health System (JHHS) between 2017 and 2022 who developed CRC following solid organ transplantation. A comparator cohort of patients treated for CRC at JHHS with molecular profiling data was also identified. In this case, 29 patients were identified that developed post-transplant CRC (renal transplant, n = 18; liver transplant, n = 8; kidney-liver transplantation, n = 3). Compared to the JHHS general population CRC cohort, patients who developed post-transplant CRC had a higher rate of mismatch repair deficiency (41% versus 12%, p-value = 0.0038), and elevated tumor mutation burden (median of 22 mut/Mb versus 3.5 mut/Mb, p-value = 0.033) (range 3.52-53.65). Post-transplant tumors were enriched for PIK3CA mutations (43% versus 24%, p-value = 0.042). Post-Transplant CRCs are associated with clinical and molecular features of immune sensitivity, supporting a potential role for impaired immune surveillance in shaping the landscape of CRCs. These results may help inform the management of patients with post-transplant CRC.

Prostate Cancer Characteristics in Renal Transplant Recipients: A 25-Year Experience From a Single Centre.

Objectives: The incidence of prostate cancer in renal transplant recipients (RTRs) is increasing, but few data are available in the literature. In this study, we reviewed the 25-year experience in the management of prostate cancer after kidney transplantation at the Florence Transplant Centre. Methods: We retrospectively reviewed the data from 617 RTR male patients who underwent renal transplantation at our institute between July 1996 and September 2016. Data regarding demographics, renal transplantation, prostate cancer and immunosuppressive treatment were analyzed. The probability of death was estimated by using the Kaplan-Meier method and differences between patients' groups were assessed by the log-rank test. Results: From July 1991 to September 2016, 617 kidney transplantations of male patients were performed at our institute. Among these, 20 patients were subsequently diagnosed with prostate cancer accounting for a cumulative incidence of 3.24%. After a median follow-up of 59 months, 10 patients underwent radical prostatectomy whereas 10 patients underwent primary radiotherapy. A biochemical recurrence was identified in five (25%) patients while a fatal event occurred in 11 (55%) patients. Univariate Cox regression showed that the basal value of PSA >10 ng/ml was the only significant factor negatively affecting the survival of patients. Conclusions: Standard treatments can be proposed to RTR with satisfactory results on both post-operative and oncological outcomes. Further studies are needed to address the issue of prostate cancer screening based on PSA levels and the optimal management of prostate cancer in RTRs.

Posttransplant Kaposi sarcoma: Analysis of a series of 13 patients.

INTRODUCTION AND OBJECTIVES: This study reflects our experience in the management of posttransplant Kaposi Sarcoma (KS) and assesses the clinical relevance of monitoring HHV-8 DNA viral load in peripheral blood by qPCR. PATIENTS AND METHODS: Retrospective study of all patients diagnosed with posttransplant KS during the period 1995-2019. In 8 patients, we performed a qPCR in serum for HHV-8 DNA detection at diagnosis and/or during follow-up. RESULTS: Data from 13 organ transplant recipients with a diagnosis of iatrogenic KS were collected. Reduction and/or discontinuation of one or more immunosuppressive agent(s) along with switching to an mTOR inhibitor was part of the treatment approach in 12 (92%) patients. Overall response rate (including complete response, partial response, and stable disease) was observed in 9 patients. At diagnosis, HHV-8 qPCR in serum was positive in 2 out of 5 patients. During follow-up, both positive cases turned negative, as a clinical response. CONCLUSIONS: Our work highlights the critical role of reduction of immunosuppression and conversion to an mTOR inhibitor in the management of posttransplant KS.

Management and prevention of post-transplant malignancies in kidney transplant recipients.

The central issue in organ transplantation remains suppression of allograft rejection. Thus, the development of immunosuppressive drugs has been the key to successful allograft function. The increased immunosuppressive efficiency obtained in the last two decades in kidney transplantation dramatically reduced the incidence of acute rejection. However, the inevitable trade-off was an increased rate of post-transplant infections and malignancies. Since the incidence of cancer in immunosuppressed transplant recipients becomes greater over time, and the introduction of new immunosuppressive strategies are expected to extend significantly allograft survival, the problem might grow exponentially in the near future. Thus, cancer is becoming a major cause of morbidity and mortality in patients otherwise successfully treated by organ transplantation. There are at least four distinct areas requiring consideration, which have a potentially serious impact on recipient outcome after transplantation: (i) the risk of transmitting a malignancy to the recipient within the donor organ; (ii) the problems of previously diagnosed and treated malignancy in the recipient; (iii) the prevention of de novo post-transplant malignant diseases and (iv) the management of these complex and often life-threatening clinical problems. In this scenario, the direct and indirect oncogenic potential of immunosuppressive therapy should be always carefully considered.

Post-transplant lymphoproliferative disease in heart and lung transplantation: Defining risk and prognostic factors.

BACKGROUND: Heart and lung transplant recipients have among of the highest incidence rates of post-transplant lymphoproliferative disease (PTLD). Despite this, there is a paucity of data specific to this group. We collated data on heart, lung and heart-lung transplant recipients with PTLD to identify disease features and prognostic factors unique to this group of patients. METHODS: Seventy cases of PTLD were identified from a single institution (41 heart, 22 lung, 6 heart-lung and 1 heart-kidney transplant) from 1984 to 2013. Demographics, immunosuppression, treatment, response, complications and survival data were analyzed. Uni- and multivariate Cox regression analyses were performed to identify prognostic factors. RESULTS: The incidence of PTLD was 7.59% in heart-lung, 5.37% in heart and 3.1% in lung transplant recipients. Extranodal disease (82%) with diffuse large B-cell lymphoma (72%) was the most common presentation. Bone marrow involvement (13%) and central nervous system disease (3%) were uncommon. Heart transplant recipients had later onset of PTLD (>1 year post-transplant), with less allograft involvement, compared with lung and heart-lung recipients. Poor prognostic markers were bone marrow involvement (HR 6.75, p < 0.001) and serum albumin <30 g/liter (HR 3.18, p = 0.006). Improved survival was seen with a complete response within 3 months of treatment (HR 0.08, p < 0.001). Five-year overall survival was 29%. CONCLUSION: This analysis is the largest to date on PTLD in heart and lung transplant recipients. It provides a detailed analysis of the disease in this group of patients and identifies unique prognostic features to aid risk stratification and guide treatment allocation.

Long-term immunosuppression and malignancy in thoracic transplantation: where is the balance?

Cancers in post-transplant patients exhibit the same molecular and cellular properties as those in their non-transplanted counterparts and arise secondary to uncontrolled/sustained growth, apoptosis resistance, inhibition of tumor suppressors, immortalization of cells with invasion, and and metastasis. Disruption of DNA repair mechanisms, upregulation of angiogenic growth factors, impaired viral immunity and activated oncogenic viruses contribute to the initiation of malignancies in this population. This article extends and addresses the concerns in this area. We propose potential cancer prevention strategies and a possible 4-pronged approach to prevent and treat malignancies in the post-transplant population. Future research should define strategies for immune modulation, immune suppression and malignancy prevention, including methods for naive B-cell repopulation, memory B-cell reduction and biomarker identification and utilization for predicting tolerance. Non-immune therapies, such as adjunct preventive methods and goals to modify risk factors, may reduce incidence of malignancies and pave the way to better outcomes. The role of statins is of particular interest in this context due to their pleiotropic effects on the cell cycle and their most direct role in inhibition of cholesterol biosynthesis.

Posttransplant Kaposi sarcoma: Analysis of a series of 13 patients / Sarcoma de Kaposi en pacientes trasplantados: análisis de una serie de 13 casos

Introduction and objectives: This study reflects our experience in the management of posttransplant Kaposi Sarcoma (KS) and assesses the clinical relevance of monitoring HHV-8 DNA viral load in peripheral blood by qPCR.Patients and methodsRetrospective study of all patients diagnosed with posttransplant KS during the period 1995–2019. In 8 patients, we performed a qPCR in serum for HHV-8 DNA detection at diagnosis and/or during follow-up.ResultsData from 13 organ transplant recipients with a diagnosis of iatrogenic KS were collected. Reduction and/or discontinuation of one or more immunosuppressive agent(s) along with switching to an mTOR inhibitor was part of the treatment approach in 12 (92%) patients. Overall response rate (including complete response, partial response, and stable disease) was observed in 9 patients. At diagnosis, HHV-8 qPCR in serum was positive in 2 out of 5 patients. During follow-up, both positive cases turned negative, as a clinical response.ConclusionsOur work highlights the critical role of reduction of immunosuppression and conversion to an mTOR inhibitor in the management of posttransplant KS. (AU)

Introducción y objetivos: Este estudio aporta nuestra experiencia en el manejo del sarcoma de Kaposi (SK) en pacientes trasplantados, y evalúa la relevancia clínica de la monitorización por qPCR de la carga viral del VHH-8 en sangre periférica.Pacientes y métodosEstudio retrospectivo de los pacientes diagnosticados de SK postrasplante en el periodo de 1995-2019. En 8 pacientes, realizamos qPCR en suero para la detección de ADN del VHH-8 en el momento del diagnóstico o durante el seguimiento.ResultadosSe recogieron datos de 13 trasplantados de órgano sólido con diagnóstico de SK. La reducción o discontinuación de uno o más fármacos inmunosupresores junto con el cambio a un inhibidor de mTOR constituyó una parte del tratamiento en 12 (92%) pacientes. Se observó respuesta al tratamiento (incluyendo respuesta completa, parcial o estabilidad) en 9 pacientes. En el diagnóstico, la qPCR en suero de VHH-8 fue positiva en 2 de 5 pacientes. Durante el seguimiento, ambos casos positivos se negativizaron al responder los pacientes al tratamiento.ConclusionesNuestro trabajo muestra el papel esencial de la reducción de la inmunosupresión y la conversión a un inhibidor de mTOR en la estrategia terapéutica de SK en pacientes trasplantados. (AU)