Risk Of Cancer In Transplant Recipients Research Articles

Update on Treatment of Hypertension After Renal Transplantation.

To incorporate novel findings on pathophysiology and treatment of posttransplant hypertension. (1) The sodium retaining effects of CNIs are mediated by stimulation of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule and in this regard chlorthalidone was proven to be an effective antihypertensive drug in renal transplantation. (2) Local and not systemic activation of the renin-angiotensin-aldosterone system plays a crucial role in the pathogenesis of posttransplant hypertension. (3) Recent randomized controlled trials failed to prove the presumed superiority of renin-angiotensin blockers in kidney transplantation. (4) Steroid-free and mammalian target of rapamycin-based immunosuppressive drug combinations did not show favorable effects on blood pressure control. (5) In a recent report the risk of non-melanoma skin cancer was higher with thiazide diuretics. But the increased cancer risk in transplant recipients is mainly attributed to comorbidities, such as diabetes and hypertension and of course to the transplantation condition itself or the obligatory application of immunosuppression, and has little to do with the antihypertensive medication Actual recommendations about BP targets in adult renal transplant recipients are coming from a post hoc analysis of a large randomized trial with another primary endpoint. Unless convincing studies on treatment of hypertension after renal transplantation are available, the ESC/ESH Guidelines 2018 should apply for these patients.

Cancer Risks in Solid Organ Transplant Recipients: Results from a Comprehensive Analysis of 72 Cohort Studies

ABSTRACT Understanding the cancer risks in different transplant recipients helps early detection, evaluation, and treatment of post-transplant malignancies. Therefore, we performed a meta-analysis to determine the cancer risks at multiple sites for solid organ transplant recipients and their associations with tumor mutation burden (TMB), which reflects the immunogenicity. A comprehensive search of PubMed, Web of Science, EMBASE, Medline, and Cochrane Library was conducted. Random effects models were used to calculate the standardized incidence ratios (SIRs) versus the general population and determine the risks of different cancers. Linear regression (LR) was used to analyze the association between the SIRs and TMBs. Finally, seventy-two articles met our criteria, involving 2,105,122 solid organ transplant recipients. Compared with the general population, solid organ transplant recipients displayed a 2.68-fold cancer risk (SIR 2.68; 2.48–2.89; P <.001), renal transplant recipients displayed a 2.56-fold cancer risk (SIR 2.56; 2.31–2.84; P <.001), liver transplant recipients displayed a 2.45-fold cancer risk (SIR 2.45; 2.22–2.70; P <.001), heart and/or lung transplant recipients displayed a 3.72-fold cancer risk (SIR 3.72; 3.04–4.54; P <.001). The correlation coefficients between SIRs and TMBs were 0.68, 0.64, 0.59, 0.79 in solid organ recipients, renal recipients, liver recipients, heart and/or lung recipients, respectively. In conclusion, our study demonstrated that solid organ transplant recipients displayed a higher risk of some site-specific cancers, providing individualized guidance for clinicians to early detect, evaluate, and treat cancer among solid organ transplantation recipients. In addition, the increased cancer risk of solid organ transplant recipients is associated with TMB, suggesting that iatrogenic immunosuppression may contribute to the increased cancer risk in transplant recipients. (PROSPERO ID CRD42020160409).

Cyclosporine A Inhibits the T-bet-Dependent Antitumor Response of CD8(+) T Cells.

Transplant recipients face an increased risk of cancer compared with the healthy population. Although several studies have examined the direct effects of immunosuppressive drugs on cancer cells, little is known about the interactions between pharmacological immunosuppression and cancer immunosurveillance. We investigated the different effects of rapamycin (Rapa) versus cyclosporine A (CsA) on tumor-reactive CD8(+) T cells. After adoptive transfer of CD8(+) T cell receptor-transgenic OTI T cells, recipient mice received either skin grafts expressing ovalbumin (OVA) or OVA-expressing B16F10 melanoma cells. Animals were treated daily with Rapa or CsA. Skin graft rejection and tumor growth as well as molecular and cellular analyses of skin- and tumor-infiltrating lymphocytes were performed. Both Rapa and CsA were equally efficient in prolonging skin graft survival when applied at clinically relevant doses. In contrast to Rapa-treated animals, CsA led to accelerated tumor growth in the presence of adoptively transferred tumor-reactive CD8(+) OTI T cells. Further analyses showed that T-bet was downregulated by CsA (but not Rapa) in CD8(+) T cells and that cancer cytotoxicity was profoundly inhibited in the absence of T-bet. CsA reduces T-bet-dependent cancer immunosurveillance by CD8(+) T cells. This may contribute to the increased cancer risk in transplant recipients receiving calcineurin inhibitors.

Spectrum of cancer risk among US solid organ transplant recipients.

Solid organ transplant recipients have elevated cancer risk due to immunosuppression and oncogenic viral infections. Because most prior research has concerned kidney recipients, large studies that include recipients of differing organs can inform cancer etiology. To describe the overall pattern of cancer following solid organ transplantation. Cohort study using linked data on solid organ transplant recipients from the US Scientific Registry of Transplant Recipients (1987-2008) and 13 state and regional cancer registries. Standardized incidence ratios (SIRs) and excess absolute risks (EARs) assessing relative and absolute cancer risk in transplant recipients compared with the general population. The registry linkages yielded data on 175,732 solid organ transplants (58.4% for kidney, 21.6% for liver, 10.0% for heart, and 4.0% for lung). The overall cancer risk was elevated with 10,656 cases and an incidence of 1375 per 100,000 person-years (SIR, 2.10 [95% CI, 2.06-2.14]; EAR, 719.3 [95% CI, 693.3-745.6] per 100,000 person-years). Risk was increased for 32 different malignancies, some related to known infections (eg, anal cancer, Kaposi sarcoma) and others unrelated (eg, melanoma, thyroid and lip cancers). The most common malignancies with elevated risk were non-Hodgkin lymphoma (n = 1504; incidence: 194.0 per 100,000 person-years; SIR, 7.54 [95% CI, 7.17-7.93]; EAR, 168.3 [95% CI, 158.6-178.4] per 100,000 person-years) and cancers of the lung (n = 1344; incidence: 173.4 per 100,000 person-years; SIR, 1.97 [95% CI, 1.86-2.08]; EAR, 85.3 [95% CI, 76.2-94.8] per 100,000 person-years), liver (n = 930; incidence: 120.0 per 100,000 person-years; SIR, 11.56 [95% CI, 10.83-12.33]; EAR, 109.6 [95% CI, 102.0-117.6] per 100,000 person-years), and kidney (n = 752; incidence: 97.0 per 100,000 person-years; SIR, 4.65 [95% CI, 4.32-4.99]; EAR, 76.1 [95% CI, 69.3-83.3] per 100,000 person-years). Lung cancer risk was most elevated in lung recipients (SIR, 6.13 [95% CI, 5.18-7.21]) but also increased among other recipients (kidney: SIR, 1.46 [95% CI, 1.34-1.59]; liver: SIR, 1.95 [95% CI, 1.74-2.19]; and heart: SIR, 2.67 [95% CI, 2.40-2.95]). Liver cancer risk was elevated only among liver recipients (SIR, 43.83 [95% CI, 40.90-46.91]), who manifested exceptional risk in the first 6 months (SIR, 508.97 [95% CI, 474.16-545.66]) and a 2-fold excess risk for 10 to 15 years thereafter (SIR, 2.22 [95% CI, 1.57-3.04]). Among kidney recipients, kidney cancer risk was elevated (SIR, 6.66 [95% CI, 6.12-7.23]) and bimodal in onset time. Kidney cancer risk also was increased in liver recipients (SIR, 1.80 [95% CI, 1.40-2.29]) and heart recipients (SIR, 2.90 [95% CI, 2.32-3.59]). Compared with the general population, recipients of a kidney, liver, heart, or lung transplant have an increased risk for diverse infection-related and unrelated cancers.

Lesion Count Predicts Cancer Risk in Transplant Recipients

Lesion Count Predicts Cancer Risk in Transplant Recipients

Malignancies in renal transplantation: an unmet medical need

Registry data show that there is an overall 3-5-fold increase in cancer risk in transplant recipients compared with the general population, with skin cancers and lymphoma particularly prevalent. Cancers in transplant recipients are often more aggressive than those in the general population, with poor prognosis, particularly for gastrointestinal tumours and lymphomas. Risk factors for post-transplant malignancy include factors common to the general population, such as increasing age, cigarette smoking and sun exposure. In addition, immunosuppression is an important factor in the development of post-transplantation cancer, although data for individual agents are not definitive. A number of studies have demonstrated that ciclosporin is associated with an increased risk of malignancy, whereas a few studies report no increase in risk of cancer after the introduction of ciclosporin into treatment regimens. Similarly, studies have shown that the mycophenolic acid-based agent mycophenolate mofetil is associated with an increased risk of malignancy, whereas other studies have demonstrated that mycophenolate mofetil is in fact associated with a lower risk. Polyclonal anti-thymocyte antibodies used for induction therapy appear to be related to an increased incidence of post-transplant lymphoproliferative disorder, but this effect is not observed with monoclonal anti-interleukin 2 antibodies. Azathioprine has been implicated in the development of skin tumours, possibly as a result of increased photosensitivity to ultraviolet light. The proliferation signal inhibitors appear to be associated with a reduced risk of some malignancies. Further research will elucidate the role of these newer immunosuppressive agents in post-transplantation malignancies.

Malignancy after Transplantation

As newer immunosuppressive regimens have steadily reduced the incidence of acute rejection and have extended the life expectancy of allograft recipients, posttransplant malignancy has become an important cause of mortality. In fact, it is expected that cancer will surpass cardiovascular complications as the leading cause of death in transplant patients within the next 2 decades. An understanding of the underlying pathobiology and how to minimize cancer risks in transplant recipients are essential. The etiology of posttransplant malignancy is believed to be multifactorial and likely involves impaired immunosurveillance of neoplastic cells as well as depressed antiviral immune activity with a number of common posttransplant malignancies being viral-related. Although calcineurin inhibitors and azathioprine have been linked with posttransplant malignancies, newer agents such as mycophenolate mofetil and sirolimus have not and indeed may have antitumor properties. Long-term data are needed to determine if the use of these agents will ultimately lower the mortality due to malignancy for transplant recipients.

Virus infection and cancer risk in transplant recipients.

with nucleoporins sequentially to export Rev-bound RNA from the nucleus. Previously, Stutz and Rosbach have shown that Rev can function in yeast to promote the export of pre-mRNA containing the RRE sequence, as is observed in mammalian cells ~s. Stutz et al., using a yeast two-hybrid system, identified a yeast protein, Rev-interacting protein 1 (Riplp), that interacts with Rev (Ref. 14). Riplp also interacts with Rex. Riplp contains 27 XaaXaa-Phe-Gly repeats characteristic of yeast nucleoporin proteins, and anti-Riplp antibodies show that it is localized in nuclear pores. Nup159p, one of the recently identified yeast nucleoporins, also contains repeats of the Xaa-Xaa-PheGly-type motif in its central region, and a temperature-sensitive mutant of Nup159p has a more rapid cessation of poly(A) RNA export than that of other nucleoporin mutants. These data suggest that Riplp and Nup159p may be members of a family of nucleoporins that are required for RNA export. The interaction between yeast nucleoporins and the Rev activating domain suggests t h a t Rev may act as a carrier of RRE-containing RNA to the nuclear pores in a manner similar to importin 4 (also called karyopherin s and nuclear-pore-targeting complex6), which promotes the nuclear import of NLS-containing proteins. Alternatively, it is possible that Riplp functions together with Rev to target RRE-containing RNA to the nuclear pores. These studies have identified important functional proteins of h o s t cells that relate to Rev/Rex function, elucidating the molecular basis of this critical step in retroviral infection. The discovery ofRab (hRIP) and Riplp, as well as of the NESs of PKI and Rev, provides fundamental information about protein and RNA export from the nucleus. This basic understanding of the significance of Rev/Rex and Revinteracting proteins to nuclear export should lead to new strategies to prevent retroviral infections. References 1 Davis, L.1. (1995) Annu. Rev. Biochem. 64, 865-896 2 Melchior, F. and Gerace, L. (1995) Curt. Opin. Cell Biol. 7, 310-318 3 Izaurralde, E. and Mattaj, I.W. (1995) Cell 81,153-159 4 G6rlich, D. et al. (1994) Cell 79, 767-778 5 Radu, A., Blobel, G. and Moore, M.S. (1995) Proc. Natl Acad. Sci. USA 92, 1769-1773 6 Imamoto, N. et al. (1995)J. Biol. Chem. 270, 8559-8565 7 Schmidt-Zachmann, M.S. et al. (1993) Cell 74, 493-504 8 Guiochon-Mantel, A. et al. (1994) Proc. Natl Acad. Sci. USA 91, 7179-7183 9 Moroianu, J. and Blobel, G. (1995) Proc. NatI Acad. Sci. USA 92, 4318-4322 10 Wen, W. et al. (1995) Cell 82, 463-473 11 Fischer, U. et al. (1995) Cell 82, 475-483 12 Bogerd, H.P. etal. (1995) Cell 82, 485-494 13 Fritz, C.C., Zapp, M.L. and Green, M.R. (1995) Nature 376, 530-533 14 Stutz, F., Neville, M. and Rosbach, M. (1995) Cell 82,495-506 15 Stutz, F. and Rosbach, M. (1994) EMBO J. 13, 4096-4104