Daniel Berg M.D., FRCPC Director Dermatologic Surgery Professor, Dermatology University of Washington

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Redesign on Skin Growth in Organ Transplant Beneficiaries 2008. Daniel Berg M.D., FRCPC Executive Dermatologic Surgery Educator, Dermatology College of Washington. Cosmas and Damien Supporter Holy people of Transplantation. What's "Old". Skin Malignancy Actualities:.

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Refresh on Skin Cancer in Organ Transplant Recipients 2008 Daniel Berg M.D., FRCPC Director Dermatologic Surgery Professor, Dermatology University of Washington

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Cosmas and Damien Patron Saints of Transplantation

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What's "Old"

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Skin Cancer Facts: Skin disease frequency and forcefulness expanded in OTRs After the fourth year post-transplant, 27% of heart patients in Australia kick the bucket of skin tumor OTRs require expanded Surveillance Education Lower limit for biopsy

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Skin Cancer Facts: Treat AKs forcefully LN2, topicals, PDT Treat Skin Cancers with common strategies all the more forcefully connected Special issues: Field resection (e.g. hand) Reduction of Immunosuppression Retinoid Chemoprevention

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Update Topics Aldara Literature Update Study indicates wellbeing and adequacy Reduction of Immunosuppression Guidance for Discussion with Transplant Docs New Survey Data Update on mTOR Inhibitors Mechanism Data for Efficacy (SCC in OTRs, KS, Tuberous Sclerosis) Side Effects Wound Healing Issue Melanoma in Transplant Patients

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Imiquimod (Aldara) Is it successful in OTRs? Are there symptoms (e.g. dismissal)?

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Imiquimod (Aldara) RCT. N=43 (little) 3X/week for four months Face, temple or uncovered scalp 100cm2 field (2 sachets/application) 4-10 AKs inside each field. 62% finish leeway versus 0% fake treatment. No proof unite dismissal Ulrich, C.et al. Brit J Derm , Volume 157, Supplement 2, December 2007 , pp. 25-31(7)

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Reduction Immunosuppression

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Changes in Immunosuppression % of all kidney transplants taking drugs at time of release Source: OPTN 2007 Report. Table 5.6e

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Evidence Supporting Reduction of Immunosuppression More NMSC with 3-versus 2-sedate regimen CAP > AP or CP Reviewed in: Otley, Maragh. Dermatol Surg 2005; 31:163-8.

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Which Agent is Worst? Heart > Kidney Less skin growth in non-transplant patients on one specialist E.g. IBD on Azathioprine Conclusion : Overall force of immunosuppression most critical

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RCT Study Kidney transplant beneficiaries on CyA/Imuran Compared high to low dosage CYA regimens Trough CyA 75-125 versus 150-250 66 months line up More dismissal scenes with low measurement however : Fewer skin and different malignancies Same Overall AND Graft Survival Dantal, J et al. Lancet1998;351(9103):623.

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Dantal, J et al. Lancet1998;351(9103):623.

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Evidence Supporting Reduction of Immunosuppression Case Series: Decreased skin tumor after end of immunosuppression (Otley et al) Prolonged malady free survival from metastatic skin growth with RI (Moloney et al) Kaposi's Sarcoma, PTLD, Merkel Cell Ca relapses with RI Reviewed in: Otley, Maragh. Dermatol Surg 2005; 31:163-8.

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Otley, Berg, Ulrich ... Br J Derm 2006:154:395-400. Otley et al. Brit J Derm 2007 157, pp1183–1188

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Proliferation Signal Inhibitors Sirolimus Everolimus

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Rapamycin May be unique in relation to different immunosuppressants and skin growth Anti-angiogenic, against neoplastic properties Both medications FDA endorsed (Sirolimus 1999) Pharmacokinetic contrasts e.g. T1/2 60 (Rapa) versus 28 (Everolimus) Sirolimus better considered for skin growth.

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PSIs M-TOR enter focus in: Translation Angiogenesis Proliferation Active trials in different diseases Efficacy IN SCC in OTRs; Kaposi's Sarcoma Angiomyolipomas in Tuberous Sclerosis

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PSIs Target mTOR Key player in: Translation Angiogenesis Proliferation Active Trials In: AML &CML Lymphoma Myeloma Sarcoma Others Curr Opin Hem 2008;15:88 The Oncologist 2007;12:1007

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Rapamycin and Skin Cancer >1000 Patients on Rapa/CyA U Texas Houston Cohort 2.4% rate of skin tumor/5 yr mean Compare with 7% verifiable controls. Proportion just 1.58 that of all inclusive community (SEER information)/5 yr Problem: No control; >50% Patients African-American or Hispanic Kahan et al. Transplantation 2005;80(6):749.

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Rapamycin and Skin Cancer Pooled (5) rapamycin studies - 2 year information Skin malignancy occurrence CyA 6.9% CyA + Aza 4.3% CyA + Rapa (low dose) 2.0% p< 0.01 CyA + Rapa (high dose) 2.8% p<0.05 Rapa versus CyA: 0% versus 1.3% (NS incline) Rapa + CyA withdrawal versus Rapa + CyA: 2.3 versus 5.1% (NS trend) Ref: Mathew Clin Transplan 2004;18:446-9.

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Rapamycin and Skin Cancer Retrospective UNOS/OPTN Review (963 days) TOR Inhibitor Maintenance demonstrated 60% diminished danger of any post-transplant harm Kauffman et al. Transplantation 2005;80:883 Case Series: 16/16 renal transplant patients with cutaneous KS finish reduction at 3 months with transformation from CyA to Rapa Stallone et al. NEJM 2005:352(13):1317.

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Rapamycin and Skin Cancer At 3 months after renal transplant. 430 patients randomized to stay on CsA-SRL-steroids versus SRL-steroids alone (SRL troughs multiplied): At 5 yr: Median time to first skin CA 491d versus 1126d Estimated rate of non skin tumor: 9.6% versus 4% Campistol JM et al. Sirolimus treatment after early cyclosporine withdrawal diminishes the hazard for disease in grown-up renal transplantation. J Am Soc Nephrol. 2006 Feb;17(2):581-9

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Recommendations of clinical direction for transformation from calcineurin inhibitors to expansion flag inhibitors in renal transplant beneficiaries From: Campistol, J. M. et al. Nephrol. Dial. Transplant. 2007 22:36-41 "There are no confirmation based rules for the utilization of PSIs in renal transplant patients with malignancies… .."

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Rapamycin and Side Effects Hyperlipidemia Wound Healing Renal Function May help CNI-initiated CAN May intensify CyA actuated nephrotoxicity if utilized at same time Increased danger of dismissal if utilized quickly post transplant Others e.g. uncommon pneumonitis Proteinuria Edema Generalized Leg Upper Body Myelosuppression Thrombocytopenia Leukopenia Anemia Dermatologic Acne Oral Ulcers

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Rapamycin and Wound Healing For General Surgery Most reviews show Increased Incidence of: Dehiscence Incisional Hernia Fluid accumulations Grim et al. Transplantation Proceedings, 38, 3520–3523 (2006) Knight et al. Clin Transplant 2007: 21: 460–465

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Rapamycin and Wound Healing For General Surgery If fancied for essential immunosuppression, ideal to hold for 3-4 weeks post transplant. For elective surgery many hold preop (60hr ½ life) and for a month and a half in the wake of changing to FK506 In Emergency Surgery, adjust method Slower absorbing  sutures, Use marlex work or pre-peritoneal  system for hernia repair Leave skin sutures in longer Personal Communication: 2007: R Hirose, D Salomon, Jeff Haldorson

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Rapamycin and Wound Healing What about Derm Surgery? Generally little experience Fewer patients, shorter time on medication, conceivable diminished skin malignancies Main issues: disease, moderate recuperating, dehiscence Typically sensible One Study: Brewer et al. Dermatologic Surgery 2008;34:216-223

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Sirolimus and Healing 26 Sirolimus Patients " Non-noteworthy" Trend to: Higher number of diseases More dehiscence Pt evaluated slower recuperating Brewer et al. Dermatologic Surgery 2008;34:216-223

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Rapamycin and Wound Healing Derm Surgery Recommendations : Do not have to stop Rapamycin Minimize pressure on terminations Use monofilament absorbable sutures Consider 2 nd aim recuperating Lower edge for anti-infection agents

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Does Skin Cancer Affect Decision to Transplant?

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Should Patients With Prior Skin Cancer Be Transplant Donors Or Recipients? Relies on upon specifics of tumor Validated prognostic variables Accentuation of hazard by immunosuppression ineffectively measured Consult with transplant dermatologist Otley,C., Hirose, R , Salasche, S. (2005). Skin Cancer as a Contraindication to Organ Transplantation. American Journal of Transplantation 5 (9),2079-2084

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American Journal of Transplantation2005; 5 (9),2079-2084

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Melanoma in Transplant Patients

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Melanoma in Transplant Patients Three Scenarios of Interest: De Novo Melanoma Recipient with past history of Melanoma from Donor

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Melanoma in Transplant Patients De Novo Melanoma Standard rules in addition to: Consider decrease of immunosuppression in: Those with > 1mm Positive Sentinel Node Consider discontinuance of immunosuppression in metastatic melanoma especially if benefactor inferred. Episodic reports recommend this may offer assistance.

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PreTransplant Melanoma in Recipient Management of Patient sitting tight for organ with history of melanoma From Christensen L. Melanoma in: Otley et al. Skin Disease in Organ Transplant Patients. Content 2008

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PreTransplant – Melanoma in Donor 20 beneficiaries from 11 givers with reflectively analyzed MM 6/11 had been determined to have essential mind tumor (3) or CV discharge (3) 17/20 beneficiaries got organize 4 metastatic MM 11 of these kicked the bucket of it 5 had finish abatement with discontinuance immunosuppression Penn. Transplantation 27 Jan 1996:274-278

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PreTransplant – Melanoma in Donor "… in light of the fact that melanoma, … pose(s) a high transmission hazard, we prescribe staying away from givers who have a previous history of … these growths." Kaufman et al. Transplantation 2002: 74(3), 358–362. ...in this way, givers with a background marked by melanoma ought not be utilized. Kaufman et al. Transplantation 2007;84:272

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PreTransplant – Melanoma in Donor In U.S. 2% of benefactors have a past hx of CA. Audit 2000-2005 (n = 40,000 contributors) 1069 benefactors with Hx CA gave 2508 transplants Most normal CA = NMSC (776/1069 = 73%) #2 CNS (642); #3 Cervix (336); Melanoma (140) 4 Recipients from 2 Donors kicked the bucket 3 from glioblastoma; 1 from MM (32 years earlier) Kaufman et al. Perished Donors With PMHx of Malignancy: An UNOS/OPTN Update Transplantation 2007;84: 272–274.

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PreTransplant – Melanoma in Donor Other no