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Journal Club 29/01/2018 Paola Ponzo

Journal Club 29/01/2018 Paola Ponzo. Background:. CRC : fourth most common cancer worldwide. Background:. Malignancy is one of the leading cause of death in SOT recipients CRC: from no association to 12-fold increase in SOT population US records : SIR 1.12 (CI 1.03-1.20)

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Journal Club 29/01/2018 Paola Ponzo

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  1. Journal Club 29/01/2018 Paola Ponzo

  2. Background: • CRC: fourthmost common cancerworldwide

  3. Background: • Malignancyisone of the leading cause of death in SOT recipients • CRC: from no association to 12-fold increasein SOT population • US records: SIR 1.12 (CI 1.03-1.20) • OLT highest SIR 2.34 (CI 1.76-3.07)

  4. Background : • General population: medianageatdiagnosis 72 y • Youngeragein SOT recipients (meanage 58y) • OLT: meanage 53 y • Earlierdevelop in SOT recipients • BIAS: olderindividualsnot candidate for transplant • More aggressive course: 5 yearsoverallsurvival30.7% (vs 63.5%)

  5. Riskfactors: • General population

  6. Riskfactors – Role of Immunosuppression: • CONS: • Increasingof localTreg inhibition of effector T cellproliferation  inhibition of local immune system • CNI increasingof TGFβproduction  inhibitionof effector T cells • CNI  angiogenesisstimulationthroughVEGF • Azathioprine: directlydamage of DNA • PROS: • mTORinhibitors antineoplasticproperties (inhibition of PI3K/AKT pathway), no clinical data abouttheirprotectiverole in CRC • MMF inhibits adhesion of CRC cells to intestinal epithelialcells

  7. Riskfactors – OLT: • 10-fold higher risk of CRC in PSC (mainly proximal to the splenic flexure) • Risk factors for CRC and cirrhosis: high alcohol intake, obesity

  8. Screening recommendations/ Pre - transplant

  9. Screening recommendations/ Post - transplant Screening test : FULL COLONOSCOPY (post-transplant increasedrisk of proximal CRC)

  10. Transplantation in patients with a history of colon cancer • Data mainly derives from follow up in kidney transplantation • Only small retrospective, single-center studiesin liver transplant recipients  recurrence rate of ~ 19% • 5 years of negative follow up prior to listing for transplantation • Well-differentiated Dukes’ A (limited to the muscularispropria) likely do not need a 5-year waiting period prior to listing.

  11. Donors with colon cancer Overall transmission rate 19% • Active cancer: • Stage 0(in situ) ONLY IF survival without transplant is “short” • Above stage 0  NOT RECOMMENDED • History of CRC: • Donors with lower-risk lesions and a 5–10 years follow up can be considered • Suggestion of using donors with a history of lower-risk lesions (in situ, T1, or T2); if they are 0, 1, and 5 years posttreatment respectively

  12. Post – transplant colon cancer Prevention mTORinhibitors: • mTOR inhibitors can prevent polyp formation in mice • mTOR inhibitors reduce the risk of de novo solid malignancies in kidney transplantation (RR 0.44; IC 0.24–0.82) • potential benefit of mTOR inhibitor in reducing CRC risk (not statistically significant) mTOR inhibitors should be considered if the risk of cancer is high

  13. Post – transplant colon cancer Prevention Prophilacticcolectomy(patients with PSC and UC): • Colectomy before or during the transplant  10 - year survival of 87% vs 60% (not statistically significant)  decreased CRC- and UC-related morbidity • Furtherstudies are needed prior to recommendcolectomy as standard of care in high risk patients Management • Loweringdosesof the immunosuppressiveregimen • Potential beneficial effects of mTOR inhibitors and MMF inhibitors and tumorpromotingmechanisms of CNI  change immunosuppressive agent

  14. Cancer and livertransplantation Pre – transplant screening • Mammogramevery 12-24 months (female > 40y, before in high riskpatients) • PAP smearevery 3 years (female, 25-64 y) • Transvaginal ECT and Ca-125 every12 months (female) • PSA and digitalrectalexamination (male; >50 y? frequency?) • EGDS • CRC: FOBT every 12 months or sigmoidoscopyevery 5 y or colonoscopyevery 10 y (> 50 y or high riskpatients) • Dermatologicalexamination 2008 • Colonoscopy (> 50 y) • EGDS • Mammogram and PAP smear (female) • Dermatological examination • Alcohol and smoking addiction: search for pulmonary neoplasia, ear-nosethroat, stomatology, oesophageal and bladder • Screening for prostate disease according to the urologist indication (male) 2016

  15. Cancer and livertransplantation Pre – transplant screening What do we do? • Colonoscopy (> 50y or high riskpatients) • EGDS • Chest-X-Ray • Abdomen CT scan (chest CT scanif HCC) • ENT visit • Mammogram and PAP smear (female) every 12 months • αFP • PSA (male) every12 months • 5 y of negative follow up in history of cancer • Melanoma and breastcancer exclusion • Mieloproliferative disorders  no controindication

  16. Cancer and livertransplantation Donors with previous or currentmalignancies • Livers from a donor with a history of malignancy can be used in selectedsituations (lowrisk of transmission) • Lowrisk for low-grade CNS tumours • CRC and breast cancer absolute contraindications to donation in advanced stage (CRC >T3 or breast cancer >T1c). • Glioblastoma multiforme, melanoma, choriocarcinoma and lung cancer  absolute contraindications to liver donation 2016

  17. Cancer and livertransplantation Donors with previous or currentmalignancies • NON STANDARD CON RISCHIO TRASCURABILE • K in situ (NO high grade breastcancer) • Basocellularskincancer G1-2 • Spinocellularskincancer • Papillaryurothelial carcinoma G1-2 intra-epithelial • Papillaryurothelial carcinoma G3 with negative f-u • Prostate cancerGleason ≤ 6 • Papillarythyroid carcinoma • Renal carcinoma (low grade, < 4) • Low grade CNS cancer (WHO G1-2-3) • MGUS – MC > 1.5 g /dl 2015 • NON STANDARD CON RISCHIO ACCETTABILE • High grade CNS cancer (WHO G4) with the exception of glioblastoma, gliosarcoma and embryonaltumours; withoutclinical high riskfactors • Prostate cancerGleason> 6

  18. Cancer and livertransplantation Donors with previous or currentmalignancies • NON IDONEO - RISCHIO INACCETTABILE • Follow-up < 10 y (high risktumors) • Metastaticcancer • Breastcancer, Melanoma, Limphoma and Leukemia • High grade CNS cancer (WHO G4) with clinical high riskfactors • Glioblastoma, gliosarcoma, embryonal CNS tumours 2015

  19. Cancer and livertransplantation Post-transplantfollow up • 2–3-fold elevated risk of solid organ cancers and a 30-fold or higher increase in the rate of lymphoproliferative malignancies compared to the general population • 3-22 % of transplanted patients • Most common de novo malignancy: non-melanoma skin cancer (20x, spinocellular > basocellular) • Alcoholic cirrhosis: increased risk of cancer of the upper GI, oropharynx and larynx • Smoking history: increased risk of head/neck and pulmonary de novo malignancies • EBV + before LT: higher risk of developing PTLD (aggressive, extra-nodal) • PSC + UC: higherrisk of CRC

  20. Cancer and livertransplantation Post-transplantfollow up • No codified/standardized screening programs • Proposed screening: • Mammogramevery 12-24 months (female,> 40y) • PAP smearevery 3 years (female) • ECT TV+ Ca 125 every 12 months • PSA and urologicalexaminationevery 12 months (male, > 50y) • CRC: FOBT every 12 months or sigmoidoscopyevery 5 y or colonoscopyevery 10 y (> 50 y or high riskpatients) • Dermatologicalevaluationevery 12 months • Chest-X-Rayevery 12-24 months high riskpatient: smokers,) • EGDS and ENT evaluationevery 12 months (high riskpatients: history of alcoholabuse, Barrett’sesophagus) 2008 • No screening programs based on scientific evidence 2016

  21. Cancer and livertransplantation Post-transplantfollow up What do we do? • Colonscopyevery 5-10 years(more frequent in high riskpatients) • Chest-X-Rayevery 12 months • Mammogramevery 12 months (female) • PAP smearevery 12 months (female) • ECT abdomen: 3-6-12 months and thenyearly. In HCC: abdomen CT scanyearly • No standardizedindications for: EGDS, ENT evaluation, dermatologicalevaluation, PSA/urologicalevaluation

  22. Cancer and livertransplantation Post-transplantfollow up Whatshouldwe do? (LiteratureReview) • HCC • No clearindications. CT/MRI every 6 months for 5 years? Liu D et al. Evidence Based surveillance Imaging Schedule After Liver Transplantation for Hepatocellular Carcinoma Recurrence. Transplantation; 2017 • Lung • No clearindications. 20% mortality reduction in heavy smokers (> 30 pack-years) • aged 55 -74 in screening with yearly low-dose chest CT scan Lung cancer screening with low-radiation dose computed tomography after liver transplantation. Herrero JI et al. Ann Transplant; 2013 • Upper GI tract • No clearindications. EGDS every 2-3 years < 40 y, thenevery 2 years Jung DH. Survival Benefit of Early Cancer Detection Through Regular Endoscopic Screening for De Novo Gastric and Colorectal Cancers in Korean Liver Transplant Recipients. Transplant Proc. 2016

  23. Cancer and livertransplantation Post-transplantfollow up Whatshouldwe do? (LiteratureReview) • Skin • Dermatologicalevaluationevery 12-24 months(6-12 monthsif: olderage, phototype I-II-III, HPV +, • CD4+ deficiency, actinickeratosis, higherlevels of immunosuppression) KrynitzB et al. Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008 – a Swedish population-based study. Int J Cancer 2013 StaskoT et al. Guidelines for the management of squamous cell carcinoma in organ transplant recipients. DermatolSurg2004 • Cervix • PAP smearevery 12 monthsif HPV +, no clearindications in otherpatients (‘prevenzione serena’?) Mukthinuthalapati PK. Incidence, risk factors and outcomes of de novo malignancies post liver transplantation.World J Hepatol 2016 • Prostate/BreastNo higherriskthen general population (no screening/ ‘prevensione serena’) Mukthinuthalapati PK. Incidence, risk factors and outcomes of de novo malignancies post liver transplantation.World J Hepatol 2016

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