Calcineurin Inhibitors In Combination Research Articles

[Radiation-induced morphea-an overview].

Radiation-induced morphea is afibro-inflammatory remodelling process of the subcutaneous connective tissue caused by ionising radiation, most commonly in the context of breast cancer treatment. The underlying pathomechanisms and putative risk factors are unknown. Therefore, misdiagnosis and inappropriate treatment pose asignificant problem in the care of those patients. The aim of the study was to provide an overview as well as guidance for the diagnosis and treatment of radiation-induced morphea based on current case reports and review articles. Radiation-induced morphea is arare condition that represents an interdisciplinary challenge for (gynaecological) oncology, radiotherapy and dermatology. Frequent misdiagnoses include infection (erysipelas), cancer recurrence or radiation dermatitis. Early histological diagnosis and the initiation of anti-inflammatory therapy using topical glucocorticoids or calcineurin inhibitors in combination with phototherapy and/or methotrexate are the most relevant success factors for an adequate clinical response.

2740. Letermovir for the Prevention and Treatment of Cytomegalovirus Infection in Solid Organ Transplant Recipients

Abstract Background Cytomegalovirus (CMV) is a common infection that can lead to end-organ damage and graft rejection in solid organ transplant (SOT) recipients. Due to the increase in drug-resistant CMV and unfavorable side effect profile of available CMV-active agents, there is a need for additional prophylactic and treatment strategies in this patient population. The goal of this study is to evaluate SOT recipients prescribed letermovir for prophylaxis and/or treatment of CMV. Methods This study was a retrospective review of adult SOT recipients in the Cleveland Clinic Health System prescribed letermovir from 11/8/2017 to 8/1/2022. The primary objective was to describe the utilization of letermovir in SOT recipients. Secondary objectives included: proportion of SOT recipients that experienced CMV breakthrough on letermovir prophylaxis, proportion of SOT recipients that experienced refractory CMV infection on letermovir treatment, prevalence of letermovir resistance, and letermovir-induced adverse effects. Results A total of 45 patients were included in the study, with 52 letermovir courses. Lung was the most commonly transplanted organ (35%), followed by kidney (22%). 78% of patients were high-risk CMV and the most common immunosuppression regimen consisted of a calcineurin inhibitor in combination with a corticosteroid (82%). 11 patients received letermovir for primary CMV prophylaxis, with only one patient experiencing new/worsening viremia while on the agent. Of the 34 patients who received letermovir for secondary CMV prophylaxis, 11 experienced new/worsening viremia. 7 patients received letermovir for CMV treatment, at a median viral load of 991 IU/mL (IQR 603-2,738) on initiation and peak viral load of 3,892 IU/mL (IQR 1,407-10,209) while on therapy. No patients in the treatment group experienced refractory infection. 7/52 (13.5%) letermovir courses were discontinued due to new/worsening viremia, with no letermovir resistance identified. No letermovir-related adverse effects were documented. Conclusion Our study shows that letermovir appears to be effective in suppressing CMV viremia. Letermovir may be an alternative option for SOT recipients who are unable to tolerate or have resistance to traditional CMV therapeutics. Disclosures All Authors: No reported disclosures

Low incidence and morbidity of Epstein-Barr virus reactivation following donor lymphocyte infusions.

Epstein-Barr virus (EBV) reactivation occurs under immunosuppression following solid organ or stem cell transplantation, leading to post-transplantation lymphoproliferative disease (PTLD) in some patients. PTLD after allogeneic hematopoietic stem cell transplantation (alloHSCT) is donor-derived, originating from B cells transmitted with the transplant. Here, we report EBV reactivations in eight of 151 consecutive patients receiving donor lymphocyte infusions (DLIs). The EBV reactivations occurred at a median interval of 52 days after initiation of DLI treatment, mostly following the second DLI graft. The mean level of EBV reactivation amounted to 6.3 × 103 copies/ml, and this triggered preemptive Rituximab treatment in four patients. EBV reactivation regressed in all patients, with no PTLD cases observed. DLIs are an effective form of adoptive immunotherapy for the treatment of disease recurrence after alloHSCT [1]. While the donor T cells exert the desired therapeutic effects, unmanipulated DLI grafts also contain donor B cells that may harbor EBV, which prompted this retrospective analysis approved by the University Medicine Goettingen (UMG) ethics committee. Out of 151 consecutive patients who had received a DLI from 2005 through 2020 at the UMG after informed consent, EBV reactivation, defined as measurable EBV load in peripheral blood or tissue biopsy was detected by quantitative polymerase chain reaction (PCR) testing in eight patients. Importantly, all of the patients with EBV reactivation had negative PCR findings prior to the initiation of the treatment with DLI, measured at the last follow-up visit. Four of these patients had a history of low-titer EBV reactivation prior to DLI treatment. In all eight cases, patients and their respective donors were EBV seropositive prior to transplantation. Peripheral blood stem cells have been used as graft-source in all eight cases. For GVHD prophylaxis, calcineurin inhibitors in combination with mycophenolate and anti-thymocyte globulin (ATG) were employed. At the time of the DLI, all patients had been free of immunosuppressive drugs for at least 6 weeks. One to a maximum of five DLIs were applied to treat disease recurrence in seven patients and failing chimerism in one patient respectively, at a median interval after alloHSCT of 518 days (range: 105–2350 days). The dose of DLI was determined according to the institutional standard of procedure. In patients with disease relapse, in a therapeutic setting, we initiated the treatment with 0.5–1 × 106 CD3 positive cells/kg. The second dose contained 5 × 106 CD3 positive cells/kg and the third dose was 1 × 107 CD3 positive cells/kg. One patient was treated in a prophylactic setting, and his treatment was initiated with 0,5 × 106 CD3 positive cells/kg. EBV was measured at every follow-up visit, once every 7–14 days, and had been detected at an average viral load of 6.3 × 103 copies/ml in the peripheral blood in five cases, as well as in the gastrointestinal biopsy or bronchoalveolar material in two cases and one case respectively. The interval from DLI application to EBV reactivation was 52 days (range: 20–83) from the first, and 30 (range: 7–65) days after the last DLI, suggesting a faster EBV reactivation associated with higher doses of DLIs. EBV reactivation regressed in all patients, spontaneously or after B-cell depletion with the anti-CD20 monoclonal antibody Rituximab, in four patients each. We have observed no case of PTLD post-DLI. The occurrence of EBV reactivations associated with any of the examined patient or transplantation characteristics was not statistically significant (Table 1). EBV via transfusion of blood products has been described, especially in immunocompromised patients [2-5]. Of note, the number of B lymphocytes in a single DLI infusion is more than 1000 times higher compared with a single red blood cell concentrate, increasing the risk of both virus transmission and the establishment of a B-cell reservoir for EBV maintenance in the immunocompromised patient. Importantly, beyond their well-established anti-tumor effects [1], DLIs have been successfully used for the treatment of both EBV reactivation and post-transplant lymphoproliferative disorder [6-9]. O'Reilly et al. reported that the adoptive transfer of peripheral blood-derived or in vitro expanded EBV-specific T cells induced durable regressions in advanced EBV lymphomas in 16 of 18 patients [7]. The efficacy of DLIs and EBV-specific cytotoxic T lymphocytes (CTLs) in the treatment of both previously untreated and Rituximab-resistant EBV-associated PTLD was confirmed by Doubrovina et al [8]. In this study, 73% of the patients treated with DLIs (n = 30) and 68% of those treated with EBV-CTLs (n = 19) achieved sustained complete response. Similarly, in a further case series, complete responses were achieved in two patients with Rituximab-refractory PTLD who were treated with unselected donor-derived DLIs [9]. We speculate that in our series the DLI may have transferred EBV through B-cell expansion in the immunocompromised environment of the recipient. At the same time, the DLI will also have transferred EBV-specific donor T cells, allowing the self-limitation of the viral reactivation in four of eight cases, as well as Rituximab-supported control in the remaining four cases. Importantly, all of our patients have received ATG as part of a conditioning regiment which may have increased the risk of reactivation. In summary, EBV reactivation after a DLI is a rare event, mostly self-limited or feasibly controlled by an anti-CD20 antibody treatment. Danilo Martinovic analyzed the data and wrote the paper, Justin Hasenkamp, Wolfram Jung, Frank Tucholski, and Jens-Holger Maas collected the data and created the database, and Gerald Georg Wulf designed the study and helped write and review the paper. The authors declare no conflict of interest. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. This analysis was approved by the University Medicine Goettingen (UMG) ethics committee (Approval Number: 29/9/22) Informed consent was obtained from all participants in the study. The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. The data are not publicly available due to privacy or ethical restrictions.

Efficacy of Induction Therapy With Calcineurin Inhibitors in Combination With Ustekinumab for Acute Severe Ulcerative Colitis

Ulcerative colitis is a chronic inflammatory bowel disease. Approximately 20% of patients experience an acute severe attack during their life. In acute severe ulcerative colitis (ASUC), first-line therapy is intravenous (IV) steroids. In the absence of clinical improvement, 2 medical options can be considered: ciclosporin or infliximab.1 In ASUC, ciclosporin is commonly used as a bridging therapy for thiopurines. Pellet etal2 found that the same bridge strategy with vedolizumab was effective and can avoid colectomy. Given that an increasing number of patients with ASUC have been exposed to thiopurines, vedolizumab, and anti-tumor necrosis factor biologic therapies, newer approaches are needed in these patients, such as tofacitinib or ustekinumab. Ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, has shown efficacy in ulcerative colitis and can be given in this indication.3 In this retrospective study, we evaluate the efficacy and safety of a bridge from calcineurin inhibitor to ustekinumab in patients with ASUC.

P393 Efficacy and Safety of Induction Therapy With Calcineurin Inhibitors in Combination With Ustekinumab for acute severe colitis

Abstract Background Ulcerative colitis is a chronic inflammatory bowel disease., 20% of patients will experienced acute severe colitis during their life. In acute severe colitis, when IV steroids failed, two strategies can be used with equivalent efficacy: Ciclosporin and Infliximab. Recently, Pellet et al reported the interest of association ciclosporin – vedolizumab. Regarding results from Varsity trial, more patients are treated before a CAG with vedolizumab. Recently, UNIFI trial showed the interest of ustekinumab in UC patients. So, it should be interesting to analyze the interest of the association Ciclosporin -Ustekinumab in case of acute severe ulcerative colitis. In this study, we retrospectively evaluated the clinical response and the rate of colectomy when we used anticalcineurin and Ustekinumab in acute severe colitis refractory to IV steroids. Methods All patients with acute severe colitis who failed to IV steroid and who were treated with calcineurin inhibitor and Ustekinumab, can be included. They were treated with a, 6mg/kg infusion and then a, 90mg subcutaneous injection every, 8 weeks. Eight referral French center and a Switzerland referral center were involved in this study. The primary endpoint was clinical response at, 6 months. We also evaluated the rate of colectomy and survival without Ustekinumab discontinuation. We reported also adverse events in this cohort. Results Eleven patients were included., 82% were women, with a median age of, 32.2 years (range, 25.5–36.5 y). The median disease duration was, 8.2 years (range, 3–9.5 y). Ten patients failed to Infliximab and, 9 to Vedolizumab. At inclusion, median Lichtiger score, Mayo score and CRP were respectively, 13,4 [IC95, 12.5–14.5], 10.6 [IC95, 10–11.5] et de, 24.5 mg/L [IC95, 4.5–35.7mg/l]. The mean Endoscopic Mayo score was, 2.6 +/-0.7. The median time between beginning of Calcineurin inhibitor and Ustekinumab was, 22 days (minimum, 6d, maximum, 128d). Median follow-up was, 11 months. None of the patients underwent colectomy at, 6 months. The mean full Mayo score was significantly lower during the follow-up (10.6 at baseline and, 1.0 at, 6 months; p = 0.005). The mean CRP level was significantly reduced (from, 24.5 mg / L [CI95, 4.5–35.7] to, 2.6 mg / L [2–3.1], p = 0.02). Only one patient stopped ustekinumab at the end of follow-up. Two patients required treatment optimization. Tolerance to treatment was well with only one case of alopecia described without withdrawal of treatment. Conclusion In this retrospective study including patients hospitalized for IV Steroid-resistant acute severe colitis, the sequence of treatment with induction anti-calcineurin with ustekinumab therapy appears to be effective and well tolerated. These results need to be confirmed on a larger number of patients.

Improved Therapeutic Approaches are Needed to Manage Graft-versus-Host Disease.

Allogeneic haematopoietic stem cell transplantation (alloHSCT) offers a potentially curative therapy for patients suffering from diseases of the haematopoietic system but requires a high level of expertise and is both resource intensive and expensive. A frequent and life-threatening complication is graft-versus-host disease (GvHD). Acute GvHD (aGvHD) generally causes skin, gastrointestinal and liver symptoms, but chronic GvHD (cGvHD) has a different pathophysiology and may affect nearly every organ or tissue of the body. In Europe, GvHD prophylaxis is generally a calcineurin inhibitor in combination with methotrexate, with high-dose systemic steroids used for advanced GvHD treatment. Between 39% and 59% of alloHSCT patients will develop aGvHD and around 36–37% will develop cGvHD. Steroid response decreases with increasing disease severity, which in turn leads to an increase in non-relapse mortality. GvHD imposes a financial burden on healthcare systems, significantly increasing post-alloHSCT costs. Increased GvHD disease severity magnifies this. Balancing immunosuppression to control the GvHD whilst maintaining a degree of immunocompetence against infection is critical. European GvHD guidelines acknowledge the lack of evidence to support a standard second-line therapy, and improved long-term outcomes and quality-of-life (QoL) remain an unmet need. Evidence generation for potential treatments is challenging. Issues to overcome include choice of comparator (extensive off-label usage); blinding; selection of relevant patient-reported outcome measures (PROMs); and rarity of the condition, which may infeasibly increase timescales to achieve clinical and statistical relevance.

Ex Vivo T Cell-Depleted and In Vivo T Cell-Depleted Allogeneic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia in First Complete Remission Resulted in Similar Overall Survival Survival: On Behalf of the ALWP of the EBMT and the MSKCC

Background. Myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established therapy for adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) with intermediate or high-risk cytogenetics. However regimen-related toxicities, in particular graft-versus-host disease (GVHD) have limited its widespread use. Therefore several strategies have been developed to deplete T cells in order to prevent GVHD. In vivo T-cell depletion (TCD) using antithymocyte globulin (ATG) with an unmanipulated graft is widely used in some centers in Europe, while other centers have develop an effective platform based on ex-vivo TCD CD34 selected (CD34+) graft. The aim of the current study was to compare these two strategies for GVHD prevention.Patients and methods. This retrospective analysis assessed the outcome of all consecutives patients over 18 years at time of transplant with an AML in CR1 with intermediate or high risk cytogenetics who received an in-vivo or ex-vivo T cell depleted myeloablative allo-HSCT using busulfan or total body irradiation based conditioning regimen between 2005 and 2011 and reported to the EBMT ALWP registry centers or at Memorial Sloan Kettering Cancer Center (MSK), respectively. Patients treated in EBMT centers received in vivo TCD with either thymoglobuline or grafalon ATG. In addition, all patients in the ATG group received GVHD prophylaxis consisting of a calcineurin inhibitor in combination with another drug. Patients treated at MSK received an ex-vivo TCD graft (CD34+). TCD was performed by immunomagnetic CD34+ cell selection of peripheral blood grafts. No additional GVHD prophylaxis was administered in those patients. Main transplant outcomes including refined GVHD-free/relapse-free survival (GRFS) were evaluated.Results. A total of 525 patients were included (363 ATG, 162 CD34+) with a median age of 46 (19-77) and 58 (range, 20-73) years, respectively (p<0.001). The ATG cohort had more unrelated donors (67.5% vs. 54.9%, p=0.006). Median follow-up was significantly longer in the CD34+ cohort [58.0 (range, 6-139.0), vs. 24.5, 51.9-131.0) months, p<0.001], therefore all patients were censored at 2 years for comparison between groups. There were no additional differences between cohorts including donor/recipient gender, CMV status and cytogenetic risk. The CD34+ cohort had less relapse (21.6% vs. 30%, p=0.03), grade II-IV aGVHD (11.3% vs. 21.2%, p=0.006), III-IV aGVHD (1.3% vs. 6.2%, p=0.01), cGVHD (2.5% vs. 27.6%, p<0.0001) and extensive cGVHD (0.6% vs. 11.3%, p=0<0.0001) and a higher GRFS (61% vs. 47%, p=0.0007) while there was no difference regarding OS (67.6% vs. 56.4%, p=0.31), LFS (61% vs. 57.9%, p=0.29) and NRM (17.4%, vs 12.1%, p=0.16). In multivariate analysis, the cumulative incidence of grade II-IV aGVHD and chronic GVHD were higher in the ATG cohort [HR 2.0 (95% CI 1.1-3.7), p=0.02 and HR 15.1 (95% CI 5.3-42.2), p<0.0001]. There were no statistical differences between both approach in terms of relapse, NRM, OS, and LFS. Parameters associated with a lower GRFS were ATG group, adverse cytogenetic and use of an unrelated donor [HR 1.7 (95% CI 1.2-2.5) p=0.001; HR 1,7 (95% CI 1.3-2.2) p=0.0002 and HR 1.5 (95% CI 1.1-2.0) p=0.01]. Cytogenetic status (high risk versus intermediate risk) also has a significant impact on relapse incidence [HR 2.1 (95% CI 1.4-3.0), p<0.0001] and LFS [HR 1.7 (95% CI 1.2-2.3) p=0.0006]. Finally there was significantly more death related to infection in the CD34 group (16/52, vs. 19/112, p=0.04).Conclusion. The cumulative incidence of acute (total and severe) and chronic GVHD were higher after allo-HSCT with ATG, leading to a lower GRFS in those patients. In contrast, enhance immunosuppression in the CD34+ group lead to a higher incidence of infectious related death. Overall NRM, OS and LFS are similar after ex-vivo CD34 selected and in-vivo ATG TCD allo-HSCT from related/unrelated donors in patients with AML in CR1 and intermediate/high-risk cytogenetic. Both approaches are associated with a good disease control and a high OS, and should be compared in a prospective randomized trial. DisclosuresMohty:Sanofi: Honoraria, Speakers Bureau.

Issue Highlights

Although anti-thrombotic agents are a known risk factor for upper gastrointestinal (GI) bleeding, their impact on patient outcomes is unclear. In this issue of Clinical Gastroenterology and Hepatology, Dunne and colleagues1Dunne P.D.J. Laursen S.B. Laine L. et al.Previous use of antithrombotic agents reduces mortality and length of hospital stay in patients with high-risk upper gastrointestinal bleeding.Clin Gastroenterol Hepatol. 2019; 17: 440-447Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar reported results from a multi-center, multi-national prospective cohort study to assess the effect of anti-thrombotic agents on outcomes in patients with high-risk upper GI bleeding. The authors evaluated 568 patients with acute upper GI bleeding who underwent endoscopy between March 2014 and March 2015, of whom 44% used anti-thrombotic agents. Patients using anti-thrombotic agents had a higher mean Rockall score and more frequently bled from ulcers but there were no differences in the levels of hemoglobin or systolic blood pressure at admission, requirements for transfusions, need for surgery or interventional radiology, or number of re-bleeding events. Patients taking anti-thrombotic agents had significantly lower bleeding-related mortality, which contributed to significantly lower all-cause mortality. In multivariable models adjusting for age, ASA score, and variceal bleeding, use of anti-thrombotic agents was associated with a 74% reduction in 30-day mortality. Overall, results from this study are consistent with prior studies and suggest that anti-thrombotic agents are not associated with worse outcomes after upper GI bleeding and endoscopy is safe in these patients. Also, see the accompanying editorial by Neil Sengupta.2Sengupta N. Endoscopic therapy for upper GI bleeding on antithrombotics – a safe option or do questions remain?.Clin Gastroenterol Hepatol. 2019; 17: 400-401Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar See page 440. Vedolizumab is efficacious for the treatment of ulcerative colitis; however there are limited data regarding outcomes using vedolizumab with calcineurin inhibitors. Two articles in this issue of Clinical Gastroenterology and Hepatology address this question. Pellet and colleagues3Pellet G. Stefanescu C. Carbonnel F. et al.Efficacy and safety of induction therapy with calcineurin inhibitors in combination with vedolizumab in patients with refractory ulcerative colitis.Clin Gastroenterol Hepatol. 2019; 17: 494-501Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar performed a retrospective multi-center study in France, including 39 patients with active steroid-refractory ulcerative colitis who received a calcineurin inhibitor as induction, followed by vedolizumab as maintenance therapy. All patients had inadequate response to prior anti-TNF therapy or use anti-TNF was contraindicated. Clinical response and remission were achieved in 56% and 38% of patients, respectively, at week 14, and the 1-year colectomy-free survival rate was 68%. Eleven patients (28%) experienced at least one adverse event, of which 4 were severe: three with renal insufficiency and one with Campylobacter colitis. Christensen and colleagues4Christensen B. Gibson P.R. Micic D. et al.Safety and efficacy of combination treatment with calcineurin inhibitors and vedolizumab in patients with refractory inflammatory bowel disease.Clin Gastroenterol Hepatol. 2019; 17: 486-493Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar reported a sub-analysis of the University of Chicago Vedizumab Database of patients with inflammatory bowel disease who received concomitant calcineurin inhibitors during the first 12 months of vedolizumab therapy. Of 9 patients with Crohn’s disease and 11 patients with ulcerative colitis who were treated with combination therapy as a bridge to vedolizumab monotherapy, clinical remission at 52 weeks was observed in 33% and 45%, respectively. Of 7 patients treated with calcineurin inhibitors after primary non-response to vedolizumab, 3 achieved steroid-free remission at 52 weeks. Both studies suggest that the combination of vedolizumab and calcineurin inhibitors is safe and effective at inducing and maintaining clinical remission in patients with severe inflammatory bowel disease. See page 486 and 494. Colorectal cancer (CRC) with mutations in BRAF is associated with adverse outcomes in patients with microsatellite stable cancers but results are conflicting in tumors with microsatellite instability. Bläker et al5Bläker H. Alwers E. Arnold A. et al.The association between mutations in BRAF and colorectal cancer–specific survival depends on microsatellite status and tumor stage.Clin Gastroenterol Hepatol. 2019; 17: 455-462Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar evaluated the prognostic value of combining microsatellite instability and BRAF testing in patients with CRC in a multi-center retrospective cohort study. Authors included 1995 patients diagnosed with CRC diagnosed between 2003 and 2010 from 22 hospitals in Germany, of whom 18% were stage 1, 34% stage II, 34% stage III, and 14% stage IV. Most tumors (85%) had microsatellite stability without BRAF mutations, 3% had BRAF mutations alone, 7% were MSI-H alone, and 5% had both microsatellite instability and BRAF mutation. BRAF mutation was not associated with survival in MSI-H patients but was associated with reduced overall survival in those with microsatellite stability. Evaluating stage-by-stage survival among microsatellite stable patients, BRAF mutations were associated with disease-specific survival in patients with stage III and IV tumors but not patients with stage II CRC. These results suggest that testing for BRAF mutations may be of limited benefit in stage I and II CRC. Also, see the accompanying editorial by Frank A. Sinicrope.6Sinicrope F.A. Evaluating the combination of microsatellite instability and mutation in BRAF as prognostic factors for patients with colorectal cancer.Clin Gastroenterol Hepatol. 2019; 17: 391-394Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar See page 455. There has been increasing emphasis on the importance of patient-reported outcomes and their correlation with endoscopic remission is unclear. In a systematic review, Narula and colleagues7Narula N. Alshahrani A.-A. Yuan Y. et al.Patient-reported outcomes and endoscopic appearance of ulcerative colitis: A systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2019; 17: 411-418Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar identified five relevant studies, with a total of 2132 patients. The sensitivity and specificity of the rectal bleeding Mayo subscore for mucosal healing was 81% and 68%, respectively. The stool frequency Mayo subscore for mucosal healing had lower sensitivity at 40% but higher specificity at 93%. Using the two subscores together resulted in a low sensitivity of 36% but high specificity of 96%. The positive and negative likelihood ratios for the two in combination were 8.4 and 0.66, respectively. The authors concluded that ulcerative colitis patients with normal rectal bleeding and stool frequency subscores likely have attained mucosal healing; however, stool frequency can remain abnormal despite mucosal healing. Also, see the accompanying editorial by Frank A. Sinicrope.6Sinicrope F.A. Evaluating the combination of microsatellite instability and mutation in BRAF as prognostic factors for patients with colorectal cancer.Clin Gastroenterol Hepatol. 2019; 17: 391-394Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar See page 411. /cms/asset/ac905132-c334-4a3b-8930-b9b60be747e5/mmc1.mp3Loading ... Download .mp3 (14.01 MB) Help with .mp3 files Audio Safety and Efficacy of Combination Treatment With Calcineurin Inhibitors and Vedolizumab in Patients With Refractory Inflammatory Bowel DiseaseClinical Gastroenterology and HepatologyVol. 17Issue 3PreviewLittle is known about the efficacy and safety of induction therapy with calcineurin inhibitors in combination with vedolizumab for patients with Crohn's disease (CD) or ulcerative colitis (UC). We analyzed the outcomes of patients receiving vedolizumab along with calcineurin inhibitors. Full-Text PDF Patient-Reported Outcomes and Endoscopic Appearance of Ulcerative Colitis: A Systematic Review and Meta-analysisClinical Gastroenterology and HepatologyVol. 17Issue 3PreviewWe aimed to evaluate the association of the patient-reported outcomes for rectal bleeding and stool frequency among patients with ulcerative colitis (UC) in endoscopic remission. Full-Text PDF Efficacy and Safety of Induction Therapy With Calcineurin Inhibitors in Combination With Vedolizumab in Patients With Refractory Ulcerative ColitisClinical Gastroenterology and HepatologyVol. 17Issue 3PreviewVedolizumab is used to treat patients with ulcerative colitis (UC), although there is a delay before it is effective. Induction therapy with a calcineurin inhibitor (cyclosporine or tacrolimus) in combination with vedolizumab as maintenance therapy could be an option for patients with an active steroid-refractory UC. We assessed the efficacy and safety of this combination. Full-Text PDF Previous Use of Antithrombotic Agents Reduces Mortality and Length of Hospital Stay in Patients With High-risk Upper Gastrointestinal BleedingClinical Gastroenterology and HepatologyVol. 17Issue 3PreviewAnti-thrombotic agents are risk factors for upper gastrointestinal bleeding (UGIB). However, few studies have evaluated their effects on patient outcomes. We assessed the effects of anti-thrombotic agents on outcomes of patients with high-risk UGIB. Full-Text PDF The Association Between Mutations in BRAF and Colorectal Cancer–Specific Survival Depends on Microsatellite Status and Tumor StageClinical Gastroenterology and HepatologyVol. 17Issue 3PreviewColorectal tumors with mutations in BRAF and microsatellite stability (MSS) have been associated with adverse outcomes of patients. Combined tests for microsatellite instability-high (MSI-H) and BRAF mutations might therefore be used in risk assessment, particularly for patients with stage II tumors. We investigate the stage-specific prognostic value of combined testing for MSI-H and BRAF for patients with colorectal cancer. Full-Text PDF

Effect of Haplotype Matching on Outcomes after Adult Single Cord Blood Transplantation

Background: High incidence of graft failure is a major obstacle for successful unrelated cord blood transplantation (UCBT). To ensure engraftment, unrelated cord blood (UCB) unit with higher total nucleated cell (TNC) and CD34 cell doses and less HLA mismatches between UCB units and patients were usually selected. However, it remains unclear whether HLA haplotype between the UCB units and patients should be matched. Using data from Japanese registry, we analyzed the effect of haplotype matching on the outcomes after single UCBT.Methods: Patients with hematologic diseases, aged 16 years or more, and have undergone their first UCBT between 2005 and 2014 were included in the study. The effect of haplotype matching (0, 1, and 2 haplotype matches) on neutrophil engraftment, overall mortality, relapse, and non-relapse mortality was analyzed after adjusting for other significant variables. Haplotype was estimated based on HLA-A, -B, -C, and -DRB1 allele information and Japanese allele frequency data. The haplotypes of both the patient and UCB unit were determined in 1,347 cases. Cases with more than 4 allele mismatches (n = 96) were excluded from the study.Results: The median age of the patients included in the study was 55 years (range 16-79 years). Median TNC and CD34 doses were 2.7 x 107/kg (range, 1.4-8.1x107/kg) and 0.8 x 105/kg (range, 0.1-5.2x105/kg), respectively. The number of allele mismatches were 0 in 82, 1 in 154, 2 in 252, 3 in 565, and 4 in 294 patients. The graft-versus-host disease (GVHD) prophylaxes were calcineurin inhibitors in combination with methotrexate in 707, calcineurin inhibitors in combination with Mycophenolate mofetil in 430, and other prophylaxes in 208 patients. The cumulative incidence of neutrophil engraftment at day 42 among groups with 0, 1, and 2 HLA haplotype matches was 79%, 82%, and 88%, respectively (Gray test, P=0.008) (Figure 1). In the multivariate analysis, the group with no haplotype match was marginally associated with worse neutrophil engraftment compared to the group with 1 haplotype match group (0 match vs. 1 match, HR 0.88, P=0.087), whereas the group with 2 haplotype matches was significantly associated with better neutrophil engraftment (2 match vs. 1 match, HR 1.39, P=0.005). Other significant variables were recipient sex, CD34 cell dose, transplant year, performance status, ABO matching, GVHD prophylaxis, and disease status. Tendency of worse neutrophil engraftment in the group with no haplotype matches was more apparent in patients with double mismatches at the same locus (0 match + no double mismatch vs. 1 match, HR 0.93, P=0.429, 0 match + double mismatch vs. 1 match, HR 0.80, P=0.050). Haplotype matching did not have any effect on overall survival and non-relapse mortality. Group with 2 haplotype matches was significantly associated with higher risk of relapse than the group with 1 haplotype match, whereas, there was no difference in the risk of relapse between the groups with no match and 1 match.Conclusions: In addition to the CD34 cell dose and HLA matching, HLA haplotype matching might be considered to obtain better neutrophil engraftment. Two haplotype matches (8 of 8 allele matches) should be avoided if the relapse risk is high. [Display omitted] DisclosuresTanaka:Pfizer: Honoraria; Otsuka: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis Pharma: Honoraria. Ichinohe:Zenyaku Kogyo Co.: Research Funding; Celgene: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Taiho Pharmaceutical Co.: Research Funding; Mundipharma: Honoraria; Otsuka Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; MSD: Research Funding; Novartis.: Honoraria; JCR Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Repertoire Genesis Inc.: Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Eisai Co.: Research Funding; CSL Behring: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Astellas Pharma: Research Funding.

Efficacy and Safety of Induction Therapy With Calcineurin Inhibitors in Combination With Vedolizumab in Patients With Refractory Ulcerative Colitis

Vedolizumab is used to treat patients with ulcerative colitis (UC), although there is a delay before it is effective. Induction therapy with a calcineurin inhibitor (cyclosporine or tacrolimus) in combination with vedolizumab as maintenance therapy could be an option for patients with an active steroid-refractory UC. We assessed the efficacy and safety of this combination. We performed a retrospective observational study, collecting data from 12 referral centers in France that were included in the Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif. We collected information on 39 patients with an active steroid-refractory UC (31 with active severe UC and 36 failed by treatment with a tumor necrosis factor antagonist) who received a calcineurin inhibitor as induction therapy along with vedolizumab as maintenance therapy. Inclusion date was the first vedolizumab infusion. The outcomes were survival without colectomy, survival without vedolizumab discontinuation, and safety. After a median follow-up period of 11 months, 11 patients (28%) underwent colectomy. At 12 months, 68% of the patients survived without colectomy (95% CI, 53%-84%) and 44% survived without vedolizumab discontinuation (95% CI, 27%-61%). No deaths occurred and 4 severe adverse events were observed. In a retrospective analysis of 39 patients with an active steroid-refractory UC (most refractory to a tumor necrosis factor antagonist), we found that initial treatment with a calcineurin inhibitor in combination with vedolizumab allowed more than two thirds of patients to avoid colectomy. Further studies are needed to assess the safety of this strategy.

Safety and Efficacy of Combination Treatment With Calcineurin Inhibitors and Vedolizumab in Patients With Refractory Inflammatory Bowel Disease

Little is known about the efficacy and safety of induction therapy with calcineurin inhibitors in combination with vedolizumab for patients with Crohn's disease (CD) or ulcerative colitis (UC). We analyzed the outcomes of patients receiving vedolizumab along with calcineurin inhibitors. We collected data on patients with CD (n= 9) or UC (n= 11) who began treatment with vedolizumab from May 20, 2014, through March 30, 2015, and received calcineurin inhibitors (tacrolimus or cyclosporin) during the first 12 months of vedolizumab therapy. Clinical activity scores and inflammatory markers were measured at baseline and at weeks 14, 30, and 52 of vedolizumab treatment. Clinical remission was defined as a Harvey-Bradshaw index score ≤4 or short clinical colitis activity index score ≤2; steroid-free clinical remission was defined as clinical remission without corticosteroids. By week 14 of treatment, 44% of the patients with CD and 55% of the patients with UC achieved steroid-free clinical remission; after 52 weeks of treatment, 33% of the patients with CD and 45% of the patients with UC were in steroid-free clinical remission. Seven patients received salvage therapy with a calcineurin inhibitor after primary nonresponse to vedolizumab-1 of the 2 patients with UC and 2 of 5 patients with CD stopped taking the calcineurin inhibitors and achieved steroid-free remission at week 52. In total, 16 patients (59%) received 52 weeks of treatment with vedolizumab. Three serious adverse events were associated with calcineurin inhibitors. Combination therapy of vedolizumab with either cyclosporin or tacrolimus is effective and safe at inducing and maintaining clinical remission in patients with CD and UC with up to 52 weeks of follow-up evaluation. Larger studies of the ability of calcineurin inhibitors to induce remission in patients on vedolizumab are warranted.

Carpe diem-Time to transition from empiric to precision medicine in kidney transplantation.

The current immunosuppressive pipeline in kidney transplantation is limited. In part, this is due to excellent one-year allograft outcomes with the current standard of care (ie, calcineurin inhibitor in combination with anti-proliferative agents). Despite this success, a recent Federal government-sponsored systematic review has identified gaps/limits in the evidence of what constitutes optimal calcineurin inhibitor use in the short- and long-term. Moreover, recent empiric approaches to minimize/withdraw/convert from calcineurin inhibitors have come with the price of increased alloreactivity. As the time horizon to replace calcineurin inhibitors on a global scale may be distant, the transplant community should seize the opportunity to develop ways to personalize calcineurin inhibitor immunosuppression to the individual-transitioning from empiricism to precision. The authors argue in this viewpoint that the path to precision will require measures capable of detecting subclinical alloreactivity to define adequacy of immunosuppression, as well as novel genetic analytics to accurately define alloimmune risk at the individual level-both approaches will require validation in clinical trials.

M-TOR Inhibitors in the Current Practice

for long time, calcineurin-inhibitors (CNIs) was the best broadly used immunosuppressant in organ transplantation; since it had proven its efficacy in the reduction of acute rejection episodes and early graft loss, though their use in the long-term, are associated with chronic allograft nephropathy (CAN), besides it increases the cardiovascular risks such as diabetes, hypertension, and dyslipidemias. Moreover, CNIs in combination with other immunosuppressant's increases the risk of fatal infections and malignancy. Ultimately the introduction of the mammalian focus of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus in 1990s, had changed the face of transplantation and conveyed a great hope to transplant physicians as an innovative class of effective immunosuppressants with a unique mechanism and less nephrotoxic effects (1-6). In this review article we will try briefly to elicit the clinical indications, advantage and disadvantage of m-TOR inhibitors over other immunosuppressant’s medications and their clinical indications inside and outside the transplant field.

Review of Atopic Dermatitis and Topical Therapies.

Atopic dermatitis is one of the most common skin disorders in the developed world, affecting up to 20% of children and 1% to 3% of adults. This review concisely explains the pathophysiology and epidemiology of atopic dermatitis, as well as potential challenges facing its successful treatment. Furthermore, mainstay topical treatment modalities are evaluated, such as emollients, topical corticosteroids, and topical calcineurin inhibitors. The use of topical corticosteroids and topical calcineurin inhibitors in combination is discussed, as studies have indicated encouraging results. The proactive use of topical corticosteroids and topical calcineurin inhibitors is also investigated, in order to bring attention to a new possibility in long-term management of atopic dermatitis. Last, new and upcoming topical medications are described, including Janus kinase inhibitors, phosphodiesterase-4 inhibitors, and benvitimod. Although topical corticosteroids and topical calcineurin inhibitors can be very effective in the treatment of atopic dermatitis, it is important that practitioners are aware of mechanistically unique and new treatments for patients for whom more traditional topical therapies have failed. Overall, this review article hopes to serve as a comprehensive overview of currently available topical treatments for atopic dermatitis, while shedding light on new treatments coming in the future.

Association Between Uric Acid Levels and Severe Acute Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation

Introduction and objectives: There is increasing knowledge on the relevance of danger signals activating the innate immune system in the pathogenesis of graft-versus-host disease (GvHD). Uric acid (UA) is a known danger signal that is released from injured cells during conditioning for allogeneic stem cell transplantation (alloSCT). UA has been identified to enhance dendritic cells maturation and to amplify T-cell responses. Previous reports analyzing the relationship between UA and acute GvHD (aGvHD) have shown controversial results (Ann Hematol 2015; 94: 139; Biol Blood Marrow Transplant 2014; 20: 730).The objective of this study is to investigate the association between UA levels pre-alloSCT and aGvHD.Patients and methods: We retrospectively analyzed data from 548consecutive patients who received an alloSCT from January 2007 to December 2014 on four institutions. The cumulative incidence of aGvHD over the first 100 days post-alloSCT was estimated in the framework of competing risks by taking relapse or death without relapse as competing events. The association between pre-alloSCT UA levels (measured between day -7 and day 0), dichotomized at the median value, and the incidence of aGvHD was investigated by calculating the subhazard rate (SHR) according to Fine & Gray (J Am Stat Assoc 1999; 94: 496).Results: Patients (median age 46y, range 16-67; 66% male) were transplanted for acute leukemia (51%), lymphoproliferative syndrome (22%), myelodysplastic syndrome (12%), multiple myeloma (8%), and other causes (7%). Disease status at the time of alloSCT was 49% complete remission, 17% partial response and 31% active disease. Fifty-one percent patients received alloSCT from related donors, 41% from unrelated donors, and 8% from alternative donors (cord blood units or haploidentical donors). The source of stem cells was peripheral blood in 84% patients. Fludarabine-based reduced intensity conditioning (RIC) regimens were used in 54% of transplants and myeloablative (MAC) in 46%. Most patients received immunosuppression with calcineurin inhibitors in combination with methotrexate (MAC) or mycophenolate mofetil (RIC). Sixteen percent also received ATG. Most patients (82%) received allopurinol 300 mg/day through conditioning regimen until day 0 of transplant. The median serum UA level prior to stem cells infusion was 3.7 mg/dL (range 0.7-8.8). Serum levels of UA (mg/dl) were higher in males than in females (4 vs. 3, p=0.0001), in patients submitted to RIC as compared with MAC alloSCT (4 vs 3.3, p=0.0001), in those not receiving ATG for GvHD prophylaxis (3.8 vs. 2.9, p=0.0002) and in the minority of patients not treated with allopurinol (4.7 vs. 3.3, p=0.0001). By day +100 post-alloSCT, 222 patients had been diagnosed of aGvHD II-IV, 79 had relapsed and 72 had died from causes unrelated to relapse or GvHD. The cumulative incidence of aGvHD II-IV was 40% (95% CI: 35%-44%) whereas the incidence of competing events (death or relapse) amounted to 11% (95% CI: 8%-13%). Patients with levels of UA above the median had an increased incidence of aGvHD II-IV (SHR: 1.4, 95% CI: 1.1-1.8; p=0.015) at the univariate analysis. However, such relationship vanished after multivariate adjustment for other factors associated with the peri-alloSCT UA levels and/or the risk of aGvHD (e.g. age, sex, type of donor, type of alloSCT, GvHD prophylaxis). Additional exploratory and subgroup analyses did not find any relationship between UA levels neither severe aGvHD (grades III/IV), early aGvHD (before day +60) nor type of conditioning regimen (RIC vs. MAC).Conclusions: There is a weak association between higher peri-alloSCT levels of uric acid and increased incidence of aGvHD. Nevertheless, our results suggest that such associations reflect confounding effects rather than causal factors and, therefore, they do not support interventions aimed at preventing aGvHD by reducing uric acid levels. DisclosuresNo relevant conflicts of interest to declare.

Renal Function Deterioration Is Higher Within The First Year After Liver Transplantation: Results of The Italian Cross-Sectional, Multicenter Study (SURF).

Background: Previous evidence suggests that renal function (RF) deterioration occurs early after liver transplantation (LT) when exposure to calcineurin inhibitors (CNI) is higher. Materials and methods: SURF was a cross-sectional, multicenter study to investigate the prevalence of renal dysfunction (eGFR <60mL/min/1.73m2) and the retrospectively recorded evolution of RF after transplantation in maintenance (5 months (M) to 5.5 years) recipients of a primary liver graft. Results: From March 2012 to June 2013 a sample of 1,002 evaluable patients were enrolled at a mean of 28.6±16.5 M from LT. From LT to inclusion, mean eGFR decreased from 95.7±36.9 mL/min/1.73m2 to 76.9±25.7 mL/min/1.73m2. Mean yearly eGFR deterioration was -12.3±32.2 mL/min/1.73m2 which resulted from a mean of -26.2±59 mL/min/1.73m2 within 1 year after LT (n=964); -13.3±24.4 mL/min/1.73m2 between 1 and 2 years (n=675); -8.5±15.5 mL/min/1.73m2 between 2 and 3 years (n=437); -5.7±9.6 mL/min/1.73m2 between 3 and 4 years (n=244 pts); and -3.9±8.2 mL/min/1.73m2 between 4 and 5.5 years (n=98). 91% patients were on CNI-based immunosuppression at inclusion (726 TAC; 187 CsA) (monotherapy 54%; combination 46%). Mean duration of CNI monotherapy was 23.16±17.62 M, and was 26.79±18.19 M for CNI in combination. Conclusions: LT recipients experience greater RF deterioration within the first post-transplant year, and the large majority are on CNI-based immunosuppression. These data call for preventative strategies early on after transplantation to slow down RF impairment. DISCLOSURES:De Simone, P.: Speaker's Bureau, Novartis, Astellas. Cillo, U.: Speaker's Bureau, Novartis. Burra, P.: Speaker's Bureau, Novartis. Donati, D.: Speaker's Bureau, Novartis. Brusa, R.: Employee, Novartis. Fagiuoli, S.: Speaker's Bureau, Novartis.

Moderne Immunsuppression nach Organtransplantation

The one common factor in solid organ transplantation is the need for lifelong maintenance immunosuppression. Drug regimens after organ transplantation typically comprise a combination of different immunosuppressive drugs. In most cases a triple drug regimen with different mechanisms of action is used. The aim is to improve both patient and graft survival while minimizing potential side effects of immunosuppressive medication. The basis of most immunosuppressive regimens is calcineurin inhibitors in combination with mycophenolic acid. There are various stages of immunosuppression after solid organ transplantation involving induction therapy, initial and long-term maintenance therapy. In each phase an individual combination of immunosuppressants is set up depending on the risk profile of the individual patient to prevent transplant rejection and organ loss. Based on these considerations, concepts of calcineurin inhibitor or steroid reduction have been established in transplant medicine in recent years. The key role in terms of development of new immunosuppressive strategies is taken by kidney transplantation, the most common solid organ transplantation performed.

Chirurgische Therapie beim Pyoderma gangraenosum

Pyoderma gangrenosum is a rare affection of unknown etiology, which is often associated with systemic diseases such as chronic inflammatory bowel disease, hematologic disorders, carcinomas and arthritis. Treatment may include topical corticosteroids or calcineurin inhibitors in combination with systemic corticosteroids, cyclosporine A, azathioprine, cyclophosphamide, mycophenolate mofetil, intravenous immunoglobulins or monoclonal antibodies against TNFα but all these approaches are off-label. Surgical therapy is difficult because of pathergy. Nevertheless, after having stopped the inflammation, the ulcers can be treated by split thickness skin grafts and simultaneous immunosuppression. We present three cases with successful surgical treatment.

Meta-Analysis of Calcineurin-Inhibitor-Sparing Regimens in Kidney Transplantation

Calcineurin-inhibitor-sparing strategies in kidney transplantation may spare patients the adverse effects of these drugs, but the efficacy of these strategies is unknown. Here, we conduct a meta-analysis to assess outcomes associated with reducing calcineurin inhibitor exposure from the time of transplantation. We search Medline, Embase, and Cochrane Register of Controlled Trials for randomized controlled trials published between 1966 and 2010 that compared de novo calcineurin-inhibitor-sparing regimens to calcineurin-inhibitor-based regimens. In this analysis, we include 56 studies comprising data from 11337 renal transplant recipients. Use of the contemporary agents belatacept or tofacitinib, in combination with mycophenolate, decreased the odds of overall graft failure (OR 0.61; 95% CI 0.39-0.96; P = 0.03). Similarly, minimization of calcineurin inhibitors in combination with various induction and adjunctive agents reduces the odds of graft failure (OR 0.73; 95% CI 0.58-0.92; P = 0.009). Conversely, the use of inhibitors of mammalian target of rapamycin (mTOR), in combination with mycophenolate, increases the odds of graft failure (OR 1.43; 95% CI 1.08-1.90; P = 0.01). Calcineurin-inhibitor-sparing strategies are associated with less delayed graft function (OR 0.89; 95% CI 0.80-0.98; P = 0.02), improved graft function, and less new-onset diabetes. The more contemporary protocols did not seem to increase rates of acute rejection. In conclusion, this meta-analysis suggests that reducing exposure to calcineurin inhibitors immediately after kidney transplantation may improve clinical outcomes.

The importance of different immunosuppressive regimens in the development of posttransplant diabetes mellitus

Solid-organ transplantation is the optimal long-term treatment for most patients with end-stage organ failure. After solid-organ transplantation, short-term graft survival significantly improved (1). However, due to chronic allograft nephropathy and death with functioning graft, long-term survival has not prolonged remarkably (2). Posttransplant immunosuppressive medications consist of one of the calcineurin inhibitors in combination with mycophenolate mofetil (MMF) or azathioprine (Aza) and steroids. All of them have different adverse effects, among which posttransplant diabetes mellitus (PTDM) is an independent risk factor for cardiovascular (CV) events and infections causing the death of many transplant patients and it may directly contribute to graft failure (3). According to the criteria of the American Diabetes Association (4), diabetes mellitus (DM) is defined by symptoms of diabetes (polyuria and polydipsia and weight loss) plus casual plasma glucose concentration ≥ 11.1 mmol/L or fasting plasma glucose (FPG) ≥ 7.0 mmol/L or 2-h plasma glucose level ≥ 11.1 mmol/L following oral glucose tolerance test (OGTT). This metabolic disorder occurring as a complication of organ transplantation has been recognized for many years. PTDM, which is a combination of decreased insulin secretion and increased insulin resistance, develops in 4.9/15.9% of liver transplant patients, in 4.7/11.5% of kidney recipients, and in 15/17.5% of heart and lung transplants [cyclosporine A (CyA)/tacrolimus (Tac)-based regimen, respectively] (5). Risk factors of PTDM can be divided into non-modifiable and modifiable ones (6), among which the most prominent is the immunosuppressive therapy being responsible for 74% of PTDM development (7). Emphasizing the importance of the PTDM, numerous studies have determined the long-term outcome. On the basis of these studies, graft and patient survival is tendentiously (8) or significantly (9, 10) decreased for those developing PTDM.