Term Remission Research Articles

Monomorphic Post Transplant Lymphoproliferative Disorder (Diffuse Large B Cell Lymphoma subtype) Successfully Treated without Chemotherapy after Solid Organ Transplant in Children

BackgroundPost-transplant lymphoproliferative disease (PTLD) represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Histology observed in the monomorphic subtype are similar to those observed in non-Hodgkin Lymphoma (NHL). Most of the PTLD are of B-cell origin, with diffuse large B-cell lymphoma (DLBCL) being the most common histology. Rituximab as a single agent to treat PTLD after organ transplant has demonstrated efficacy in adult patients, but data is limited in pediatric patients1. Recent adult data confirmed that obtaining complete remission after induction with Rituximab identifies a group with B-cell PTLD who do not need chemotherapy2. Low-intensity chemotherapy has been effective in EBV-positive, CD20-positive B-lineage PTLD in children. A study from Children's Oncology using a low intensity chemotherapy including Rituximab, cyclophosphamide and prednisone in children with PTLD after solid organ transplantation in whom immune suppression was reduced, demonstrated a 67% event-free survival3.We aim to determine if long-term overall survival can be achieved in pediatric monomorphic PTLD DLBCL subtype without chemotherapy.MethodsA single institution descriptive retrospective study (November 1998 to April 2017) was conducted in pediatric patients with solid organ transplant who developed monomorphic PTLD (DLBCL subtype). Kaplan-Meier analysis was performed for PTLD overall survival.ResultsFourteen out of forty-three patients (32%) presented with monomorphic PTLD (DLBCL subtype). Solid organ transplantation included 7 heart, 4 liver, 2 kidney and 1 liver and small bowel transplant. Eight patients were male and 6 were female. Average age at the time of the transplant was 3.74 years (range 0.03-16.02) and at the time of the PTLD presentation was 8.05 (range 1.13-21.98) years. Epstein Barr Virus (EBV) serology prior to transplant showed 8 patients were EBV naive, 1 was seropositive and 5 were indeterminate or unknown. Four patients had been previously treated for other events of PTLD different than DLBCL. All patients were B cell subtype, 10 patients had EBER positive in the biopsy, 3 negative and 1 unknown. Thirteen/fourteen were CD20 positive. Two patients presented with stage II, 7 with stage III and 5 with stage IV (Table 1). Four patients (29%) were treated with reduction of immunosuppression (RIS) +/- antiviral +/- Intravenous Immunoglobulin G (IVIG), 8 patients (57%) received Rituximab + RIS +/- antiviral +/- IVIG, 2 patients (14%) Rituximab and chemotherapy concomitantly. Only one patient treated with Rituximab + RIS initially, presented with progressive disease after being in remission for 3 months requiring chemotherapy treatment. In this cohort, eleven/fourteen patients (79%) did not received chemotherapy. Nine/fourteen (64%) patients remained alive at 5.41 (range 0.01-19.05) years follow-up. The overall survival at 5 years was 73% in the group of patients who did not receive chemotherapy versus 50% in the group who received chemotherapy (Figure 1). None of the patients died as a result of PTLD. Causes of death included graft failure in 2 patients, severe infection with acute respiratory distress syndrome (ARDS) and hepatic failure in 1 patient, chronic lung disease and immunodeficiency in 1 patient and progressive hepatoblastoma, multi-organ failure and ARDS secondary to infection in 1 patient. One patient presented with Classical Hodgkin Lymphoma PTLD 48 months later.ConclusionThis study suggests that for the majority of pediatric patients with Monomorphic PTLD (DLBCL subtype) long term remission and survival can be achieved without chemotherapy. Prospective data is required to further assess this treatment approach.References1 Evens AM et al J Clin Oncol 28(6):1038-46, 2010.2 Trappe RU et al. J Clin Oncology 34: 1-7, 2016.3 Gross TG et al. Am J Transplant 12 (11): 3069 - 75, 2012. [Display omitted] DisclosuresDesai:Bristol Myers: Research Funding; St Judes Children's Research Hospital: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees. Peters:Lundbeck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria; Abbvie: Honoraria.

Sequential Azacitidine (Aza) and Lenalidomide (Len) for Patients (Pts) with Relapsed and Refractory (R/R) Acute Myeloid Leukemia (AML): Clinical Results and Predictive Modeling Using Computational Analysis and Serial Genomics

▪Introduction: Pts with R/R AML have few effective treatment options. Len has activity in myeloid malignancies including AML, and may have additive properties with aza. Based on encouraging data using sequential aza with high dose len in untreated elderly AML pts, we designed a phase 2 pilot study exploring this therapy (tx) in pts with R/R AML.Methods: Adult pts with R/R AML or myelodysplastic syndromes (MDS) and preserved organ function with a WBC<10,000/μL (hydroxyurea permitted) were eligible. The tx consisted of aza 75 mg/m2 d1-7, a bone marrow biopsy on cycle (C) 1 day 8, len 50 mg d8-28, and 2 weeks off tx, constituting a 42-day cycle. Response assessments were made per International Working Group (IWG) criteria. Cycles were repeated if tolerated and in the setting of response. Next generation sequencing (NGS) was performed with Illuimina MiSeq at repeated time points serially for each pt (baseline, C1 day 8, C1 day 42) through multiplex PCR amplification of 548 amplicons targeting mutational hot spots in 49 recurrently mutated genes, and analyzed with SoftGenetics NextGENe software. The UCSC hg19 and GRCh 37 reference genome were used as the reference sequence. Genomic information was entered into computational biology modeling (CBM) software (Cellworks), which generates disease specific protein network maps using PubMed and other online resources. Digital drug simulations of aza and len were conducted by quantitatively measuring drug effect on a cell growth score. Each pt specific protein network map was screened for the extent to which tx reduced simulated disease growth.Results: 37 pts were eligible and received at least one day of tx. Median age was 73 (18-86); 34 had AML, 3 had high-risk MDS (Table 1). The most common possibly related/related > grade 2 adverse events (AEs) were thrombocytopenia (44%), neutropenia (44%), leukopenia (43%), fatigue (32%), anemia (30%) and febrile neutropenia (16%). During C1, 2 pts required len dose decreases and 11 pts did not receive the entire course of len, for infection, rash, neuropathy, renal insufficiency, GI toxicity or progression.9 pts did not live to complete cycle 1; all died of AML. The overall response rate (ORR, complete remission [CR] + CR with incomplete count recovery [CRi] + partial remission [PR] + morphologic leukemia free state [MLFS]) was 14/37 (38%); 4 CR/CRi and 10 MLFS. 6 additional pts had blast reductions that did not meet IWG criteria for response. Median number of cycles was 1 (0-5); median time to achieve best response was 1 cycle (1-3). 16 pts were identified at baseline as potential candidates for a 1st/2nd allogeneic transplant or donor lymphocyte infusion; 4/16 (25%) achieved this endpoint and 1 remains alive. Median follow up time is 3 years. 36/37 patients have died; 33 from progression and 3 from treatment related causes. 5/36 (14%) died within 30 days of study initiation. Median progression free survival (PFS) was 112 days; 132 for responders and 98 for non responders (p=0.7). 1 year PFS was 7%. Median overall survival was 150 days, 216 for responders and 124 for non responders (P=0.5); 1 year OS was 25%. (Fig 1). No clinical features predicted response (Table 2).CBM analysis has been performed on 5 pts (2 non responders and 3 responders). None were predicted to respond to len, 4/5 were predicted to respond to aza. 4/5 (80%) were predicted correctly; 3/3 responders and 1/2 non responder. Analysis of the entire cohort is ongoing.Serial quantitative NGS was performed at multiple time points for most patients; results have been analyzed for 7 (3 responders, 4 non responders). These preliminary results do not reveal a correlation between response and specific mutations. However, there is a trend toward a correlation between increased total number of mutations at baseline and lack of response (p=0.099) (Fig 2). This is being further explored with clonal analysis to measure the heterogenous responses of individual pts over time.Conclusion: Len has activity in a subpopulation of pts with AML, perhaps with additive value from sequential use with aza; responses are transient but can provide sufficient reduction in disease burden to allow for a transplant, which can result in long term remissions. However, the toxicity of this regimen is significant and typical clinical features are not predictive for response, limiting its widespread use. Therefore other tools, such as CBM or serial NGS, must be employed to select pts most likely to respond. [Display omitted] DisclosuresAbbasi:Cellworks Group Inc.: Employment. Vali:Cellworks Group Inc.: Employment. Singh:Cellworks Research India Pvt. Ltd: Employment. Pollyea:Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding.

Outcome of NPM1 Mutated Acute Myeloid Leukemia (AML) Treated with Hypomethylating Agents (HMAs): A Report on 71 Cases

Background: NPM1 mutation is seen in 25 - 30 % of AML, and its incidence does not decrease with older age. While NPM1 mutation is associated with better prognosis in AML patients treated with intensive chemotherapy (IC), it is unknown if it also confers a good prognosis to patients unfit for IC who are treated with HMA.Methods: 71 AML patients with mutated NPM1 treated by HMA from 2007 to 2016 in 8 European and 1 US centers were retrospectively analyzed. 48 (68%) received azacitidine (AZA), 16 (22%) received decitabine (DAC), and 7 (10%) guadecitabine (SGI 110).All patients were tested for NPM1 and FLT3 mutations.Results: M/F was 25/46; median age was 75 years (36-85), 76% being 65 or older. 34 patients, considered unfit for IC, received HMA as first line treatment, and 37 after primary or secondary IC failure. Median WBC count at HMA onset was 5.3 x109/L (1.5 - 83). Sixty patients (84%) had normal cytogenetics, 6 had intermediate prognosis abnormalities, one had a complex karyotype, and two had missing data. In addition to NPM1 mutation, 26 patients (37%) had FLT3-ITD, one FLT3-TKD, and 10 (14%) had IDH1 or IDH2 mutation.The median number of HMA cycles received was 4. The overall response rate (ORR) was 35.1% (n=25), including 16 (22.5%) CR, 5 (7%) CRi, and 4 (5.6%) PR. The number of previous treatments before HMA, the type of HMA used, and baseline WBC had no impact on ORR. The ORR was 45.5% and 27% respectively in patients receiving HMA as first line or subsequent treatment (p=0.137); 45% and 27% respectively in mutated and non-mutated FLT3 (p= 0.302); 20% and 38.3% respectively in mutated and non-mutated IDH1/2 patients (p= 0.314). Among the 26 FLT3-ITD patients, 11 received concomitant therapy with sorafenib, without any impact on ORR or survival (OS), compared to FLT3-ITD patients who did not receive sorafenib (p= 0.73).Median OS was 280 days, 1 year OS was 17% and only one patient was alive after 2 years, but he died at 24.5 months. We failed to identify any prognostic markers for OS including whether HMA was administered as first line or subsequent treatment (median 289 vs 269 days, p= 0.90), and FLT3-ITD status (median 217 days vs 312 in FLT3-ITD negative, p=0.44). OS was significantly longer in responders (median 553 days vs 123 days, p<10-4). Four of the 6 patients in whom marrow NPM1 MRD was performed achieved a >3log reduction after six cycles of treatment, but 3 of them relapsed within less than six months, while one was alive in CR 12 months after the onset of HMA.We compared patients of the present series with 92 NPM1 unmutated AML patients previously treated upfront with AZA by our group (Desoutter, Leukemia, 2016). In this cohort, median age was 74 years, 69% had unfavorable cytogenetics, and 63% TP53 mutation. Despite a different molecular profile, there was no OS difference in patients with mutated or non-mutated NPM1 (median 280 vs 291 days, p= 0.53, respectively). This finding was also true when the analysis was restricted to NPM1 mutated patients treated with HMA as first line therapy (Figure 1, p=0.48)Conclusion: This is to our knowledge the first study reporting the efficacy of HMA in NPM1 mutated AML. Contrary to what is observed with conventional AML chemotherapy, HMA do not seem to improve the outcome of NPM1 mutated compared to unmutated AML cases, and are unable to provide long term remissions. Thus, in elderly AML patients, presence of a NPM1 mutation could contribute to decide the administration of intensive chemotherapy rather than a HMA, when possible. [Display omitted] DisclosuresRecher:Novartis, Celgene, Jazz, Sunesis, Amgen: Consultancy; Celgene, Sunesis, Amgen, Novartis: Research Funding. Fenaux:Astex: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Presence of Minimal Residual Disease at End of Induction in Acute Myeloid Leukemia Is Predictive of Poor Outcome

Introduction: One of the mainstays of chemotherapy in acute myeloid leukemia (AML), other than acute promyelocytic leukemia, is induction with a goal to achieve morphological complete remission (CR) as evident by less than 5% blasts. Post remission strategies then focus on either consolidation chemotherapy or allogeneic bone marrow transplantation (aBMT). However, not all patients by this remission criterion achieve long term remission and a subset of patients relapse. This relapse originates from further expansion chemoresistant clones. Detection of minimal residual disease (MRD) following chemotherapy, early in the course of treatment, is highly predictive of outcome and offers a window of opportunity to intensify treatment and prevent relapse. Here, we describe assessment of immunophenotypic MRD using a 10-colour two tube assay and a “difference from normal” approach.Methods: We accrued 280 consecutive patients of adult (>18 years) AML, other than with t(15;17), over a 30 month period after obtaining consent. All patients received “3+7” induction therapy with daunorubicin and cytarabine. If patients were in morphological CR at end of induction, they either received 3 courses of 12-18 gm/m2 high dose cytarabine (HiDAC) or aBMT if feasible.MRD testing was done at end of induction and if feasible, post 1st Cycle HiDac using a two tube 10 colour assay. (CD15, CD13, CD19, CD34, CD56, CD7, CD45, CD11b, HLA-DR, CD117, CD14, CD123, CD64, CD33, CD36 & CD38). A minimum of 1.6 million events were acquired per tube on a Navios flow cytometer. Identical panel was used at MRD time points as well as on the diagnostic sample. Analysis of MRD was done using Kaluza 1.3 by a difference from normal approach that focused on the development of progenitors to monocytes. Conventional karyotyping and FISH was done as per standard recommendations and patients were classified into favorable, intermediate and poor cytogenetic risk. The presence of FLT3 -ITD, NPM1 and CEBPA mutations was detected by a fragment length analysis based assay. Overall survival (OS) was calculated from date of diagnosis to time of last follow up or death. Relapse free survival (RFS) was calculated after achieving of 1st remission (CR) till relapse or death or last follow up if in CR. Results of the MRD assays, cytogenetic and molecular risk groups were analyzed for their impact on OS and DFS using Log Rank test of Kaplan-Meier survival analysis.Results: A total of 280 AML patients were treated and followed up till maximum of 30 months period. Based on cytogenetics, 28.6% were classified as favorable risk whereas 61.4% and 10% were intermediate and poor risk respectively. FLT3-ITD, NPM1 and CEBPA mutations were harbored by 20.7%, 26.4% and 10.3% of patients respectively. The median follow up was of 9 months (Ranging from 17 days to 30 months). Of these, 35 had induction death and 59 had refractory disease. Median OS was 50.3% and RFS was 50.9%. Post induction MRD was assessed in 235 patients of which 108 (45.9%) had detectable residual disease (range 0.01-66%, median:1.38%). Post consolidation MRD was assessed in 98 patients of which 22 (22.4%) were MRD positive (range 0.002-7.7%, median: 0.05%). Favorable risk cytogenetics in cases excluding induction deaths was predictive of better OS than intermediate (p= 0.031) and poor risk (p=0.003) cytogenetic profiles but not RFS. Patients harboring MRD at the end of induction were associated with worse OS (p=0.04) but not RFS, whereas post consolidation positive MRD status did not show significant change in OS and RFS.Conclusion: Our data is in agreement with other studies that determination of immunophenotypic MRD is extremely important in predicting outcome. AML MRD is a very useful guide for guiding post remission strategies in AML and should be incorporated into routine treatment algorithms. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Genomic Characteristics Clinical Phenotype and Disease Course of TP53 Mutated Diffuse Large B Cell Lymphoma at Diagnosis and Relapse

Genomic Characteristics Clinical Phenotype and Disease Course of TP53 Mutated Diffuse Large B Cell Lymphoma at Diagnosis and Relapse

A Preliminary Analysis of Inherited Immune Checkpoint Control in Multiple Myeloma: Relative Frequency of Inhibitory or Activating Type Killer Immunoglobulin like Receptors and Their Cognate Ligands HLA-C1 and -C2

Background and Aim: Multiple Myeloma development is under polygenic control and as an evidence for inheritance, we have recently reported positive and negative HLA-myeloma associations with: HLA-C*07:02g (OR:1.27, p=5.27 x 10 -7) and HLA-C*05:01 (OR: 0.85, p=0.039)(Beksac et al Leukemia 2016:1-4). HLA-C*07:02g (Group C1) and HLA-C*05:01 (Group C2) are listed among the KIR ligands, These ligands usually interact with inhibitory KIRs(iKIR) while having weaker binding with activating KIRs(aKIR). KIRs play a major role in regulation of immunity and self-tolerance. Attempts to inhibit the inhibition exerted by immune check point regulators is an evolving field. Such monoclonal antibodies in combination with agents augmenting NK cell activation have exerted acceptable responses. However the distribution of KIRs or their ligands have not been studied extensively in myeloma. The aim of this study was to analyze the frequency of KIR genotypes and their cognate ligands among myeloma patients comparing with healthy controls.Patients, controls and treatment: 117 myeloma patients admitted to our clinic and consented between Sept 2016-July 2017 were enrolled in the study. Patient characteristics were: 34- 91(median: 61), ISS:I/II/III:46 /45 /25 ; IgG/IgA/Light chain: 67/18 /20 . 65 % of patients had received at least one ASCT. 68 of myeloma cases were on long term remission of min 2-8 years. 49 patients had experienced either early progression within 60 days from the induction or multiple relapses. As a control group 215 healthy subjects and related/unrelated hematopoietic stem cell donors aged 18-65 and screened for HLA and KIR genotyping were included. All controls had KIR and HLA typing but only 172 had HLA-C data available for Group C1 and C2 assessments.KIR and KIR ligand genotyping: The Olerup SSP KIR Genotyping Kit (Olerup, Stockholm, Sweden) enabled us to detect 16 KIRs: KIR2DL1, 2DL2, 2DL3, 2DL4, 2DL5A/B, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DL1, 3DL2, 3DL3, 3DS1, 2DP1, 3DP1. The Olerup KIR HLA Ligand Detection Kit was used to type HLA-ABw4+, HLA-BBw4+Thr80, HLA-BBw4+Ile80, HLA-BBw4+Asp77,Thr80, HLA-CAsn80, and HLA-CLys80.Statistical analysis: The Statistical Package for the Social Sciences (SPSS 11.5 for Windows, IBM Statistics, USA) was used for data analysis. Pearson's chi-square test and Fisher's exact test were applied for categorical variables. For continuous variables, t-test was applied. Variables found positive in all subjects of both groups were excluded from analysis.Results: Comparison of healthy controls and all myeloma subjects are summarized in Table1. Myeloma patients had similar median number of aKIR and iKIRs. There were more iKIR (n:7) genes expressed than aKIRs (n:3) among normals and patients. However there were less cases expressing haplotype AA among the myeloma group compared to healthy controls(4.3 vs 12.6%). Overall iKIRs were expressed widely among controls (66-100%) and myeloma (57.2-100%) cases. Among the iKIRs only 2DL3 was found to have a statistically significant difference : less frequent among patients. As for aKIRs only 2DS2 was significantly different: less frequent in myeloma. The ligand for both 2DL3 and 2DS2 is HLA-Group C1. We were able to detect Group C1/C2 heterozygosity to be less frequent and a trend to increase in the frequency of C1 or C2 homozygotes among myeloma patients. Two aKIRs 2DS2, 3DS1 and two iKIRs 2DL2,2DL3 were less frequent among C1/C2 heterozygous myeloma patients.Conclusion: This study, to our knowledge, is the first to compare KIR and KIR ligand genotype frequencies between myeloma patients and healthy controls. The significant difference between patients and controls was a less frequent observation of an aKIR and/or iKIR among patients. The trend to increase in HLA group C1 homozygosity, is compatible with our previous HLA-Myeloma association study. In this preliminary analysis, from one geographical region, we were not able to detect a strong correlation between KIR genotype and myeloma. In future we are planning to analyze the outcome of patients with distinct iKIR or aKIR profiles.Acknowledgment: The study has been supported by Scientific and Research Council of Turkey (TUBITAK grant no: 115S579) and Turkish Academy of Sciences. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

MO1028EFFECTIVENESS AND KIDNEY PROGNOSIS IN THE TREATMENT OF CORTICORRESISTANT NEPHROTIC SYNDROME IN PEDIATRICS

Abstract Background and Aims To report the response to different treatments and the renal prognosis in a cohort of patients with corticosteroid-resistant nephrotic syndrome (CRNS). Method Retrospective observational study in patients with CRNS. For this, the results of the histology, the different treatment guidelines used in each case and the evolution of renal function were collected, determining the results in terms of remission and renal survival in the different groups. Results Of the initial cohort of 37 patients, 33 were included, excluding 4 patients with Finnish-type genetic CRNS. The mean age at diagnosis was 6.1 years. 54.5% were women. Regarding the initial biopsy, 45.5% corresponded to minimal changes (15 patients), 27.3% (9) focal and segmental glomerulosclerosis, 15.1% (5) diffuse mesangial proliferation and 12.1% (4) others. The mean follow-up was 53 months (3-115 months). 27 patients (84.4%) received cyclosporine (CyA), 66.7% (18) of them presented complete remission and 22.2% (6) partial response. Of the patients in complete remission, 33% had at least one relapse after 17 months of treatment (7–27 months). Rituximab was administered in 12 patients (37.5%), of which 7 had not previously responded to immunosuppressants. 100% of frequent relapsers presented complete remission after administration of Rituximab, although 3 had subsequent relapses (60%) after 21 months of treatment (12-34 months). 57% of the patients who did not respond to immunosuppressants did not respond to Rituximab either, with Ofatumumab allowing complete remission in one of them. When relating the results with the histology, we saw how the remission in minimal changes and diffuse mesangial proliferation was 100% and 80%, respectively, although it was 33.3% in focal and segmental glomerulosclerosis. Similarly, renal failure was more frequent in patients with focal segmental glomerulosclerosis (77.7%). Of the remissions (24; 72.7%), 3 were partial (9.1%) and 6 (18.2%) did not respond to any immunosuppressive treatment, with the need for kidney transplantation in 2 of them (6%) and with 1 deceased due to an infectious cause (3%). Conclusion Histology and, especially, focal and segmental glomerulosclerosis, play a prognostic role in the CRNS with a lower remission rate and a greater deterioration in renal function and the need for associated kidney transplantation.

P207 Clinical outcome of patients with Ulcerative colitis after anti-TNF discontinuation -\t10 years follow up

Abstract Background Biological therapy for ulcerative colitis (UC) such as anti-TNF have shown high efficacy in achieving remission. There is a lack of information about the long-term outcomes after biologic withdrawal and validated clinical, immunologic, genetic or laboratory markers that can predict outcome after withdrawal accurately. The aims of this study were to describe the long-term outcomes after anti-TNF withdrawal and discover potential biomarkers to predict long-term remission as an approach to towards personalized medicine. Methods 75 patients with moderate to severe UC treated to remission with anti-TNF were included in the study. These patients were categorized as either “Long term remission” (LTR) or “Relapse”. The “Relapse” group were divided in subgroups by the highest treatment level needed to obtain remission the last 3 years of observation: non-biological therapy, biological therapy or colectomy. LTR were divided in LTR + immunomodulating (imids) drugs and a new clinical phenotype “Near the Cure of disease” (NCD), defined as &amp;gt; 3 years in remission with no medication or 5ASA only. Results The median (IQR) observation time of all patients included were 121(111–137) months. Of the 75 patients 46 (61%) did not receive biological therapy including 23 (31%) in LTR + imids. Of the 23 patients 16 were defined as NCD with an observation time of median (IQR) 95(77–113) months. Fourteen patients underwent colectomy and 15 patients received biological therapy the last 3 years of the follow-up. Mucosal TNF copies/µg mRNA &amp;lt; 10 000 at anti-TNF discontinuation predicted long-term remission, biological free remission and lower risk of colectomy with a HR 0.36 (0.14–0.92) for long term remission, HR 0.17 (0.04–0.78) for biological free remission and HR 0.12 (0.01–0.91) for coelctomy. Conclusion This 10-year anti-TNF discontinuation follow up study of UC shows that 61% of patients experience an altered phenotype to a milder disease course without need of biological therapy. Normalized mucosal TNF transcript predict this mild disease course and lower risk of colectomy. Of special interest is that 21% of the patients defined as “Near the cure of disease” were in long-term remission without any medication or receiving 5ASA only.

P190 Ileo-caecal Crohn’s Disease; medical or surgical management. Cost and outcomes

Abstract Background An ileo-caecectomy is known to be an effective treatment for Crohn’s disease limited to the terminal ileum that can lead to a long term remission. ECCO guidelines recommend that patients with active inflammation should be treated medically. However the LIR!C trial suggested there are QOL benefits and reduced costs to performing primary surgery. Methods We aimed to compare the outcomes of patients treated with primary medical treatment to primary surgery for patients with Crohn’s disease limited to the terminal ileum. We reviewed our database to identify all these patients and analysed outcome data. Results 49 patients were identified: Mean age was 50 yrs (range 22 - 93). 23 were male. Mean length of follow-up was 96 months (range 3 - 404). 1st line treatment was: medical; 33 (67.3%), surgery; 16 (32.6%). Outcomes after medical treatment: 27 of 33 patients failed primary medical treatment, they required surgery at a mean of 38 months (range 1–900) after initiating medical treatment. Colonoscopy after surgery to assess for disease recurrence: Colonoscopic assessment or calprotectin post was undertaken ileo-caecectomy in 4 of 16 patients at a mean of 6.2 months (range 1–10) who underwent primary surgery; and in 25 of 27 patients who underwent surgery following failure of medical treatment. Outcomes after surgery: 4 of 16 patients who had primary surgical treatment had endoscopic recurrence, requiring medical treatment after a mean of 4.4 months (range 0–10). 8 of 27 patients who had surgery post-failure of medical treatment developed disease recurrence, requiring medical treatment after a mean of 40 months (range 7–136) Bile acid malabsorption (BAM): BAM occurred after surgery in 10 of 43 patients. No medically managed patient developed BAM. Conclusion These data suggest that in our population the vast majority of patients with ileo-caecal Crohn’s disease will fail medical treatment and require surgery. 25% of those who undergo surgery will develop BAM (requiring medication), and 40% of those treated surgically will require immunosuppressant treatment in the medium term. These outcomes should be discussed with patients so that they appreciate that ileo-caecectomy is unlikely to lead to long term drug free treatment, and medical treatment is unlikely to lead to the avoidance of surgery. From a health-economics point of view it could be argued there is little point in offering primary medical therapy and ileo-caecectomy should be the initial treatment of choice for patients with limited ileo-caecal Crohn’s disease. Unfortunately endoscopic/calprotectin assessment following primary surgery was often not performed in the majority of patients, and changes in our local practice need to be undertaken to correct this.

P391 Antibiotics in pediatric Inflammatory Bowel Diseases: a systematic review

Abstract Background Dysbiosis is the central concept in the current thinking regarding IBD pathogenesis. Current available therapies in pediatric Inflammatory Bowel Disease (IBD) focus on targeting the immune system by suppressing the immune response and often fail to sustain long term remission. Antibiotics directly target bacteria but are underrepresented in current (pediatric and adult) IBD treatment guidelines. We aimed to describe available evidence concerning the use of antibiotics in the treatment of pediatric IBD. Methods We systematically assessed efficacy and safety of antibiotics in pediatric IBD. CENTRAL, EMBASE (Ovid) and Medline (Pubmed) were searched for Randomized Controlled Trials (RCTs). Quality assessment of included articles was conducted with the Cochrane risk-of-bias tool. Results Two RCT’s (n=101, 4.4-18 years, 43% male) were included. Both studies had overall low risk of bias. In mild-to-moderate Crohn’s disease, azithromycin+metronidazole (AZ+MET) (n=35) compared to metronidazole (MET) alone (n=38) did not induce a significantly different response (PCDAI drop ≥12.5 points or remission) (p=0.07). For induction of remission (PCDAI≤10), AZ+MET was more effective than MET (p=0.025). In Acute Severe Colitis, the mean 5-day PUCAI was significantly lower in the antibiotic (vancomycin, amoxicillin, metronidazole, doxycycline)+intravenous corticosteroids (IVCS) group (n=16) compared to IVCS (n=12) alone (p=0.037), whereas remission (PUCAI&amp;lt;10) did not differ (p=0.61). No significant drug-related adverse events were reported. Conclusion Our results highlight the lack of evidence in pediatric IBD. More evidence is needed to assess if implementation in daily practice is necessary.

P314 TNF gene activation used as criterion to discontinue biologic therapy – A patient series introducing the NovaPrime TNF kit

Abstract Background Severe inflammatory bowel disease can be successfully treated with biologic drugs such as anti-TNF. However, there is no consensus on if and how to stop treatment. Our group has earlier shown that normalization of TNF gene expression may be a beneficial prognostic factor when attempting to discontinue biologic therapy. We here present data from a series of patients in endoscopic remission and with normalized TNF gene expression. Methods Severe inflammatory bowel disease can be successfully treated with biologic drugs such as anti-TNF. However, there is no consensus on if and how to stop treatment. Our group has earlier shown that normalization of TNF gene expression may be a beneficial prognostic factor when attempting to discontinue biologic therapy. We here present data from a series of patients in endoscopic remission and with normalized TNF gene expression. A total of 91 patients were recruited at hospitals in Norway and Italy: 55 patients (32 UC, 23 CD) in remission (picked by normalization of TNF using our in-house TNF qPCR), and for comparison: 14 patients with active disease, and 22 normal controls. Mucosal samples taken prior to drug discontinuation from all patients were re-measured for TNF mRNA by the NovaPrime TNF kit. Results A clear difference could be seen between normal controls and patients with active disease, showing highly elevated TNF mRNA values in the active disease group. The patients in remission had values resembling the normal controls with values generally below a cut-off of 9060 copies/µg total RNA by the NovaPrime TNF kit. The patients in remission were followed for up to 5 years noting two endpoints: relapse triggering any adjustment of medication, and relapse triggering restart of biologics. Median survival time before adjusting medication was 12 months for ulcerative colitis and 17 months for Crohn’s disease. Median time to restart of biologics was 21 months (2 – 40) overall, and after 3 years 43% still were not in need of biologic therapy. Conclusion We conclude that the NovaPrime TNF kit yields consistent readings comparable to our in-house assay, and that this industrial standard kit enables any PCR lab to perform TNF gene expression in samples from intestinal mucosa. A considerable proportion of patients with normalized TNF gene expression can maintain long term remission without biologic therapy, relieving health care costs and potential side effects of long-term therapy.

P244 Clinician preferences in treating steroid resistant ulcerative colitis: a discrete-choice experiment (DCE) survey

Abstract Background The optimum treatment for steroid resistant ulcerative colitis (SRUC) is not clear and a range of options can be considered. The aim of this study was to quantify the relative importance of different treatment characteristics to clinicians and understand their preferences for benefit-risk trade-offs. Methods A discrete choice experiment (DCE) was conducted in the UK via online survey of clinicians with expertise in inflammatory bowel disease. This involved 12 tasks where respondents selected a preferred treatment option when presented with two competing, hypothetical treatment profiles for a SRUC scenario. Profiles described five treatment characteristics focusing on clinical outcomes and safety, identified from qualitative interviews with clinicians and evidence from systematic reviews. DCE responses were analysed using conditional logistic regressions. Regression coefficients were used to calculate benefit-risk trade-offs, to find the rate at which clinicians are willing to trade levels of risks in exchange for the preferred levels of clinical outcomes. Regression coefficients were also used to predict uptake rates for selected drugs currently prescribed to patients with SRUC. Results 116 clinicians completed the survey (age 46y; female 42%; consultant 60%; nurse 26%; mean experience 11y). Figure 1 shows the treatment characteristics that make respondents more likely (positive coefficient) or less likely (negative coefficient) to choose a treatment. One unit increase in both lymphoma risk and serious infection risk were strongly considered when clinicians were choosing a treatment compared to one unit increase in the symptom improvement characteristics. Clinicians would accept a higher lymphoma risk of 5 per 10,000 patient years for a 10% improvement in remission rate compared to 4 and 2 cases per 10,000 patient years for 10% better rates of clinical response and mucosal healing respectively. Clinicians at secondary hospitals accepted a lymphoma risk of 4 cases per 10,000 patient years for a 10% improvement in remission vs 7 per 10,000 patient years at tertiary centres. Similar trade-off results were found for serious infection risks. Predicted uptake comparing preferred characteristics to existing treatments was infliximab (62%), tofacitinib (18%), vedolizumab (15%) and adalimumab (5%). Conclusion Clinicians are willing to make difficult trade-offs and tolerate elevated safety risks in exchange for therapeutic benefits. Risk tolerance was highest if the treatment improved long term remission rate, lowest for mucosal healing and higher in clinicians at tertiary centres. The results help to better understand treatment decisions and identify outcomes that might be considered in choosing agents to evaluate in clinical trials.

Thyroid Microcarcinoma in Pediatric Population in Romania.

Thyroid microcarcinoma in pediatric population in Romania Non-medullary thyroid cancer (TC) is the most common endocrine malignancy, with an increasing incidence in the recent years, due to the increase of the thyroid microcarcinoma. Thyroid microcarcinoma (mTC) is defined, according to WHO criteria, as ≤1 cm dimension thyroid carcinoma, being a rare disease in children population. In adults, the current guidelines recommend a limited surgical approach. In children, however, there are no specific guidelines for mTC. Due to the scarcity of these tumors, mTC in children have largely been understudied, to our knowledge with only one previous publication reporting on the outcomes of a large historic series of patients with mTC from the USA. In Romania, the incidence of TC is rising, one of the reason may be the effect of Chernobyl nuclear accident in the past and the iodine deficiency. The purpose of this study was to describe the characteristics and outcome of children diagnosed with mTC in Romania diagnosed from 1 January 2000 to 31 December 2018. During the study period we identified 77 cases of differentiated TC (papillary and follicular) and of these 20 cases (19.4%) were mTC. The mTC represented roughly one fifth of our nationwide pediatric population diagnosed in the last 20 years, the majority of cases being recorded in adolescents aged between 15–18 years. Although patients with apparently more unfavorable local phenotype were identified, this was not reflected in the outcome of the patients in terms of remission of the disease and survival. Our study illustrates the heterogeneity of the real-life practice with respect to the pediatric mTC, and underscores the need for carefully designed multicenter international studies, including larger cohorts of patients in order to provide the data required for establishing evidence based uniform protocols. The European Reference Networks (ERN), such as the ERN for Rare Endocrine Diseases (Endo-ERN) provides an ideal platform to initiate such collaborative studies.

NUP-98 Rearrangements Led to the Identification of Candidate Biomarkers for Primary Induction Failure in Pediatric Acute Myeloid Leukemia.

Conventional chemotherapy for acute myeloid leukemia regimens generally encompass an intensive induction phase, in order to achieve a morphological remission in terms of bone marrow blasts (<5%). The majority of cases are classified as Primary Induction Response (PIR); unfortunately, 15% of children do not achieve remission and are defined Primary Induction Failure (PIF). This study aims to characterize the gene expression profile of PIF in children with Acute Myeloid Leukemia (AML), in order to detect molecular pathways dysfunctions and identify potential biomarkers. Given that NUP98-rearrangements are enriched in PIF-AML patients, we investigated the association of NUP98-driven genes in primary chemoresistance. Therefore, 85 expression arrays, deposited on GEO database, and 358 RNAseq AML samples, from TARGET program, were analyzed for “Differentially Expressed Genes” (DEGs) between NUP98+ and NUP98-, identifying 110 highly confident NUP98/PIF-associated DEGs. We confirmed, by qRT-PCR, the overexpression of nine DEGs, selected on the bases of the diagnostic accuracy, in a local cohort of PIF patients: SPINK2, TMA7, SPCS2, CDCP1, CAPZA1, FGFR1OP2, MAN1A2, NT5C3A and SRP54. In conclusion, the integrated analysis of NUP98 mutational analysis and transcriptome profiles allowed the identification of novel putative biomarkers for the prediction of PIF in AML.

Plasmablastic lymphoma of nose and para-nasal sinuses in an immunocompetent patient

&lt;p class="abstract"&gt;Plasmablastic lymphoma (PbL) is a rare and aggressive neoplasm with heterogeneous clinical, histological and genetic features. It has been reported in both immuno-compromised and immuno-competent patients and commonly presents in the extra-nodal regions, but it is more heterogeneous in immuno-competent patients. Its clinical course is aggressive with early dissemination and poor response to therapy. A 61 year old male presented with left sided nasal bleeding and nasal obstruction for last 6 months, snoring and disturbed sleep for last 2 months. On examination, there was fullness over left side of nose and obliteration of left naso-facial groove. A mass lesion was seen in the left nasal cavity on endoscopy. There was bulge in the soft palate and the mass extended into the oropharynx. CECT showed a locally aggressive sino-nasal mass. Histopathology and immuno-histo-chemistry (IHC) of the biopsy were suggestive of plasmablastic lymphoma. A debulking surgery was done to relieve his obstructive symptoms. The patient received 3 cycles of EPOCH chemotherapy and radiotherapy to local site. At 9 months of follow up he presented with recurrence of the mass. Plasmablastic lymphoma presents in patients other than those with HIV. Awareness about its unique characteristics is crucial for establishing a correct diagnosis. Currently available treatments are ineffective in achieving long term remission and prognosis remains unfavourable with high incidence of recurrence&lt;/p&gt;

Results of Endoscopic Surgery in Patients with Pituitary Adenomas : Association of Tumor Classification Grades with Resection, Remission, and Complication Rates.

ObjectiveThe endoscopic endonasal transsphenoidal approach is a widely-used method for the surgical treatment of pituitary adenomas. We aimed to evaluate the results of endoscopic surgery by comparing preoperative classification methods and investigating their relationship with postoperative resection and remission rates and complications. MethodsWe retrospectively reviewed the medical records of 236 patients (118 males) who underwent surgery for pituitary adenomas. Preoperative Knosp classification, tumor size (TS), suprasellar extension (SSE), postoperative resection and remission rates, and complications were evaluated. ResultsThe follow-up period was 3 months to 6 years. The patients’ ages ranged between 16 and 84 years. Endocrinologically, 114 patients (48.3%) had functional adenoma (FA), and 122 patients (51.7%) had non-functional adenoma (NFA). Among the FA group, 92 (80.7%) showed remission. A statistically significant difference was found between patients with and without remission in terms of the Knosp, TS, and SSE classifications (p<0.01). Knosp, TS, and SSE classification grades were found to be correlated with the resection rates (p<0.01). Meningitis was seen in seven patients (3.0%), diabetes insipidus in 16 (6.9%; permanently in two [0.9%]), and rhinorrhea in 19 (8.1%). Thirty-six patients (15.3%) developed pituitary insufficiency and received hormone replacement therapy. ConclusionThe resection categories and remission rates of FAs were directly proportional to the adenoma sizes and Knosp grades, while the degree of suprasellar growth further complicated resection and remission rates. Adenoma sizes less than 2 cm and SSEs less than 1 cm are associated with favorable remission and resection rates.

The significance of metalloproteinase 3 (MMP-3), chemokine CXC ligand 13 (CXCL-13) and complement component C5a in different stages of ANCA associated vasculitis

The aim of the study was to evaluate the significance of metalloproteinase 3 (MMP-3), chemokine CXC ligand 13 (CXCL-13) and complement component 5a (C5a) in different stages of ANCA associated vasculitis (AAV). 89 adults were included into the study. 28 patients with active AAV (Birmingham Vasculitis Activity Score, BVAS > 3) formed the Active Group. 24 individuals who were in remission after 6 months of induction therapy formed the Short R Group, while 34 patients with longitudinal remission formed the Long R Group. 28 patients without autoimmune diseases similar in terms of age, gender and stage of kidney disease formed the Control Group. Receiver operating characteristic curve analysis (ROC) was used to evaluate MMP-3, CXCL-13 and C5a as markers of the different phases of vasculitis. In ROC analysis, MMP-3, CXCL-13 and C5a presented a good ability in distinguishing active vasculitis (Active Group) from the Control Group (AUC > 0.8), whereas only CXCL-13 displayed potential ability in distinguishing active vasculitis (Active Group) from long term remission (Long R Group, AUC = 0.683). MMP-3 significantly and positively correlated with serum creatinine concentration (r = 0.51, p = 0.011; r = 0.44, p = 0.009; r = −0.66, p < 0.001) and negatively with eGFR (r = −0.5, p = 0.012; r = −0.35, p = 0.039; r = −0.63, p < 0.001) in the Short R, Long R and Control Groups. MMP-3, CXCL-13, C5a can be potential markers in differentiating an active phase of vasculitis from other pathologies. However they can be treated as complementary to the well-known markers. CXCL-13 seems to be a potential marker in distinguishing active vasculitis from long term remission. MMP-3 level can be related to kidney function expressed by eGFR, therefore its elevation should be interpreted with caution in patients with kidney failure.

A concept analysis of remission within the domain of cancer survivorship.

This concept analysis aims to formulate a unique theoretical definition of the term remission as used in cancer survivorship. Inadequate communication between healthcare providers and cancer survivors is a shared burden affecting survivor well-being. Healthcare providers regularly use the term remission in cancer prognosis, treatment, and long-term cancer management; yet, how healthcare providers and cancer survivors define and interpret the concept of remission is less understood. The Walker and Avant method of concept analysis was applied to define the term remission within the domain of cancer survivorship. DATASOURCE: Three health sciences databases were chosen for the literature search, including PubMed, the Cumulative Index to Nursing and Allied Health Literature, and Ovid Medline. REVIEWMETHODS: Included research articles were evaluated to define the antecedents, attributes, consequences, and empirical referents of the term remission. A cancer diagnosis is the most commonly cited antecedent to cancer remission. During remission, most cancer patients are free of measurable or symptomatic disease; however, the remission milestone is complemented by multiple physical and psychological symptoms. More specific cancer remission attributes include anxiety, recurrence fears, self-perseverance, and loss of social support. Both positive and negative outcomes accompany cancer remission, including acceptance of the treatment journey, appreciation for life, hope, persistent anxiety, personal relief, and triggered memories. This concept analysis reviewed numerous publications to understand remission in the context of cancer survivorship. Advanced practice and registered nurses have a continued opportunity to improve the communication methods of patient-centered teaching and care planning for cancer patients in remission.

Type 2 diabetes mellitus status in obese patients following sleeve gastrectomy or one anastomosis gastric bypass

This study aims to compare sleeve gastrectomy (SG) and one anastomosis gastric bypass (OAGB) in terms of remission of type 2 diabetes mellitus (T2DM) in obese patients. All T2DM patients were followed-up for at least 36 months. The primary outcome was remission of T2DM. Secondary endpoints included weight reduction and the procedure’s impact on quality of life. In total, 53/1177 morbidly obese patients who underwent SG (Group A, n = 28) or OAGB (Group B, n = 25) had T2DM. Preoperatively, the mean Body Mass Index (BMI) values were 52.2 ± 8.5 kg/m2 and 52.9 ± 10.9 kg/m2 for Group A and Group B, respectively. Six patients in Group A were insulin dependent, while 8 were insulin dependent in Group B. After 36 months, diabetes remission was achieved by only 10 patients (35.7%) in Group A. However, in Group B, 22 patients (88%) remained off antidiabetic agents (p < 0.0001), with ΔHbA1c (%) reaching 1.4 ± 1.5% in Group A and 2.7 ± 2.1% in Group B (p = 0.02). Excess weight loss% (%EWL) was again significantly different between the two groups (MA = 79.8 ± 14.5%, MB = 93.3 ± 16.0%, p = 0.003). OAGB is more effective in improving glycaemic control and %EWL, with almost immediate resolution of diabetes, as well as long-term weight loss.

Early course of newly diagnosed moderate-to-severe ulcerative colitis in Korea: Results from a hospital-based inception cohort study (MOSAIK).

No inception cohort study has ever evaluated the early course of moderate-to-severe ulcerative colitis (UC) within 1year of diagnosis in the non-Caucasian population. We aimed to investigate the early clinical course of moderate-to-severe UC patients in terms of remission, relapse, UC-related hospitalizations, colectomy, mortality, and overall use of medications. In the MOSAIK inception cohort, which is an ongoing multicenter, prospective, hospital-based, observational cohort, 354 patients with moderate-to-severe UC were followed up for 1year. Main outcomes of UC and predictive factors for medication use over the course of 1year were evaluated. Among 354 patients, 276 (78.0%) patients were followed up for 1year. The rates of remission, relapse, UC-related hospitalizations, and proximal disease extension were 95.3%, 39.6%, 15.2%, and 12.3%, respectively. Systemic corticosteroids, thiopurines, and biologics were administered to 61.2%, 30.4%, and 10.5% of patients, respectively, throughout 1year. One year after, 58.2% patients experienced remission or mild endoscopic activity. Overall disease courses did not show much difference according to moderate or severe disease activity at baseline. In addition, no colectomy and mortality were observed for 1year. Predictive factors for medication use included disease severity, disease extent, endoscopic severity, and presence of periappendiceal inflammation at baseline for corticosteroid, disease extent and initial corticosteroid use for thiopurine, and only initial corticosteroid use for biologics. Korean patients with moderate-to-severe UC may have more favorable early outcomes than Western patients. However, outcomes of them need to be further looked into for a longer time.