Adverse Features Research Articles

Lintuzumab-Ac225 with Combination with Intensive Chemotherapy Yields High Response Rate and MRD Negativity in R/R AML with Adverse Features

Background: Actimab-A (lintuzumab-Ac225) is a humanized CD33 antibody conjugated to an alpha emitting isotope, Ac225, delivering high energy radiation over a short radius to CD33 expressing AML blasts and requiring no isolation. Preclinical studies also indicate that Actimab-A effectively depletes the anti-apoptotic protein MCL-1, potentially indicating another mechanism of action, which may benefit venetoclax resistant patients (pts). In this study, we hypothesized that low dose Actimab-A after salvage chemotherapy is feasible and improves clearance of residual, resistant AML thereby improving remission rates, and depth of remission. Herein, we report results of our Phase I study, and results of pts enrolled in an expansion cohort to characterize PK. Methods: This study enrolled R/R AML pts deemed fit, with adequate organ function, and with CD33 expression on >25% of leukemic blasts. The primary endpoint of the Phase I study was determination of MTD of Actimab-A in combination with CLAG-M. Secondary endpoints included the composite complete remission (CRc) rate after one induction cycle, the MRD (-) CRc rate determined by multiparametric flow cytometry, median overall survival (OS), and estimated 1- and 2-year OS. Furthermore, we are performing an expansion cohort to characterize PK. Induction consisted of G-CSF, 300mcg/d, given D1-6, cladribine 5mg/m2, given D2-6, cytarabine 2g/m2, given D2-6, and mitoxantrone 10mg/m2, given D2-4. Actimab-A was administered as a single dose on day 8 ±1 day The trial enrolled to 4 cohorts, with Actimab-A at doses ranging from 0.25uCi/kg to 1.0uCi/kg. One induction cycle was administered in all pts. Results: Of the 21 pts evaluable for response, median age was 63 yrs, 52% (n=11) had s-AML/t-AML, 67% (n=14) had adverse cytogenetics, and TP53 mutations were present in 52% (n=11) of pts. Median blast CD33 expression at baseline was 77% (range: 29-100%). Pts received a median 2 lines of therapy, including 57% (n=12) who received prior venetoclax. 57% (n=12) of pts enrolled after relapse post allogeneic HCT (alloHCT) (Table 1). The MTD was determined to be 1.0 uCi/kg, and the RP2D was set at 0.75uCi/kg. Within the 1.0uCi/kg dosing cohort, 2 DLTs were observed in 5 pts; severe mucositis and delayed ANC recovery (>42 days). Among all pts, Grade 3/4 toxicities observed in >10% of pts included febrile neutropenia, infection, rash and hypokalemia. Overall, 52% (n=11) achieved CRc, an additional 14% (n=3) achieved an MLFS, for an ORR (CRc+MLFS) of 67%. MRD negativity by flow was observed in 72% of pts achieving a CRc. At the RP2D, 67% (n=4) achieved CRc, and 75% of these pts achieved MRD negativity by flow. An additional 1 patient achieved MLFS for an ORR=83%. Actimab-A+CLAG-M was active in pts with TP53 mutations (ORR 73%) and in those who received prior venetoclax (ORR 55%) (Table 1). Median OS among all pts was 1.0 year (95% CI, 0.2 to 1.8); 1-year OS was 53% and 2-year OS was 32% (Figure 1). After therapy, 75% (n=6) of pts successfully bridged to alloHCT. Among patients who underwent 1st alloHCT, median OS was 2.5 years (95%CI, 1.0-3.9). PK studies measuring blood radioactivity were performed in 3 pts. Blood Ac225 radioactivity studies revealed median tmax of 0.6 hrs after infusion start. After achieving Cmax, mean half-life of radioactivity was 9.8 hrs. Ac225 radioactivity was below the limit of quantification (BLQ) by 48 hrs in all pts. Conclusions: Actimab-A at 0.75uCi/kg, combined with CLAG-M is feasible and safe, and this combination demonstrates a high response rate and MRD negativity in a high-risk AML population. Pharmacokinetics at the RP2D indicate rapid drug clearance. Furthermore, responses appear durable, particularly among patients who are able to proceed to alloHCT. In conclusion, with no viable options for both R/R TP53 mutated AML and R/R AML previously treated with venetoclax, this regimen represents a potentially important option, and efforts are underway for a confirmatory study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of 5-Day Vs. 10-Day Decitabine in Combination with Venetoclax in Newly Diagnosed AML Patients Ineligible for Induction Chemotherapy

BACKGROUND. Standard dosing of decitabine 20mg/m 2 daily given over 5 days in combination with the Bcl-2 inhibitor venetoclax (5-day DEC/VEN), in elderly or chemotherapy ineligible patients with Acute Myeloid Leukemia (AML), induces both a high rate of complete remission (CR/CRi rate 71%) and prolonged survival (median OS 14.2 months). (DiNardo CD et al. Blood. 2019) Extending the duration of decitabine treatment to 10-days (10-day DEC/VEN) may increase efficacy of the combination. In a phase 2 study of newly diagnosed chemotherapy ineligible AML patients aged ≥ 60 years, 10-day DEC/VEN led to a high CR/CRi rate of 89%, with 67% of these being negative for measurable residual disease and a median OS of 18 months. (DiNardo, CD et al. Leukemia. 2020). As a prospective clinical trial comparing efficacy of the different dosing schedule of decitabine in combination with venetoclax is unlikely to be performed, we conducted a single center retrospective analysis comparing 5-day and 10-day DEC/VEN outcomes. METHODS. We retrospectively studied patients with newly diagnosed AML receiving either 5-day or 10-day DEC/VEN between January 2016 to May 2022 at City of Hope National Medical Center. Patients receiving prior AML therapies including hypomethylating agents were excluded. Responses were evaluated per the ELN criteria (Dohner, H et al. Blood. 2017) Measurable residual disease (MRD) flow cytometry was performed at the University of Washington. Patient characteristics were summarized by frequency and associations between overall response and patient and disease characteristics were tested by Fisher's exact test. Overall Survival (OS) was evaluated by the Kaplan-Meier method and the difference between groups was determined by log-rank test. All statistical analyses were performed using R software. RESULTS. 139 patients were included: 48% (n=67) treated with 5-day decitabine and 52% (n=72) treated with 10-day decitabine. The baseline characteristics of the patients are summarized in table 1. At baseline, 5-day decitabine + venetoclax treated patients were older with a median of age of 73 vs. 70 years (p=0.01). The 5-day and 10-day groups were otherwise well balanced with no significant difference in AML type, ELN risk or adverse molecular features. Rates of CR/CRi, CR/CRi, MRD negativity, and the percentage of responders proceeding to allogeneic stem cell transplant were similar between regimens (Table 1). There was also no difference in 8-week mortality (p = 0.44). With a median follow-up of 12 months for responding patients, the median OS (figure 1) and RFS for 5-day and 10-day DEC/VEN were 14 vs. 27 months, p=0.091 and 12.9 vs. 14.3 months, p= 0.75 respectively. In subgroup analysis, patients without therapy- related AML (non-tAML) receiving the 10-day-regimen had a longer median OS (42.5 vs. 14.6 months, p= 0.03). No other subgroups, including those with high-risk molecular (eg.TP53) or cytogenetic risk factors (e.g. complex karyotype) demonstrated a significant difference between the 5 and 10-day DEC/VEN regimen. CONCLUSION. Among newly diagnosed AML patients receiving venetoclax in combination with either 5-day or 10-day decitabine, there was no significant difference in response (CR/CRi or MRD negativity) or survival outcomes (OS or RFS). Although a significant difference was not observed, 10-day DEC/VEN led to an increased median OS, which may reach significance with more patients and longer follow-up. Additionally, the 10-day DEC/VEN regimen may benefit certain subpopulations; it demonstrated longer median OS in patients without t-AML. Further analysis to confirm a survival benefit among patients without t-AML receiving either 5-day or 10-day DEC/ VEN is needed and will be presented at ASH. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Therapy-Related AML: Clinical/Biological Features and Long-Term Outcome in a Cohort of 1133 Adult AML Patients

Introduction: Therapy-related acute myeloid leukemia (t-AML) affects approximately 7% of AML patients and exhibits adverse genetic features that are assumably caused by increased DNA damage after antecedent radiation/chemotherapy. There is an ongoing medical need for a better understanding of differences between patients with t-AML and de novo AML. Here, we assess clinical and biological characteristics of patients with t-AML and compare long-term survival with de novo AML in a large cohort of AML patients. Methods: 225 t-AML patients who were newly diagnosed between 1995-2018 were retrospectively analyzed and compared to a cohort of 908 patients with de novo AML. Mann-Whitney U- and Chi square test were used to assess differences in baseline characteristics between subgroups. Kaplan Meier procedure was applied to calculate overall survival (OS). Cox regression was used to identify hazard ratios (HR) of independent prognostic risk factors. Non-relapse mortality (NRM) and risk of relapse (RR) were calculated by the cause-specific hazard method. Results: As compared to de novo AML, t-AML patients were older (61 vs. 55 years, p<0.001), had increased comorbidity and a higher frequency of adverse genetic alterations (e.g. monosomal or complex karyotypes, -5/-5q, -7, t(v;11)(v;23)). Prior to t-AML, solid cancer was diagnosed in 61% of patients (138/225), whereas 31% had hematologic malignancies (69/225) and 8% had autoimmune diseases (18/225). Previous malignancies had been treated with combined radiochemotherapy in 33% (75/225), chemotherapy in 27% (60/225), radiation therapy in 22% (50/225), immunosuppressive therapy (Cyclophosphamide, Mitoxantrone, Methotrexate, Azathioprine) in 7% (16/225), radio-iodine therapy in 4% (9/225) or multiple preceding cytotoxic therapies in 7% (15/225). Median latency period between cytotoxic therapy and t-AML was 5.8 years. In intensively treated t-AML patients (172/225), median OS was 13.7 months as compared to 39.4 months in de novo AML (823/908, p<0.001). The substantial difference in median OS particularly applied to patients <60 years with a 5-year OS of 31% in t-AML (96/225) as compared to 51% in de novo AML (562/908, p<0.001). In patients ≥60 years, there was a tendency towards better OS in de novo AML, however, this did not reach statistical significance (p=0.066). Interestingly, OS in patients receiving intensive therapy for t-AML was comparable with de novo AML within the favorable genetic risk groups (APL p=0.927, ELN-favorable p=0.714). In contrast, a significant difference in favor of de novo AML was observed within the ELN-intermediate (p=0.009) and ELN-adverse (p=0.016) risk groups, which was most likely caused by age differences between these groups. However, there was no age difference within the favorable ELN risk group (p=0.878). Considering only patients who received non-intensive therapy, OS (p=0.394), age (p=0.087), ECOG status (p=0.123) and ELN risk group (p=0.098) did not differ significantly between t-AML (53/225) and de novo AML (85/908). Multivariate analysis (including several covariates such as age, ELN risk, ECOG and CCI) did not confirm t-AML per se as an independent risk factor for OS (p=0.081), RR (p=0.982) or NRM (p=0.320) in intensively treated patients. Interestingly, OS was particularly favorable after radio-iodine therapy as compared to other treatment modalities (p=0.042) and highly unfavorable after pretreatment with multiple cytotoxic therapies (p=0.009). Multivariate analysis revealed ECOG score >1 (HR 2.3, p=0.002), adverse ELN risk (HR 1.7, p=0.003), BMI <18,5 kg/m2 (HR 2.7, p=0.029), diabetes (HR 2.0, p=0.029) and intensive treatment (HR 0.3, p<0.001) as independent prognostic factors in t-AML. Conclusion: Our data indicate that inferior OS in t-AML as compared to de novo AML rather results from an accumulation of adverse genetic alterations and patient-associated risk factors than from t-AML itself. Thus, our study strongly supports the current view that risk stratification in t-AML (including indication for allo-HSCT) should align with strategies used in de novo AML patients (based on genetic features), both in the case of intensive and non-intensive therapy. Regarding the new International Consensus Classification of AML, our data are in accordance with the classification of t-AML as a "diagnostic qualifier" within the different AML subgroups rather than a separate subcategory.

Epigenetic Priming with 5-Azacytidine Prior to Allogeneic Stem Cell Transplantation for Myeloid Malignancies with In Vivo T Cell Depletion: Results of a Phase II Trial

Background: Relapse is the main cause of death in patients who undergo allogeneic hematopoietic stem cell transplantation (HCT) for myeloid malignancies. Recent improvements in survival have been mainly due to reduction in non-relapse mortality (NRM). Acquired abnormalities of DNA methylation are frequent in myeloid malignancies and are particularly observed among patients with adverse risk features. Epigenetic priming with decitabine to induce DNA hypomethylation was investigated in a phase I trial for acute myeloid leukemia (AML) and has proven safe and feasible (Scandura et al Blood 2011). Applying the principle of chemotherapy-sensitization through hypomethylation in myeloid malignancy, we conducted a phase II trial (NCT02497404) of the epigenetic modulator -5-azacytidine given prior to a reduced intensity conditioning (RIC) regimen. Here we report the results of this trial. Methods: We designed an open label phase II study to determine the feasibility and efficacy of epigenetic priming with 5-Azacytidine prior to RIC for HCT with in-vivo T-cell depletion. Inclusion criteria were AML, myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) with an intermediate or poor risk profile by ELN and IPSS-R, respectively, and adequate organ function. Stem cell grafts were GCSF- mobilized peripheral blood stem cells from either a matched related donor (MRD) or matched unrelated donor (MUD), matched for HLA at loci A, B, C, DR, and DQ. The epigenetic priming regimen was 5-Azacytidine 75 mg/m2/daily X 5, given between days -11 to -7 (Dose reduction to 50 mg/m2/daily after 14 patients due to toxicity). The conditioning regimen consisted of Fludarabine 40 mg/m2/daily, days -6 to -3, and Melphalan 140 mg/m2, on day -3. Graft versus host disease (GVHD) - prophylaxis consisted of Alemtuzumab (total dose 60 mg for MUD and 30 mg for MRD), and Tacrolimus for 3-6 months post-transplant. The Primary objectives were overall survival (OS) and progression free survival (PFS) at 1 year. Secondary objectives were incidence of GVHD and NRM. Results: 39 adult patients with AML, MDS, and chronic neutrophilic leukemia (CNL) were enrolled prospectively between 2/2015 and 6/2018. The median age was 60 years (range, 26-74). The majority of patients had AML (33, 85%), or MDS (5, 13%). Nineteen AML patients (58%) had a poor risk karyotype. Nine cases (23%) had mutated TP53. The donor was MUD in 22 (44%), MRD in 17 (56%) of patients. Other patient characteristics are listed in Table 1. The median follow up for survivors is 6.7 years (5.8 - not reached). Thirty-eight patients engrafted neutrophils at a median of 13 days (9-16) and platelets at a median of 16 days (12-102). One patient was not evaluable due to early death on day 9. OS at 1 year was 64% (95% CI 51-81%) and 36% (95% CI 24-55%) at 4 years, (Figure 1). PFS at 1 year was 54% (95% CI 40-72%) and 33% (95% CI 21-52%) at 4 years. At 1 year, relapse was the cause of death in 21% (95% CI 18-22%) and NRM was 15% (95% CI 13-17%). At 4 years, relapse was the cause of death in 41% (95% CI 38-43%), while NRM reached 23% (95% CI 20-25%). The most common cause of NRM was infection in 5 patients (46%), followed by thrombotic microangiopathy and GVHD. The incidence of acute GVHD by day 100 was 29% (95% CI 13-43%) with grade III-IV acute GVHD found in 8% (95% CI 6-9%). The incidence of chronic GVHD at 1 year was estimated at 22% (95% CI 7.4-35%). No new cases of chronic GVHD were seen thereafter. The most common grade 3/4 toxicities were infections in 8 patients (21%) and renal failure (23%). We found 6/14 patients to have grade 3/4 renal toxicity with 2 requiring hemodialysis. After reducing the 5-azacytidine dose to 50 mg/m2/daily, we observed only 3/25 cases of grade 3/4 renal dysfunction. Conclusion: Preconditioning treatment with 5-azacytidine as epigenetic priming is tolerable with a toxicity profile overall similar to conditioning with fludarabine/melphalan. But the addition of azacytidine at 75 mg/m2/daily (total 5 doses) causes significant renal toxicity, which abates with dose reduction. The PFS in this very high-risk population with historically high relapse rates is promising. A larger number of patients is needed to further evaluate the efficacy of this approach. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic Significance of Circulating Plasma Cells Detected By Next Generation Flow Cytometry in Light (AL) Chain Amyloidosis

In light chain (AL) amyloidosis misfolded light chains that are produced by a generally small or moderate plasma cell clone residing in the bone marrow (BM) form amyloid fibrils and cause organ dysfunction. In asymptomatic myeloma (MM) and patients with MGUS, the presence of circulating clonal plasma cells (CPCs) detected by next generation flow cytometry (NGF) is associated with higher risk of progression to symptomatic disease and in patients with symptomatic MM, higher levels of CPCs are associated with poorer prognosis. In an older study in patients with AL amyloidosis, using 6-color flow cytometry and with a limit of detection (LOD) of ~ 0.01%, CPCs were detected in 42% of patients and their presence was associated with poorer prognosis. In the current study we aimed to evaluate the prognostic and biological impact of CPCs in previously untreated patients with AL amyloidosis by using NGF with a LOD of <0.001%. The presence of CPCs was prospectively evaluated in 114 consecutive patients with AL amyloidosis who were diagnosed and treated in the Department of Clinical Therapeutics, Athens, Greece. CPCs were assessed in peripheral blood (PB) according to the Euroflow guidelines, using two independent 8-color panels, both containing CD19-PC7, CD27-BV510, CD38-FITC, CD45-PerCPCy5.5, CD56-PE, CD138-BV421, and additionally CD117-APC and CD81-APCC750 only in the surface tube or CyIgκ-APC and CyIgλ-APCC750 only in the intracytoplasmic tube. A median number of 5 million events (range 3.9x106-6.1x106) were acquired for each tube and median sensitivity level was 2.3x10-6 (range 2-3.1x10-6) The median age of the cohort was 67 years (38-87), 57% were males, 86% had cardiac, 56% renal, 34% soft tissue, 24% PNS and 19% liver involvement. Mayo stage distribution was 13%, 33% and 54% for stages 1, 2 & 3 and renal stage was 20%, 57% & 23% for stages 1, 2 & 3 respectively. Median iFLC and dFLC levels were 299.3 and 288.5 mg/L respectively and median BM infiltration was 10% (range 0-60%). By FISH, 46% had t(11;14), 40% del13q, 29% +1q21, 6% del17p, 2% t(4;14) and 4% t(14;16). Treatment was bortezomib-based in 96% and contained daratumumab in 34%. CPCs were detectable in 64% of patients and their median level in those with detectable CPCs was 0.002% (range 0.0001%-11.4%). Patients with detectable CPCs had higher LDH (p=0.003), iFLCs (p=0.029), BM infiltration (p=0.002) and NTproBNP (p=0.009). Among patients with detectable CPCs, there was also a correlation of their levels with iFLC levels (p<0.001) and BM infiltration (p<0.001). CPCs were more often detectable (81.5% vs 60%, p=0.053) and their levels were also higher (p=0.014) in those with +1q21; there was no association with any other cytogenetic abnormality. Median follow up of the cohort is 2 years. There was no difference in the OS (2-year OS 65% vs 63%) or in early mortality for patients with or without detectable CPCs (p=0.965). Due to the high sensitivity of NGF in the detection of CPCs, we also evaluated different cutoffs of CPCs for their possible prognostic impact, including cutoffs proposed in the earlier study and in patients with newly diagnosed symptomatic MM (0.01%), but we found no prognostic impact on OS in our patients with AL amyloidosis (2-year OS:55% vs 66%, p=0.374). Higher BM infiltration has been associated with worse outcome in patients with AL amyloidosis: in bivariate analysis CPCs>0.01% overcame the prognostic impact of higher BM infiltration, indicating that CPCs is a more sensitive biomarker of tumor burden in patients with AL amyloidosis. Even after adjustment for Mayo stage the presence of CPCs or of CPCs >0.01% were not prognostically significant. However, patients with CPCs>0.01% had a lower probability of hematologic CR/VGPR at 1 month (23% vs 56%, p=0.03) and at 3 months (44% vs 76%, p=0.043) from start of therapy. In conclusion, circulating clonal plasma cells can be detected in the majority of patients with AL amyloidosis with more sensitive NGF methods. Their presence is associated with higher FLC levels and BM infiltration and adverse prognostic features such as higher NTproBNP level, and a lower probability of deep hematologic response at 1 and 3 months after start of therapy. However, in the era of modern therapies, CPCs do not seem to independently affect the prognosis of patients with AL amyloidosis, which is dominated by the degree of cardiac dysfunction.

High Karyotypic Complexity and Translocations Are Adverse Prognostic Features in Patients with Chronic Lymphocytic Leukemia without TP53 Aberrations Treated with Venetoclax-Based Time-Limited Combinations

Background: The presence of ≥3 (complex karyotype, CKT) and specifically ≥5 (high-CKT, hCKT) chromosomal aberrations (CA) is associated with a poor prognosis in patients (pts) with chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy (CIT). Studies on the prognostic impact of CKT with targeted agents are not only heterogeneous in size and methodologies but also conflicting, with reports on both negative impact (venetoclax [ven] + rituximab [RVe] and ibrutinib monotherapy) and no impact (ven + obinutuzumab [GVe], ven + ibrutinib, idelalisib + rituximab) on progression-free (PFS) and overall survival (OS). Here, we prospectively evaluate the impact of CKT in a large cohort of pts treated with ven-based time-limited combinations within the GAIA/CLL13 trial. Methods: The phase 3 GAIA/CLL13 trial compared 3 different time-limited ven-based combinations against CIT in fit, treatment-naïve pts with CLL. Pts with TP53 aberrations were excluded. Pts were randomized to CIT (FCR in pts ≤65y; BR in pts >65y), RVe, GVe, or GVe plus ibrutinib (GIVe). Chromosome banding analyses were performed following IL-2/CpG-stimulation, karyotypes were analyzed according to ISCN 2020. No CKT (nCKT) was defined as ≤2, CKT as ≥3, intermediate CKT (iCKT) as 3-4 and hCKT as ≥5 CA. Undetectable MRD (uMRD) was defined as less than 1 CLL cell/10 000 leukocytes measured by 4-color flow cytometry. Results: Chromosome analysis was successfully performed at baseline in 895 of 926 pts. Of these, 672 (RVe: 231; GVe: 218; GIVe: 223) were in the pooled ven population (pooled ven) and 223 in the CIT arm. nCKT was present in 79.4%, 81.0%, 83.5%, and 87.9%, iCKT in 13.5%, 14.7%, 11.5%, 9.4% and hCKT in 7.2%, 4.3%, 5.0% and 2.7% of pts treated with CIT, RVe, GVe and GIVe, respectively. Male gender, del(11q), del(6q) and trisomy 12 were associated with CKT. No correlation was observed between IGHV status or CLL-IPI and CKT. With CIT, uMRD rates in peripheral blood at month 15 were lower in pts with CKT compared with nCKT (37.0% vs 57.1%; OR 0.44, p=0.016). In none of the ven arms, uMRD rates were significantly different between pts with CKT and nCKT (RVe: 52.3% vs 56.7%, GVe: 86.1% vs 86.3%, GIVe: 92.6% vs 92.3%). Across all treatment arms, pts with ≥5 CA had significantly shorter PFS than pts with <5 CA (Figure 1). With CIT, also iCKT was associated with shorter PFS (vs nCKT: HR 2.49, p=0.003), while in none of the ven arms there was a significant PFS difference between iCKT and nCKT (RVe: HR 1.35, p=0.376; GVe: HR 0.94, p=0.912; GIVe: HR 0.38, p=0.341). Pts harboring translocations (TL) (CIT: n=52 [23.4%], pooled ven: n=160 [24.1%]) had inferior PFS compared to pts without TL irrespective of the treatment arm (Figure 2). Focusing on the ven-treated population, this difference was mostly driven by unbalanced TL (vs no TL: HR 3.83, p<0.001) however balanced TL still conferred inferior PFS compared to pts without any TL (HR 1.66, p=0.035). Pts with CKT but without TL had comparable PFS to nCKT (HR 0.53, p=0.217) whereas pts with CKT and TL had significantly shorter PFS (HR 2.79, p<0.001). In pooled ven, particularly pts with TL involving 8q (n=22) or 18q (n=29) showed significantly shorter PFS (HR t(8q;x) 3.94, p<0.001; HR t(18q;x) 2.48, p=0.006), while with CIT numbers were too small for reliable conclusions (n=5 and n=6, respectively). In a multivariate analysis, CKT was identified as an independent prognostic factor for PFS with CIT, while in pooled ven, only hCKT and TL were identified as independent adverse factors for PFS. OS was shorter for CKT vs nCKT with CIT (HR 3.25, p=0.044), but not in the ven arms. At progression (PD), karyotyping data was available in 88 of 161 (54.7%) pts. With CIT, 7 of 20 (35.0%) pts with nCKT at baseline acquired CKT at PD, in the pooled ven group this fraction was substantially smaller (6/45, 13.3%). With CIT, the number of CA increased between baseline and PD (mean, 2.0 to 3.4) while it remained stable after ven (2.1 to 2.0). Conclusions: In pts lacking TP53 aberrations, hCKT (≥5 CA) but not iCKT (3-4 CA) was associated with shorter PFS following treatment with time-limited ven combinations. While this study confirms the adverse impact of CKT with CIT, it identifies hCKT as an adverse prognostic factor in the context of ven-based combination treatment in CLL. Presence of translocations was associated with inferior PFS in all treatment arms. Karyotyping at relapse shows increased genomic complexity after CIT as opposed to ven-based treatments. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lasting Hematopoietic Memory Induced By Gestational Diabetes Contributes to Atherosclerosis Development in Adult Offspring

One in six pregnancies is affected by some form of gestational diabetes (GD), a prevalence that is steadily rising in the context of the worldwide epidemics of obesity and early diabetic onset. Early diagnosis and advances in maternal glucose control have greatly mitigated the perinatal consequences of gestational diabetes on the mothers and the offspring. However, these advances have only marginally impacted its long-term consequences. As such, exposure to hyperglycemia in utero remains associated with long-term morbidities in adult offspring, including an increased risk of atherosclerosis and cardiovascular diseases. The mechanisms driving this pathological transmission across generations have not been established. We hypothesized that the hematopoietic system and particularly the hematopoietic stem cells (HSCs) are stably altered by GD and are essential "effectors" of its long-term pathological effects in offspring. We established two reliable genetic and pharmacological GD mouse models that reproduce the perinatal adverse features of the human pathology. In these models, we showed that gestational diabetes alters the hematopoiesis of the adult offspring even as they do not present any signs of diabetes. At steady state, we observed the skewing of the hematopoietic production toward the myeloid lineage and the expansion of key myeloid progenitors including multipotential progenitor (MPP) and granulocyte-macrophage progenitor (GMP) compartments. We also found marks of activation of the hematopoietic stem cell (HSC) compartment, which were associated with a loss of fitness in regenerative condition. Upon inflammatory challenge, GD offspring displayed an altered hematopoietic stress response that mimics the phenotype observed in mice with overt diabetes. Similar results were obtained in vitro as bone marrow-derived macrophages (BMDM) generated from GD offspring displayed functional characteristics similar to those generated from diabetic mice. Altogether these results suggest that non-diabetic GD offspring maintain, during adulthood, some hematopoietic features associated with diabetes. Importantly, this GD hematopoietic memory persisted in a hematopoietic transplantation setting, therefore indicating that this property is supported by intrinsic HSC alterations. We used atherosclerosis-prone Apoe knock-out mice to assess the impact of GD hematopoietic memory on the health of adult offspring. Consistent with the observations made in human populations, we found that GD favors atherosclerosis development in offspring with increased inflammation and cartilaginous metaplasia in the aortic valves. Importantly, similar results were obtained in a transplantation setting, therefore indicating that the alterations of the hematopoietic system in GD offspring directly contribute to the atherosclerotic phenotype. Altogether these results establish that the hematopoietic system of GD offspring maintains a long-term functional glycemic memory, even as these animals are not displaying any gross metabolic disruptions. Importantly, these results show that this hematopoietic diabetic memory contributes to the development of pathology in the adult offspring born to diabetic pregnancy.

What are the preoperative predictors of a futile pelvic exenteration in rectal cancers?

IntroductionEarly recurrences and deaths after a morbid procedure like pelvic exenteration are devastating events. The present study aimed at determining the incidence and predictors of futile pelvic exenterations. MethodsConsecutive pelvic exenterations for advanced and recurrent rectal adenocarcinomas operated between January 2013 and January 2021 were included with a minimum of six months follow-up. Futility of exenteration was defined as recurrence or death within six months of operation. Multivariate logistic regression was used to define predictors of futility. ResultsTwo-hundred eighty-five patients were included and 61 patients (21.4%) had a futile resection. Poorly differentiated (or signet) histology, presence of lateral pelvic nodes, M1 disease, and the need for pelvic bone resections predicted a futile resection. The probability of futility was 10%, 20%, 35–40%, 55–60%, and >75% when none, one, two, three, and all four of the predictors were present. The model was able to correctly predict futility in 70% of the cases suggesting moderate discrimination, and showed good calibration. ConclusionsFutile pelvic exenterations were observed in one-fifth of patients. Four strong predictors of futility were identified. The risk of early failures was additive when combination of these adverse features was present, and can be used for patient selection and prognostication.

Tertiary Gleason Pattern 5 and a High Genomic Classifier Score Better Predicts Lymph Node Invasion at Radical Prostatectomy in 20,441 Intermediate-Risk Disease Patients

<h3>Purpose/Objective(s)</h3> The POP-RT and SSPORT trial showed that pelvic lymph node radiation therapy (PLNRT) can improve prostate or bed-only oncologic outcomes. Grade groups 2 (GG2) or 3 (GG3) and Tertiary Gleason pattern 5 (TP5) are heterogeneous patient groups with varied prognoses. Genomic classifiers (GC) may provide additional information essential to identifying optimal pelvic radiotherapy candidates. We hypothesized that TP5, and a GC, could improve prognostication of lymph node invasion (LNI) after radical prostatectomy (RP) over traditional clinicopathologic risk factors alone. <h3>Materials/Methods</h3> The Decipher GRID database (Veracyte, San Diego, CA) contains de-identified GC testing and pathology results for patients tested between November 2015 and March 2020. Intermediate risk patients with GG2 or GG3 were included in the analysis of continuous GC scores (range 0-1) and GC risk groups (low, intermediate, and high). Multivariable logistic regression (MVA) was used to quantify the relationship between LNI with GC, TP5, and other clinicopathologic features (age, race, extraprostatic extension, seminal vesicle invasion, bladder neck invasion). <h3>Results</h3> 20,441 patients were included (11,934 with GG2 (58.4%) and 8,507 (41.6%) with GG3 disease). Of those with GG2 and GG3 disease, 1,451 (12.2%) and 2,911 (34.2%) had TP5, respectively. Patients with TP5 had a significantly higher GC score (median [interquartile range (IQR)]: 0.39 [0.24-0.61] vs 0.53 [0.32-0.75], p<0.001 for GG2 and median [IQR]: 0.58 [0.35-0.81] vs 0.66 [0.43-0.86, p<0.001 for GG3. In MVA adjusted for clinicopathologic features, TP5 and higher GC score were independently associated with the presence of LNI in both GG2 (TP5: odds ratio [OR] 1.60, 95% CI 1.07-2.38, p=0.02 and GC: OR 1.20 per 0.1 increase, 95% CI 1.11-1.29, p<0.001) and GG3 (TP5: OR 1.47, 95% CI 1.16-1.87, p<0.01 and GC: OR 1.13 per 0.1 increase, 95% CI 1.07-1.19, p<0.001) patients. TP5 patients with GG2 or GG3 and high GC have a 3.8- and 1.8-fold risk of LNI over those with a low GC, respectively. Patients with GC high and GG2 or GG3 have a 2.7- and 1.8-fold risk of LNI over those with or without TP5, respectively (Table 1). <h3>Conclusion</h3> TP5 was associated with higher GC scores and adverse clinicopathologic features. TP5 and higher GC are independently associated with LNI while controlling for other clinicopathologic risk factors, demonstrating their importance in future studies of pelvic RT treatment intensification or de-intensification for these patients.

The Association between Dose Escalation and Risk of Developing Metastases in Intermediate and High-Risk Prostate Cancer Patients Treated with Radiotherapy

<h3>Purpose/Objective(s)</h3> Radiotherapy dose escalation through brachytherapy or simultaneous integrated boost have been successfully introduced to clinical practice, facilitating improved local control of the tumor in intermediate and high-risk prostate cancer (PCa) patients, but not necessarily improved metastasis-free survival. Moreover, the improvement in clinical endpoints is often associated with increased risk of adverse effects. In this article, we analyzed effect of high dose-rate (HDR) brachytherapy boost (BT) dose escalation on freedom from metastases (FFM), based on real-world data. <h3>Materials/Methods</h3> The analysis was based on a multi-institutional retrospective database of 1641 consecutive intermediate (30%) or high risk (70%) prostate cancer patients treated with external beam radiotherapy (EBRT; 70.9%) or EBRT, combined with single or double fraction BT boost (29.1%). The majority of the patients (95%) received anti-androgen therapy (ADT). The biologically effective dose was calculated using α/β of 3 Gy. The follow-up data was acquired from institutional databases. The analysis included the Kaplan-Meier method and Cox regression models. A multivariable model was constructed utilizing backward stepwise feature selection based on Akaike information criterion. The model presented adjusted hazard ratios (HR) in multivariable analysis, and was further used to create a nomogram. C-index was used to assess the model. <h3>Results</h3> The median age was 63.8 years (IQR 62.9 – 73.5). Median FFM was not achieved, metastasis occurred in 234 patients (14.1%) over the course of follow up. The univariate analysis showed that BED was significantly associated with FFM (HR 0.99; CI 95% 0.98-0.99; p<0.001), along with Gleason grade group, PSA density, maximum PSA, pre-treatment PSA, T and N stage according to TNM, previous transurethral resection of the prostate, and NCCN risk group. Backward stepwise feature selection allowed to create multivariable model which included BED, prostate volume, Gleason grade group and NCCN risk groups. This model presented c-index of 0.665 and 5-fold cross-validation-corrected c-index of 0.652. The results are presented in Table 1. This model was used to create a clinical nomogram for FFM. <h3>Conclusion</h3> Biologically effective dose is an independent prognostic factor for developing metastases in patients treated with radiotherapy for intermediate or high-risk group prostate cancer. Dose escalation through brachytherapy boost can be used to decrease the risk of developing metastases in patients with adverse features.

Impact of Depth of Invasion Tumor Budding and Worst Pattern of Invasion on Clinical Outcome in Post-Operative Oral Cavity Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Definitive treatment for oral cavity squamous cell carcinoma (OCSCC) is surgery followed by post-operative radiotherapy (PORT) with or without chemotherapy. Risk factors for PORT are T3/T4, node positive, lympho-vascular space invasion (LVI) or perineural invasion (PNI), close margin etc. Depth of invasion (DOI), tumor budding (TB) and worst pattern of invasion (WPOI) and tumor infiltrating lymphocytes (TILS) may have prognostic implications. We aim to report the incidence of these factors and its association with clinical outcome post-operative OCSCC patients treated at our institute. <h3>Materials/Methods</h3> 150 post-operative patients of OCSCC undergoing curative oncological resection were analyzed with median follow up time 18 months from year 2019 to 2021. WPOI (WPOI-5) was defined as tumor dispersion of ≥1mm between tumor satellites. High risk WPOI was defined as (WPOI 4/5). Tumor budding is defined as the presence of single cancer cell or cluster of <5 cancer cells at the invasive front. DOI and staging were used as per AJCC 8^th edition. Disease free survival (DFS) and overall survival (OS) were estimated with Kaplan- Meier method. <h3>Results</h3> Median age was 50 years with M:F ratio of 135:15. Tumor site was buccal mucosa: tongue:alveolus:others as 84 (56%):49 (32%):13 (8.6%):4 (2.6%). LVI:PNI: close/positive margin: extra nodal extension was seen in 57 (38%):52 (34%):35 (23%):33 (22%) patients respectively. DOI=>10, DOI<10, high risk WPOI, tumor budding and TILS were observed in 79(52.6%), 71(47.3%), 102(72.8%), 97(71.3%) and 30(21.5%) patients respectively. Association of these have been listed in Table 1. AJCC eighth stage was I:II:III:IV as 30 (20%):32 (21.3%):38 (25.3%):50 (33.3%). Median RT Dose was 60 Gray. Sixty-four patients received CTRT (Median 5 cycles). Median Overall Treatment Time (OTT) was 98 (95-120) days. 2-year OS and DFS for the entire cohort was 81% and 67% respectively. 2-year DFS for patient with TILS was 86% vs.64% without TILS (p=0.07). PNI (60% vs. 72%; p=0.06) and bone invasion (47% vs 84%; p=0.04) portended poorer DFS. TB, WPOI and DOI did not statistically impact DFS in our cohort. <h3>Conclusion</h3> TB, WPOI and DOI are often associated in post-operative OCSCC with other adverse risk features. Patients with TILS tend to have a better clinical outcome

Multiparametric MRI as a Predictor of PSA Response in Patients Undergoing Stereotactic Body Radiation (SBRT) Therapy for Prostate Cancer

<h3>Purpose/Objective(s)</h3> In order to maximize the therapeutic ratio, it is important to identify adverse prognostic features in men with prostate cancer, especially amongst those with intermediate risk disease, which represents a heterogeneous group. These men may benefit from treatment intensification. Prior studies have shown pretreatment mpMRI may predict biochemical failure in patients with intermediate and/or high-risk prostate cancer undergoing conventionally fractionated external beam radiotherapy and/or brachytherapy. This is the first study to evaluate pretreatment mpMRI findings as a marker for outcome in patients undergoing SBRT. <h3>Materials/Methods</h3> We identified all patients treated at our institution with linear accelerator-based SBRT to 3625 cGy in 5 fractions, with or without androgen deprivation therapy (ADT) from November 2015 to March 2021. All patients underwent SpaceOAR placement followed by pre-treatment MRI. Post-treatment PSA measurements were obtained 4 months after SBRT, followed by every 3-6 months thereafter. A two-sample t-test was used to compare preoperative mpMRI features with clinical outcomes. <h3>Results</h3> 123 men were included in the study. The table below summarizes the pretreatment patient characteristics. Patients with higher pretreatment diameter of the largest intraprostatic lesion, number of prostate lesions, and maximal PI-RADS score were associated with higher PSA nadir and longer time to PSA nadir (p<0.0001). When separated by ADT treatment, this association remained for patients who were not treated with ADT (p<0.001). In patients who received ADT, the pretreatment MRI variables were each significantly associated with time to PSA nadir (p<0.01) but not with PSA nadir (p>0.30). <h3>Conclusion</h3> Our experience shows a significant association between mpMRI features and PSA outcome in patients treated with SBRT with or without ADT. Since PSA nadir has been shown to correlate with biochemical failure, this information may help radiation oncologists better counsel their patients regarding outcome after SBRT and can help inform future studies regarding who may benefit from treatment intensification with, for example, ADT and / or boost to dominant intraprostatic lesion.

Low–Grade Appendiceal Mucinous Neoplasia: A Rare Case Report

Low-grade appendiceal mucinous neoplasms (LAMN) are rarely seen. They are incidentally detected during an appendectomy for appendicitis. Treatment is appendectomy in low-grade appendiceal mucinous neoplasms. Those having adverse features based on the appendix, lymph node metastasis, and tumour size greater than 2 cm, appendectomy with hemicolectomy is done. We present a rare case report of appendiceal neoplasm diagnosed with low-grade appendiceal mucinous neoplasm (LAMN) managed by appendectomy with right hemicolectomy.

Coexistent diabetes is associated with the presence of adverse phenotypic features in patients with hypertrophic cardiomyopathy

Abstract Background Type 2 diabetes mellitus (DM) is associated with worsened clinical outcomes in hypertrophic cardiomyopathy (HCM) patients. The reasons for this adverse prognostic association are incompletely understood. Although distinct entities both HCM and DM share common features of impaired myocardial energetics and coronary microvascular function. Purpose We sought to test the hypothesis that co-existent diabetes is associated with greater reductions in myocardial energetics and perfusion, and higher scar burden in HCM. Research design and methods Seventy-five age- and sex-matched participants with concomitant HCM and DM (HCM-DM, n=20), isolated HCM (n=20), isolated DM (n=20) and healthy volunteers (HV, n=15) underwent 31phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance imaging. The HCM groups were matched for HCM phenotype. The DM groups were matched for diabetes treatment, duration, HbA1c, body mass index and hypertension comorbidity. Results ESC sudden cardiac death risk scores were comparable between the HCM groups (HCM: 2.2±1.5%, HCM-DM: 1.9±1.2%; p=NS) and sarcomeric mutations were equally common. HCM-DM had the highest NT-proBNP levels (HV: 42 ng/L [IQR: 35–66], DM: 118 ng/L [IQR: 53–187], HCM: 298 ng/L [IQR: 157–837], HCM-DM: 726 ng/L [IQR: 213–8695]; p&amp;lt;0.0001). Left-ventricular ejection fraction, mass and wall thickness were similar between the HCM groups. HCM-DM displayed a greater degree of fibrosis burden with higher scar percentage, and lower global longitudinal strain compared to the isolated HCM. PCr/ATP was similarly decreased in the HCM-DM and DM (HV: 2.17±0.49, DM: 1.61±0.23, HCM: 1.93±0.38, HCM-DM: 1.54±0.27; p=0.0003). HCM-DM had the lowest stress myocardial blood flow (HV: 2.06±0.42 ml/min/g, DM: 1.78±0.45 ml/min/g, HCM: 1.74±0.44 ml/min/g, HCM-DM: 1.39±0.42 ml/min/g; p=0.004). Conclusions We show for the first time that HCM patients with DM comorbidity display greater reductions in myocardial energetics, perfusion, contractile function and higher myocardial scar burden and serum NT-proBNP levels compared to patients with isolated HCM despite similar LV mass and wall thickness and presence of sarcomeric mutations. These adverse phenotypic features may be important components of the adverse clinical manifestation attributable to a combined presence of HCM and DM. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Diabetes UK

Association of serum MMP9 with adverse features of plaque progression in patients with chronic coronary syndrome (CCS)

Abstract Background Previous studies have demonstrated that MMP-9 may be a predictor of atherosclerotic plaque instability and future adverse cardiovascular events, but longitudinal data on the association between MMP9 and coronary disease progression are lacking. Purpose This study is aimed at investigating whether MMP9 is associated with atherosclerotic plaque progression. Methods MMP9 serum levels were measured in stable patients with chronic coronary syndrome (CCS) undergoing coronary computed tomography angiography at baseline and after a period of 6.5±1.1 years of follow up to assess progression of Total, Fibrous, Fibro-fatty, Necrotic Core, and Dense Calcium plaque volume (PV). The relationship of serum MMP9 with plaque progression was assessed using linear regression analysis, adjusting for clinical variables including, age, sex, risk factors, medical therapy, LDL-C, TG/HDL-C ratio, hs-CRP, and the presence of obstructive CAD (&amp;gt;50% coronary stenosis in at least one major coronary vessels). Results A total of 157 patients (58±8 years of age; 66% males) were included in the analysis, with median MMP9 values of 135±186 mg/dL (mean ± SD). Annual changes of Total, Fibrous-Fatty and Necrotic Core PV were significantly different across MMP9 tertiles (Figure 1). Multivariable linear regression analysis demonstrated a positive association between serum levels of MMP9 and annual change of Total and Necrotic Core PV (Figure 1). Conclusion Among patients with CCS, MMP9 serum levels were an independent predictor of progression of coronary plaque burden and, in particular, of adverse plaque features, such as Necrotic Core PV. This association was robust and independent from baseline traditional cardiovascular risk factors and medications, supporting for MMP9 a role as a novel marker of residual coronary risk. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020 - Project “Simulation Modeling of coronary ARTery disease: a tool for clinical decision support–SMARTool”

Albumin and its association with lung cancer: An Indian perspective

Studies have been carried out world over, to evaluate the role of albumin in lung cancer. However, limited studies which have addressed association of albumin with patient factors such as type of lung cancer, gender, performance status, stage, hemoglobin levels, and neutrophil lymphocyte ratio. In our study, we aimed to evaluate the association of albumin with these factors. Amongst the 100 lung cancer cases, 69 were adenocarcinoma, 16 squamous cell, 13 small cell and 2 adenosquamous and, value of albumin below 3.4gm/dl was taken as hypoalbuminemia. Hypoalbuminemia was seen in 84% of small cell, 65% of adenocarcinoma, performance score (PS) of 1 - 47%, PS2- 61%, PS3- 75%, 65% of females, 61% of males, 70% of cases with symptoms less than 3 months duration, 41% of more than 3 months duration, 76% of stage IV, 13% of stage III, 68% of the males with anemia, 35% males with normal hemoglobin, 86% of females with anemia, and 14% with normal Hb. Lower albumin values co-relate with advanced disease and is considered as an adverse prognostic factor. However, this association is not absolute, as a significant number of patients without adverse features also have hypoalbuminemia. There are probably multiple roles of albumin in a cancer patient along with multiple factors effecting albumin levels whether treating hypoalbuminemia with albumin improve overall survival also need to be elucidated by further studies.

A streamlined, machine learning-derived approach to risk-stratification in heart failure patients with secondary tricuspid regurgitation

Abstract Background Secondary tricuspid regurgitation (sTR) is the most frequent valvular heart disease and has significant impact on mortality. A high burden of comorbidities often worsens the already dismal prognosis of sTR, while tricuspid interventions remain underused and initiated too late. Objectives To examine the most powerful predictors of all-cause mortality in moderate and severe sTR using machine learning techniques and to provide a streamlined approach to risk-stratification using readily available clinical, echocardiographic and laboratory parameters. Methods This large-scale, long-term observational study included 3359 moderate and 1509 severe sTR patients encompassing the entire heart failure spectrum (preserved, mid-range and reduced ejection fraction). A random survival forest was applied to investigate the most important predictors and group patients according to their number of adverse features (Figure 1). Results The identified predictors and thresholds, that were associated with significantly worse mortality were higher age (≥75 in moderate and ≥70 years in moderate and severe sTR respectively), higher NT-proBNP (≥4000 pg/ml), increased high sensitivity C-reactive protein (≥1.0 mg/dl), serum albumin &amp;lt;40 g/L and hemoglobin &amp;lt;13 g/dL. Additionally, grouping patients according to the number of adverse features yielded important prognostic information, as patients with 4 or 5 adverse features had a sevenfold risk increase in moderate sTR (7.11 [2.27–4.30] HR 95% CI, P&amp;lt;0.001) and fivefold risk increase in severe sTR (5.08 [3.13–8.24] HR 95% CI, P&amp;lt;0.001) (Figure 2: A moderate sTR derivation, B moderate sTR validation, C severe sTR derivation, D severe sTR validation). Conclusion This study presents a streamlined, machine learning-derived and internally validated approach to risk-stratification in patients with moderate and severe sTR, that adds important prognostic information to aid clinical decision-making. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund

Comparative diagnostic and prognostic implications of right versus left bundle branch block in patients with suspected ST-segment elevation myocardial infarction

Abstract Background Current ESC guidelines on management of acute myocardial infarction in patients presenting with ST-segment elevation (STEMI) recommend emergent invasive management in patients with ischemic symptoms and bundle branch block (BBB). While left bundle branch block (LBBB) is a well-known high-risk feature in patients with acute myocardial infarction, data on the diagnostic and prognostic impact of right bundle branch block (RBBB) in comparison to LBBB in the context of STEMI are scarce. Methods A prospective cohort of 2,139 patients with suspected STEMI were triaged by the on-call cardiologist to acute coronary angiography based on a prehospital, tele-transmitted digital 12-lead electrocardiogram. All discharge diagnoses were independently adjudicated. The diagnostic accuracy of RBBB or LBBB was calculated. 30-day and 1-year all-cause mortality were from a central national registry and compared for LBBB, RBBB and patients without BBB using the Kaplan Meier method. Unadjusted and adjusted (age, sex, hypertension, hyperlipoproteinemia, smoking status and history of coronary artery disease) hazard ratios for 1-year mortality were calculated for both BBB-types. Results The final diagnosis of STEMI was adjudicated in 1,832/2,139 (85.6%) of patients. RBBB was present in 117 (5.5%), LBBB in 61 (2.9%) patients, respectively. Patients with BBB were older than non-BBB patients: Median age was 69.7 years in RBBB, 68.9 years in LBBB and 62.6 years in non-BBB patients. Comparing both BBB types, LBBB patients more often had prior heart failure (6.3% in RBBB vs 11.5% in LBBB), while RBBB patients more often developed cardiac arrest before angiography (15.3% vs 3.7% in RBBB and LBBB patients respectively) and more frequently revealed Thrombolysis in Myocardial Infarction (TIMI) grade flow of 0 (61.0% vs 47.2%, respectively). Specificity for the final diagnosis of STEMI was not significantly different in both BBB-types: 95.1% (95% CI 92.1–97.0) in RBBB versus 92.8% (95% CI 89.4–95.2) in LBBB patients (p=0.25). Patients with RBBB had significantly higher 30-day and 1-year mortality (Figure 1), while LBBB and non-BBB patients showed similar outcome. Unadjusted hazard ratio for 1-year mortality comparing RBBB to non-BBB patients was 3.35 (95% CI 2.11–5.34, p&amp;lt;0.001) and 1.4 (95% CI 0.57–3.44, p=0.46) when comparing LBBB to non-BBB patients. After adjustment hazard ratio for RBBB patients was 2.3 (95% CI 1.25–4.21, p=0.007). Conclusion In the context of suspected STEMI, RBBB is an ominous sign associated with adverse clinical features like cardiac arrest prior to PCI, TIMI grade 0 flow, compared to LBBB or non-BBB presenters. Consequently, RBBB patients had poorer outcome after 12 months. Our data therefore reinforce current guidelines in designating RBBB-patients as very high-risk, demanding immediate management and triage. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Regional Research Foundation in Region Sjaelland, Denmark

Candidacy for heart transplantation in adult congenital heart disease patients: a cohort study

Abstract Objective The object of the present study is to evaluate factors precluding heart transplantation (HTx) in adult congenital heart disease patients (ACHD) with end-stage heart failure (HF) referred for HTx evaluation. Methods This retrospective cohort study enrolled consecutive ACHD patients considered for HTx in our institution between 2014 and 2020 and patients receiving HTx between 2001 and 2013. HTx refusal due to poor candidacy status for excess risk of mortality after transplantation, served as the main study outcome. Results Between 2014 and 2020, 46 ACHD patients were evaluated for HTx, 14 ACHD patients underwent HTx between 2001 and 2013. We compared clinical, anatomical and demographic data of 41 patients suitable for transplantation (including both listed/transplanted patients, not yet listed because too well and patients who chose to refuse transplantation) with 15 patients refused after screening (excluding 4 patients with ongoing screening). Risk factors for refusal were: multiple high risk features (odds ratio [OR]: 3.6; 95% confidence interval [CI]: 1.1 to 12.9; p 0.048); anatomical factors (OR: 14.5; 95% CI: 3.1 to 68.4; p 0.001), out-of-center ACHD/HTx program referral (OR: 5.3; 95% CI: 1.5 to 19.0; p 0.01). HTx refusal identifies a high risk ACHD patient subgroup (hazard ratio for overall mortality: 3.1; 95% CI: 1.1 to 8.3; p 0.02). Conclusions In our study risk factors for refusal from HTx are adverse anatomical features, multiple conventional HTx high risk factors and out-of-center referral. ACHD patients refused from HTx present shorter time to death. Efforts to increase HTx candidacy are strongly necessary for this growing population. Funding Acknowledgement Type of funding sources: None.

Spontaneous coronary artery dissection: current evidence from cardiac magnetic resonance and angiography screening

Abstract Purpose To assess the distribution and extent of myocardial infarction, as well as possible clinical significance of peripheral arteriopathy screening in a cohort of patients presented with spontaneous coronary dissection (SCAD) using cardiovascular magnetic resonance (CMR) for cardiac and vascular imaging. The adverse CMR features and predictors of infarction in subgroup analysis were also investigated. Methods This is an observational, single centre study of 144 consecutive, angiographically confirmed SCAD survivors &amp;gt;18 years old, based on collected data from Jan 2008-Nov 2020. All scans were performed on a 1.5-Tesla scanner. Cardiac structural and functional indices, myocardial infarct size and distribution were evaluated. In addition, vascular imaging was performed in all patients for thoracic aorta screening as part of the routine protocol, and in 75 patients peripheral arteriopathy screening from Circle of Willis to the iliac arteries was performed using 2D multi-slice and cine imaging, as well as 3D imaging methods. Results In the total population, 64% had infarction. Infarct size (%) was predictive of reduced left ventricular ejection fraction (LVEF) (p&amp;lt;0.001) and increased diastolic volumes (p&amp;lt;0.001 for both). Logistic regression showed SCAD in right coronary artery (Odds Ratio (OR): 5.2, p=0.034) predicted the presence of infarction. In the group who also underwent peripheral vascular screening, the overall prevalence of extra-coronary arteriopathy was 27% with fibromuscular dysplasia accounting for one-fourth of the cases (Figure 1). Of note, most positive vascular screening patients (73.3%) exhibited infarction (OR: 7.0, p=0.041), distributed in more than one territory (OR: 4.0, p=0.015) (Figure 2), while infarct size was negatively correlated with LVEF (p&amp;lt;0.001). Right ventricular ejection fraction was significantly reduced in positive screening patients (58.8±7.4 vs. 63.0±8.0, p=0.045). Further subgroup analysis showed pregnancy associated SCAD patients had significantly larger sized infarcts (25.1±6.1 vs. 6.2±0.7%, p&amp;lt;0.001) with reduced LVEF (51.0 vs 63.6±7.6, p&amp;lt;0.001). In logistic regression, this condition also predicted large infarcts &amp;gt;10% (OR: 9.8, p=0.009) in anterior walls (p&amp;lt;0.001). Conclusions Patients with SCAD require careful assessment of myocardial structure, function and characterization of infarction which may reflect the underlying pathophysiology. Extra coronary vascular screening, although not established in clinical practice, seems a rational strategy to potentially identify a subgroup with more severe infarction and likely to have vascular pathology. Funding Acknowledgement Type of funding sources: None.