Relapse Disease-free Survival Research Articles

Treosulfan- Versus Busulfan-based Conditioning in Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome: A Single-center Retrospective Propensity Score-matched Cohort Study

Treosulfan has shown promise in allogeneic hematopoietic cell transplantation (HCT) for its myeloablative properties and low toxicity. In this single-center retrospective propensity score-matched cohort study we compared treosulfan- and busulfan-based conditioning in allogeneic HCT for patients with myelodysplastic syndrome (MDS). This study included 138 adults who underwent allogeneic HCT for MDS or chronic myelomonocytic leukemia (CMML) at Princess Margaret Hospital, Toronto 2015-2022. Using propensity score matching, we compared transplant outcomes between two well-matched cohorts who received conditioning with either fludarabine-treosulfan (FT) (n=46) or fludarabine-busulfan with total body irradiation (FBT200) (n=92). A scoring system based on patient age, Karnofsky performance score and hematopoietic cell transplant comorbidity index was used to assign patients based on fitness to low-dose (30 g/m2) or high-dose (42 g/m2) treosulfan: 32 (69.6%) received high-dose treosulfan. The racial composition of the two groups was similar, with 27.2% and 21.7% of FBT200 and FT recipients, respectively, identifying as non-Caucasian (P=0.61). Primary outcomes were analyzed at a median follow-up of 747 days. Of all participants, 116 (84.0%) received graft-vs-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCY) and anti-thymocyte globulin (ATG) . Patients who received FT had a superior 2-y overall survival (OS) compared to those who received FBT200: 66.9% (95% confidence interval (CI): 46.1-81.2) vs. 44.5% (95% CI: 34-54.4), hazards ratio (HR): 0.43, 95% CI: 0.22-0.84 (P=0.013). In multivariate analysis (MVA), only the use of fresh grafts (P=0.02) and FT (P=0.01) were associated with improved OS. FT was associated with superior 2-y relapse-free survival (RFS) compared to FBT200: 63.1% (95% CI: 42.6-77.9) vs. 39.1% (95% CI: 29.1-49.1), HR: 0.44 (95% CI: 0.24-0.81), P=0.008. In MVA, the use of fresh grafts (P=0.03) and FT (P=0.009) were associated with improved RFS. Recipients of FT demonstrated superior 2-y graft versus host disease relapse-free survival (GRFS) compared to those who received FBT200: 57.4% (95% CI: 37.8-72.8) vs. 35.1% (95% CI: 25.5-45). In MVA, only FT was associated with superior GRFS (P=0.02). FT recipients exhibited markedly superior 1-y event-free survival (EFS) compared to recipients of FBT200 in univariate analysis (40.3% (95% CI: 25.9-54.2) vs. 9.2% (95% CI: 4.4-16.3), HR: 0.47 (95%CI: 0.30-0.72), P<0.001) and MVA (P=0.004). FT was associated with lower 1-y non-relapse mortality (NRM) compared to FBT200 in univariate analysis (9.9% (95% CI: 3.0-21.8) vs. 29.7% (95% CI: 20.6-39.3), HR: 0.41 (95% CI: 0.17-0.96), P=0.04) and MVA (P=0.04). Our study utilized propensity score matching to demonstrate superiority of treosulfan- over busulfan-based conditioning in stem cell transplantation of patients with MDS and is the first to evaluate the performance of treosulfan-based conditioning in combination with ATG and PTCY. As such, it contributes to the increasing body of evidence supporting the safety of treosulfan, even at the dose of 42 g/m2.

Immunohistochemical Expression of Immune Checkpoints; CTLA-4, LAG3, and TIM-3 in Cancer Cells and Tumor-infiltrating Lymphocytes (TILs) in Colorectal Carcinoma.

Colorectal cancer is considered the third most prevalent cancer in both sexes. Immune checkpoint receptors that regulate T-cell response, stimulation, and development include lymphocyte activating gene 3 (LAG-3), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and T-cell immunoglobulin and mucin domain 3 (Tim-3). In addition, they are crucial for the advancement of cancer and tumor immune escape. This work's aim was to assess the immunohistochemistry expression of Tim-3, CTLA-4, and LAG-3 in cancer cells and tumor-infiltrating lymphocytes (TILs) in colorectal cancer (CRC) and the correlation between these markers and clinicopathological variables and survival data. This study involved 206 CRC specimens processed for CTLA-4, LAG3, and TIM-3 immunohistochemistry and correlated with the clinicopathological and survival parameters of the patients. High CTLA-4 epithelial expression was highly related to the old age group, large tumor size, low tumor-stroma ratio (TSR), high grade, advanced stage, the presence of distant metastasis (DM), perineural invasion (PNI), necrosis, lymphovascular invasion (LVI), relapse, mortality, overall survival (OS), and disease-free survival (DFS), while negative CTLA-4 TILs expression was highly linked with the presence of gross perforation, low TSR, high tumor budding (TB) score, high grade, advanced stage, the existence of lymph node (LN) metastasis, DM, necrosis, LVI, PNI, DFS, mortality, and OS. Positive LAG-3 TILs expression was highly correlated with large tumor size, gross perforation, low TSR, high TB score, high grade, advanced phase, the presence of LN, necrosis, LVI, PNI, relapse DFS, mortality, and OS. High Tim-3 epithelial expression was extremely linked with low TSR, advanced phase, the presence of LN, LVI, PNI, relapse, DFS, mortality, and OS, while positive Tim-3 TILs expression was related to gross perforation, low TSR, high TB score, advanced stage, the presence of LN, DM, necrosis, relapse, DFS, mortality, and OS. The patients' poor prognosis may be related to the immunohistochemistry expression of LAG-3, Tim-3, and CTLA-4 in CRC cancer tissue and TILs. Poor patient consequences can result from the CTLA-4, Tim-3, and LAG-3 co-expression, but CTLA-4 TILs' expression of these proteins may inhibit the growth of tumors.

Allogeneic hematopoetic stem cell transplant for patients with refractory T-Cell lymphomas.

Allogeneic stem cell transplantation (allo-SCT) may have a curative potential due to the graft versus lymphoma effect. In this study, we aimed to compare transplant outcomes between refractory-T-NHL (ref-NHL) and Chemosensitive-T-NHL (CS-T-NHL). We retrospectively reviewed the records of 26 ref-NHL and 29 CS-T-NHL consecutive patients who underwent allo-SCT at our center and compared the transplant outcomes between the groups. All patients were heavily pretreated with 27% of patients relapsing post-auto-SCT and two patients in the ref-T-NHL post-allo-SCT. Patients were transplanted mainly from unrelated donors. There were no differences in leucocytes and platelet engraftment between the two groups. At 3 years, the relapse incidence was 34% in Ref-TNHL and 19% in CS-TNHL (p = .33), with non-relapse mortality rates of 28% and 22%, respectively (p = .52). Female patients and those with a previous auto-SCT had lower relapse incidence (p = .045, p = .003). The 3-year overall survival was 39% in Ref-TNHL and 56% in CS-TNHL (p = .15). Trends for improved progression-free survival (PFS) and graft-versus-host disease relapse-free survival (GRFS) were observed in the CS-TNHL group (PFS: 60% vs. 30%, p = .075; GRFS: 38% vs. 21%, p = .1). Acknowledging the retrospective nature of our study, our results indicate that allo-SCT has a curative potential in patients with T-NHL even in refractory status.

Influence of conditioning regimen intensity on outcomes post-allogeneic hematopoietic cell transplantation for acute myeloid leukemia in complete morphological remission.

The literature comparing outcomes between myeloablative (MAC) and reduced intensity conditioning (RIC) for acute myeloid leukemia (AML) is conflicting. We retrospectively analyzed 451 patients who underwent allogenic hematopoietic cell transplantation (alloHCT) for AML in complete remission (CR) with either RIC (n = 331) or MAC (n = 120) with the use of dual T-cell depletion as graft-versus-host disease (GVHD) prophylaxis. Univariate analysis demonstrated nonrelapse mortality (NRM) at 2 years was 19.1% for MAC and 22.5% for RIC (p = .44). Two-year cumulative incidence of relapse (CIR) was 19.8% for MAC and 24.5% for RIC (p = .15). Two-year overall survival (OS) was 61% and 53% for MAC and RIC, respectively (p = .02). Two-year graft-versus-host disease relapse-free survival (GRFS) was 40.8% for MAC and 33.7% for RIC (p = .30). A propensity score-matched analysis was done matching patients for age, HLA match, in vivo T-cell depletion, and Disease Risk Index (DRI). Two-year OS was 67% for MAC, 66% for RIC (p = .95). A subgroup analysis identified that matched related donor transplants benefit from MAC with OS at 2 years 82.6% versus 57.3% for RIC (p = .006). In the matched-related donor setting, MAC regimens may offer superior survival. Overall, for our cohort of predominantly in vivo T-cell depleted patients the outcomes of MAC and RIC were similar.

Donor Age Influences Graft-Versus-Host Disease Relapse-Free Survival after Allogeneic Stem Cell Transplant in Elderly Patients in Two Countries from Latin America.

Allogeneic stem cell transplantation (Allo-SCT) in elderly patients is a growing practice. We aimed to determine the graft-versus-host disease (GVHD) relapse-free survival (GRFS) in patients ≥65 years who underwent Allo-SCT in two countries from Latin America. We performed a retrospective analysis of patients ≥65 years who underwent Allo-SCT in Argentina and Brazil from 2007 to 2019. Ninety-eight patients were evaluated, with primary diagnoses of acute myeloid leukemia and myelodysplastic syndrome; 30% of patients had a hematopoietic cell transplant-comorbidity index (HCT-CI) score ≥3 and 49% were in complete remission. Donor types included matched sibling (n = 41), matched unrelated (n = 31), and haploidentical (HID; n = 26) donors. The conditioning regimen was myeloablative in 28 patients (14 busulfan pharmacokinetically [PK]-guided) and reduced-intensity in 70 patients. The two-year non-relapse mortality (NRM) was 29%, with a higher NRM in melphalan-based compared to other conditionings (51% vs. 33%, p = 0.02). The two-year relapse rate was 24%, with a reduction in PK-guided busulfan (0% vs. 28%, p = 0.03). The two-year overall survival (OS) and GRFS was 52% and 38%, respectively, with a significant reduction in GRFS in HCT-CI ≥3 (27% vs. others 42%, p = 0.02) and donors ≥40 years (29% vs. <40 years 55%, p = 0.02). These variables remained significantly associated with GRFS after multivariate analysis. In this cohort of elderly patients from Argentina and Brazil undergoing Allo-SCT, donor age and comorbidities significantly influenced GRFS. The role of the conditioning regimen in this population deserves further investigation.

AML-446: CD34+ Dosing and Correlation with Cytokine Release Syndrome in Haploidentical SCT

Introduction: Optimum dosing of CD34+ haploidentical stem cells in allogeneic stem cell transplant is not clear. Investigators have shown better outcomes with higher doses of CD34+ stem cells, but there is a concern for higher rates of cytokine release syndrome (CRS). We investigated the dosing of CD34+ stem cells at our institute. The aim of this study was to find out if higher dosing resulted in higher rates of CRS and if CD34+ dose affected 1-year GRFS (graft-vs-host disease relapse-free survival), OS (overall survival), and RFS (relapse-free survival). Method: Retrospective chart review of patients who underwent haploidentical stem cell transplant at Norris Cancer Center. Patients who received CD34+ + ≤ 5×106/kg were included in group A, and CD34+ >5×106/kg were included in group B. Results: A total of 103 patients were reviewed, 55% male and 45% female, the majority of which were Hispanic (62%). The most common diagnoses were AML (40%) and ALL (34%). CD34 did not correlate with aGVHD, cGVHD, grade 2 CRS, or pressor requirement, but it was significantly correlated with the grade 3 CRS requirement for oxygen, and ICU admission increased with higher CD34 doses. We did not find any significant difference in 1-year GRFS (p-value=0.297), OS (p-value=0.151), or RFS (p-value=0.175) between both groups. Conclusion: Our review raises some concerns that higher doses of CD34+ are correlated with higher rates of cytokine release syndrome, and optimum dosing should be studied in prospective trials.

On Behalf of the SFGM-TC: Retrospective Comparison of Reduced and Higher Intensity Conditioning for High-Risk Myelodysplastic Syndrome Treated With Allogeneic Stem-Cell Transplantation

BackgroundAllogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains the best curative option for high-risk myelodysplastic syndrome . We retrospectively compared patient outcomes after allo-HSCT according to the intensity of the conditioning regimen. Patients and MethodsThree conditioning regimens were compared in 427 patients allografted for high-risk myelodysplastic syndrome: reduced-intensity conditioning (RIC), fludarabine (150-160 mg/m2) and busulfan (6.4 mg/kg); sequential FLAMSA-RIC, fludarabine, amsacrine, and aracytine followed by RIC; and myeloablative with reduced toxicity (RTC), fludarabine and busulfan (9.6 mg/kg or 12.8 mg/kg). ResultsThe patients in the 3 conditioning groups were different in regards to the number of treatment lines (P< .001), percentage of blasts in bone marrow (P< .001), and disease status at transplantation (P< .001). No significant differences in outcomes (overall survival, progression-free survival, nonrelapse mortality, relapse incidence, and graft versus host disease relapse-free survival) were observed between the 3 groups. Using propensity score analysis to overcome baseline imbalances, we compared 70 patients receiving FLAMSA-RIC to 260 patients receiving RIC, and compared 83 patients receiving RTC to 252 patients receiving RIC. The only factor influencing overall and progression-free survival was cytogenetic risk at transplantation. After the covariate adjustment using propensity score to reduce baseline imbalances, the only factor influencing overall and progression-free survival was still cytogenetic risk at transplantation. ConclusionOverall survival appears to be similar with the 3 conditioning regimens. The only factor influencing survival is cytogenetic risk at transplantation, suggesting that new promising drugs in the conditioning and/or early interventions after transplantation are needed to improve outcomes in these patients.

Intraductal Papillary Neoplasm of the Bile Duct: Case Series

The intraductal papillary neoplasm of the bile duct (IPNB) traditionally called “biliary papillomatosis” is a extremely rare entity, regarded as the biliary equivalent of intraductal papillary mucinous neoplasm of the pancreas. It is considered a premalignant lesion, which progresses in a multistep fashion towards invasive cholangiocarcinoma. IPNB can occur in any segment of the bile duct. The most common radiological findings are dilatation of the bile duct and the presence of intraductal masses. Free margin resection is the treatment of choice for IPNB but could require extreme HPB surgery including liver transplantation. Published papers about IPNB are usually from Asia. Methods: Retrospective study 2014-2020 made in two HPB Units. We checked our prospective database looking for IPNB. We studied patient data, diagnostic methods, surgical procedures performed, pathologic findings and follow-up. Results: We found three cases. After several diagnostic methods, we found intraductal biliary mass and dilatation of the bile duct Results are in Table I.EP229_Table ICaseAge/GenderMain SymptomDiagnostic Methods (DM)LocationMultifocal/UniqueType of SurgeryClavien168 FemaleJaundiceUS,CT,CPRE, SPYGLASSExtrahepatic BDMultifocalBD resection + HJIIIA262 FemaleAbdominal painUS,CT,USE,MRIExtrahepatic BDUniqueBD resection + HJII373 MaleJaundiceUS,CT,USEExtrahepatic BD+ PancreasMultifocalPancreatoduodenectomyIISize Big TumorTNM/RFinal HistologyFollow-Up (M)RelapseDisease Free Survival (M)Overall Survival11,5 CMT1N0M0R1Colangiocarcinoma on IPNB Pancreatobiliary4NO4422 CM-R0IPNB Gastric44NO444432,5 CMT2N2M0R1Colangiocarcinoma on IPNB Pancreatobiliary14SI914 Open table in a new tab Conclusions: IPNB is an extremely rare disease. Diagnosis is not easy and many diagnostic methods are needed to obtain a correct preoperative diagnosis. Extrahepatic bile duct was the most frequent location. In two patients, cholangiocarcinoma was present in surgical specimen, one of them with lymph node spread who implied short survival. Multifocal and unique mass cases are two very different scenarios of the same entity. A European retrospective multicentric study could give information about incidence and characteristics of European patients with IPNB.

A national real-world prospective study to assess the effectiveness of adjuvant trastuzumab-dkst in HER2 breast cancer.

e13023 Background: Real-World Evidence (RWE) are gain importance once they are designed to evaluate the effectiveness of drugs whose efficacy has already been demonstrated in randomized controlled trials. In 2017, Brazil approved the first biosimilar of trastuzumab for treatment of breast cancer (BC) with overexpression of HER2. The anti-HER2 treatment significantly improves outcome in patients with HER2-positive BC. Trastuzumab-dkst is clinically effective biosimilar and help to increase access to BC treatment. The aim of this RWE is to address the effectiveness of adjuvant biosimilar trastuzumab-dkst in Brazilian women with early HER2+ BC. Methods: This is a national, multicenter, observational, prospective, RWE study conducted in Brazilian institutions. A hundred and seventy female adult patients, with diagnosis of early stage HER2-positive BC, who received at least one dose of trastuzumab-dkst as adjuvant therapy will be included. The follow-up period will be 5 years after the first dose of trastuzumab-dkst, unless tumor recurrence or death. The safety endpoints are the occurrence adverse events. The effectiveness endpoints are invasive disease relapse-free survival rate at 18, 24, 30 and 36 months after the start of biosimilar use, the invasive disease relapse-free survival after curative-intent surgery and overall survival after curative intent surgery. Given the inexistence of a specific hypothesis to be tested, sample size was based on the accuracy of the two-sided 95% confidence interval (95% CI) for the invasive disease relapse-free survival rate. Results: The recruitment planning covered 21 sites across the five regions of Brazil: North, Northeast, Midwest, Southeast, and South. From those 21 sites, 14 ( &gt; 50%) have already been approved by their local ethical committee for patient recruitment. At 7 months, we have enrolled 50 patients over the five Brazilian regions, which means 29.4% of the total. Conclusions: To conduct RWE in Brazil is still challenging and we have listed 5 possible reasons: (1) there are few RWE studies running in the country, (2) we do not have trialists experienced in RWE design; (3) low medical commitment to adverse event report in RWE; (4) low budget for RWE; (5) slow ethics and regulatory process approval in Brazil. Considering the pioneering and challenges to develop the RWE in Brazil, we are achieving optimum adherence from medical sites. Moreover, roughly one quarter of the target recruitment was reached in the first 7 months after the study start date. Clinical trial information: NCT03892655 .

Abstract OT2-01-05: A prospective real-world national study to evaluate the efficacy and safety of adjuvant biosimilar trastuzumab in the treatment of HER2-positive breast cancer

Abstract Background: Treatment with anti-HER2 therapy significantly improved survival outcomes in patients with HER2-positive Breast Cancer (BC). In Brazil, Trastuzumab was the first biosimilar approved in the treatment of patients with breast (any disease setting) and advanced gastric cancer with overexpression of HER2. Increase access to this important treatment may be enhanced with biosimilar approval. The aim of this Real-World study is to assess the efficacy and safety of adjuvant biosimilar trastuzumab in Brazilian patients with early HER2+ BC. Methods: This is a national, multicenter, observational prospective, real-world study in a variety of Brazilian institutions. A hundred and seventy adult patients, with diagnosis of early stage HER2-positive breast cancer, who received at least one dose of biosimilar trastuzumab (Zedora) as adjuvant therapy will be included. Patients will be followed for 5 years after the use of biosimilar trastuzumab (Zedora), unless recurrence or death. Safety outcomes will be recorded. Efficacy outcomes include invasive relapse-free survival (IRFS) rate at 18, 24, 30 and 36 months treatment initiation. Given the inexistence of a specific hypothesis to be tested, sample size was based on the accuracy of the two-sided 95% confidence interval (95% CI) for the invasive disease relapse-free survival rate. Results: In development countries such as as Brazil, oncology treatments with biological drugs have high costs and represent an import ibarrier to patients access to anti HER2 therapy. The use of biosimilars may result in significant health care savings. Conclusions: Considering the HERITAGE study, in which biosimilarity was clearly demonstrated between the reference monoclonal antibody and the biosimilar, we do expect to find the same safety and efficacy profile. Citation Format: Leandro Alves, Débora Gagliato, Mayara de Paula, Ana Carolina Cardoso, Alexandre Alcantara, Maristela Precivale, Vivienne Castilho. A prospective real-world national study to evaluate the efficacy and safety of adjuvant biosimilar trastuzumab in the treatment of HER2-positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-01-05.

Sirtuin6 (SIRT6) Promotes the EMT of Hepatocellular Carcinoma by Stimulating Autophagic Degradation of E-Cadherin.

EMT is a pivotal mechanism involved in tumor metastasis, which is the leading cause of poor prognosis for hepatocellular carcinoma (HCC). Sirtuin family members function as NAD+-dependent deacetylases that are essential for tumor metastasis and epithelial-mesenchymal transition (EMT). However, no causal association has been established between Sirtuin6 (SIRT6) and HCC metastasis. SIRT6 expression pattern and its association with HCC metastasis were investigated by informatic analysis, and verified by qRT-PCR and immunochemistry in HCC tissues. Transwell assay, qRT-PCR, and immunofluorescence assay were utilized to assess the effects of SIRT6 on metastasis and E-cadherin expression in vitro and in vivo. Immunoprecipitation assay was performed to observe whether SIRT6 deacetylated Beclin-1 in HCC cells. Immunofluorescence assay and inhibitor treatment rescue experiments were used to clarify the mechanism by which SIRT6 facilitated EMT and metastasis. SIRT6 upregulation was quite prevalent in HCC tissues and closely correlated with worse overall survival, disease-relapse free survival, and HCC metastasis. Furthermore, SIRT6 promoted HCC cell migration, invasion, and EMT. Mechanistically, we found that SIRT6 deacetylated Beclin-1 in HCC cells and this event led to the promotion of the autophagic degradation of E-cadherin. Noticeably, E-cadherin degradation and invasion, migration induced by SIRT6 overexpression could be rescued by dual mutation of Beclin-1 (inhibition of acetylation), CQ (autophagy inhibitor), and knockdown of Atg7. In addition, SIRT6 promoted N-cadherin and Vimentin expression via deacetylating FOXO3a in HCC. These results established a relationship between SIRT6 and HCC EMT and further elucidated the mechanisms underlying HCC metastasis, helping provide a promising approach for the treatment of HCC. IMPLICATIONS: Inhibiting SIRT6 represents a potential therapeutic approach to suppress HCC metastasis partially through reduction of autophagic degradation of E-cadherin.

Phototherapy as a First Line Treatment for Mycosis Fungoides: A 10-year Retrospective Study

Introduction: Phototherapy, particularly psoralen plus ultraviolet A (PUVA) and narrowband ultraviolet B (nbUVB), is a mainstay in the treatment of Mycosis Fungoides (MF).&#x0D; Methods: We analyzed outcomes of MF patients treated for the first time with either PUVA or nbUVB at the Photodermatology Unit, in the Department of Dermatology of Centro Hospitalar Universitário do Porto, from 2007 to 2017. The primary outcome was response to treatment. The secondary outcome was disease relapse free survival.&#x0D; Results: From a total number of 34 patients with MF identified, nine (26.5%) patients were diagnosed at stage IA and 25 (73.5%) patients were diagnosed at stage IB. Of these patients, 30 (88.2%) were treated with PUVA and four (11.8%) with nbUVB. Overall, 24 (80%) patients treated with PUVA and two (50%) patients treated with nbUVB had complete responses (CR). Relapse was observed in 17 (70.8%) PUVA treated patients and two (100%) nbUVB treated patients. Median disease relapse free survival was 12 months for PUVA and 6 months for nbUVB.&#x0D; Conclusion: PUVA is an effective therapy in early MF. Narrowband UVB could be a valid therapeutic alternative for these patients. However, the small size of nbUVB group in our study limits the conclusions about its efficacy.

582P - Microsatellite Instability (MSI) status and prognosis in colorectal cancer: Meta-analysis

BackgroundMicrosatellite instability (MSI) is thought to be a marker of immunogenicity and better prognosis in colorectal cancer (CRC). However, the mechanism by which MSI confers a survival advantage is not well known and there is a range of results reported in the literature. MethodsA systematic literature search of original studies was performed on Ovid searching Medline, Embase, Cochrane Library, CINAHL, Clinical Trials databases from inception of database to current. Data extracted included age, stage, MSI-H, MSS and MSI-L, proximal (right) vs. distal (left), colon vs. rectal, BRAF status, type of MSI or IHC test used, incidence of Lynch within cohort. The primary endpoint was survival (overall survival (OS), disease/relapse free survival (DFS) and disease (cancer) specific survival DSS). Statistical analysis was performed using RevMan Ver 5.3 Cochrane Collaboration. ResultsFrom 11,747 studies, 117 met the inclusion criteria (n=100,257; MSI-H n=12,263, (MSI-H 12.2%). Overall, MSI was associated with improved OS (OR 0.80 (0.71, 0.91). When stratified by stage, there was no difference in OS in stage I and IV, but a protective effect in stage II (OR 0.69 (0.51, 0.92)) and III (0.70 (0.54, 0.91)) CRC. By age, there was benefit in studies where reported median age < 60 (OR 0.66 (0.54,0.82)) but not ≥ 60. There was no difference in OS between MSI-L and MSS. In studies including only mucinous/signet cell/poor differentiation, there was no difference in OS. In both right and left colon, MSI status was associated with improved OS, but not in the rectum. MSI status was associated with improved DFS (HR 0.75 (0.66, 0.84)), but there was no difference in DSS (HR 0.78 (0.60, 1.03)), and this was seen in all stages (I-IV). ConclusionsMSI is associated with improved overall survival in stage II and III colorectal cancer. Improved prognosis is seen in younger patients, in both right and left sided colon cancer, but evidence is limited in rectal cancer. MSI was associated with less relapse, but was not associated with cancer specific survival at any stage. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Identification of α-N-catenin as a novel tumor suppressor in neuroblastoma.

The lost expression of α-catenin has been found in cancers, and reinstalling α-catenin inhibits tumor growth. Here we hypothesized that the α-N-catenin, a homologous member of α-catenin and neural-specific expressed, functions as a novel tumor suppressor in neural crest-derived tumor, neuroblastoma. We correlated CTNNA2 (encodes α-N-catenin) expression to neuroblastoma disease relapse-free survival probability using publicly accessible human neuroblastoma datasets in R2 platform. The result showed that it negatively correlated to relapse-free survival probability significantly in patients with neuroblastoma with non-MYCN amplified tumor. Conversely, overexpressing CTNNA2 suppressed the neuroblastoma cell proliferation as measuring by the clonogenesis, inhibited anchorage-independent growth with soft agar colony formation assay. Forced expression of CTNNA2 decreased cell migration and invasion. Further, overexpression of CTNNA2 reduced the secretion of angiogenic factor IL-8 and HUVEC tubule formation. Our results show, for the first time, that α-N-catenin is a tumor suppressor in neuroblastoma cells. These findings were further corroborated with in vivo tumor xenograft study, in which α-N-catenin inhibited tumor growth and reduced tumor blood vessel formation. Interestingly, this is only observed in SK-N-AS xenografts lacking MYCN expression, and not in BE(2)-C xenografts with MYCN amplification. Mechanistically, α-N-catenin attenuated NF-κB responsive genes by inhibiting NF-κB transcriptional activity. In conclusion, these data demonstrate that α-N-catenin is a tumor suppressor in non-MYCN-amplified neuroblastomas and it inhibits NF-κB signaling pathway to suppress tumor growth in human neuroblastomas. Therefore, restoring the expression of α-N-catenin can be a novel therapeutic approach for neuroblastoma patients who have the deletion of CTNNA2 and lack of MYCN amplification.

Allogeneic haemopoietic transplantation for acute myeloid leukaemia in second complete remission: a registry report by the Acute Leukaemia Working Party of the EBMT.

Allogeneic haemopoietic cell transplant (allo-HCT) may be curative in acute myeloid leukaemia (AML) in second complete remission (CR2) but the impact of reduced intensity (RIC) versus myeloablative conditioning (MAC) is uncertain. The Acute Leukaemia Working Party of the European Society for Blood and Bone Marrow Transplantation Registry studied an AML CR2 cohort characterised by age ≥ 18 years, first allo-HCT 2007-2016, available cytogenetic profile at diagnosis, donors who were matched family, volunteer unrelated with HLA antigen match 10/10 or 9/10 or haplo-identical. The 1879 eligible patients included 1010 (54%) MAC allo-HCT recipients. In patients <50 years (y), two year outcomes for MAC vs RIC allo-HCT were equivalent with leukaemia-free survival (LFS) 54% for each, overall survival (OS), 61% vs 62%, non-relapse mortality (NRM) 18% vs 15% and graft versus host disease relapse-free survival (GRFS) 38% vs 42%. In patients ≥50 y, 2 y outcomes for MAC vs RIC allo-HCT were equivalent for LFS 52% vs 49%, OS 58% vs 55% and GRFS 42.4% vs 36%. However, NRM was significantly inferior after MAC allo-HCT, 27% vs 19% (P = 0.01) despite worse cGVHD after RIC-allo (32% vs 39%). These data support the need for ongoing prospective study of conditioning intensity and GVHD mitigation in AML.

Autologous hematopoietic stem cell transplant for autoimmune diseases: evolution,evidence of efficacy, and real-world economics.

Despite an increase in the development of biological therapies for autoimmune disease (AID), a proportion of patients remain treatment refractory, resulting in long term morbidity and increased rates of mortality. Furthermore, maintenance biologic therapies are associated with treatment-related side effects, significant financial cost,and restricted access, which is of particular relevance in the developing world. Although it carries a significant 'front loaded' cost both financially and regarding adverse events, autologous hematopoietic stem cell transplantation (AHSCT) represents a potential single therapeutic intervention, which in the appropriate patient, condition, and transplant center, may offer sustained disease remission resulting in improved overall survival, disease relapse-free survival, improved quality of life, and decreased financial burden. Emerging Phase II and III trial and registry data, to which our center has been a significant contributor over the past two decades, are providing invaluable evidence as to which AIDs are most likely to receive a sustained benefit from AHSCT and which conditioning regimens are preferable. Similar to trends for the treatment of malignant disease, AHSCT for AID may find a place in both developed and developing countries as nations become more familiar with the transplantation process. If this occurs, benchmarking by key regulatory bodies, collaboration between medical specialties, and the development of experienced 'centers of excellence' will be key to enhance safety and benefit to patients and society at large.

PHF8 upregulation contributes to autophagic degradation of E-cadherin, epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma

BackgroundPlant homeodomain finger protein 8 (PHF8) serves an activator of epithelial-mesenchymal transition (EMT) and is implicated in various tumors. However, little is known about PHF8 roles in hepatocellular carcinoma (HCC) and regulating E-cadherin expression.MethodsPHF8 expression pattern was investigated by informatic analysis and verified by RT-qPCR and immunochemistry in HCC tissues and cell lines. CCK8, xenograft tumor model, transwell assay, and tandem mCherry-GFP-LC3 fusion protein assay were utilized to assess the effects of PHF8 on proliferation, metastasis and autophagy of HCC cells in vitro and in vivo. ChIP, immunoblot analysis, rescue experiments and inhibitor treatment were used to clarify the mechanism by which PHF8 facilitated EMT, metastasis and autophagy.ResultsPHF8 upregulation was quite prevalent in HCC tissues and closely correlated with worse overall survival and disease-relapse free survival. Furthermore, PHF8-knockdown dramatically suppressed cell growth, migration, invasion and autophagy, and the expression of SNAI1, VIM, N-cadherin and FIP200, and increased E-cadherin level, while PHF8-overexpression led to the opposite results. Additionally, FIP200 augmentation reversed the inhibited effects of PHF8-siliencing on tumor migration, invasion and autophagy. Mechanistically, PHF8 was involved in transcriptionally regulating the expression of SNAI1, VIM and FIP200, rather than N-cadherin and E-cadherin. Noticeably, E-cadherin degradation could be accelerated by PHF8-mediated FIP200-dependent autophagy, a crucial pathway complementary to transcriptional repression of E-cadherin by SNAI1 activation.ConclusionThese findings suggested that PHF8 played an oncogenic role in facilitating FIP200-dependent autophagic degradation of E-cadherin, EMT and metastasis in HCC. PHF8 might be a promising target for prevention, treatment and prognostic prediction of HCC.

THE EFFICACY OF HIGH-DOSE CONSOLIDATION AND AUTOLOGOUS BONE MARROW TRANSPLANTATION IN FIRST REMISSION OF ACUTE MYELOID LEUKEMIA

Introduction. The question of the most adequate treatment strategy of AML in cases when it is impossible to perform allogeneic HSCT because of any reason still remains open. The aim of this study was to assess the long-term survival of patients with AML who received chemotherapy (CT) or autologous HSCT as consolidation in the first remission of the disease. It was included 135 patients aged 18 to 67 years, with a verified diagnosis of AML (except FAB M3) in the study. Of these, 100 patients received only CT, 35 patients received consolidation with autologous bone marrow transplantation. Patients who achieved remission after completion of induction CT courses received one of three treatment options as consolidation: 1) chemotherapy of standard-intensity (sCT), 2) high-dose chemotherapy (HDCT), 3) autologous HSCT (autoHSCT) conducted after 1–2 courses of high-dose CT. Adverse prognostic factors were identified as: age over 40 years, hyperleucocytosis more than 50,0 × 10 9/L and unfavorable cytogenetic and molecular-biological risk group. Materials and methods. Depending on the number of prognostic factors at the onset of disease relapse-free survival (RFS) was 47 % in their absence, 45 % in the presence of 1 factor, in the presence of 2 factors – 14 % (p = 0,000), regardless of the variant of consolidation therapy (sCT, HDCT, autoHSCT). A high level of white blood cells adversely affects OS (38 % vs. 22 %) and increases the frequency of relapse (52 % vs. 69 %) when performing only CT (sCT and HDCT). At initial white blood cells level more than 50,0 × 10 9/L the 5-year OS was 60 % when performing both autoHSCT and HDCT. Performance of autoHSCT at failure to achieve remission after the 1st induction course CT is associated with the best 2-year OS (62 % vs. 35 %, p = 0,05), EFS (50 % vs. 22 %, p = 0,05) and RFS (50 % vs. 37 %, p = 0,05) in comparison with HDCT and sCT. In favorable cytogenetic risk group 5-year RFS was 80 % when performing autoHSCT and 67 % when performing HDCT; the 5-year OS was 80 % regardless of consolidation therapy option. Conclusion. AutoHSCT is the preferred consolidation option in favorable risk group patients, and after failure to achieve remission after the 1st CT course.

Hematopoietic Cell Transplantation Comorbidity Index Predicts Outcomes in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Receiving CD34+ Selected Grafts for Allogeneic Hematopoietic Cell Transplantation

To evaluate the association between the hematopoietic cell transplantation-comorbidity index (HCT-CI) and the recently developed age-adjusted HCT-CI (HCT-CI/age) and transplant outcomes in the setting of CD34-selected allogeneic HCT, we analyzed a homogeneous population of patients undergoing allogeneic HCT with CD34-selected grafts for acute myeloid leukemia and myelodysplastic syndrome (n = 346). Median HCT-CI and HCT-CI/age scores were 2 (percentile 25 to 75, 1 to 4) and 3 (percentile 25 to 75, 1 to 5), respectively. Higher HCT-CI and HCT-CI/age scores were associated with higher nonrelapse mortality (NRM) and lower overall survival (OS). The HCT-CI distinguished 2 risk groups (0 to 2 versus ≥3), whereas, with the HCT-CI/age, there was a progressive increase in NRM and decrease in OS with increasing scores in all 4 groups (0 versus 1 to 2 versus 3 to 4 versus ≥5). Higher scores in both models were associated with lower chronic graft-versus-host disease relapse-free survival but not with higher relapse. Both models showed a promising predictive accuracy for NRM (c− = .616 for HCT-CI and c− = .647 for HCT-CI/age). In conclusion, the HCT-CI and HCT-CI/age predict transplant outcomes in CD34-selected allo-HCT, including NRM, OS, and chronic graft-versus-host disease relapse-free survival and may be used to select appropriate patients for this approach.

Abstract LB-139: Prognostic value of a BCSC-associated microRNA signature in hormone receptor-positive her2-negative breast cancer

Abstract Background: Breast cancer patients with high proportion of cancer stem cells (BCSCs) are more chemotherapy-resistant and have unfavorable clinical outcomes. MicroRNAs (miRNAs) can function as oncogenes or tumor suppressor genes, which regulate key features of BCSCs. Since BCSCs have unique miRNA expression profile, we hypothesized that a biology-driven model based on BCSC-associated miRNAs could provide prognostic information for low recurrent-risk HR+HER2- breast cancer patients. Methods: A systematic literature reviewing suggested 50 BCSC-associated miRNAs that regulate the BCSC features. We excluded 15 of these miRNAs as they were not constantly detectable in the 40 paraffin embedded tumor samples by qRT-PCR (A pilot assay). A total of 35 BCSC-associated miRNAs were identified. We randomly assigned 303 patients into a training group (n = 202) and an internal validation (n = 101) group. We built a 10-miRNA-based classifier using a LASSO Cox model in the training group and validated its prognostic in the internal validation group, and two external independent groups of 308 patients. Results: In this multicenter study, we developed build a 10-miRNA classifier to predict disease-relapse free survival (DRFS). With this classifier, HR+HER2- breast cancer patients were classified into high-risk and low-risk group of diseases recurrence. The DFS was significantly different between these two groups in all of the patient groups. In the training group, the 5-year DRFS was 90.83% and 35.0% for the low-risk and the high-risk group, respectively (hazard ratio [HR] 15.85, 95% CI 8.15-30.82; p&amp;lt;0•0001). In the internal validation group, the 5-year DRFS was 91.95% and 7.14% for the low-risk and the high-risk group, respectively (HR 20.62, 95% CI 8.31-51.20; p&amp;lt;0•0001). Furthermore, in the 1st external validation group, the 5-year DRFS for low-risk group and high-risk group were 87.50% and 37.50%, respectively (HR 6.623, 95% CI 3.54-12.39; p&amp;lt;0•0001). In the 2nd external validation group, it was 91.74% for the low-risk group and 57.14% for the high-risk group (HR 6.99, 3.12-15.64; p&amp;lt;0•0001). Moreover, the 10-miRNA-based classifier outperformed the traditional clinicopathological risk factors and IHC4 scoring in predicting the 5-year DRFS. In addition, the patients in the high-risk group were associated with a more favorable response to chemotherapy than the low-risk group (HR 1.806, 95% CI 1.10-2.98; p = 0.0278). Interpretation: Our 10-miRNA-based classifier provides a reliable prognostic model for disease recurrence in HR+HER2- breast cancer patients. This classifier may facilitate patient counseling and serve in personalized treatment for breast cancer patients. Citation Format: Chang Gong, Weige Tan, Kai Chen, Na You, Shan Zhu, Wei Luo, Xinhua Xie, Yunjie Zeng, Nengtai Ouyang, Zhihua Li, Mushen Zeng, ShiMei Zhuang, Wan-Yee Lau, Qiang Liu, Fengxi Su, Xueqin Wang, Erwei Song. Prognostic value of a BCSC-associated microRNA signature in hormone receptor-positive her2-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-139.