Journal articles on the topic 'Bi-negativity'

This study was performed to determine the false negativity rates of ultrasonography with mammography in the assessment of women with palpable breast lumps. The relevant data on 202 female patients aged above 14 years of age, who had presented to our institution with a breast lump, had been retrospectively reviewed from our hospital database. Out of these, 155 patients for whom mammography with sonography imaging (MSI) was done were included in the study population. It consisted of tissue-positive cases, tissue-negative cases, and false-negative MSI confirmed on pathology. All cancer cases and false-negative cases using MSI were identified. Cancer rates, false-negative rates, and negative predictive values were calculated based on MSI breast imaging reporting and BI-RADS categories. Among patients who had undergone MSI, 73.55 % (114/155) of patients had BI-RADS 1–2. Despite a benign result, 10.5% (12/114) of them had gone ahead with a tissue diagnosis, whereas BI-RADS 4 and 5 had a 100% biopsy rate (28/28, 4/4, respectively). Out of the seventeen cancers detected in toto, only one belonged to BI-RADS 1–2. The false-negative rate of MSI (i.e., BI-RADS 1–2) was found to be 1.75% (1/114). As none of the remaining cases had progressed into malignancy post-follow-up (Median: 9 months, Range: 2 – 13 months), The negative predictive value (NPV) and cancer rate were estimated to be 99.12% and 0.88% respectively. Therefore, low false negativity and high negative predictive value of mammography with ultrasonography imaging for breast lumps were established.

AbstractEarly behaviors that differentiate later biomarkers for psychopathology can guide preventive efforts while also facilitating pathophysiological research. We tested whether error-related negativity (ERN) moderates the link between early behavior and later psychopathology in two early childhood phenotypes: behavioral inhibition and irritability. From ages 2 to 7 years, children (n = 291) were assessed longitudinally for behavioral inhibition (BI) and irritability. Behavioral inhibition was assessed via maternal report and behavioral responses to novelty. Childhood irritability was assessed using the Child Behavior Checklist. At age 12, an electroencephalogram (EEG) was recorded while children performed a flanker task to measure ERN, a neural indicator of error monitoring. Clinical assessments of anxiety and irritability were conducted using questionnaires (i.e., Screen for Child Anxiety Related Disorders and Affective Reactivity Index) and clinical interviews. Error monitoring interacted with early BI and early irritability to predict later psychopathology. Among children with high BI, an enhanced ERN predicted greater social anxiety at age 12. In contrast, children with high childhood irritability and blunted ERN predicted greater irritability at age 12. This converges with previous work and provides novel insight into the specificity of pathways associated with psychopathology.

In this paper, the authors propose a new approach to detect opinion by SentiWorNet with the introduction of the concept of fuzzy logic. In this vein, the authors will build detection system fuzzy opinion “Fuzzy Opinion.” To give flexibility to their system, they will use a threshold of opinion. The texts are represented by a vector of word (bag of words) which will be reduced to vector the word bearer opinion by filtering with SentiWordNet. Consequently, the heart of their approach is to associate each text into two scores (bi- scoring): Sp represents the positivity of text and Sn represents the negativity of text; this is the stage of Fuzzification. To identify opinion of a text and to ensure flexibility, the authors have used a threshold of opinion. Further, they have adapted the defuzzification step for identifying opinion. Finally, they compared the results of this approach with the results of the same approach without fuzzy logic in using the same corpus.

In an optomechanical system consisting of two Fabry–Pérot cavities fed by squeezed light and coupled via Coulomb interaction, we respectively use the logarithmic negativity, Gaussian discord and Gaussian coherence to analyze the behavior of three different indicators of nonclassicality, namely the entanglement, quantum discord and quantum coherence. We perform the rotating wave approximation and work in the resolved sideband regime. In two bi-mode states (optical and mechanical), the coherence is generally found to be greater than entanglement and discord. More interestingly, we show that the Coulomb interaction can be used either to degrade or enhance the nonclassical properties of the optical subsystem. In addition, compared with the discord and coherence, the mechanical entanglement is found strongly sensitive to both thermal and Coulomb effects, and it requires a minimum value of cooperativity to be generated. Remarkably, this minimum increases when increasing the Coulomb coupling strength. Finally, we notice that an optimal transfer of quantum correlations between the optical and mechanical subsystems is achieved in the absence of the Coulomb interaction.

Most previous research has focused on the relationships between specific personality traits and specific facets of mental health. However, in reality most of the Big Five are associated at non–trivial levels with mental health. To account for this broad correlation, we proposed the ‘barometer hypothesis’, positing that behind both ratings of mental health and personality lies a barometer that indicates one's general feelings of positivity or negativity. To the extent that both the general factors of personality and mental health reflect this same barometer, we would expect them to be correlated. We tested alternative models using data from a large longitudinal panel study that includes two cohorts of participants who were assessed every two years, resulting in parallel 4–year longitudinal studies. Similar results were obtained across both studies. Supporting the ‘barometer hypothesis’, findings revealed that the optimal model included general latent factors for both personality traits and mental health. Compared to the broad raw pairwise correlations, the bi–factor latent change models revealed that the relation among levels and changes in the specific factors were substantially reduced when controlling for the general factors. Still, some relations remained relatively unaffected by the inclusion of the general factor. We discuss implications of these findings. Copyright © 2016 European Association of Personality Psychology

A better understanding of animal emotion is an important goal in disciplines ranging from neuroscience to animal welfare science. The conscious experience of emotion cannot be assessed directly, but neural, behavioural and physiological indicators of emotion can be measured. Researchers have used these measures to characterize how animals respond to situations assumed to induce discrete emotional states (e.g. fear). While advancing our understanding of specific emotions, this discrete emotion approach lacks an overarching framework that can incorporate and integrate the wide range of possible emotional states. Dimensional approaches that conceptualize emotions in terms of universal core affective characteristics (e.g. valence (positivity versus negativity) and arousal) can provide such a framework. Here, we bring together discrete and dimensional approaches to: (i) offer a structure for integrating different discrete emotions that provides a functional perspective on the adaptive value of emotional states, (ii) suggest how long-term mood states arise from short-term discrete emotions, how they also influence these discrete emotions through a bi-directional relationship and how they may function to guide decision-making, and (iii) generate novel hypothesis-driven measures of animal emotion and mood.

In this paper, a modified Leslie–Gower predator-prey model with Beddington–DeAngelis functional response and double Allee effect in the growth rate of a predator population is proposed. In order to consider memory effect on the proposed model, we employ the Caputo fractional-order derivative. We investigate the dynamic behaviors of the proposed model for both strong and weak Allee effect cases. The existence, uniqueness, non-negativity, and boundedness of the solution are discussed. Then, we determine the existing condition and local stability analysis of all possible equilibrium points. Necessary conditions for the existence of the Hopf bifurcation driven by the order of the fractional derivative are also determined analytically. Furthermore, by choosing a suitable Lyapunov function, we derive the sufficient conditions to ensure the global asymptotic stability for the predator extinction point for the strong Allee effect case as well as for the prey extinction point and the interior point for the weak Allee effect case. Finally, numerical simulations are shown to confirm the theoretical results and can explore more dynamical behaviors of the system, such as the bi-stability and forward bifurcation.

INTRODUCTION. Bortezomib, lenalidomide and dexamethasone (VRd) is considered a standard of care combination therapy for newly diagnosed multiple myeloma patients. Prior studies show that ~25% of patients treated with 8 cycles of VRd achieve minimal residual disease (MRD) negativity. Recently, 42% stringent complete response (sCR) rates were reported with the use of VRd combined with the CD38-targeted monoclonal antibody daratumumab (VRd-D). Prior studies using 8 cycles of bi-weekly carfilzomib 36 mg/m2 with lenalidomide and dexamethasone (bKRd) combination therapy in newly diagnosed multiple myeloma show ~40% MRD negativity rates. We were motivated to develop a phase 2 study (total N=82) using weekly dosing of carfilzomib 56 mg/m2 with lenalidomide and dexamethasone (wKRd) in combination with daratumumab (wKRd-D). Our study also included a parallel cohort of bi-weekly dosing of carfilzomib 36 mg/m2 with lenalidomide and dexamethasone (bKRd) in combination with daratumumab (bKRd-D). Primary end-point of our study was to rule out 60% and to target up to 80% MRD negativity rate. METHODS. This is a two-arm, Phase II clinical trial based on Simon's optimal two-stage design. The once-a-week carfilzomib (wKRd) (N=41) has the following treatment schedule: 8 cycles of treatment; 28-day cycles with carfilzomib 20/56 mg/m2 days 1, 8, and 15; lenalidomide 25 mg days 1-21; dexamethasone 40 mg weekly cycles 1-4, 20 mg after cycle 4; and daratumumab 16 mg/kg days 1, 8, 15, and 22 cycles 1-2, days 1 and 15 cycles 3-6, and day 1 cycles 7-8. The bi-weekly carfilzomib (bKRd) (N=41): 8 cycles of treatment; 28-day cycles with carfilzomib 20/36 mg/m2 days 1, 2, 8, 9, 15 and 16; lenalidomide, dexamethasone, and daratumumab are given at the same doses/schedules as the weekly cohort. For fit patients, stem cell collection is recommended after 4 to 6 cycles of therapy; DKRd therapy is resumed after collection to a total of 8 cycles DKRd. Treatment response is being assessed with parallel bone marrow-based MRD assays (10-color single tube flowcytometry and invivoscribe IGHV sequencing); per IMWG guidelines both MRD assays allow detection of 1 myeloma cell in 100,000 bone marrow cells (10^-5). Baseline bone marrow samples are evaluated with targeted DNA sequencing for FISH-Seq and somatic mutational characteristics (myTYPE). RESULTS. The first stage of the weekly cohort (wKRd-D) is fully enrolled (N=28) and the second stage of the cohort (N=13) is anticipated to complete enrollment shortly (total N=41). Currently, 29 patients meeting eligibility criteria were enrolled (14 males, 15 females) between October 2018 and August 2019. Baseline characteristics include; median age 59 years (range 36-70 years); 12 (41%) patients had high-risk FISH/SNP signature defined as one or more of the following: 1q+, t(4;14), t(14;16), t(14;20), and 17p-. At the submission of this abstract, 28 patients have completed one or more cycles wKRd-D; among these, 10 patients have completed therapy. The median number of cycles delivered is currently 6 (range 1-8). Seven of the 10 patients who have completed study treatment are MRD negative. So far, additional 8 patients have become MRD negative while on therapy. Thus, among patients treated on the weekly cohort (wKRd-D) and who were evaluable for the MRD primary end-point at this analysis, we found 15/18 (83%) to be MRD negative. We further show no added major clinical toxicities with wKRd-D compared to our institution standard of care bKRd. The bi-weekly carfilzomib cohort (bKRd-D) shows similar results to the weekly cohort (wKRd-D). With a comparable efficacy and safety profile coupled with a substantial reduction of the number of infusions (total of 51 vs 27 infusions with bKRd-D vs wKRd-D, respectively), we conclude that the weekly dosing (wKRd-D) may offer an attractive treatment modality for newly diagnosed multiple myeloma patients. CONCLUSIONS. Among patients evaluable for the MRD primary end-point, in the absence of an autologous bone marrow transplant, we show an unprecedented 15/18 (83%) MRD negativity rate among newly diagnosed multiple myeloma patients treated on the weekly cohort (wKRd-D) using carfilzomib 56 mg/m2 dosing. Our promising results have prompted the development of a large randomized multi-center study ("ADVANCE") evaluating wKRd-D in relation to established standard of care, which is anticipated to start enrollment in Q3/Q4 of 2019. Disclosures Landgren: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Theradex: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Lesokhin:GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Janssen: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Janssen: Research Funding. Smith:Fate Therapeutics and Precision Biosciences: Consultancy; Celgene: Consultancy, Patents & Royalties, Research Funding. Shah:Physicians' Education Resource: Honoraria. Landau:Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Roshal:Auron Therapeutics: Equity Ownership, Other: Provision of services; Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services. Dogan:Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Roche: Consultancy, Research Funding. OffLabel Disclosure: Dara-KRd is not an FDA approved combination therapy for newly diagnosed multiple myeloma.

Abstract Recently, a novel subgroup of B Cell Precursor (BCP) Acute Lymphoblastic Leukemia (ALL), called Philadelphia-like (Ph-like) ALL, has been described. This high-risk group, despite the absence of BCR-ABL1 rearrangement, shows genomic abnormalities that result in aberrant expression of cytokine receptors genes or tyrosine-kinase-activating signaling. These patients are poor responder to conventional chemotherapy but potentially sensitive to Tyrosine-Kinase Inhibitors (TKIs). Herein we report the case of a 10 year-old girl who received diagnosis of precursor B-ALL on February 2018. She started therapy according to observational protocol ALL 2017 of the Italian Association of Pediatric Hemato-Oncology (AIEOP). After pre-phase, the patient resulted prednisone poor responder and continued induction therapy, including daunorubicin, vincristine, PEG-L-Asparaginase, prednisone and intrathecal methotrexate. Bone marrow evaluation showed persistence of disease on day 15 (88% of lymphoblasts) and 33 (60% of blasts) in flow cytometry. At the end of IA induction phase, Minimal Residual Disease (MRD) in RT-PCR showed high positivity (marker 1 = 7.2x10-1, marker 2= 8.11x10-1). At this time, further molecular studies, using RNA targeted next generation sequencing (PanCancer, Illumina), revealed the presence of EBF1-PDGFRβ gene fusion. Since the patient was resistant to conventional therapy and literature's evidences demonstrated potential sensitivity of EBF1-PDGFRβ to TKIs therapy, we decided to add dasatinib, a second generation TKI, to IB induction, with cyclophosphamide, cytarabine and 6-mercapthopurine. After one week of therapy, clinical course was complicated by Klebsiella Pneumoniae sepsis, followed by digestive hemorrhage. Since we retained that the hemorrhagic event could be related to dasatinib, the drug was temporarily discontinued. However, bone marrow evaluation, after only 10 days of dasatinib administration, showed hematologic remission (3% of lymphoblast) and MRD reduction >1 logarithm (markers 1=1-10-2 e markers 2= 9.9 x 10-3). Given the resistance to chemotherapy alone and the excellent response to dasatinib but its related toxicity in combination, we decided to start immunotherapy with blinatumomab, a bi-specific CD3-CD19 monoclonal antibody, alternated to dasatinib, in order to achieve MRD negativity before to proceed with allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling. The patient received 2 courses of blinatumomab for 28 days continuous infusion (15 mcg/mq days 1-28), interspersed by 15 days of dasatinib (60 mg/mq/day). After the first cycle the patient achieved complete hematological remission and MRD negativity. MRD negativity was confirmed after first course of dasatinib, second course of blinatumomab and second course of dasatinib. Dasatinib, given alone, was well tolerated and no serious adverse event were reported. Actually, the patient is undergoing HSCT by HLA-identical sister. To our knowledge, only few cases of EBF1-PDGFRβ ALL, treated with TKIs, are described in literature and this is the first in which MRD negativity was obtained with a sequential combination of dasatinib and blinatumumomab, a chemo-free approach, showing efficacy and good tolerability. This case highlights also that screening for targetable lesions at diagnosis or in case of resistance to induction phase is mandatory to identify patients who might benefit from alternative therapies as TKIs, immunotherapy or their combination. A longer follow-up is required to definitively establish the long-term efficacy of this biological approach in our patient. Nevertheless, it is interesting to speculate that alternative treatment with TKIs or immunotherapy could avoid, in the future, an intensive chemotherapy, or probably a transplant approach in selected patients, in order to achieve a durable cure in these Ph-like patients. Disclosures Locatelli: Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Parasole:Baxalta: Membership on an entity's Board of Directors or advisory committees; behring: Consultancy; jazz: Honoraria, Speakers Bureau.

Objectives: Fibromatosis is a rare breast lesion that is considered locally aggressive tumor without metastasis. It doesn't need more than surgical excision with clean margins as a treatment but the recurrence is very common. Breast fibromatosis clinically mimics other lesions as fibromatosis like metaplastic tumor of breast. Therefore, recognition of breast fibromatosis is important for surgeons and histopathologists, in order to set a proper plan for management and avoid unnecessary extensive surgery. Comprehensive search revealed only 33 case reports as it's compromising less than 0.2% of all primary breast tumor. Case summary Methods and Materials: A 35 years old female patient complained of palpable left breast mass for four months. Her imaging belonged to BI-RAD (4) assessment category. The pathological examination of the core biopsy showed B3; spindle cell lesion. The patient underwent surgical excision of the mass and the histopathologic assessment revealed an infiltrative uncapsulated lesion composed of proliferated spindle shaped cells (mixed fibroblasts and myofibroblast like cells) arranged in sweeping fascicles with occasional extravasated RBCs. There was no mitosis, necrosis or atypia. There was no associated hyperplasia, atypical hyperplasia, insitu or invasive components. Results: Immunohistochemical studies showed positivity for SMA and B- Catenine and negativity for Pan CK and P63 that confirm our diagnosis. Conclusion: The conclusion of this case report is to stress upon keeping breast fibromatosis in mind as a potential differential diagnosis for fibromatosis like metaplastic carcinoma and other mimics of spindle cell lesions in breast.

Abstract Abstract 2547 Acute lymphoblastic leukemia (ALL) in children less than 1 year old is the relatively rare disease with specific biological features and poor outcome. It is also characterized by high incidence of MLL gene rearrangements. Immunophenotype of infants' leukemia varies due to presence or absence of MLL-rearrangements. Aim of the study. description of immunophenotype in infant acute lymphoblastic leukemia. Methods. Totally 421 cases of pediatric acute leukemia (AL) were studied. 81 patients (39 boys and 42 girls) aged from 5 days to 11 months were included in the study group. Their data was compared to 332 cases of acute leukemia in older children. Tumor cells immunophenotyping was performed by 6–8-color flow cytometry. Detection of various types of MLL-gene rearrangements was done by simultaneous application of chromosomal banding analysis, fluorescence in-situ hybridization, reverse-transcriptase polymerase chain reaction (PCR) and long-distance inverse PCR. Results. There were 54 (66.7%) ALL cases in the study group. ALL was found less frequently in infants than in older children (66.7% and 88.5% respectively, p<0.0001) while percentage of acute myeloid leukemia cases was higher in infants (27.2% and 10.0% respectively, p=0.0001). EGIL immunophenotypes distribution also differed between infants and older children. BI-ALL was the most common immunological ALL type in infant ALL (55.6% vs 3.3% in older age group, p<0.0001), while BII-ALL was notably less frequent compared with other age groups (33.3% and 77.1% respectively, p<0.0001). T-lineage ALL was also less frequent in infants (3.7% vs 14.3% in older age group) although difference did not achieve statistical significance (p=0.0536). Totally infant ALL were mainly presented by B-cell precursor ALL (BCP-ALL) – 51 patients (94.4%). Various types of MLL-rearrangements were found in 40 (74.1%) patients (pts) out of 54 infants ALL cases. Among them 21 pts (52.5%) carried MLL-AF4 fusion gene, 8 pts (20.0%) – MLL-MLLT1, 5 pts (12.5%) – MLL-MLLT3, 3 pts (7.5%) – MLL-EPS15, 1 pt (2.5%) – MLL-MLLT10, 1 pt (2.5%) – MLL-AFF3 and 1 pt (2.5%) had MLL-rearrangement with unidentified partner gene. Significant immunophenotypic differences were observed in patients with and without MLL gene rearrangements. Number of cases in those tumor cells expressed CD10, CD20, CD45, CD133, CD15, NG2 significantly varied between MLL-positive and MLL-negative groups (p=0.0001, p<0.0001, p=0.0008, p=0.0018, p=0.0306 and p<0.0001 correspondingly). NG2-positivity represented the highest overall correct prediction (OCP) rate for presence of MLL-rearrangements (95.5%). Diagnostic accuracy of CD20-negativity and CD45-positivity was slightly lower (87.5% and 86.3% respectively) while OCP for CD10-negativity (78.4%), CD133-positivity (75.0%) and CD15-positivity (66.7%) was not sufficient enough. Nevertheless CD10-positive BCP-ALL with MLL-rearrangements differed from CD10(+) cases in MLL-germline group. CD10 homogeneous expression was noted in 10 out of 11 MLL-germline patients and in 1 of 10 MLL-rearranged cases (p=0.0011). Although there were found no significant differences in CD22-positive patients' number, CD22(+)-cells percentage was significantly lower in MLL-positive cases (median 89.9%, range 25.2–99.7% and median 99.9%, range 96.0–99.9% respectively, p=0.0026). Thus CD20-negativity, CD10-negativity/low expression, high CD45, CD15, CD65 and NG2 expression, decreased CD22-expression are immunophenotypic signatures of MLL-rearranged infant ALL, although NG2 has the highest diagnostic efficacy. Interestingly there were no markers able to distinguish MLL-AF4-positive cases from patients carrying other types of MLL-rearrangements. Even NG2 expression intensity did not differ between these groups (p=0.2720). Except BCP-ALL pts, two cases of T-lineage ALL and one mature B-ALL (without other Burkitt lymphoma features) were found. Conclusion. Thus immunophenotype of ALL in children less than 1 year old differs significantly from patients of older age groups. Infants' B-cell precursor ALL immunophenotype varies greatly due to the presence of MLL gene rearrangements. Complex diagnostic immunophenotyping of infants' ALL allows predicting presence of MLL rearrangements and NG2 is the most applicable single marker. Disclosures: No relevant conflicts of interest to declare.

Twin relationships have a significant effect on the twins’ life and their families. In the first comprehensive study of this topic, our purpose was to examine the developmental courses of four dyadic dimensions of twins’ relationships: closeness, dependence, conflict and rivalry, and the impact of zygosity and parenting on their relationships. Parents reported on their twins’ relationships ( N = 1547 mothers and 536 fathers with data from at least one of four measurement points from 3 to 8–9 years of age). The sample included 322 monozygotic twin dyads (sharing virtually 100% of their genes), and 1194 dizygotic twin dyads (sharing 50% of their genetic variance, on average). Our findings indicated that closeness and dependence decreased while rivalry increased through childhood. Dependence and rivalry also presented quadratic change. The twins’ conflict increased only for dizygotic twins. As expected, we found that the twins’ closeness and dependence were highly associated, as did the associations between conflict and rivalry. The mostly nonsignificant associations of closeness with conflict and rivalry reinforced the notion that they are not bi-polar opposites. However, dependence was positively related to the twins’ conflict and rivalry. A zygosity effect was also evident as monozygotic twins had higher levels of closeness and dependence than dizygotic twins through childhood, but there was no significant difference in the levels of their conflict and rivalry. In congruence with family system theories, parental positivity predicted the twins’ closeness and dependence, and parental negativity predicted the twins’ dependence, conflict and rivalry. The results were discussed in light of an evolutionary perspective and the twins’ developmental challenges through childhood.

Background Metaplastic carcinomas are ductal carcinomas that display metaplastic transformation of the glandular epithelium to non-glandular mesenchymal tissue. Metaplastic carcinoma has a poorer prognosis than most other breast cancers, so the differential diagnosis is important. Although many clinical and pathologic findings have been reported, to our knowledge, few imaging findings related to metaplastic carcinoma have been reported. Purpose To investigate whole-breast imaging findings, including mammography, sonography, MRI, and pathologic findings, including immunohistochemical studies of metaplastic carcinomas of the breast. Material and Methods We analyzed 33 cases of metaplastic carcinoma between January 2001 and January 2011. Mammography, ultrasonography, and MRI were recorded retrospectively using the American College of Radiology (ACR) breast imaging reporting and data system (BI-RADS) lexicon. Immunohistochemical studies of estrogen receptor (ER), progesterone receptor (PR), p53, and C-erbB-2 were performed. Results The most common mammographic findings were oval shape (37%), circumscribed margin (59%), and high density (74%). The most common sonographic findings were irregular shape (59.4%), microlobulated margin (41%), complex echogenicity (81%), parallel orientation (97%), and posterior acoustic enhancement (50%). Axillary lymph node metastases were noted for 25% of the sonographic examinations. On MRI, the most common findings of margin and shape were irregularity (57% and 52.4%, respectively). High signal intensity was the most common finding on T2-weighted images (57%). Immunohistochemical profile was negative for ER (91%, 29/32) and PR (81%, 26/32). Conclusion Metaplastic carcinomas might display more benign features and less axillary lymph node metastasis than IDC. High signal intensity on T2 MRI images and hormone receptor negativity would be helpful in differentiating this tumor from other breast cancers.

TPS8055 Background: Len maintenance post ASCT is standard of care for patients (pts) with NDMM. Deep responses (CR or better) post ASCT correlates with better progression free survival (PFS). In a meta-analysis of len maintenance post ASCT (McCarthy PL et al. J Clin Oncol. 2017), only 10.7% of pts achieve CR post ASCT, and 72% of pts who discontinued len maintenance did so because of progressive disease (PD). Selinexor is a selective inhibitor of nuclear export that blocks exportin 1, thus retaining tumour suppressor proteins within the nucleus while blocking proto-oncoprotein translation. It is approved in combination with bortezomib and dexamethasone (dex) for pts with MM who have had at least 1 prior line of treatment, or with dex for pts with penta-refractory MM by the FDA. The oral bioavailability and weekly schedule of selinexor makes it suitable in combination with len for maintenance therapy. Given the encouraging activity (ORR 92%) and tolerability of selinexor, len and dex from the phase 1b/2 STOMP study, we hypothesise that combination low-dose selinexor and len (XR) will be well tolerated and effective, increasing CR and MRD negativity rate post ASCT, thus prolonging PFS compared to len. Methods: ALLG MM23 SeaLAND, is an ongoing randomised, multi-centre, phase 3 trial. Eligible pts ( > 17 years of age) have measurable disease, have undergone 3-6 cycles (C) of induction containing a proteasome inhibitor (PI) and/or immunomodulatory drug and recovered post melphalan-conditioned ASCT with adequate haematopoiesis, renal and liver function, and with ECOG performance status. Registration occurs prior to ASCT with screening between 75 to 115 days post ASCT. The study includes a lead-in safety phase of 20 patients with XR: Len 10mg daily days 1 to 21 and Selinexor 40mg weekly in a 28-day cycle. If well tolerated, Selinexor escalates to 60mg po weekly from C2 and Len to 15mg po daily from C4. Two safety reviews will occur after the 10th and 20th patients completes C2, respectively. Upon meeting safety criteria, a sample size of 290 pts will be randomised 1:1 to XR or lenalidomide (R). Therapy will continue until PD. The primary endpoint is PFS at 3 years post randomisation. Secondary endpoints include ORR and MRD-negativity rate (International Myeloma Working Group Response Criteria), PFS on next treatment line (PFS2), OS, safety and tolerability, quality of life, and cost effectiveness. Main analysis occurs after 232 patients complete 3-years of follow-up. Exploratory objective is to correlate immunological and molecular profiles to treatment response and resistance. ALLG MM23 SeaLAND is a multisite bi-national investigator-initiated trial lead by Australia and New Zealand’s national cooperative group, the Australasian Leukaemia & Lymphoma Group. Clinical trial registration: ACTRN12620000291987p. Clinical trial information: 12620000291987.

Abstract INTRODUCTION Anaplastic Large Cell Lymphomas (ALCL) are rare T-cell neoplasms grouped according to whether they express the fusion protein anaplastic lymphoma kinase (ALK+) or not (ALK-). ALK+ ALCL has consistently been found to have a favorable outcome compared to ALK- ALCL, but ALK+ ALCL is also associated with young age and other low risk features and not all studies have found ALK-expression to be an independent prognostic factor. In this population-based study, we aimed at analyzing the outcome and risk factors for survival in a bi-national cohort of patients with systemic ALCL. METHODS All adult (>18 years) patients with systemic ALCL in the Swedish and Danish Lymphoma Registries diagnosed between 2000 and 2010 were included in the study. Primary cutaneous ALCL cases were excluded. The diagnosis of ALCL was established in routine care and no study-specific pathology review was performed. RESULTS A total of 371 patients (ALK+ ALCL n=122) were identified, representing 1.3% of all lymphomas, through both national registries. ALK-status was missing in 33 patients (ALK u ALCL). The median follow-up was 7.2 years. ALK+ patients were younger than ALK- patients (median age 40 versus 66 years, p<0.001). In all, 209 patients died (ALK+ n=32, ALK- n=151, ALK u n=26) and among the 328 patients with available relapse data, 118 patients experienced relapse or progression (ALK+ n=20, ALK- n= 83, ALK u n=15). The 5-year overall and progression-free survival (OS and PFS, respectively) were 78% and 64% in ALK+ ALCL, 37% and 32% in ALK- ALCL and 27% and 25% in ALK u ALCL. Data on primary treatment was available in 341 out of 371 patients (92%). The majority of patients (n=278, 82%) was treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP plus etoposide (CHOEP). Up-front autologous stem cell transplantation (ASCT) was performed in 38 patients with ALK- ALCL and in 6 patients with ALK+ ALCL. Most ALK- ALCL patients undergoing up-front ASCT consolidation received CHOEP as induction treatment. Age had a profound impact on survival and based on the Kaplan-Meier estimates the age cut-offs described for the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) were used. All features, including treatment with CHOP compared to CHOEP, that were associated with survival at the level of p<0.1 in univariable analysis were tested in a multivariable model. The only independent risk factors in the multivariable analysis were treatment with CHOEP, which was associated with better OS (HR 0.48 95% CI 0.32-0.74, p=0.001), and increasing NCCN-IPI score (HR [for each increment] 1.6 95% CI 1.5-1.8, p<0.001), which was associated with inferior OS. A separate multivariable risk factor analysis for OS was performed in patients treated with CHOEP (N=108). In this analysis, age (HR 2.9 95% CI 1.5-5.3, p=0.001), ALK-negativity (HR 2.6 95% CI 1.2-6.0, p=0.020) and elevated LDH (HR 2.1 95% CI 1.0-4.3, p=0.047) were independently associated to worse OS. Assigning 0,1 and 2 points for age <40, 40-60 and 60-75 respectively, ALK negativity 1 point and elevated LDH 1 point, we created a score that identified 4 groups with significantly different OS. Patients with a score of 3 or 4 had a similar OS, and were thus combined. DISCUSSION This population-based study based on two national registries reports the outcome of the largest cohort of adult ALCL patients published so far. Our study confirms the favourable outcome of ALK+ ALCL patients and the association with low-risk features. The addition of etoposide to CHOP was independently associated with a superior OS, and when adjusting for this treatment modification, the impact of ALK-expression on OS was mitigated. We also performed a separate risk factor analysis in the group of patients receiving CHOEP treatment. Age, ALK-negativity and elevated LDH were independent risk factors for OS in this group and were assembled in a proposed novel score, which could represent a useful tool in future management strategies in ALCL. Our data supports that the addition of etoposide to CHOP, if tolerated, is an important component in the treatment of ALCL and that the impact of ALK-expression on outcome is affected by treatment. Based on multivariable risk factor analysis in CHOEP treated patients, we propose a novel ALCL-specific score for future validation in independent cohorts. Disclosures Relander: Respiratorius: Patents & Royalties: valproate for DLBCL.

Introduction: Venetoclax (VEN) in combination with a hypomethylating agents (HMA) is associated with a high rate of composite remission (complete remission [CR] and complete remission with incomplete recovery [CRi]) among older and unfit patients with untreated AML. However, data regarding the activity of VEN-HMA in those patients with favorable-risk AML is limited, particularly in those with core-binding factor (CBF) alterations. Although more frequent among younger patients, favorable-risk alterations are also observed among older patients, often unfit for intensive regimens. Even among the subset of older patients (&gt;60 years) with favorable-risk AML eligible for intensive regimens, long-term outcomes are poorer in comparison to younger patients. Methods: We retrospectively analyzed outcomes of 46 patients with favorable-risk AML who underwent therapy with VEN-HMA between 2016-2020 at 4 academic cancer centers in US. Favorable-risk AML was defined by the presence of either CBF [t(8;21) and inv(16) or t(16;16)], NPM1 mutation in the absence of FLT-3 ITD mutations; or bi-allelic CEBPA mutations. Results: Forty-six patients with favorable risk AML were treated with HMA-VEN, including 26 (57%) with newly diagnosed (ND) and 20 (43%) with relapsed/refractory (R/R) AML (Table1). Ten (22%) patients had CBF, 21 (46%) had NPM1 mutations (NPM1m), and 13 (28%) had bi-allelic CEBPA mutations (CEBPAm). The median age was 70 years, and 54% were females. Patients with R/R AML were younger than ND patients (56 vs. 72 yrs, p=0.003). Twenty (44%) patients had secondary or therapy-related AML, including half of ND patients. The median lines of prior therapy were 2(1-4) in patients with R/R AML, including 6 (30%) who had failed prior allogeneic HCT. Eleven (24%) patients had received HMA prior to HMA-VEN therapy, including 1 patient in the ND cohort for prior MDS. Eleven (24%) patients received azacitidine in combination with VEN, while the rest (76%) of patients received decitabine, including 14 patients who received 10-day decitabine during the first cycle. The CR/CRi rate among the whole cohort was 80%, including 52% CR and 28% CRi. There was no statistically significant difference in CR/CRi rate between ND and R/R patients (88% vs. 70%, P =0.15). However, patients with history of prior HMA exposure had lower response rate compared to HMA-naïve patients (55% vs. 88%, p= 0.025). No difference in response was observed based on the favorable genetic alteration subgroups (80% in CBF vs. 86% in NPM1m vs. 77% in CEBPAm, p=0.44). Furthermore, no difference in response was observed according to patient age (p= 0.83), AML types (de novo vs. secondary; p= 0.47), prior transplant (p=1.00), or the type and schedule of HMA (P=0.66). Among the responders who had MRD assessment done (n= 26), 22 (85%) achieved MRD negativity by multicolor flow cytometry. Post response, 13 (35%) patients underwent allogeneic transplant consolidation. The median overall survival (OS) for the whole cohort was 18 months (12.5-NA). Median leukemia-free survival (LFS) was 13.2 months (7-20.2) for all responders, 11.2 months (1.7-NA) for ND responders, and 14.0 months (1-NA) for RR responders (p=0.986). The 30- and 60-day mortality for the whole cohort was 0% and 9%, respectively. Conclusion: In patients with favorable-risk AML, VEN-HMA combination is associated with a highly promising CR/CRi rate, with durable responses. The majority of responders achieved MRD negativity. Patients with prior use of HMA had lower response rate with VEN-HMA, nonetheless, over half of these patients responded despite most being treated in the R/R setting. Disclosures Pullarkat: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Marcucci:Abbvie: Speakers Bureau; Merck: Other: Research Support (Investigation Initiated Clinical Trial); Novartis: Speakers Bureau; Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Takeda: Other: Research Support (Investigation Initiated Clinical Trial); Iaso Bio: Membership on an entity's Board of Directors or advisory committees. Yaghmour:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau. Bhatt:Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Partnership for health analytic research: Consultancy; Takeda: Consultancy; Jazz: Research Funding; National Marrow Donor Program: Research Funding; Oncoceutics: Other. Fathi:Takeda: Consultancy, Research Funding; Jazz: Consultancy; Forty Seven: Consultancy; Daiichi Sankyo: Consultancy; Amphivena: Consultancy; Blueprint: Consultancy; Kura Oncology: Consultancy; Boston Biomedical: Consultancy; Astellas: Consultancy; Trovagene: Consultancy; Novartis: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Pfizer: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Newlink Genetics: Consultancy.

Abstract Introduction: Most patients with advanced-stage follicular lymphoma(FL) cannot be cured by conventional chemotherapy and have median survival of 7 to 10 years. High-dose chemotherapy (HDT) supported by autologous stem cell transplantation(ASCT) gives a survival benefit for patients with aggressive lymphoma. Recent several multicenter studies have shown that clinical and molecular remissions can be attained in patients with FL receiving intensified high-dose sequential chemotherapy and autografting. We have reported the efficacy and safety of high-dose bi-weekly THP-COP with G-CSF support (HDBW-TCOPG) for non-Hodgkin’s lymphoma. Therefore, we performed a pilot clinical trial to evaluate the efficacy and toxicity of HDBW-TCOPG followed by HDT with ASCT as first-line therapy in patients with advanced-stage FL. Patients and methods: Between August 1998 and December 2003, 10 Japanese patients with previously untreated FL from whom informed consent was obtained were included in this single-center pilot study. Median age was 48 years. All patients had stage 3 or 4 disease, aaIPI LI 8 and HI 2. Histological subtypes of FL included grade 1 4; grade 2 4; grade 3a 2. HDBW-TCOPG consisted of pirarubicin 70 mg/m2 on day 1; cyclophosphamide 1000 mg/m2 on day 1; vincristine 1.4 mg/m2 on day 1; predonisolone 50 mg/m2 from day 1 to 5; lenograstim 2.0 mg/kg/day from day 3. Five patients who enrolled after rituximab was approved for indolent B-cell lymphoma in Japan received induction therapy combined HDBW-TCOPG with rituximab 375mg/m2 on day -2 (R-HDBW-TCOPG). Six cycles were administered at intervals of two weeks. PBSC were collected during the later cycles of HDBW-TCOPG or on the recovery of high-dose etoposide regimen (500mg/m2 for 3 days) administered after the completion of HDBW-TCOPG. Leukaphereses were performed until a minimum of 2.0x106/kg CD34+ cells had been collected. The conditioning regimen consisted of ranimustine 200mg/m2 on day-7 and -2; paraplatin 300mg/m2 on day -6, -5, -4, -3; etoposide 500mg/m2 on day −5, −4, −3; cytarabine 2.5 g/m2 every 12 hours on day −2, −1 (MCE-CA regimen) in 2 patients or cyclophosphamide 50mg/kg on day −2, −1 (MCEC regimen) in 8 patients. Results: Sufficient numbers of PBSC were collected in 5 of 7 patients mobilized with HDBW-TCOPG and in all 5 patients with high-dose etoposide. The median time to reach total number of leukocytes of 1.0 x109/l was nine days (range 8–11). All 10 patients who were in PR at the end of HDBW-TCOP(G) achieved CR post APBSCT. After a median follow up of 36.6 months (range 7–66 months) PFS and OS are 90% and 90%, respectively, for all patients. One patient developed secondary myeloid leukemia with t(3;21) and died at 35 months after APBSCT without signs of recurrence of lymphoma. Another patient who relapsed at 35 months after transplantation. IgH or BCL2 rearrangement was detected by PCR analysis prior to therapy in three patients and one of them still showed detectable disease after HDBW-TCOPG induction. However, all three patients demonstrated MRD negativity after HDT with ASCT. Conclusion: HDBW-TCOPG as induction therapy followed by HDT with ASCT is feasible for advanced-stage FL with acceptable toxicity, and this short term highly intensified therapy may induce cure of the disease by minimizing MRD, but longer follow up is needed to evaluate the impact on survival.

Abstract Introduction: Downregulation or loss of B-cell ALL surface antigens (most notably CD19) in patients with acute lymphoblastic leukemia (ALL) targeted by various therapeutic modalities including CART and bi-specific T-cell engagers (BiTEs) has been implicated in acquired resistance to those therapies. Inotuzumab Ozogamicin (InO) is a calicheamicin-conjugated antibody targeting CD22 on ALL blast cells. In the Phase 3 INO-VATE trial, patients with refractory (R/R) ALL who received InO vs standard of care chemotherapy (SC) achieved greater remission, MRD negativity, and improved survival. This study reports CD22 expression levels at baseline, end of treatment (EOT) and relapse in R/R ALL patients who received InO or SC as salvage therapy and subsequently relapsed; the goal of this analysis was to understand if relapse was associated with changes in CD22 expression. Methods: The study population consisted of R/R ALL patients who were treated with InO or SC as part of two clinical trials: Phase 1/2 Study 1010 (NCT01363297; Phase 1, Expansion Phase, + Phase 2 at a dosage of 1.8 mg/m2) and Phase 3 Study 1022 (NCT01564784). This analysis incorporated CD22 expression levels at baseline, at end of treatment, and at relapse. Central laboratory flow cytometry was used to assess CD22 expression, which was quantified as % CD22-positive leukemic blasts and as Molecules of Equivalent Soluble Fluorochrome (MESF), a quantitative measure of CD22 density on leukemic blasts. Outcomes are reported in InO (Study 1022 or 1010) and SC patients who responded to treatment (patients who achieved complete remission/complete remission with incomplete hematologic recovery [CR/CRi]) and subsequently relapsed. CR was defined by <5% marrow blasts and the absence of peripheral blood leukemic blasts; with recovery of hematopoiesis. Results: 25 InO patients (Study 1022, n=19; Study 1010, n=6) and 11 SC patients who responded to treatment and subsequently relapsed were evaluable for central-lab CD22 analysis at baseline. Among InO patients who responded to treatment, the majority had leukemic blasts that were ≥90% CD22-positive at baseline (Study 1022, 66.7%; Study 1010, 66.7%); of the evaluable patients at EOT (Study 1022, n=4; Study 1010, n=0), leukemic blast CD22-positivity was >0-<70%. At relapse, all evaluable InO patients had leukemic blasts with detectable CD22-positivity; with blasts that were predominately <90% CD22 positive (Study 1022, n=6/7; Study 1010, n=5/6 [Table 1]). In contrast, the majority of evaluable subjects who received SC and achieved CR/CRi exhibited CD22 positivity that remained ≥90% at EOT and at relapse When CD22 expression was quantified as MESF, a similar trend was evident (Table 2). In Study 1022, InO patients had a median CD22 MESF of 4085.0 at baseline, which declined to 94.0 at EOT and 418.0 at relapse. In contrast, the median CD22 MESF at EOT and at relapse (3738.0 and 3738.0, respectively) was similar to baseline (4065.0) for SC patients. Conclusions: Among R/R ALL patients who responded to InO treatment and subsequently relapsed, a decrease in CD22 positivity and receptor density was evident from baseline to EOT and relapse, but emergent CD22 negativity was not evident. These results suggest that recurrent disease is associated with decreased CD22 expression, but is not generally attributable to the outgrowth of CD22-negative clones. Disclosures Stock: Jazz Pharmaceuticals: Consultancy. Cassaday:Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Incyte: Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Kite Pharma: Research Funding; Adaptive Biotechnologies: Consultancy; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. DeAngelo:Pfizer Inc: Consultancy, Honoraria; BMS: Consultancy; Glycomimetics: Research Funding; Shire: Honoraria; ARIAD: Consultancy, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Amgen: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Takeda: Honoraria; Incyte: Consultancy, Honoraria. Jabbour:Novartis: Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. O'Brien:Pharmacyclics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Alexion: Consultancy; Sunesis: Consultancy, Research Funding; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Gilead: Consultancy, Research Funding; Aptose Biosciences Inc.: Consultancy; Vaniam Group LLC: Consultancy; Pfizer: Consultancy, Research Funding; Amgen: Consultancy; Acerta: Research Funding; Abbvie: Consultancy; Astellas: Consultancy; Kite Pharma: Research Funding. Stelljes:Novartis: Honoraria; Amgen: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; JAZZ: Honoraria. Wang:Pfizer: Employment, Equity Ownership. Liau:Pfizer: Employment, Equity Ownership. Nguyen:Navigate BioPharma Services, Inc., a Novartis Subsidiary: Employment. Sleight:Pfizer Inc: Employment, Equity Ownership. Vandendries:Pfizer: Employment, Equity Ownership. Neuhof:Pfizer: Employment, Equity Ownership. Laird:Pfizer: Employment, Equity Ownership. Advani:Novartis: Consultancy; Amgen: Research Funding; Glycomimetics: Consultancy; Pfizer: Honoraria, Research Funding.

Introduction: Daratumumab (DARA) is a human, CD38-targeted, IgG1κ monoclonal antibody approved as monotherapy in heavily pretreated relapsed/refractory multiple myeloma (RRMM) and in combination with standard-of-care regimens for transplant-ineligible NDMM and RRMM. The addition of DARA to standard-of-care regimens in phase 3 studies has consistently demonstrated a near doubling of complete response (CR) rates, tripling of minimal residual disease (MRD)-negativity rates, and reduction in the risk of disease progression or death by ≥44% in patients with transplant-ineligible NDMM or RRMM. In the primary analysis of the phase 3 MAIA study (median follow-up: 28.0 months), a significant progression-free survival (PFS) benefit (median not reached [NR] vs 31.9 months; hazard ratio [HR], 0.56; P<0.001) and a >3-fold increase in MRD-negativity rates (10-5 sensitivity threshold; 24.2% vs 7.3%; P<0.001) were observed for D-Rd vs Rd in patients with transplant-ineligible NDMM (Facon T, N Engl J Med 2019). Here, we report updated efficacy and safety findings from MAIA after 9 months of additional follow-up. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age ≥65 years or comorbidities were randomly assigned (1:1) to receive Rd ± DARA. Stratification factors included International Staging System stage (ISS [I vs II vs III]), region (North America vs other), and age (<75 vs ≥75 years). All patients received 28-day cycles of Rd (R: 25 mg orally once daily on Days 1-21; d: 40 mg orally on Days 1, 8, 15 and 22). In the D-Rd arm, DARA (16 mg/kg intravenously) was given weekly for Cycles 1-2, bi-weekly for Cycles 3-6, and every 4 weeks thereafter. Patients were treated until disease progression or unacceptable toxicity in both treatment arms. The primary endpoint was PFS. Key secondary endpoints included overall response rate (ORR), MRD-negativity rate (10-5 sensitivity, clonoSEQ® version 2.0), and safety. PFS on the next line of therapy (PFS2), defined as the time from randomization to progression on the next line of therapy or death, was also measured. Results: A total of 737 patients were randomized (D-Rd, N = 368; Rd, N = 369). Patient baseline characteristics were well balanced between the two treatment arms. Median (range) age was 73 (45-90) years, with 44% of patients ≥75 years of age. 27%, 43%, and 29% of all patients were ISS stage I, II, and III, respectively. Among 642 patients evaluable for FISH/karyotyping analysis, 86% had standard and 14% had high cytogenetic risk. After a median follow-up of 36.4 months, median PFS was NR with D-Rd vs 33.8 months with Rd (HR, 0.56; 95% confidence interval [CI], 0.44-0.71; P<0.0001; Figure). The estimated 36-month PFS rate was 68% with D-Rd vs 46% with Rd. The PFS benefit of D-Rd vs Rd was observed in all prespecified subgroups, except for patients with impaired hepatic function. Adding DARA to Rd continued to result in deeper responses with higher rates of ≥CR and ≥very good partial response (VGPR; Table). Median duration of response among responders was NR with D-Rd vs 40.7 months with Rd. Median PFS2 was NR vs 47.3 months with D-Rd vs Rd, respectively (HR, 0.69; 95% CI, 0.53-0.91; P=0.0079); follow up is ongoing. 143 (39%) vs 233 (64%) patients with D-Rd vs Rd, respectively, have discontinued treatment. 85 (23%) patients with D-Rd vs 103 (28%) patients with Rd have discontinued the study due to death. Grade 3/4 treatment-emergent adverse events (TEAEs; D-Rd/Rd) occurring in ≥10% of patients were neutropenia (51%/35%), lymphopenia (15%/11%), pneumonia (15%/9%), anemia (14%/21%), leukopenia (11%/6%), and hypokalemia (10%/10%); grade 3/4 infection rates were 36%/27%. The most common serious TEAE was pneumonia (14%/9%). 9% of patients in the D-Rd arm and 18% of patients in the Rd arm discontinued treatment due to TEAEs. The complete updated data set will be presented at the meeting with additional efficacy endpoints, including MRD-negativity rate. Conclusion: After longer follow up, the addition of DARA to Rd continues to demonstrate a significant PFS benefit and improved rates of deeper and more durable responses vs Rd alone in patients with transplant-ineligible NDMM. The longer follow-up also demonstrated a significant improvement in PFS2 favoring D-Rd, and no new safety concerns were observed. These results continue to support the use of D-Rd in the first line of treatment for transplant-ineligible patients with NDMM. Disclosures Bahlis: Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Usmani:Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Plesner:Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Genmab: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Quach:Sanofi: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldschmidt:ArtTempi: Honoraria; John Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product; Mundipharma: Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Molecular Partners: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding. O'Dwyer:GlycoMimetics Inc: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy. Venner:Janssen: Honoraria; J&J: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Weisel:GSK: Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Celgene Corporation: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Krevvata:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Wang:Janssen: Employment. Van Rampelbergh:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Uhlar:Janssen: Employment. Kobos:Janssen: Employment. Perrot:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Amgen: Honoraria; Sanofi: Honoraria.

Abstract Background: Hairy Cell Leukemia (HCL) is a rare hematological malignancy, comprising only of 2% of all leukemias, with an estimated 900 new cases diagnosed each year in the United States. HCL displays a characteristic immunophenotypic profile that include pan-B cell markers including CD103, CD11c, and CD25. World Health Organization guidelines defines two forms of HCL, classic HCL (cHCL) and variant HCL (HCLv) as two distinct clinical entities. Patients with cHCL have a distinct immunophenotypic profile on their malignant leukemic cells including CD20+, CD19+, CD11c+, CD25+, CD103+, and CD123+, while the leukemic cells from patients with HCLv show CD11c+, CD20+ and CD19+, while lacking CD25 and CD123 expression. Some patients with cHCL will retain CD25 positivity while demonstrating negativity for other typical markers, herein termed atypical HCL (aHCL). Presence or absence of CD25 is an important determinant in classifying patients into cHCL and HCLv. Although it has previously been reported that CD25 expression may be lost during treatment with the targeted agent vemurafenib, we sought to identify whether this immunophenotypic change occurs following other treatment types, including standard purine nucleoside analog therapy and with targeted BTK inhibition. Methods: Adult patients (≥18 years) with a diagnosis of HCL whom had immunophenotype data collected before and after treatment between 2010 and 2018 were included in the study. Immunophenotype and morphological characteristics of initial and follow-up peripheral blood, bone marrow aspirate, and core biopsy specimens were reviewed and correlated with the treatment received. Results: We evaluated 30 HCL patients who underwent different therapies. All available specimens were reviewed and showed morphologic features characteristic for cHCL (n=26, 86.7%), and aHCL (n=4, 13.3%). The median age at HCL diagnosis was 50 years (44-76 years) with male predominance (76%). Patients with aHCL were treated with ibrutinib (n=2) and pentostatin (n=2). Patients with cHCL were treated with pentostatin (n=12), ibrutinib (n=8), vemurafenib (n=4), dabrafenib (n=1), and cladribine (n=1). Bone marrow analyses showed that all the patients had leukemic B-lymphocyte co-expression of CD19, CD20, CD103, CD11c, CD25, and CD123 prior to treatment. Some patients also had a smaller percentage of lymphocytes lacking CD25 expression along with the CD25 positive lymphocytes. Follow-up bone marrow and peripheral blood analysis showed that almost half (n=14, 46%) of treated patients had a partial or complete loss of CD25 expression regardless of the treatment type. Leukemic cells continued to express other HCL signature markers. Conclusion: Our study indicates that during the course of disease some patients display a loss of CD25 expression after therapy. This phenomenon was observed across different therapies and is not specific to the type of treatment. This is the first study to show treatment-dependent CD25 variability with pentostatin, ibrutinib and dabrafenib. Our results advocate for caution when using CD25 for the differential diagnosis of cHCL versus HCLv in treated patients. Future studies are needed in larger patient cohorts to determine the overall role and utility of CD25 in the diagnosis of cHCL and HCLv. Disclosures Lozanski: Genentech: Research Funding; Stem Line: Research Funding; BI: Research Funding; Novartis: Research Funding; Beckman: Research Funding; Coulter: Research Funding. Andritsos:Astra Zeneca: Consultancy; HCLF: Membership on an entity's Board of Directors or advisory committees.

Background: Multiple myeloma (MM) is a plasma cell disorder and demonstrates overexpression of B cell maturation antigen (BCMA). Our objective is to evaluate the safety and efficacy of chimeric antigen receptor T cells (CAR-T) against BCMA in patients with relapsed/refractory multiple myeloma (RRMM). Methods: We conducted a systematic literature search using PubMed, Cochrane, Clinicaltrials.gov, and Embase databases. We also searched for data from society meetings. A total of 935 articles were identified, and 610 were screened for relevance. Results: Data from thirty-one original studies with a total of 871 patients (pts) were included based on defined eligibility criteria, see Table 1. Hu et al. reported an overall response rate (ORR) of 100% in 33 pts treated with BCMA CAR-T cells including 21 complete response (CR), 7 very good partial response (VGPR), 4 partial response (PR). Moreover, 32 pts achieved minimal residual disease (MRD) negative status. Chen et al. reported ORR of 88%, 14% CR, 6% VGPR, and 82% MRD negative status with BCMA CAR-T therapy in 17 RRMM pts. In another clinical trial by Han et al. BCMA CAR-T therapy demonstrated an ORR of 100% among 7 evaluable pts with 43% pts having ≥ CR and 14% VGPR. An ORR of 100% with 64% stringent CR (sCR) and 36% VGPR was reported with novel anti-BCMA CART cells (CT103A). Similarly, Li et al. reported ORR of 87.5%, sCR of 50%, VGPR 12.5%, and PR 25% in 16 pts. BCMA targeting agent, JNJ-4528, showed ORR of 91%, including 4sCR, 2CR, 10MRD, and 7VGPR. CAR-T- bb2121 demonstrated ORR of 85%, sCR 36%, CR 9%, VGPR 57%, and MRD negativity of 100% (among 16 responsive pts). GSK2857916, a BCMA targeting CAR-T cells yielded ORR of 60% in both clinical trials. Three studies utilizing bispecific CART cells targeting both BCMA & CD38 (LCARB38M) reported by Zhao et al., Wang et al., and Fan et al. showed ORR of 88%, 88%, & 100% respectively. Topp et al. reported ORR of 31% along with 5 ≥CR and 5 MRD negative status in 42 pts treated with Bi T-cells Engager BiTE® Ab BCMA targeting antigen (AMG420). One clinical trial presented AUTO2 CART cells therapy against BCMA with an ORR of 43%, VGPR of 14%, and PR of 28%. CT053CAR-BCMA showed 14sCR and 5CR with a collective ORR of 87.5% and MRD negative status of 85% in 24 and 20 evaluable pts, respectively. Likewise, Mikkilineni et al. reported an ORR of 83%, sCR of 16.7%, and VGPR & PR of 25% and 41% in 12 pts treated with FHVH-BCMA T cells. Similar results are also reported in other clinical trials of BCMA targeting CART therapy (Table 1). The most common adverse effects exhibited were grade 1-3 hematologic (cytopenia) and cytokine release syndrome (CRS) (mostly reversible with tocilizumab). Conclusion: Initial data from ongoing clinical trials using BCMA targeting CAR-T therapy have yielded promising results both in terms of improved outcome and tolerable toxicity profiles. Although two phase 3 trails are ongoing, additional data is warranted to further ensure the safety and efficacy of anti-BCMA CAR-T cells therapy in pts with RRMM for future use. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Abstract Abstract 4333 Adult acute lymphoblastic leukemia (ALL) differs from pediatric ALL by higher frequency of unfavorable biological features including cytogenetics (often t(9;22), rare t(12;21)), slower molecular response (MRD negativity is lower at day near +30 in adults - 47% vs 80%; Bruggemmann, Blood, 2006; Borowitz, Blood, 2010), more toxicity followed by less complience, all this translating in less efficacy. Another very important, early and simple predictor of antileukamia effect in ALL is prednisolone (PRD) sensitivity, that is to say tumor clearance within one week of prephase. It's a well documented fact in childhood ALL, but scarcely characterized in adults. 35% of adults with ALL are considered to be resistant to PRDN compaired to 10% children after evaluation of PB blast count on day +8 (Annino, Blood, 2002; Shrappe, Leukemia 2002), but few data exists about bone marrow blasts clearance. We initiated a prospective multicenter trial for Ph-negative ALL under the age of 55 based on: 1.evaluation of blast clearance in b/m after 7 days of PRD and its substitution by dexamethazone (DEXA) if blast count was 25% and more. 2. “no interruptions” protocol with 8 weeks induction and 5 consolidation phases followed by 2-years maintenance. 3. prolonged L-asparaginase application at 10.000 IU weekly in induction, once in two weeks in consolidations, twice a month in maintenance (total proposed dose 560.000 IU). The study started in April, 2009. 20 participating centers enrolled 77 patients (median age 27y (16-55), 44f, 33m, 61,5%=B-lin, 38,6%=T-lin; 41% with normal karyotype (NK)). 30,7% of patients were in the standrad risk (SR) group (WBC <30 for B-Lin, <100 for T-Lin, EGIL BII-III, T-III; LDH < 2N, No late CR, t(4;11)-), 69,3% - in the high risk (HR) group (WBC >30 for B-Lin, >100 for T-Lin, EGIL BI, T-I-II-IV; LDH > 2N, No late CR, t(4;11)+). The analysis was performed in June, 2010, and comprised 70 pts. The data on the day +8 b/m count was reported in 67 pts: 70% of them had b/m blasts 25% and more, thus were considered as non-responders to PRD (60 mg/m2) and were switched to DEXA (10 mg/m2). It's worth to note that the proportion of non-responders to PRD was almost equal in the SR and HR groups: 12 of 20 (60%) in SR and 35 of 47 (74,5%). CR rate was high in both risk groups (SR=95,5%; HR=89,4%) and immunological subsets (B=91,4%;T=91,6%). For the whole group of analysed patients (n=70) there were 5 induction deaths (7,1%) and 1 resistant leukemia (1,4%). Median of days without treatment during induction period was 8 days (0-56). Death in remission was reported in 2 of 64 CR pts (3,1%). Relapses occurred in 4/64 (4,2%). Within the short period of follow-up (14 mo) the probability of OS for 70 patients constituted 78,8%, DFS – 76,7%, continuous CR – 81,2%. The difference in DFS between PRD responders and non-responders was at borderline: 63,3% vs 93,8% (p=0,1), and statistically proved in pts with NK vs all other abnormalities: 100% vs 72% (p=0,03). Age, WBC, immunophenotype, risk group, time without treatment did not influence survival. We concluded that in adult Ph-negative ALL the proportion of non-responders to PRD is very high (70%), thus providing much poorer results than in children; sensitivity to PRD may still be used as very simple discriminative marker of unfavorable prognosis. Disclosures: No relevant conflicts of interest to declare.

Abstract Acute myeloid leukemia with normal cytogenetics (CN-AML) is biologically and clinically heterogeneous. Better prognostication and therapeutic strategies are required to improve outcomes. Evasion of host immunity is an important hallmark of cancer. Conversely, robust immune responses have been associated with improved outcomes in solid organ and hematological malignancies, for example, Hodgkin lymphoma. Moreover, targeting immune responses specifically at leukemic cells utilizing bi-specific T cell-engaging antibodies and chimeric antigen receptor T cell immunotherapy demonstrates efficacy primarily in lymphoid malignancies. We therefore sought to explore the effect of immune response on outcomes in myeloid cancers by aiming to determine whether T cell numbers in CN-AML at diagnosis would predict survival. Using diagnostic trephine sections from patients with CN-AML at our institution between 2006 and 2013, we performed immunohistochemistry for CD3, CD8 and Granzyme B (GB) expression. CD4 was not assessable due to high background staining. For each trephine section, three representative fields at 200x magnification were analyzed with a mean of 4245 cells per field. Positive cells, enumerated using Fiji© image analysis software (v1.48o), were expressed as a percentage of total cells. The primary outcome was overall survival (OS). Cox regression was used for univariate and multivariate analyses. Survival was estimated by Kaplan-Meier analyses and categories compared using the log-rank test. Seventy-five patients (52% male, median age 61 years) were analyzed with a median follow-up of 15.9 months. Fifty-six (75%) patients were treated with curative intent with 21 (28%) proceeding to allogeneic transplant either in first complete remission (CR1) (11 patients) or CR2 (10 patients). Of the 33 (44%) patients who died, 18 never achieved CR and 15 relapsed including 3 patients who were allografted in CR1 and 3 patients allografted in CR2. OS was superior in patients with CD3% above the 75th centile (>11.89%) compared with those below (p = 0.0323) (Figure 1). Factors significantly associated with better OS on univariate analyses were younger age, allograft, absence of preceding myelodysplastic syndrome, absence of primary refractory disease, and FLT3-ITD negativity. CD3 (p=0.096), CD8, GB, gender, NPM1 positivity, relapse and blast percentage at diagnosis were not statistically significant. However, in a multivariate analysis of CD3 and the variables found to be significant in the univariate analyses, higher CD3 was found to be an independent predictor of OS (Hazard ratio 0.922 for death, 95% CI 0.851-0.998, p=0.045). Relapse-free survival was evaluable in 49 patients who achieved a CR and was not influenced by CD3, CD8 or GB expression. FLT3 and NPM1 status were available for 53 (71%) patients. Within molecular subgroups FLT3-ITD+ (n=20) and NPM1+/FLT3-ITD- (n=11), there was no survival difference between groups above and below the median for CD3, CD8 or GB. However, in FLT3-ITD-/NPM1- patients (n=22), CD3 > median (11.89%) (Figure 2A) and CD8 > median (10.66%) (Figure 2B) were associated with significantly superior OS whilst GB > median (1.17%) was not significantly associated (p=0.2330). Our findings show that in CN-AML, especially in the FLT3-ITD-/NPM1- subgroup, higher CD3 T cell numbers are associated with improved survival. This suggests baseline immune status may have prognostic value. These results provide impetus for studies into immune therapies in AML and prospectively assessing baseline immune status as a potential prognostic marker in CN-AML. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 2572 Adult ALL regardless recent advantages in adolescents and young adults is still considered to be a therapeutical problem. So called “a pediatric-like approach” applied in adult ALL is reported to be more reasonable even in the older adults (up to 55 y). RALL has initiated a prospective multicenter trial for adult Ph-neg ALL based on: 1) evaluation of b/m blast clearance after 7 days of Prednisolone (PRD) prephase and its substitution by Dexamethasone (DEXA) if b/m blast count was >25%; 2) continuous 2,5 years treatment schedule with prolonged L-asparaginase (Σ=590.000 IU); 3) evaluation of the impact of the late intensification (2 courses of HD of methotrexate and ARA-C) on MRD clearance. The study is registered on the ClinicalTrials.gov public site; NCT01193933. From Nov, 2008, till June, 2012, 24 centers enrolled 173 pts: median age 28 y (15–55), 71f/101m, 112 (64,7%) = B-lin, 54 (31,2%) = T-lin, 1 pt -undifferentiated AL (0,6%), 6 - uknown phenotype (3,5%), median LDH=848 ME (72–13061), median L=13,5 (0,6–556*109/l). Cytogenetics was evaluable in 58,3% of pts (n=101) and 46,5% of them (n=47) had normal karyotype (NK). Initial risk group was evaluated in 154 pts among whom 46 patients (29,9%) were in the standard risk (SR) group (WBC <30 for B-Lin, <100 for T-Lin, EGIL BII-III, T-III; LDH < 2N, No late CR, t(4;11)-negative), 109 (60,1%) - in the high risk (HR) group (WBC >30 for B-Lin, >100 for T-Lin, EGIL BI, T-I-II-IV; LDH > 2N, No late CR, t(4;11)-positive). 19/173 pts (11%) were not qualified. The analysis was performed in June, 2012. +8 day b/m blast count was reported in 149 pts and b/m blasts less than 25% were detected in 36,2% of pts. The portion of PRD non-responders was statistically different in SR and HR groups: 24/45 (53,3%) and 68/101 (67,3%) (p=0,01), confirming the initial risk groups identification. Induction results were obtained in 150 pts, and CR rate was identical in both risk groups (SR=86,9%; HR=84,1%) with total 12 induction deaths (8,0%) and 6 resistant leukemias (4,0%). With a median follow-up of 12 mo (1–36 mo) death in CR was reported in 9/132 (6,8%) pts. OS at 36 mo was 58,6%, DFS-68,3%. MRD analysis for clonal IgH and TCR rearrangements was carried out in 25 pts. And as in our previous studies (ASH 2006, abstr 2294) the clearance was slow with only 41,6% pts negative for MRD at day +133 (4mo) of the protocol. Two late intensification courses (day +157 = 5 mo) increased MRD negativity only up to 50%. Such slow MRD clearance did not correspond to higher relapse rate so far. Age, WBC, immunophenotype, LDH, risk group, +8 day b/m blast count, time to CR, time without treatment (<>8days), L-asparaginase cessation did not influence survival. OS and DFS differed in pts with NK vs all other abnormalities: 87,4% vs 57,9% (p=0,002) and 88,9% vs 66,5%, respectively (p=0,02). So, our data demonstrated that ALL-2009 protocol provided 58% 3-years overall survival and 68,3% DFS. In adult Ph-neg ALL normal karyotype predicts better survival. The MRD clearance is very slow while on this protocol. Disclosures: No relevant conflicts of interest to declare.

In acute myeloid leukemia (AML), the assessment of post-induction minimal residual disease (MRD) is largely utilized for choosing post-remission therapies aimed at maintaining complete remission (CR) and preventing relapse. This latter is still the major cause of treatment failure in pediatric AML, and even if several efforts have been spent to validate MRD as a prognostic marker, numerous studies demonstrated that MRD negativity cannot be considered a completely reliable surrogate biomarker predicting outcome, since it does not exclude a relapse. The current interpretation is that disease relapse is due to mechanisms leading to therapy resistance mainly depending on driver chimeric or oncogenic protein-coding genes, which are monitored during treatment, and does not consider that chemotherapy resistance may arise from other genetic markers, phenomenon linked to methylation and non-coding RNAs genomic pressure. We, thus, hypothesized that other markers need to be explored to re-interpret leukemia progression. We showed an overall hyper-expression of the lncRNA BALR2 in 132 de novo AML bone marrow samples collected at diagnosis and analyzed the gene expression profile (GEP) of 58 cases. By unsupervised clustering analysis, we produced important advances in identifying BALR2 as a robust novel molecular marker of a new subgroup of AML characterized by a high rate of resistance to induction therapy, independently from the genetic lesions detected at diagnosis and any other prognostic clinical and genetic features. We demonstrated in vitro that BALR2 has a direct role in controlling bi-directionally its own and of its neighbor gene CDK6 promoter activity. This latter finding of high CDK6 expression was shown to sustain its complex with RUNX1 in order to inhibit RUNX1 binding to its target promoters, thus preventing the process of hematopoietic differentiation progression. To support BALR2 as a new proto-oncogene involved in the control of the myeloid differentiation program, we ranked the genes across the expression profile obtaining a signature of 337 transcripts able to cluster CD34+ human stem cell precursors (HSCPs) separately from more mature CD14+ cells. These in silico findings were validated in vitro by showing that, after BALR2 depletion, CD34+ cells had a skewed myeloid differentiation. Furthermore, we found that AML differentiation toward mature myeloid cells with increased phagocytic capacity was obtained through BALR2 level reduction, and enhanced by combinatorial differentiation stimuli. Our findings attribute a distinct role to BALR2 in the block of myeloid stem cell differentiation occurring during leukemogenesis. At the same time, we interrogated GEP ontology, finding that enrichments of genes involved in mitochondrial synthesis pathways were significantly correlated to patients with highest BALR2 levels, and confirmed the same mitochondriogenesis profile in the immature CD34+ HSCPs. We moved to deconvolute this feature and demonstrated that BALR2, by controlling mitochondria gene balance, was directly controlling the mitochondrial mass, which dramatically decreased after BALR2 silencing, this supporting the hypothesis that BALR2 would maintain mitochondrial functions to confer AML resistance to cytotoxicity. Consistently with this line of reasoning, we inhibited mitochondria by tigecycline, demonstrating that its activity was dramatically strengthened in BALR2 depleted cells, when used either alone or in combination with cytosine-arabinoside (Ara-C). Concomitantly, tigecycline treatment in BALR2 silenced AML cells reduced mitochondria depolarization, and increased the number of differentiated M-CFU colonies formation, confirming that BALR2, together with CDK6, forms novel transcriptional networks to create a circuit able to impair myeloid differentiation and to lower chemo-sensitivity in AML. We speculate that a novel therapeutic window of mitochondrial targeting in defined AML subgroups, identified through assessment of BALR2 levels at diagnosis or persistent MRD levels, could be envisaged to optimize the outcome of childhood AML. Disclosures Locatelli: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria.

Background - Conventional chemotherapy for adults with Acute Lymphoblastic Leukaemia (ALL) is associated with considerable treatment-related toxicity. Blinatumomab is a CD19/CD3 targeting bi-specific T-cell engager that has demonstrated promising efficacy in relapsed/refractory ALL, and in combination with chemotherapy in newly diagnosed patients. Preliminary studies also suggest less toxicity and good efficacy (CR/CRh 66%) when delivered as induction to older adults (median age 75) with newly diagnosed B-ALL (Advani, ASH 2018). Of responders, Minimal Residual Disease (MRD) negativity in this trial was achieved in 92%. Given this, the Australasian Leukaemia & Lymphoma Group (ALLG) has explored the potential for upfront Blinatumomab as induction for younger adults with Ph- B-lineage Acute Lymphoblastic Leukaemia, alternating with CNS-directed chemotherapy cycles. Aim - To assess response to therapy of the first 10 patients enrolled on this study by molecular MRD analysis as a surrogate measure of short-term efficacy of this combination. Method - The ALLG ALL8 study (ACTRN12617000084381) is a phase II proof-of-concept front-line study for patients fit for treatment with a Hyper-CVAD-like regimen (between 40-65 years) with newly diagnosed Ph- B-lineage ALL. Those with CNS positive disease are excluded. Patients receive a steroid pre-phase (Prednisolone 100mg daily for 7 days) followed by a disease debulking phase of cyclophosphamide 150mg/m2 BD day 1-3, vincristine 2mg day 1 & 11 and dexamethasone 10mg/m2 day 1-4 and 11-14. Patients then receive alternating cycles of Blinatumomab (at 9mcg/d for the first 7 days of cycle 1 followed by 28mcg/d until day 28) with B-cycles of Hyper-CVAD (Methotrexate 1g/m2 day 1, Cytarabine 3g/m2 BD day 2,3, Methylprednisolone 50mg BD day 1-3) (figure 1). All patients receive intrathecal prophylaxis with methotrexate, cytarabine and hydrocortisone prior to blinatumomab treatment blocks and day 1 and 8 of each B-cycle until a total of 8 doses were administered. At the completion of therapy, high-risk patients (MLL translocations, hypodiploid, complex karyotype or MRD positive at TP3) are recommend to proceed to allogeneic stem cell transplant while others receive 24 months of POMP maintenance. Minimal residual disease analysis was performed at a centralised EuroMRD accredited laboratory utilising Taqman probes and patient specific PCR primers targeted at immunoglobulin heavy chain or T-cell receptor (Ig/TCR) gene rearrangements. MRD positivity was defined as a detectable level of ≥ 1 x 10-4. Results - The following results are based upon the first 10 patients enrolled on ALL8. Median age of 54.7 years (range 43 to 66 years) and 70% were male. Median ECOG PS was 0 (range 0 - 2). 6 patients had an abnormal karyotype, 2 high-risk (one with hypodiploid karyotype, one with t(1;19). Median white cell count at diagnosis was 3.36 x 109/L (range 1.95 - 12.05 x 109/L). All patients (10/10) attained CR/CRi following induction therapy with no treatment related deaths. At the end of the induction phase (MRD TP1) 4 out of 10 had attained MRD negativity, 2 had detectable unquantifiable MRD and 4 were MRD positive. By the end of the 1st consolidation cycle (MRD TP2) 1 additional patient had become MRD negative and 1 MRD positive patient had become MRD unquantifiable. 1 patient was not evaluable at TP2 being withdrawn prior to this, 2 do not have TP2 available at this time (1 being MRD negative at TP1, 1 with unquantifiable low-level MRD). One patient had MRD increase between TP1 and TP2, this subject had a hypodiploid karyotype. Thus, by completion of 1st consolidation an aggregate of 7 out of 10 patients were MRD negative or had unquantifiable low-level MRD, 3 remaining MRD positive (with 1 MRD progression). Updated results will be presented at the meeting. Conclusion - Front-line therapy with Blinatumomab in combination with chemotherapy is feasible in adults and results in high levels of MRD response by the end of the first consolidation block with the majority of MRD negative responses attained after the first treatment block. Despite early incorporation of Blinatumomab into this treatment protocol, MRD progression was seen in one patient with high-risk cytogenetic abnormalities. Disclosures Fleming: Astellas: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Reynolds:Novartis Australia: Honoraria; Novartis AG: Equity Ownership; AUSTRALASIAN LEUKAEMIA & LYMPHOMA GROUP (ALLG): Consultancy; Alfred Health: Employment, Other: Biostatistician for trials funded by the Australian government and Abbvie, Amgen, Celgene, GSK, Janssen-Cilag, Merck, Novartis, Takeda, but sponsored by Alfred Health.. Nguyen:Australasian Leukaemia & Lymphoma Group: Employment. Yeung:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria. Greenwood:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Verner:Janssen-Cilag Pty Ltd: Research Funding. Bajel:AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: travel funding. Wei:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria. OffLabel Disclosure: Blinatumomab is not currently approved for the front-line treatment of adults with Ph- B-ALL

Background The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy improves the prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Single agent blinatumomab, a bi-specific T-cell engaging CD3-CD19 antibody construct, is more effective than multi-agent chemotherapy in relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and successfully achieves minimal residual disease (MRD) negativity in MRD positive patients. Limited data is available on the safety and efficacy of these agents in combination and uncertainties remain regarding the optimal use of blinatumomab +TKIs. Dual therapy with blinatumomab and TKIs may offer a safe and effective treatment option for relapsed and refractory patients without the incorporation of chemotherapy. Patients and Methods We report our retrospective experience in 18 patients who received blinatumomab +TKI for relapsed/refractory (R/R) Ph+ ALL (n=14), MRD+ Ph+ ALL (n=2) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC) (n=2). Ten patients received ponatinib; 8 patients received second generation TKIs (dasatinib, n=5; nilotinib, n=2; bosutinib, n=1). Blinatumomab was administered according to the package insert and TKI was initiated on day 1. Median follow up was 15 months and median number of blinatumomab +TKI cycles was 2 (range, 1-5). The median age was 47 years (range, 22-77). The median number of prior therapies was 2 (range, 1-8) and the median number of prior TKIs was 2 (range 1-4). Preexisting T315I mutations were present in one third of patients and 5 patients had relapsed following allogeneic stem cell transplant (alloHSCT). Results Transient grade 2-3 transaminase elevation was observed in 3 patients (ponatinib=2, dasatinib=1). Cytokine Release syndrome was observed in 2 patients. Transient neurotoxicity was observed in 3 patients (1patient with grade 3). All grade 2 and 3 toxicities were observed during the first cycle and all patients were successfully able to complete induction with blinatumomab +TKI. One patient on dasatinib experienced a PICC-associated DVT. There were no other vascular events observed. For patients with r/r disease the CR rate was 88% (14/16) with most of these remissions being MRD negative by flow and PCR (12/14). Both of the patients treated for MRD positivity achieved an MRD negative response. Among T315I mutated patients, 5/6 achieved a CR and 4/5 were MRD negative. The median time to remission was 35 days. The 1 year survival was 80% and the median overall survival following blinatumomab therapy was 45 months. Among 16 pts who achieved an initial response to blinatumomab +TKI, six have expired at the time of this analysis. At the time of relapse on combination therapy, 3/8 pts exhibited new T315I mutations. Of note, all of these were treated with blinatumomab in combination with a second generation TKI. All patients maintained their CD19 positivity at the time of relapse. Both pts with CML-LBC were able to move to a transplant following therapy with blinatumomab +TKI and both attained MRD negative status as measured by Bcr/Abl PCR values. In total, 10 patients treated with blinatumomab +TKI proceeded to alloHSCT, 7 of these are still alive. Median duration of response (DOR) was 5.1 months with maximum DOR of 23.3 months. Discussion While limited due to its retrospective nature and relatively small sample size, this data set begins to answer important regarding the safety and efficacy of blinatumomab +TKI. Combination therapy was effective at achieving rapid and deep responses in this refractory patient population. The toxicities observed with blinatumomab +TKI were in keeping with those seen with blinatumomab alone. However, care should be taken in regard to potential overlapping toxicities of TKIs and blinatumomab, such as hepatotoxicity. The study also suggests a role for blinatumomab treatment in patients with CML-LBC, a rare and difficult disease state to treat. The identification of T315I mutation at relapse in 40% of patients on blinatumomab +second generation TKIs supports further prospective studies with ponatinib and blinatumomab in combination. Finally, loss of C19, which has relevance with regards to the potential benefit of subsequent CD19-directed therapies such as chimeric antigen receptor T-cell therapy was not seen in patients treated with blinatumomab +TKI. Disclosures McCloskey: Jazz: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Gagnon:Amgen: Speakers Bureau. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Pfizer: Honoraria; Novartis: Speakers Bureau; Abbvie: Speakers Bureau.

Abstract The prognosis of elderly patients (pts) with acute lymphoblastic leukemia (ALL) remains poor, and novel therapeutic approaches are clearly needed. CD19 is expressed on the majority of precursor-B ALLs and represents an attractive therapeutic target. The anti-CD19 bi-specific engager antibody blinatumomab has demonstrated significant activity in both relapsed/refractory ALL and minimal residual disease (MRD) positive ALL. Therefore, we evaluated blinatumomab as a single agent in the upfront treatment of newly diagnosed elderly pts with Philadelphia chromosome (Ph) negative B-lineage ALL to determine response rates and overall survival (OS). Methods: Pts were treated at National Clinical Trial Network sites from June 2015 to September 2017. The primary objective of the study was to estimate 3-year OS. An IND was approved by the FDA and the protocol was approved by a central institutional review board. Eligibility: age > 65 years, newly diagnosed Ph negative B-lineage ALL with adequate organ function and no evidence of central nervous system (CNS) disease. Pts received blinatumomab for induction at standard dosing for 1-2 cycles until attainment of complete response (CR) or CR with incomplete count recovery (CRi) (defined below). Pts then received 3 cycles of blinatumomab post-remission therapy followed by 18 months of maintenance POMP (prednisone, vincristine, 6-mercaptopurine, methotrexate). A total of 8 doses of intrathecal methotrexate were administered as CNS prophylaxis. Cytogenetic risk was ascribed by NCCN 2018 criteria and bone marrow samples were analyzed for the presence of the Ph-like signature. MRD was assessed centrally by 8 color flow cytometry pre-treatment, on Day 35 of induction cycle 1, and on Day 35 of re-induction (if applicable). Response was assessed at the completion of 1-2 cycles of blinatumomab. CR was defined as < 5% marrow blasts with no evidence of extramedullary disease and recovery of counts [absolute neutrophil count (ANC) > 1000/uL, platelets >100,000/uL]. CRi was defined the same as CR but ANC < 1000/ uL and/ or platelets ≤ 100,000/ uL. OS was measured from day of registration on trial until the date of death. Disease-free survival (DFS) was measured from the date the pt achieved CR/ CRi until relapse or death. Toxicities were graded according to NCI CTCAE version 4.0. Results: Of 31 pts enrolled, 29 were eligible. The median age was 75 years (range 66 - 84), 22 (76%) were male, median baseline white blood count was 3.7 x 103/uL (range 0.3 - 7,100), and median bone marrow blast count percentage was 86.5% (range 30-100). Three pts received hydroxyurea or steroids prior to treatment initiation. Cytogenetic risk at diagnosis was: poor (34% of pts; n=10), standard (55% of pts; n=16), good (3% of pts; n=1) and unknown (7% of pts, n=2). Testing for the Ph-like signature is being completed. The most common Grade 3-5 non-hematologic toxicities related to treatment during induction were hyperglycemia (14%), dyspnea (10%), febrile neutropenia (10%), hypertension (10%), and lung infection (7%). One pt developed Grade 3 cytokine release syndrome and 1 developed Grade 3 neurotoxicity. No pts died during the first 28 days of treatment. The overall response rate (CR + CRi) was 66% (all CRs). Thirteen of the 19 responders have available MRD data post-treatment. Of these, 12 pts (92%) achieved MRD negativity, all at Cycle 1 Day 35. One pt required 2 cycles of blinatumomab to achieve CR. One pt proceeded to allogeneic hematopoietic stem cell transplant. The median follow-up time is 1 year and median duration on trial is 170 days (6 pts are still on maintenance therapy). OS estimated by Kaplan Meier at 6 months is 79% (95% CI 58%-90%) and at 1 year is 65% (95% CI 43%-80%). DFS estimated at 6 months is 68% (95% CI 43%-84%) and at 1 year is 56% (95% CI 31%-75%). No baseline features including CD19 expression (by percentage or mean-fluorescent intensity) or presence of a CD19 negative subpopulation were associated with response. Conclusions: Blinatumomab was well tolerated and effective in the treatment of newly diagnosed elderly patients with Ph negative B-lineage ALL. Further follow up will determine the durability of these responses. Disclosures Advani: Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy; Glycomimetics: Consultancy. Wieduwilt:Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Park:Adaptive Biotechnologies: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy. Stock:Jazz Pharmaceuticals: Consultancy. Erba:Immunogen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Agios: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Juno: Research Funding; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Takeda/Millenium: Research Funding; Incyte: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Jazz: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Agios: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; MacroGenics: Consultancy; Takeda/Millenium: Research Funding; Seattle Genetics: Consultancy, Research Funding; MacroGenics: Consultancy; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Janssen: Research Funding; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Amgen: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Pfizer: Consultancy, Other: grant; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Astellas: Research Funding; Pfizer: Consultancy, Other: grant; Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Incyte: Consultancy, Speakers Bureau; Juno: Research Funding; Jazz: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Juno: Research Funding; Jazz: Consultancy, Speakers Bureau.

ABSTRACTThis paper discusses a crystallization model that takes difference of covalent bond and ionic bond into consideration. Ionic bond makes crystallization easier than covalent bond because ionic bond is more flexible than covalent bond. The diameter and spaces around large minus-ions should also be taken into consideration. Elements••having electronic negativity far from that of Te or Sb has a tendency to form ionic bonds. For example, Tb and In are considered to make chemical bonds having more ionic characteristics than Ge. In the case of already reported Sn or Bi addition, large ion diameter seems to increase crystallization speed.

BACKGROUND: Given the importance of the roles of psychological contract and voice in organizational life, this study highlights the effect of contract breach on managers and their voice directed at top management members, key representatives of the organization. OBJECTIVE: Drawing on social exchange theory, this study examines the relationship between a psychological contract breach (PCB) and concurrent organizational cynicism resulting in a considerate and aggressive managerial voice behavior. METHODS: Data came from an online survey on PCB and subsequent behaviors from a sample of 336 in-company European and Asian employees with managerial responsibilities working in France. RESULTS: The results provide partial support for the hypothesized relationships and show the consequences of the bi-dimensionality of aggressive voice behavior (fight and negativity). Moreover, organizational cynicism mediates the relationship between PCB and the negativity dimension of aggressive voice. However, data analysis shows no support for organizational cynicism’s mediating role in the relationship between PCB and considerate voice. CONCLUSIONS: The study results of 336 in-company European and Asian employees having a managerial position, like project managers, middle managers, executives, employs a great insight into managerial voice behavior. This study contributes to the limited research conducted on the managerial voice in response to PCB. The findings have important implications for employers to understand managers’ psychological contracts and related voice behavior.

Introduction: Breast synovial sarcoma is extremely rare, with few cases described. It corresponds to 6–9% of soft tissue sarcomas and is more frequent in extremities (80%), trunk (8%), and abdomen (7%) in young adults. It usually does not affect the breast. Objectives: To report a rare case of monophasic breast synovial sarcoma and provide data for the global literature. Method/Case report: G.S.B., 97 years old, presented a 7 cm nodule in the left breast and negative axillary nodes. Ultrasound (US) revealed a heterogeneous nodule of 6.0 x 5.5 cm, BI-RADS 5. She did not have mammography. Core biopsy showed spindle cell neoplasm. Immunohistochemistry (IHC) indicated mesenchymal lesion, without differentiating stromal components of fibroepithelial tumor from the mesenchymal lesion. Rapid growth with ulceration and tumor bleeding were identified. Urgent mastectomy showed a malignant neoplasm of spindle cell pattern and high grade, with 12 cm, involved lateral margin, and 19 negative axillary lymph nodes. IHC of the surgical specimen indicated monophasic synovial sarcoma. Before the wide excision, she had a rapidly progressive recurrence in the sternum, making it non-resectable. During radiotherapy (RT), local progression was identified. She has been receiving chemotherapy (CT) with ifosfamide and adriamycin. No evidence of distant disease was found after 9 months of diagnosis. Results/Discussion: Synovial sarcoma corresponds to approximately 0.06% of all breast neoplasms, originating from their mesenchymal tissue, with variable epithelial differentiation. The term synovial sarcoma is inadequate, deriving from its frequent juxta-articular location. Its incidence is approximately 1.5 per 1 million individuals, with a mean age of 32 years and a male:female ratio of 1.2:1. The main histological subtypes are: classic biphasic and monophasic. Translocation t(X;18) (p11.2; q11.2) and expression of SYT/SSX gene fusion are present in more than 95% of cases. IHC shows an intense expression of vimentin and CD99, and focal of Bcl2, EMA, CKAE1-AE3, actin, and desmin, as well as negativity for S100, cytokeratins, hormone receptors, myosin, and caldesmon. The differential diagnosis is made with other spindle cell entities, such as fibromatosis, solitary fibrous tumor, myofibroblastoma, metaplastic carcinoma, and other sarcomas. Synovial sarcoma has a moderate response to chemotherapy with anthracyclines. The treatment includes wide surgical resection and RT. Metastases occur in about 50% of cases and are present at diagnosis in 16% to 25%; they are more frequent in the lung (75%), regional lymph nodes (15%), and bones (10%), tending to late recurrence and metastases. The 5-year disease-free survival is 60%. Conclusion: The heterogeneity of the disease and its low incidence hinder prospective studies addressing therapeutic options with better long-term results.

The L Word: Generation Q is the reboot of The L Word, a long running series about a group of lesbians and bisexuals in Los Angeles in the early 2000s. Both programmes are unique in their positioning of lesbian characters and have been well received by audiences and critics alike. These programmes present a range of characters and narratives, previously excluded from mainstream film and television, bringing a refreshing change from the destructive images typically presented before. We argue that the reboot Generation Q now offers more meaningful representation of the broader lesbian and transgender communities, and discuss its relevance in the changing portrayals of gay representation. Gay visibility has never really been an issue in the movies. Gays have always been visible. It is how they have been visible that has remained offensive for almost a century. (Russo 66) In 2004 The L Word broke new ground as the very first television series written and directed by predominantly queer women. This set it apart from previous representations of lesbians by Hollywood because it portrayed a community rather than an isolated or lone lesbian character, that was extraneous to a cast of heterosexuals (Moore and Schilt). The series brought change, and where Hollywood was more often “reluctant to openly and non-stereotypically engage with gay subjects and gay characters” (Baker 41), the L Word offered an alternative to the norm in media representation. “The L Word’s significance lies in its very existence” according to Chambers (83), and this article serves to consider this significance in conjunction with its 2019 reboot, the L Word: Generation Q, to ascertain if the enhanced visibility and gay representation influences the system of representation that has predominantly been excluding and misrepresentative of gay life. The exclusion of authentic representation of lesbians and gays in Hollywood film is not new. Over time, however, there has been an increased representation of gay characters in film and television. However, beneath the positive veneer remains a morally disapproving undertone (Yang), where lesbians and gays are displayed as the showpiece of the abnormal (Gross, "Out of the Mainstream"). Gross ("Out of the Mainstream") suggests that through the ‘othering’ of lesbians and gays within media, a means of maintaining the moral order is achieved, and where being ‘straight’ results in a happy ending. Lesbians and gays in film thus achieve what Gerbner referred to as symbolic annihilation, purposefully created in a bid to maintain the social inequity. This form of exclusion often saw controversial gay representation, with a history of portraying these characters in a false, excluding, and pejorative way (Russo; Gross, "What Is Wrong"; Hart). The history of gay representation in media had at times been monstrous, playing out the themes of gay sexuality as threatening to heterosexual persons and communities (Juárez). Gay people were incorrectly stereotyped, and gay lives were seen through the slimmest of windows. Walters (15) argued that it was “too often” that film and television images would narrowly portray gays “as either desexualized or over sexualized”, framing their sexuality as the sole identity of the character. She also contested that gay characters were “shown as nonthreatening and campy 'others' or equally comforting and familiar boys (and they are usually boys, not girls) next door” (Walters 15). In Russo’s seminal text, The Celluloid Closet, he demonstrated that gay characters were largely excluded from genuine and thoughtful presentation in film, while the only option given to them was how they died. Gay activists and film makers in the 1980s and beyond built on the momentum of AIDS activism (Streitmatter) to bring films that dealt with gay subject matter more fairly than before, with examples like The Birdcage, Philadelphia, To Wong Foo, Thanks for Everything! Julie Newmar, and In and Out. Walters argues that while “mainstream films like Brokeback Mountain and The Kids are Alright entertain moviegoers with their forthright gay themes and scenes” (12), often the roles have been more of tokenisation, representing the “surprisingly gay characters in a tedious romcom, the coyly queer older man in a star-studded indie hit, the incidentally gay sister of the lead in a serious drama” (Walters 12). This ambivalence towards the gay role model in the media has had real world effects on those who identify themselves as lesbian or gay, creating feelings of self-hatred or of being ‘unacceptable’ citizens of society (Gamson), as media content “is an active component in the cultural process of shaping LGBT identities” (Sarkissian 147). The stigmatisation of gays was further identified by the respondents to a study on media and gay identity, where “the prevailing sentiment in these discussions was a sense of being excluded from traditional society” (Gomillion and Guiliano 343). Exclusion promotes segregation and isolation, and since television media are ever-present via conventional and web-based platforms, their messages are increasingly visible and powerful. The improved portrayal of gay characters was not just confined to the area of film and television however, and many publications produced major stories on bi-sexual chic, lesbian chic, the rise of gay political power and gay families. This process of greater inclusion, however, has not been linear, and in 2013 the media advocacy group known as the Gay and Lesbian Alliance against Defamation (GLAAD) mapped the quantity, quality, and diversity of LGBT people depicted in films, finding that there was still much work to be done to fairly include gay characters (GLAAD Studio Responsibility Index). In another report made in 2019, which examined cable and streaming media, GLAAD found that of the 879 regular characters expected to appear on broadcast scripted primetime programming, 10.2% were identified as gay, lesbian, bisexual, transgender and or queer (GLAAD Where Are We on TV). This was the highest number of queer characters recorded since the start of their reporting. In January 2004, Showtime launched The L Word, the first scripted cable television to focus chiefly on lesbians. Over the course of six seasons it explored the deep bonds that linked the members of an evolving lesbian friendship circle. The central themes of the programme were the love and friendship between the women, and it was a television programme structured by its own values and ideologies. The series offered a moral argument against the widespread sexism and anti-gay prejudice that was evident in media. The cast, however, were conventionally beautiful, gender normative, and expensively attired, leading to fears that the programme would appeal more to straight men, and that the sex in the programme would be exploitative and pornographic. The result, however, was that women’s sex and connection were foregrounded, and appeared as a central theme of the drama. This was, however, ground-breaking television. The showrunner of the original L Word, Ilene Chaiken, was aware of the often-damning account of lesbians in Hollywood, and the programme managed to convey an indictment of Hollywood (Mcfadden). The L Word increased lesbian visibility on television and was revolutionary in countering some of the exclusionary and damaging representation that had taken place before. It portrayed variations of lesbians, showing new positive representations in the form of power lesbians, sports lesbians, singles, and couples. Broadly speaking, gay visibility and representation can be marked and measured by levels of their exclusion and inclusion. Sedgwick said that the L Word was particularly important as it created a “lesbian ecology—a visible world in which lesbians exist, go on existing, exist in forms beyond the solitary and the couple, sustain and develop relations among themselves of difference and commonality” (xix). However, as much as this programme challenged the previous representations it also enacted a “Faustian bargain because television is a genre which ultimately caters to the desires and expectations of mainstream audiences” (Wolfe and Roripaugh 76). The producers knew it was difficult to change the problematic and biased representation of queer women within the structures of commercial media and understood the history of queer representation and its effects. Therefore, they had to navigate between the legitimate desire to represent lesbians as well as being able to attract a large enough mainstream audience to keep the show commercially viable. The L Word: Generation Q is the reboot of the popular series, and includes some of the old cast, who have also become the executive producers. These characters include Bette Porter, who in 2019 is running for the office of the Mayor of Los Angeles. Shane McCutchen returns as the fast-talking womanising hairdresser, and Alice Pieszecki in this iteration is a talk show host. When interviewed, Jennifer Beals (executive producer and Bette Porter actor) said that the programme is important, because there have been no new lesbian dramas to follow after the 2004 series ended (Beals, You Tube). Furthermore, the returning cast members believe the reboot is important because of the increased attacks that queer people have been experiencing since the election of Donald Trump in 2016. Between the two productions there have been changes in the film and television landscape, with additional queer programmes such as Pose, Orange Is the New Black, Euphoria, RuPaul’s Drag Race, and Are You the One, for example. The new L Word, therefore, needed to project a new and modern voice that would reflect contemporary lesbian life. There was also a strong desire to rectify criticism of the former show, by presenting an increased variation of characters in the 2019 series. Ironically, while the L Word had purposefully aimed to remove the negativity of exclusion through the portrayal of a group of lesbians in a more true-to-life account, the limited character tropes inadvertently marginalised other areas of lesbian and queer representation. These excluded characters were for example fully representative trans characters. The 2000s television industry had seemingly returned to a period of little interest in women’s stories generally, and though queer stories seeped into popular culture, there was no dedicated drama with a significant focus on lesbian story lines (Vanity Fair). The first iteration of The L Word was aimed at satisfying lesbian audiences as well as creating mainstream television success. It was not a tacky or pornographic television series playing to male voyeuristic ideals, although some critics believed that it included female-to-female sex scenes to draw in an additional male viewership (Anderson-Minshall; Graham). There was also a great emphasis on processing the concept of being queer. However, in the reboot Generation Q, the decision was made by the showrunner Marja-Lewis Ryan that the series would not be about any forms of ‘coming out stories’, and the characters were simply going about their lives as opposed to the burdensome tropes of transitioning or coming out. This is a significant change from many of the gay storylines in the 1990s that were seemingly all focussed on these themes. The new programme features a wider demographic, too, with younger characters who are comfortable with who they are. Essentially, the importance of the 2019 series is to portray healthy, varied representations of lesbian life, and to encourage accurate inclusion into film and television without the skewed or distorted earlier narratives. The L Word and L Word: Generation Q then carried the additional burden of countering criticisms The L Word received. Roseneil explains that creating both normalcy and belonging for lesbians and gays brings “cultural value and normativity” (218) and removes the psychosocial barriers that cause alienation or segregation. This “accept us” agenda appears through both popular culture and “in the broader national discourse on rights and belongings” (Walters 11), and is thus important because “representations of happy, healthy, well integrated lesbian and gay characters in film or television would create the impression that, in a social, economic, and legal sense, all is well for lesbians and gay men” (Schacter 729). Essentially, these programmes shouldered the burden of representation for the lesbian community, which was a heavy expectation. Critiques of the original L Word focussed on how the original cast looked as if they had all walked out of a high-end salon, for example, but in L Word: Generation Q this has been altered to have a much more DIY look. One of the younger cast members, Finlay, looks like someone cut her hair in the kitchen while others have styles that resemble YouTube tutorials and queer internet celebrities (Vanity Fair). The recognisable stereotypes that were both including and excluding have also altered the representation of the trans characters. Bette Porter’s campaign manager, for example, determines his style through his transition story, unlike Max, the prominent trans character from the first series. The trans characters of 2019 are comfortable in their own skins and supported by the community around them. Another important distinction between the representation of the old and new cast is around their material wealth. The returning cast members have comfortable lives and demonstrate affluence while the younger cast are less comfortable, expressing far more financial anxiety. This may indeed make a storyline that is closer to heterosexual communities. The L Word demonstrated a sophisticated awareness of feminist debates about the visual representation of women and made those debates a critical theme of the programme, and these themes have been expanded further in The L Word: Generation Q. One of the crucial areas that the programme/s have improved upon is to denaturalise the hegemonic straight gaze, drawing attention to the ways, conventions and techniques of reproduction that create sexist, heterosexist, and homophobic ideologies (McFadden). This was achieved through a predominantly female, lesbian cast that dealt with stories amongst their own friend group and relationships, serving to upend the audience position, and encouraging an alternative gaze, a gaze that could be occupied by anyone watching, but positioned the audience as lesbian. In concluding, The L Word in its original iteration set out to create something unique in its representation of lesbians. However, in its mission to create something new, it was also seen as problematic in its representation and in some ways excluding of certain gay and lesbian people. The L Word: Generation Q has therefore focussed on more diversity within a minority group, bringing normality and a sense of ‘realness’ to the previously skewed narratives seen in the media. In so doing, “perhaps these images will induce or confirm” to audiences that “lesbians and gay men are already ‘equal’—accepted, integrated, part of the mainstream” (Schacter 729). 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