Journal articles on the topic 'Chalan bil'

El objetivo del estudio fue evaluar los modelos no lineales Gompertz, logístico, Von Bertalanffi y Richards para hallar el modelo que mejor describa el crecimiento de cuyes de saca temprana. La investigación se desarrolló en una granja comercial de cuyes de raza Perú ubicada en la provincia de Huaura, Perú. Se utilizaron 10 machos y 12 hembras que fueron pesados periódicamente desde el nacimiento hasta los 69 días. La alimentación fue básicamente con forraje verde (maíz chala). El grado de ajuste de los modelos no lineales del peso y edad de los animales fue evaluado a través del cuadrado medio del error (CME) y los criterios Akaike (AIC) y Bayesiano (BIC). El modelo no lineal logístico fue el que mejor describió el crecimiento de los cuyes alimentados con forraje verde y permitió elaborar el estándar de crecimiento a la saca temprana.

Bloomsbury Design Library (BDL) provides information, much of it scholarly, on art, artists, and architecture from 1500 BCE to the present. It offers access to books published by Bloomsbury Publishing, and also information about certain museums and their exhibits and some images of items in these collections. The site also offers tools for educators, such as lesson plans and bibliographic guides. The site has a clear layout that is consistent across most pages and the content seems to be abundant. However, on closer inspection the content is less robust than it appears; it is repeated in various forms throughout the website. On the plus side, this makes things more discoverable; for example, someone looking for Southern African design can find it more easily in the “place” category than by searching through the entire Bloomsbury Encyclopedia of Design. On the downside, the redundancy makes it difficult to remember where one is on the site, as the same thing can be seen multiple times and there is sometimes a lack of sufficient breadcrumbs to show users how they got to a particular page. In addition, some of the topics have only one to three items on their pages. Though it is valuable to have access to entire scholarly books such as the abovementioned encyclopedia and the overall design of the website is clear and pleasing, the lack of varied content and the insufficient use of breadcrumbs keep BDL from reaching its full potential.

This study evaluated the degradation of octylphenol polyethoxylates by Pseudomonas nitrore-ducens TX1 using secondary kinetics analysis. Nonlinear kinetic regression was employed through the utilization of curve-fitting software in order to fit the digitized growth degradation data. A comprehensive analysis was conducted using various statistical metrics including root-mean-square error (RMSE), adjusted coefficient of determination (adjR2), bias factor (BF), accu-racy factor (AF), corrected AICc (Akaike Information Criterion), Bayesian Information Criterion (BIC), and Hannan-Quinn information criterion (HQC). The accuracy and statistical analysis of the kinetic models used showed that only the Huang, Baranyi Roborts, modified Gompertz, Bu-chanan-3-phase, modified Richards and Von Bertalanffy model fit the data, with modified Logis-tics having the best model with low RMSE and AICc values, highest adjusted R2 values, and Bias Factor and Accuracy Factor values closest to unity. The calculated values for the modified Logis-tics constant maximum growth rate (m), maximum growth value (A) and lag period (l), were 0.179 (h-1), 2.199 and 13.015 h, respectively. Growth curve of the bacterium on varying concen-trations of this compound can then be modelled using this model and the maximum growth rate value can be utilized for secondary modelling works further revealing important parameters.

Abstract Abstract 2861 Poster Board II-837 Bcl-2 protein family has the unique capability to balance between the cell survival and death by regulating the expression of its individual members. AT-101 is a BH3 mimetic and a potent inducer of noxa and puma, the natural ligands of BH3 family proteins. It is known to bind and inhibit the anti-apoptotic functions of Bcl-2 family members Bcl-2 and Bcl-XL and Mcl-1. In vitro it has been shown to induce apoptosis in several tumor models systems including multiple myeloma. In this report we investigated the effect of AT-101 on a model cell line, BCWM.1 (a known WM cell line, BCWM.1/WT), representing Waldenström Macroglobulinemia. This disease is characterized by the presence of lymphoplasmacytic cells in the bone marrow and the secretion of IgM monoclonal protein into the serum. Several conventional therapies are available but the disease remains incurable. Therefore there remains a need to develop new therapies for this orphan disease. Recently, bortezomib (a proteasomal inhibitor) has shown promising anti-WM activity with enhanced responses when combined with traditional therapies. But continued treatment with bortezomib result in the development of resistance in the clinic. We developed an in vitro model of bortezomib resistance from BCWM.1 (hereafter referred as BCWM.1/BR). These cells also developed cross resistance to conventional therapies used for WM such as fludarabine and doxorubicin. Biological characterization of this cell line demonstrated Bcl-2 as a potentially important therapeutic target. We therefore assessed the effect of AT-101 to identify preclinically if this could be a potential clinical strategy in future. AT-101 induced a dose and time dependent inhibition in the viability of both BCWM.1/WT as well as BCWM.1/BR cells. Cell death was observed at as low as 1uM concentration of AT-101 and at 10uM a maximum of 50-70% death was observed by 24h. While BCWM.1/WT cells showed a significant death at 12h, treatment with AT-101 induced cell death in BCWM.1/BR cells as early as 6h. These results indicate that AT-101 induced a potent and quick inhibition in viability in BCWM.1/BR cells as compared to their parental wild type cells. Investigation into the mechanism of cell death showed that AT-101 induced apoptosis in a mitochondrial dependent pathway in these cells. A comparative analysis of the signal transduction pathways operated in BCWM.1/WT and BCWM.1/BR cells showed that many of the cellular activation and survival pathways such as AKT, ERK1/2 that are present in BCWM.1 cells are inhibited in the resistant cells. Interestingly, BCWM.1/BR cells expressed a fivefold increase in the Bcl-2 protein as compared to BCWM.1/WT cells suggesting a Bcl-2 dependent survival of these cells in the absence of other cellular activation and survival signals. Increased susceptibility of BCWM.1/BR cells to AT-101 thus can be understood to be a direct consequence of an increased expression of Bcl-2 and a dependence of the resistant cells on Bcl-2 family of anti-apoptotic proteins for their survival. Results presented in this report suggest that AT-101 has a unique therapeutic potential against Waldenström Macroglobulinemia that is independent of resistance to bortezomib. These observations highlight bcl-2 as a potential target, and AT-101 as possible therapeutic avenue for WM patients. Disclosures: Chanan-Khan: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Abstract 4919 Waldenstrom's macroglobulinemia (WM) is characterized by the presence of lymphoplasmacytic cells in the bone marrow and the secretion of IgM monoclonal antibody in the serum. Several conventional therapies are available but the disease remains incurable. Recently, bortezomib (a proteasomal inhibitor) has shown promising anti-WM activity with enhanced responses when combined with traditional therapies. Resistance to bortezomib therapy is an important event that is associated with continued treatment. In order to understand the mechanism of bortezomib resistance in WM we exposed BCWM.1 (a known WM cell line) in vitro to increasing concentrations of bortezomib over prolonged periods of time and isolated the bortezomib resistant clone (BCWM.1/BR). This clone was compared with its parent wild type cell line (BCWM.1/WT). Investigation to understand the susceptibility of BCWM.1/Br cells to various therapeutic agents showed that these cells are resistant to many of the agents such as melaphalan, fludarabine or doxorubicin. Interestingly, verapamil, a broad spectrum inhibitor of multidrug resistance, failed to reverse the resistance induced by bortezomib indicating that bortezomib resistance is not because of an activation of multidrug resistance in these cells. While BCWM.1/WT cells showed an IC50 of 7.8nM when treated for 72h with bortezomib, the BCWM.1/BR cells were not inhibited at any concentration of the compound up to 100nM. Furthermore, the cells with the acquired resistance showed a 4 fold increase in the proteasomal activity as measured by the release of a fluorescent product (7-Amino-4-methylcoumarin (AMC)) from its peptide substrate, suc-LLVY-AMC. Biochemical analysis further revealed that many of the proteasomal components are altered in BCWM.1/BR cells as compared to their parental control cells. Interestingly, protein levels of two of the proteasomal catalytic subunits, PSMB5 and PSMB9 are upregulated in resistant cells suggesting a reason for the enhanced proteasomal activity of these cells. The resistant cells showed an altered gene expression profile that indicates a transformation of the parental wild type cell line to acquire resistance. A comparative analysis of the signal transduction pathways operated in these cells showed that many of the activation and cell survival pathways that are present in BCWM.1 cells are inhibited in the resistant cells. For example, BCWM.1 cells show a constitutive activation of AKT and ERK1/2 which are inhibited in the resistant cells thus making them insensitive to the inhibitors of these pathways. Similarly, HSP27 which was earlier shown to contribute to bortezomib induced resistance was completely inhibited in BCWM.1 resistant cells. Interestingly, there is an increase in Bcl-2 protein in BCWM.1/BR cells as compared to WT cells indicating that the resistant cells might be dependent on Bcl-2 family for their survival. Inhibition of Bcl-2 induced potent apoptosis in BCWM.1/BR cells. Thus the results presented here indicate that acquired bortezomib resistance in BCWM.1 cells alters their proteasomal activity, cellular signaling pathways to make them resistant to many of the known therapies but these cells retain the Bcl-2 mediated pathway for targeting thus inhibitors of Bcl-2 may be used in therapy against bortezomib-resistant WM. Disclosures Chanan-Khan: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Indigenous Peoples of North America is included in the Gale Primary Sources series and is in two parts. This database, The Indian Rights Association, 1882‐1986, is the second of the two. The Indian Rights Association (IRA) is the first organization to address American Indian rights and interests, and this collection includes its organizational records; incoming and outgoing correspondence; annual reports; draft legislation; photographs; administrative files; pamphlets, publications, and other print materials (including documents from the Council on Indian Affairs and other American Indian organizations); and manuscripts and research notes on Indian traditions, both social and cultural. Founded in 1882 by White philanthropists, the IRA's initial approach to American Indians was both assimilationist and paternalistic, leading it to advocate for the detribalization of America's Indigenous peoples, maintaining it would improve their social and economic status. Nevertheless, it was one of the first organizations to report on and expose the corruption of federal government officials tasked with working with and for American Indians. Eventually, the IRA would discard assimilationism and work with other, newer, occasionally Indian-run organizations such as the Association on American Indian Affairs, the Society of American Indians, and the National Indian Defense Association. The IRA sought to debunk misconceptions and half-truths about American Indians and their condition in the United States, which were too often the basis for policy and legislation related to Native Americans. It also sent association representatives to Indian reservations to make note of local conditions there, not only to evaluate the actions of the Bureau of Indian Affairs (BIA) but also to provide background information for legislation related to Indigenous peoples.This database's search functions often produce results relevant to the query submitted, and both its search and browse functions can be navigated with relative ease. This database can be subscribed to or purchased with an annual hosting fee. The purchase price, based on a variety of factors, can start as low as $2,796 for public libraries or $3,994 for academic libraries, with starting annual hosting fees of $22 and $32, respectively. Whether institutions find this pricing reasonable depends on their need for the materials covered by the Indigenous Peoples of North America collection. The licensing agreement for this database is too long and detailed but standard in its composition and therefore is of no concern.

Background: The development of novel treatment strategies has extended the median survival of MM to nearly a decade but the disease remains incurable and relapse is inevitable. The Bcl-2 pathway is highly relevant to MM cell survival and can be mitigated therapeutically. AT-101 is a novel, orally available pan Bcl-2 inhibitor (Bcl-2, Bcl-xl, Mcl-1, and Bcl-w). Preclinical in vitro and in vivo studies showed that AT-101 enhanced cytotoxicity of lenalidomide-dexamethasone (Rd). We conducted a phase I study in RRMM patients to establish the effective dose of AT-101 with Ld as well as record safety and preliminary efficacy of this combination (NCT02697344). Methods: Key eligibility criteria included: RRMM with measurable disease (serum monoclonal protein ≥1.0 g/dL or urine monoclonal protein >200mg/24 hour or serum immunoglobulin free light chain >10mg/dL AND abnormal serum free light chain ratio). Patients must have received 1-3 prior treatment regimens and have an absolute neutrophil count ≥1.0 x 109, platelets 75 x 109, creatinine clearance ≥50 mL/min, and ECOG performance status ≤2. AT-101 dosing was designed to reach a maximum daily target of 20mg (Cohort 1; 10 mg PO QD, Cohort 2; 20 mg PO QD) utilizing a standard 3 +3 dose escalation design in combination with standard doses of Rd. Treatment was given as outpatient for a maximum of 12, 28-day cycles. For pharmacodynamic studies, AT-101 alone was given in cycle 1, with R (25 mg on days 1-21) and d (40 mg weekly) added cycle 2 onwards. Results: Enrolled patients (n=10) included 60% males with median age 68.5 years (range 55-75) and median time since MM diagnosis 4.5 years (range 0.6-8.3). MM ISS stage was II/III in 7 patients and 8/10 had high-risk cytogenetics with 4 each having del17p and 1q+. Only 1 patient had t(11;14).Patients had received median 2 prior lines of therapy (range 1-3), with 7 having had prior autologous stem cell transplant (ASCT) and the initial induction regimen being bortezomib (V), R and dexamethasone (d) (VRd) in 8, Rd in 1 and cyclophosphamide (C) with Vd (VCd) in 1 patient. At the time of study entry, 3 patients were R refractory while 2 were refractory to both, V and daratumumab (Dara). Median duration of treatment was 7.5 cycles (range 2-12) and 3 patients completed all planned 12 cycles of treatment. Among the evaluable patients, dose limiting toxicities (DLTs) at 20 mg daily dose of AT-101 with 25 mg of R and 40 mg weekly included one patient with grade 4 febrile neutropenia and grade 4 neutropenia lasting 9 days and one patient with grade 4 thrombocytopenia lasting 8 days. G3/4 adverse events (AEs) included atrial flutter (n=1), white blood cell count decrease (n=3), neutropenia (n=5), febrile neutropenia (n=1) and thrombocytopenia (n=2), and back pain (n=1) . No G3/4 non-hematological AEs were noted. Any grade non-hematologic AEs seen in at least 20% (n=2) patients included fatigue (n=9), neuropathy (n=6), nausea (n=3), diarrhea (n=5), constipation (n=3), and creatinine increased (n=2). No patients experienced tumor lysis syndrome. Overall response rate (ORR) was 44% (2 each with very good partial response, VGPR and PR) and clinical benefit rate (CBR) was 89% with 2 additional patients showing minor response (MR) and 2 experiencing stable disease (SD) (Fig 1). Patients with high-risk disease had an ORR of 43% and a CBR of 100%. Median progression-free survival (PFS) for all patients was 8.1 months. Correlative analysis from patients who showed an objective response to treatment revealed a significant increase in bone marrow Th-effector cells, NK cells and cytotoxic CD8+ T-cells along with a significant decrease in immunosuppressive T-regulatory and B-regulatory cells was noted after 1 complete cycle of the combination therapy (p<0.05, Fig 2). Conclusions: This is the first reported clinical trial combining a Bcl-2 inhibitor with immunomodulatory drugs (IMiDs) in MM. AT-101-Rd is a clinically active regimen with an ORR of 40% in predominantly high-risk RRMM patients with an acceptable toxicity profile. Additional patients with MM experienced clinical benefit despite refractory status to prior therapy in this early phase clinical trial. These early findings support the further investigation of AT-101 specifically, and Bcl-2 inhibitors in general, with IMiDs in patients with MM. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy. Chanan-Khan:Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: AT-101 is not currently FDA-approved for treatment of any condition.

Abstract Abstract 2832 Poster Board II-808 Bortezomib, a novel proteasomal inhibitor, is an important treatment for patients with multiple myeloma (MM). Despite its clinical success, acquired resistance to bortezomib is an unresolved challenge experienced in the clinic. Limited therapeutic options are available for patients with bortezomib resistant disease and novel therapies are urgently required to target bortezomib resistant MM. In this report, we evaluated the efficacy of Mapatumumab, a fully human agonistic antibody that targets and activates the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor-1, on MM cell lines. Myeloma cell lines OPM2, KMS11 and U266 wild type (WT) and their respective bortezomib resistant (BR) derivatives were utilized to investigate the efficacy of mapatumumab to overcome bortezomib resistance. Biochemical analyses showed BR cells to have a higher proteasomal activity with cross-resistance to many of the conventional therapeutic agents. Treatment of both WT and BR cells with mapatumumab resulted in a significant (p<0.005) inhibition in their viability by 24h, compared to cells treated with the control antibody. Inhibition of tumor cell viability varied between 20-70%, depending on the cell line. The inhibitory response was higher in WT cells, as compared to the BR cells. Annexin-V staining of mapatumumab treated cells showed the decrease in viability was due to the induction of apoptosis. Immunoblot analyses revealed that mapatumumab treatment resulted in the activation of caspase-8 and caspase-3, suggesting activation of the extrinsic apoptosis pathway in the presence of the antibody. A pan caspase inhibitor, z-vad-fmk (at 25mM), blocked apoptosis induced by mapatumumab. Investigation into the effect of mapatumumab on intracellular signaling showed that treatment with the antibody inhibited the phosphorylation of AKT, and ERK1/2, as well as the expression of Bcl-2 in these cells as early as 4h post-treatment. This suggests mapatumumab treatment affects cellular proliferation and survival pathways. Furthermore, combined treatment of MM cells with mapatumumab and bortezomib resulted in enhanced cell killing compared to mapatumumab or bortezomib alone in both WT and BR cells, thus indicating that there a co-operation in apoptosis signaling induced by these agents. Results presented in this report suggest that TRAIL-R1 mediated apoptosis can be exploited as a therapeutic option in bortezomib resistant MM and warrant clinical evaluation of mapatumumab in bortezomib resistant MM. Disclosures: Chanan-Khan: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Background: MEN1611 (MEN) is an oral PI3K inhibitor active on the p110α mutant and wild type, β and γ isoforms, while sparing the δ. B-PRECISE-01 is an open-label, 2-arm, phase 1b study investigating MEN1611 in combination with trastuzumab ± fulvestrant in patients with HER2 positive/PIK3CA mutated metastatic breast cancer (MBC). No dose-limiting toxicities were observed during the dose-escalation step and MEN1611 48 mg BID was selected as the recommended phase 2 dose (RP2D) for cohort expansion (CE). Methods: Eligible patients had HER2+/PIK3CA-mutated MBC and were treated with at least 2 prior lines of anti-HER2-based therapy in the advanced/metastatic setting including trastuzumab. Patients received MEN1611 + trastuzumab (MEN+T); hormone receptor positive (HR+) postmenopausal women received M+ T + fulvestrant (MEN+T+F). Recruitment was closed in December 2021. Pooled safety and efficacy data from the two subpopulations of CE are presented herein. Results: As of June 2022, 62 female patients were treated: 56 of them with MEN1611 48 mg BID (25 MEN+T and 31 MEN+T+F). Median age 55.5 years (range 34-78), 21% premenopausal, ECOG PS 0-1: 95.2%. Median metastatic regimens 4; 71.0% had prior pertuzumab and 91.9% had prior T-DM1. Common treatment-emergent adverse events (TEAEs, ≥20%) were diarrhea 66.1%, nausea 45.2%, hyperglycemia 43.6%, anemia 35.5%, asthenia 29.0%, decreased appetite 27.4%, rash 25.8%, aspartate aminotransferase increased 22.6%, vomiting 22.6%, and pyrexia 22.6%. Common TEAEs with CTCAE grade ≥3 (≥10%) were hyperglycemia (22.6%) and diarrhea (11.3%). Most treatment-related AEs (TRAEs) were reversible and manageable by supportive care. TEAEs leading to permanent treatment discontinuation occurred in 9 patients (14.5%), the only TEAE occurring in more than one patient was lipase increased (3.2%). TEAEs caused temporary treatment interruptions in 32 patients (51.6%), the most common being hyperglycemia (21.0%) and diarrhea (9.7%). TEAEs leading to dose reduction occurred in 14 patients (22.6%), the most common being diarrhea (6.5%), hyperglycemia (3.2%) and stomatitis (3.2%). Serious TRAEs were experienced by 12 patients (19.4%): hyperglycemia 6 patients, diarrhea 3 patients, anemia, general physical health deterioration, generalized edema, lipase increased, ketoacidosis and pneumonitis (1 patient each). In the efficacy-evaluable population at the RP2D (n=41) 14 patients (34.1%) showed partial response (MEN+T 5/15, MEN+T+F 9/26), 1 patient (2.4%) had a complete response (MEN+T 1/15) and 23 patients (56.1%) had stable disease (MEN+T 6/15, MEN+T+F 17/26) as best response. At the RP2D, the median (95% CI) overall survival (OS) was 21.9 (11.9, NE) months and the median (95% CI) progression free survival (PFS) 5.6 (3.7, 7.2) months. In the MEN+T group, the median OS was 11.9 (5.7, NE) months and median PFS 3.9 (2.3, 6.7) months. In the MEN+T+F group the median OS was 21.9 (16.9, NE) months and median PFS 5.7 (3.7, 11.5) months. Five patients continue on treatment. Conclusions: Updated results from B-PRECISE-01 demonstrated that MEN1611 combined with trastuzumab ± fulvestrant continued to show a manageable safety profile with encouraging anti-tumor activity and duration of response in heavily pre-treated patients with HER2+/PIK3CA-mutated advanced or metastatic breast cancer. Citation Format: Martine Piccart, Audrey Hennequin, Manuel Ruiz Borrego, Santiago Escrivá-de-Romani, Anja Williams, Begoña Jiménez Rodríguez, Gianluca Del Conte, Sacha J. Howell, Michela Palleschi, Matteo Simonelli, Francois P. Duhoux, Diego Tosi, Bernard Doger de Speville Uribe, Yolanda Jerez Gilarranz, Pierfrancesco Tassone, Giuseppe Curigliano, Simon Waters, Philippe Aftimos, Hans Wildiers, Simona Scartoni, Bartomeu Piza Vallespir, Ram Charan Shankaraiah, Krzysztof Grzegorzewski, Nassir Habboubi. MEN1611, a PI3K inhibitor, combined with trastuzumab ± fulvestrant for HER2+/PIK3CA mutant advanced or metastatic breast cancer: updated safety and efficacy results from the ongoing phase 1b study (B-PRECISE-01) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-05.

Abstract Background: Metaplastic Breast Cancer (MBC) is rare (0.2-5%), aggressive form of BC characterized by chemotherapy resistance and has worse outcomes in comparison to other BC subtypes. Resistance to chemotherapeutic agents is related to defects in intact intrinsic apoptosis pathway and the BCL2 family of proteins are the central regulators of this pathway. Majority of MBC have triple-negative receptor status and have no standard therapeutic approach and validated prognostic markers. Here, we examine the association of BCL2 family pro-apoptotic and anti-apoptotic genes expression with metaplastic TNBC (MTNBC) patient survival. Methods: 13,036 BC samples (MTNBC, n=102; metaplastic non-TNBC, n=20) were analyzed by next-generation sequencing (592, NextSeq; WES, NovaSeq), Whole Transcriptome Sequencing (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). A total of 10 pro-apoptotic (BAX, BAK1, BID, BAD, BIK, BCL2L11, BMF, HRK, PMAIP1, BBC3) and 6 anti-apoptotic (BCL2, BCL2L1, BCL2L2, MCL1, BCL2A1, BCL2L10) BCL2 family genes were analyzed. MTNBC with PMAIP1-high(H) and -low(L) expression was classified by top and bottom quartile, respectively. Pathway enrichment was determined by GSEA (Broad Inst). Real world overall survival (OS) was extracted from insurance claims and calculated from tissue collection to last contact using Kaplan-Meier estimates. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q &lt; 0.05). Results: MTNBC had enrichment of apoptosis (NES: 1.4, FDR: 0.05), glycolysis (NES: 1.48, FDR: 0.03), PI3K/AKT/mTOR signaling (NES: 1.43, FDR: 0.05), P53 (NES: 1.51, FDR: 0.06), NOTCH signaling (NES: 1.39, FDR: 0.05), TGFβ signaling (NES: 1.41, FDR: 0.05), WNTβ catenin signaling (NES: 1.41, FDR: 0.05) and IL2/STAT5 signaling (NES: 1.33, FDR: 0.09) pathways compared to metaplastic non-TNBC. MTNBC had higher expression of BCL2 pro-apoptotic genes BAX (Fold Change (FC): 1.6), BAK1 (FC: 1.3), BID (FC: 2), BAD (FC: 1.6), BCL2L11 (FC: 2.5) and BBC3 (FC: 1.5), and anti-apoptotic genes BCL2L1 (FC: 1.6) and BCL2L2 (FC: 1.3) (all p &lt; 0.05) compared to metaplastic non-TNBC. Higher PMAIP1 gene expression was associated with worse MTNBC patient survival (mOS: 14.3 month; HR: 0.37; 95% CI 0.19-1.41; p=0.002) (Table 1), but not in metaplastic non-TNBC (mOS: Inf; HR: 1.96; 95% CI 0.64-6.02; p=0.23). PMAIP1-H MTNBC had higher expression of immune checkpoint genes CD274 (FC: 2.8), PDCD1 (FC: 2.2), TIM3 (FC: 1.8), LAG3 (FC: 2.1) and IDO1 (FC: 5.7) (all p &lt; 0.05), compared to PMAIP1-L MTNBC. PMAIP1-H MTNBC had higher frequency of IHC-PD-L1 positivity (68.4% vs 14.3%, p &lt; 0.05). PMAIP1-H MTNBC had higher expression of stem cell related genes CD44 (FC: 1.7), ALDH1A2 (FC: 2.2), ALDH1A3 (FC: 2.6), SOX2 (FC: 5.21) and NANOG (FC: 2.13) (all p &lt; 0.05) compared to PMAIP1-L MTNBC. Conclusion: This is the first comprehensive analysis of expression and prognostic role of BCL2 family proteins in MBC. Our data suggest a strong association of higher expression of PMAIP1 with worse MTNBC patient survival, potentially attributed to higher immune checkpoint, stem cell-related genes expression, and higher frequency of PD-L1 positivity in PMAIP1-H tumors. These findings indicate PMAIP1 as a potential prognostic biomarker candidate in MTNBC but needs further validation in large prospective studies Table 1. Overall survival of metaplastic TNBC patient based on BCL2 family gene expression. Citation Format: Pooja Advani, Sachin Deshmukh, Sharon Wu, Jacob Andring, Joanne Xiu, Alex Farrell, Milan Radovich, George Sledge Jr, Dario Trapani, Evanthia Roussos Torres, Stephanie Graff, Asher Chanan-Khan. Comprehensive Characterization of BCL2 Family Genes in Metaplastic Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-24-02.

Abstract Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease and characterized by poor outcomes with a lack of targeted therapies. A comprehensive analysis of the molecular and immune landscape of invasive ductal TNBC can help improve our understanding of TNBC biology and identify novel targets and/or pathways for better management of this disease. Here, we characterized the molecular and immune signature of invasive ductal (ID) TNBC. Methods: 13,036 BC samples (ID TNBC, n=392; ID non-TNBC, n=927) were analyzed by NGS (592, NextSeq; WES, NovaSeq), WTS (NovaSeq) (Caris Life Sciences, Phoenix, AZ). A total of 10 pro-apoptotic (BAX, BAK1, BID, BAD, BIK, BCL2L11, BMF, HRK, PMAIP1, BBC3) and 6 anti-apoptotic (BCL2, BCL2L1, BCL2L2, MCL1, BCL2A1, BCL2L10) BCL2 family genes were analyzed. Immune cell fractions were calculated by deconvolution of WTS: Quantiseq. Real world overall survival (OS) and treatment-associated survival was extracted from insurance claims and calculated from tissue collection or treatment start to last contact using Kaplan-Meier estimates. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q &lt; 0.05). Results: ID TNBC had a higher frequency of TP53, RB1, NF1, PIK3R1, NOTCH1, CREBBP, BRCA1, FANCI, and HRAS mutations (Table 1), NOTCH2 (4.3% vs 0.47%), EGFR (3.4% vs 0%), NFIB (4% vs 0.6%), MYB (3.5% vs 0.5%), CCNE1 (4.4% vs 1.1%) and AKT2 (2.4% vs 0.3%) copy number alterations, and NOTCH2 (1.6% VS 0.2%) fusion (all p &lt; 0.05) compared to invasive ductal non-TNBC. Analysis of inferred immune cell infiltrates showed that ID TNBC had increased infiltration of Tregs (2% vs 1.7%), DC (3.2% vs 2.4%), CD8 T cells (0.5% vs 0.1%), and M1 macrophages (M) (3.4% vs 2.9%), but decreased infiltration of B cells (4.5% vs 6%) and M2M (2.9% vs 4.5%) (all p &lt; 0.05). ID TNBC had increased T cell inflamed score (23 vs -9, p &lt; 0.05), IFNy score (-0.24 vs -0.34, p &lt; 0.05), MHC class I genes (HLA-A, HLA-B, TAP1, TAP2, FC: 1.1-1.5, all p &lt; 0.05), immune checkpoint genes (CD274, PDCD1, CTLA4, PD-L2, FOXP3, IDO, FC: 1.1-2, all p &lt; 0.05) and PD-L1 protein expression (SP142: 49.8% vs. 28.4%; 22c3: 41.7% vs. 16.8%, all p &lt; 0.05). ID TNBC had differential expression of BCL2 family genes (upregulation: BAK1, BID, MCL1, BCL2A1, BCL2L10, FC: 1.1-2.0; downregulation: BAD, BIK, BBC3, BCL2, BCL2L1, BCL2L2, FC: 1.2-2.8, all p &lt; 0.05) compared to invasive ductal non-TNBC. ID TNBC was associated with worse OS compared to ID non-TNBC (mOS: 24.5 vs 54.6 months; HR: 0.5, 95% CI 0.47-0.57; p &lt; 0.00001) but trend towards better survival with pembrolizumab (mOS: 29.4 vs 8.8 month; HR: 0.67, 95% CI 0.28-1.5; p=0.3) treatment. No significant OS difference was noted for by high vs. low pro and anti-apoptotic BCL2 genes except for anti-apoptotic BCL2A1 (higher expression associated with better OS (mOS: 5.7 months, HR: 0.78, 95% CI 0.6-0.99; p=0.047). Conclusion: These data indicate that ID TNBC is associated with distinct mutational profile compared to non-TNBC, has increased T cell inflamed score, IFNy score, MHC class I and immune checkpoint gene expression, and differential immune cell infiltration. Interestingly, TNBC was associated with increased M1 and decreased M2M. There is evidence to suggest that transcriptomically defined M1 high tumors are clinically aggressive and have worse OS in TNBC. BCL2 family genes are not prognostic for TNBC outcomes except BCL2A1, which needs further prospective validation. Table 1: Mutation frequency in invasive ductal TNBC and invasive ductal non-TNBC Citation Format: Pooja Advani, Sachin Deshmukh, Sharon Wu, Jacob Andring, Joanne Xiu, Alex Farrell, Jose Leone, Priya Jayachandran, Stephanie Graff, Matthew Oberley, George Sledge Jr, Asher Chanan-Khan. Comprehensive Molecular and Immunological Characterization of Invasive Ductal Triple-Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-24-01.

Abstract Background: Triple-negative invasive lobular carcinoma (TN-ILC) is a rare (0.1-1.4%) breast cancer with prognosis worse than ER positive ILC. Currently there are no targeted therapies or clinical trials specifically for TN-ILC. A comprehensive analysis of the molecular and immune landscape can help identify novel targets and pathways for TN-ILC to improve patient outcomes. Here, we characterized the molecular and immune signature of TN-ILC. Methods: 11,760 breast cancer samples (Invasive ductal (ID) TNBC, n=364; TN-ILC, n=31) were analyzed (592, NextSeq; WES, NovaSeq), (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) totaled somatic mutations per tumor (high ≥10 mt/MB) was tested by NGS. Microsatellite-instability (MSI) was tested by NGS. Immune cell fractions were calculated by deconvolution of WTS. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q &lt; 0.05). Results: TN-ILC had higher frequency of CDH1 (0.83% vs. 66.67%), ERBB2 (0.84% vs.28.57%), ARID1A (1.65% vs. 23.33%), CBFB (0.55% vs.16.67%), AKT1 (2.22% vs.16.13%) and KMT2C (3.83% vs.13.79%), but lower frequency of TP53 (89.7%5 vs. 38.71%) mutations (all p&lt;0.05) compared to ID-TNBC. TN-ILC had higher frequency of TMB high (23.3% vs. 5.2%, p&lt;0.05) but there was no difference in dMMR/MSI-H (0% vs 1.1%, p=1). TN-ILC had higher AR RNA (FC: 14.2), protein expression (80.6% vs. 24.8%) and higher frequency of fusion variant-AR (16.1% vs 4.9%) (all p &lt; 0.05) compared to ID-TNBC. Analysis of inferred immune cell infiltrates showed that TN-ILC had higher infiltration of M2 macrophages (5.34% vs. 2.94%) and neutrophils (4.83% vs. 2.65%) but lower infiltration of M1 macrophages (3.46% vs 2.17%) and CD8 T cells (0.58% vs. 0.11%) (all p&lt;0.05). TN-ILC had lower T cell inflamed signature (16.1% vs 35.7%, p&lt;0.05), decreased immune checkpoint genes (CD274, CTLA4, FOXP3, LAG3, IDO, FC: 1.2-2.7, all p &lt; 0.05), PD-L1 protein expression (SP142: 30.4% vs. 50.2%, p=0.06; 22c3: 15.4% vs. 42.6%, p = 0.05) and differential expression of BCL2 family genes (upregulation: BIK, FC: 2.2; downregulation: BAX, BAK1, BID, PMAIP1, MCL1, BCL2A1, BCL2L10, FC: 1.0-6.3, all p &lt; 0.05) compared to ID-TNBC. Conclusion: These data suggest that TN-ILC had higher frequency of CDH1, ERBB2, AKT1, ARID1A mutations, higher M2 macrophages and neutrophils and lower M1 macrophages and CD8 T cells infiltration and, lower T cell inflamed signature. High TMB and AR expression can translate into use of immunotherapy (ICI) and AR antagonists in these patients. Additonal analysis to determine the optimal biomarker for ICI response in TN-ILC is needed. Results of our study need to be validated in larger studies with survival correlation. Citation Format: Pooja Advani, Sachin Deshmukh, Sharon Wu, Jacob Andring, Joanne Xiu, Jose Leone, Priya Jayachandran, Stephanie Graff, Mathew Oberley, George Sledge, Asher Chanan-Khan. Comprehensive molecular and immune profiling of triple negative invasive lobular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7037.

Abstract Abstract 618 Introduction: Steroids have been an important component of multiple myeloma (MM) therapeutics. High doses steroids as used in MM are associated with significant toxicity and morbidity. Development of steroid independent or steroid-lite regimens remains an important area of investigation in MM. Orlowski et al combined Doxil (D) with bortezomib (V) and showed enhanced anti-myeloma activity. In a phase II study in relapsed refractory MM patients, we observed further improvement in clinical efficacy with addition of thalidomide (T) to VD combination (VDT regimen). Encouraged by high response rates of this steroid sparing novel combination we investigated VDT regimen in treatment naïve MM patients. Final results of this phase II trial are reported here. Methods: Patients with previously untreated MM were eligible for this phase II trial. VDT regimen (V 1.3mg/m2 on days 1, 4,15,18; D 20mg/m2 on days 1,15 and T 200 mg daily continuously) given on a 4-week cycle for a maximum of 8 cycles. Acyclovir (400 mg BID) and weight adjusted low-dose warfarin (1 or 2mg for absolute body weight <70kg or ≥70kg, respectively) was given for prophylaxis of herpes zoster and deep vein thrombosis (DVT), respectively. Response was assessed using the modified Blade criteria. Results: Forty patients (26 males, 14 females; median age 60.5, range 40-80 yrs) were enrolled on this study. Among these 58%(n=23) had stage III (Durie-Salmon) disease with a median b2 microglobulin of 3.7 (range 1.6-16.5 mg/L) and median LDH of 443 (range 152-129 IU/L). Thirty-nine patients are eligible for response evaluation (1 too early for assessment). Overall response rate (CR/nCR+PR) was 79.4% (n=31) with 38% (n=15) patients achieving CR/nCR. The median progression free (PFS) and overall survival (OS) has not been reached. At 1 year the PFS and OS is 81% and 97%, respectively (1 patient died from disease progression to leukemic phase). Toxicity: Neutropenia was the most significant hematological toxicity with grade 3 and 4 neutropenia observed in 22.5% and 2.5% of the patients, respectively. Only 1 (2.2%) patient had febrile neutropenia. Clinically significant neuropathy (grade ≥2) was seen in 20% while grade ≥2 palmer planter erythrodysesthesia was seen in 15% (n=6) of the patients. Other grade 3 non-hematological toxicities included pneumonia (20%), pleural effusion (10%), pulmonary embolism (2%), DVT (2%), congestive heart failure (5%) and interstitial pneumonitis (2%). Conclusion Although effective, steroid based treatment regimen can be associated with significant toxicity especially among patients with concurrent co morbid conditions such as hypertension and diabetes mellitus. Furthermore, recent investigations demonstrate that decreasing steroid doses may actually improve PFS and OS despite a comparatively low initial ORR. In this clinical trial we hypothesized that rational combination of novel myeloma agents may actually preclude the need to rely on high-dose steroids without significantly compromising ORR. Consistent with our expectations, the VDT regimen has ORR comparable to some of the steroid-inclusive triple drug combinations. The toxicity profile of this combination was acceptable and the regimen was well tolerated. Thus we note that VDT is an effective and well tolerated steroid-independent induction regimen for MM patients. Disclosures: Off Label Use: A Phase II study of a novel combination in newly diagnosed myeloma patients. Miller:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Czuczman:Centocor Ortho Biotech: Research Funding. Sood:Celgene: Stock. Chanan-Khan:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Introduction: Clinical availability of highly effective novel agents (including Bruton tyrosine kinase [BTK] and B-cell lymphoma 2 [BCL-2] inhibitors) is rapidly altering the therapeutic landscape of chronic lymphocytic leukemia (CLL) necessitating a review of treatment guidelines. However, there is limited real-world data to validate if the availability of these novel agents has translated to a true shift in treatment paradigm for patients treated in the community. As the majority of CLL patients are treated in non-academic community-based settings, we investigated the clinical adoption trends of commercially available FDA approved novel agents for treatment of CLL patients. In addition, given that the COVID-19 pandemic led to major alteration in clinical oncology practices, we further studied if this contributed to an alteration in the selection of therapeutic agents resulting in changes of CLL treatment patterns and the utilization of novel agents in the real-world setting. Thus, the objectives of this study were to examine the utilization pattern of various CLL therapies, as well as evaluate the pattern of adoption of novel agents for treatment and the impact of COVID. Methods: A retrospective observational study was conducted using the Flatiron Health database that comprised EHR-derived de-identified data. Adult patients (≥18 years) with newly diagnosed CLL from January 2014 to May 2021, with no prior treatment and who were continuously enrolled for at least 6 months before and 3 months after the index date, defined as the first date of CLL/SLL diagnosis were included. Treatment regimens were classified into seven mutually exclusive categories: bendamustine-based chemotherapy, other chemotherapy, anti-CD20-based therapy, ibrutinib, idelalisib, acalabrutinib and venetoclax. Further treatment categorization included chemotherapy vs. targeted therapy, and traditional IV vs. novel oral agents. The impact of the pandemic was examined by comparing the pre- and post-COVID cohorts (defined as 15 months pre- and post- of March 1, 2021). Descriptive analyses were conducted to examine the frequency of use of treatment regimens by quarter in each year, line of therapy and between different age, gender, US geographical region, insurance status, and race/ethnicity subgroups. Multivariable regression was conducted to examine factors associated with the likelihood of adoption of novel and oral agents. Statistical significance was determined at a p-value of less than 0.05. Results: A total of 3,037 newly diagnosed CLL patients (median age =73) were included in the study. Over half were male (62.3%), white (74.6%) and commercially-insured (54.1%). Patients were primarily treated in community practices (92%). Overall, a significant trend in adoption of novel agents was observed throughout the years following their approval (Figure 1A). Across the evaluation period, a significant decrease in chemotherapy use was observed from 61.3% (quarter 1, 2014) to 20% (quarter 2, 2021) in favor of targeted therapy as first-line therapy (Figure 1B). In contrast, the utilization of novel oral agents (vs. traditional IV agents) for first-line therapy increased from 9.5% to 70.9% for the same period (Figure 1C). Similar trends were observed for second-line and third-line therapies. Encouragingly, this change in treatment patterns was adopted comparably in all sociodemographic subgroups with no evidence of disparity. While there was no statistically significant difference between the pre- and post-COVID treatment landscape, the adoption of target and novel oral agents has been more pronounced with the COVID pandemic. Conclusions: Results from real-world data suggest that there is a clear shift towards the adoption of novel therapies with preference given to targeted agents and oral therapies in the US since 2014. Further research examining real-world outcomes associated with treatment regimens are needed to inform decision makers. Figure 1 Figure 1. Disclosures Chanan-Khan: Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Ascentage: Research Funding; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BeiGene, Jansen, Ascentage: Honoraria; BieGene, Jansen, Ascentage: Consultancy. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Zimmerman: BeiGene, Ltd.: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.

Abstract Background: The phase 3 head-to-head trial of acalabrutinib (acala) vs ibrutinib (ibr) (NCT02477696) demonstrated noninferior efficacy and improved tolerability with acala in previously treated CLL (Byrd J Clin Oncol 2021). We now report additional data to further characterize BTKi-related adverse events (AEs) and the safety profile of acala and ibr, including measures of AE burden that account for frequency, duration, and drug exposure, which are not captured by incidence alone. Methods: Patients (pts) received oral acala 100 mg BID or ibr 420 mg QD until disease progression or unacceptable toxicity. Overall incidence, exposure-adjusted (exp-adj) incidence, and exp-adj time with event (sum of event durations [all grades]*100/sum of treatment-emergent period [for all pts in each arm]) were assessed for the most common BTKi-related AEs. Atrial fibrillation (afib)/flutter, hypertension (htn), and bleeding events were further characterized by time to onset, cumulative incidence by Kaplan-Meier method, pt subgroup, and AE management. Results: A total of 533 pts (acala, n=268; ibr, n=265) were randomized; median treatment exposures were 38.3 and 35.5 mo, respectively. Incidence and exp-adj incidence and time with event are reported for the most common AEs and events of clinical interest (ECIs) (Table). Among cardiovascular (CV) ECIs, incidences of any-grade afib/flutter, htn, and bleeding were statistically higher with ibr, with higher exp-adj incidence (2.0-, 2.8-, and 1.6-fold, respectively) and exp-adj time with event (2.8-, 3.7-, and 1.8-fold). Ventricular arrhythmias were reported in 3 ibr-treated pts vs 0 pts in the acala arm. Among other BTKi-related AEs, incidences of any-grade diarrhea, arthralgia, contusion, urinary tract infection (UTI), back pain, muscle spasms and dyspepsia were statistically higher with ibr, with a 1.5- to 4.1-fold higher exp-adj incidence, and a 1.4- to 13.1-fold higher exp-adj time with event (except for UTI, which had a 1.4-fold lower exp-adj time with event for ibr). Incidences of headache and cough were statistically higher with acala, with a 1.6- and 1.2-fold higher exp-adj incidence, respectively, and a 1.4- and 1.1-fold higher exp-adj time with event. The total exp-adj time with event for all any-grade AEs was 37% higher with ibr (234 [acala] vs 320 [ibr] mo/100 person-mo). For any-grade afib/flutter, median time to onset was longer for acala vs ibr (28.8 vs 16.0 mo), and cumulative incidence was lower for acala at 6 mo (2% vs 6%), 12 mo (3% vs 8%), 18 mo (4% vs 10%), and 24 mo (5% vs 12%). Afib/flutter also occurred less frequently with acala vs ibr in subgroups of age (&lt;65 y: 3% vs 7%; ≥65 y: 15% vs 23%), prior line of therapy (1-3: 10% vs 16%; ≥4: 7% vs 19%), and among pts without prior history (6% vs 15%). Cox proportional-hazards (PH) analysis of new-onset afib/flutter showed a 63% rate reduction favoring acala (Figure 1). Among all pts, concomitant medication use for afib/flutter was less common for acala (8%) vs ibr (14%), with antithrombotic use reported in 5% vs 9% of pts, respectively. For any-grade htn, median time to onset was similar for acala and ibr (8.1 vs 7.0 mo), but cumulative incidence was lower for acala at 6 mo (5% vs 12%), 12 mo (6% vs 16%), 18 mo (8% vs 20%), and 24 mo (8% vs 23%). Htn also occurred less frequently with acala vs ibr in subgroups of age (&lt;65 y: 9% vs 23%; ≥65 y: 10% vs 23%), prior line of therapy (1-3: 10% vs 25%; ≥4: 4% vs 11%), and among pts without prior history (7% vs 23%). Cox PH analysis of new-onset htn showed a 77% rate reduction favoring acala (Figure 2). No dose reductions or treatment discontinuations due to htn occurred in either arm. Concomitant medication use for htn was less common for acala (5%) vs ibr (19%). For any-grade bleeding events, the median time to onset was similar for acala vs ibr (1.2 vs 1.2 mo), and cumulative incidence was lower for acala at 6 mo (29% vs 42%), 12 mo (32% vs 45%), 18 mo (34% vs 49%), and 24 mo (38% vs 51%). Bleeding events also occurred less frequently with acala vs ibr in most subgroups of age (&lt;65 y: 26% vs 47%; ≥65 y: 49% vs 55%) and prior line of therapy (1-3: 39% vs 54%; ≥4: 32% vs 30%). Bleeding events were associated with dose reduction in 3 vs 2 pts in the acala vs ibr arms, respectively, and led to treatment discontinuation in 2 vs 4 pts. Conclusions: In this head-to-head trial of BTKis in CLL, event-based analyses demonstrated a higher BTKi-related toxicity burden with ibr, with a lower impact of CV-related toxicity with acala across subgroups. Figure 1 Figure 1. Disclosures Seymour: AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: 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; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Hillmen: Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria; BeiGene: Honoraria. Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Sunesis: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Chanan-Khan: Ascentage: Research Funding; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; BeiGene, Jansen, Ascentage: Honoraria; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BieGene, Jansen, Ascentage: Consultancy. Furman: Genentech: Consultancy; Sanofi: Consultancy; Morphosys: Consultancy; Incyte: Consultancy; Beigene: Consultancy; Loxo Oncology: Consultancy; TG Therapeutics: Consultancy; X4 Pharmaceuticals: Consultancy; Sunesis: Consultancy; Acerta/AstraZeneca: Consultancy; Abbvie: Consultancy, Honoraria, Other: Expert testimony; Pharmacyclics: Consultancy; Oncotracker: Consultancy; Janssen: Consultancy, Honoraria; Verastem: Consultancy; AstraZeneca: Honoraria. O'Brien: Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy; Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding. Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy. Mato: Genmab: Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Nurix: Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; MSKCC: Current Employment; Acerta/AstraZeneca: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding. Kuptsova-Clarkson: AstraZeneca: Current Employment, Current equity holder in publicly-traded company; AbbVie: Current holder of individual stocks in a privately-held company. Miranda: ASTRAZENECA: Current Employment; ASTRAZENECA: Current equity holder in publicly-traded company. Wagner: AstraZeneca: Current Employment. Higgins: AstraZeneca: Current Employment; PROMETRIKA, LLC: Ended employment in the past 24 months. Sohoni: AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Revolution Medicines: Current Employment, Current equity holder in publicly-traded company; Theravance: Current equity holder in publicly-traded company. Jurczak: AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; Jagiellonian University: Ended employment in the past 24 months; European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy.

This article is a reflection on the application of the Cuban literacy methodology Yo, Sí Puedo to the Australian setting. The Yo, Sí Puedo / Yes, I Can! model developed in Cuba by the Instituto Pedagógico Latinoamericano y Caribeño, IPLAC (Institute of Pedagogy for Latin America and the Caribbean) has been successfully implemented across the Global South as a strategy of adult literacy. It is a legacy of our Latin American revolutionary roots, with its origin in the Freirean pedagogy of the oppressed. Expanding across continents this model continues to teach reading and writing to disenfranchised adults in marginal and Indigenous communities, from the Argentinean Chaco to Brewarrina in northern NSW, Australia. Its aim is to contribute to the hope of improving the health and educational outcomes of the country’s First Peoples. This article is indebted to conversations with the Cuban advisor of Yes, I Can!, José Manuel Chala Leblanch. Observing him working in the classroom setting of Brewarrina touched me at different levels: personally because it reminded me of my own family experiences with the education system in my country, Argentina; and professionally as an educator negotiating different languages and cultures. It also reinforced my belief in the importance of incorporating Indigenous ways of learning and teaching to Western styles of teaching and learning. I built this reflection moving from personal and poetic—visual and textual—narratives and observations to academic interventions informed by researched literature on adult and Indigenous education.

The BID (Board of Industrial Development) framed the legislation and it was introduced before the state legislation and passed in the form of Maharashtra Industrial Act which gave birth to Maharashtra Industrial Development Corporation (MIDC), as a separate corporation on August 1, 1962. The BID was the first personnel strength of MIDC. A small ceremony at Wagle Estate Thane, under the Chairmanship of the Chief Minister Shri Y.B. Chavan, marked the birth of MIDC on August 1, 1962. The Board of Industrial Development during its existence between October 1, 1960 and August 1, 1962 has done enough spade work to identify the locations for setting up industrial areas in different parts of the state. Thus, right in the first year of establishment MIDC came up with 14 industrial areas, to initiate action for infrastructure and help entrepreneurs set up the industrial units in those areas. Maharashtra Industrial Development Corporation is the nodal industrial infrastructure development agency of the Maharashtra Government with the basic objective of setting up industrial areas with a provision of industrial infrastructure all over the state for planned and systematic industrial development. MIDC is an innovative, professionally managed, and user friendly organization that provides the world industrial infrastructure. MIDC has played a vital role in the development of industrial infrastructure in the state of Maharashtra. As the state steps into the next millennium, MIDC lives up to its motto Udyamat Sakal Samruddhi i.e., prosperity to all through industrialization. Indeed, in the endeavor of the state to retain its prime position in the industrial sector, MIDC has played a pivotal role in the last 35 years. MIDC has developed 268 industrial estates across the state which spread over 52653 hectares of land. The growth of the Corporation, achieved in the various fields, during the last three years, could be gauged from the fact that the area currently in possession of MIDC has doubled from 25,000 hectares in 1995.