ALBERT

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Muller, Carol B -- Ride, Sally M -- Fouke, Janie -- Whitney, Telle -- Denton, Denice D -- Cantor, Nancy -- Nelson, Donna J -- Plummer, Jim -- Busch-Vishniac, Ilene -- Meyers, Carolyn -- Rosser, Sue V -- Schiebinger, Londa -- Roberts, Eric -- Burgess, David -- Beeson, Craig -- Metz, Susan Staffin -- Sanders, Lucinda -- Watford, Bevlee A -- Ivey, Elizabeth S -- Frank Fox, Mary -- Wettack, Sheldon -- Klawe, Maria -- Wulf, William A -- Girgus, Joan -- Leboy, Phoebe S -- Babco, Eleanor L -- Shanahan, Betty -- Didion, Catherine -- Chubin, Daryl E -- Frize, Monique -- Ganter, Susan L -- Nalley, E Ann -- Franz, Judy -- Abruna, Hector D -- Strober, Myra H -- Zimmer Daniels, Jane -- Carter, Emily A -- Rhodes, Jean H -- Schrijver, Iris -- Zakian, Virginia A -- Simons, Barbara -- Martin, Ursula -- Boaler, Jo -- Jolluck, Katherine Rose -- Mankekar, Purnima -- Gray, Robert M -- Conkey, Margaret W -- Stansky, Peter -- Xie, Aihua -- Martin, Pino -- Katehi, Linda P B -- Miller, Jo Anne -- Tess Thornton, Amelia -- Lapaugh, Andrea -- Rhode, Deborah L -- Gelpi, Barbara C -- Harrold, Mary Jean -- Spencer, Cherrill M -- Schlatter Ellis, Carla -- Lord, Susan -- Quinn, Helen -- Murnane, Margaret -- Jones, Patricia P -- Hellman, Frances -- Wight, Gail -- O'hara, Ruth -- Pickering, Mary -- Sheppard, Sheri -- Leith, David -- Paytan, Adina -- Sommer, Matthew H -- Shafer, Audrey -- Grusky, David -- Yennello, Sherry -- Madan, Ashima -- Johnson, Denise L -- Yanagisako, Sylvia -- Chou-Green, Jennifer M -- Robinson, Sandra -- New York, N.Y. -- Science. 2005 Feb 18;307(5712):1043.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15718449" target="_blank"〉PubMed〈/a〉

Description: Phloem tissue from a Middle Devonian member of the Aneurophytales (Progymnospermopsida) is described. This may be the oldest firm evidence of conducting elements of the phloem, extending our knowledge of this tissue back some 35 million years. The discovery indicates a close phylogenetic relation between progymnosperms and gymnosperms and provides a basis for investigating patterns of specialization in the phloem of these groups of plants.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wight, D C -- Beck, C B -- New York, N.Y. -- Science. 1984 Sep 28;225(4669):1469-71.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17770075" target="_blank"〉PubMed〈/a〉

Description: Adherent cells from long-term marrow cultures from 23 individuals were transformed with wild-type simian virus 40 (SV40). After transformation, cloned cell lines were developed that even after rigorous subcloning invariably produced both stromal cells and round cells. The stromal cells expressed cytoskeletal filaments similar to those of long-term marrow culture adherent cells and produced interstitial and basal lamina collagen types. The round cells had the electron microscopic appearance of primitive hematopoietic cells and when examined with cytochemical stains and monoclonal antibodies to hematopoietic differentiation antigens had reaction patterns suggestive of cells from several lineages. Most round cells expressed the pan- hematopoietic T-200 determinant, and lesser percentages expressed the early T cell antigens CD-1 and CD-3, HLA-DR determinants, the monocytic antigen recognized by Leu M3, and the myeloid antigens detected by monoclonal antibodies 1G10 and 12.8. In addition, when plated in semisolid medium in the presence of a source of colony-stimulating activity, up to 11% of the cells formed colonies consisting of blastlike cells that also expressed hematopoietic cell surface determinants. The data suggest that adherent cells in long-term marrow cultures contain a cell that after transformation by SV40 obligately produces cells with hematopoietic as well as stromalike features.

Description: Proteoglycans within the extracellular matrix of human bone marrow have been implicated in the process of hematopoiesis, but little is known about the structure and composition of these macromolecules in this tissue. Hematopoietically active human long-term bone marrow cultures were incubated with medium containing 35S-sulfate and 3H-glucosamine as labeling precursors. Proteoglycans present in the medium and cell layer were extracted with 4 mol/L guanidine HCI and purified by diethylaminoethyl (DEAE)-Sephacel ion exchange and molecular sieve chromatography. Both culture compartments contain a large chondroitin sulfate proteoglycan (MI, CI) that eluted in the void volume of a Sepharose CL-4B column and contained glycosaminoglycan chains of molecular weight (mol wt) approximately 38,000. A second population of sulfate-labeled material was identified as a broad heterogenous peak (MII, CII) that was included on Sepharose CL-4B at Kav = 0.31. This material when chromatographed on Sepharose CL-6B could be further separated into a void peak (MIIa, CIIa) and an included peak eluting at Kav = 0.39 (MIIb, CIIb). The void peaks (MIIa, CIIa) were susceptible to chondroitinase ABC digestion (99%) but slightly less susceptible to chondroitinase AC digestion (90%). Papain digestion of these peaks revealed them to be proteoglycans with glycosaminoglycan chains of mol wt approximately 38,000. The included peaks on Sepharose CL-6B (MIIb, CIIb) from both medium and cell layer compartments resisted digestion with papain, indicating the presence of glycosaminoglycan chains of mol wt approximately 38,000 either free or attached to a small peptide. Although this material was susceptible to chondroitinase ABC (98%), it was considerably less susceptible to chondrotinase AC (approximately 60%), indicating that it contained dermatan sulfate. A small amount of heparan sulfate proteoglycan was also identified but constituted only approximately 10% of the total sulfated proteoglycan extracted from these cultures. Additionally, approximately 40% of the incorporated 3H- activity radioactivity was present as hyaluronic acid. Electron microscopy revealed a layer of adherent cells covered by a mat containing ruthenium red-positive granules that were connected by thin filaments. The extracellular matrix layer above the adherent cells contained a mixture of hematopoietic cells. Chondroitinase ABC treatment of the cultures completely removed the ruthenium red-positive granules overlying the cells and resulted in a loss of approximately 70% of the 35S-sulfate-labeled material from the cell layer.(ABSTRACT TRUNCATED AT 400 WORDS)

Description: Adherent cells from long-term marrow cultures from 23 individuals were transformed with wild-type simian virus 40 (SV40). After transformation, cloned cell lines were developed that even after rigorous subcloning invariably produced both stromal cells and round cells. The stromal cells expressed cytoskeletal filaments similar to those of long-term marrow culture adherent cells and produced interstitial and basal lamina collagen types. The round cells had the electron microscopic appearance of primitive hematopoietic cells and when examined with cytochemical stains and monoclonal antibodies to hematopoietic differentiation antigens had reaction patterns suggestive of cells from several lineages. Most round cells expressed the pan- hematopoietic T-200 determinant, and lesser percentages expressed the early T cell antigens CD-1 and CD-3, HLA-DR determinants, the monocytic antigen recognized by Leu M3, and the myeloid antigens detected by monoclonal antibodies 1G10 and 12.8. In addition, when plated in semisolid medium in the presence of a source of colony-stimulating activity, up to 11% of the cells formed colonies consisting of blastlike cells that also expressed hematopoietic cell surface determinants. The data suggest that adherent cells in long-term marrow cultures contain a cell that after transformation by SV40 obligately produces cells with hematopoietic as well as stromalike features.

Description: Background and Aims The detection of sequence variants and copy number changes can improve diagnosis, inform prognosis and guide treatment in patients with bone marrow failure syndromes (BMFS). We aimed to establish and prospectively assess the impact of comprehensive genomic evaluation on diagnostic categorisation and clinical outcomes in patients with genomically uncharacterised BMFS. Methods Eligible patients were recruited from four participating institutions across Victoria, Australia. Inclusion criteria were (i) age 〉3 months (ii) clinicopathological diagnosis or suspicion of either acquired aplastic anaemia (AA), inherited BMFS, hypoplastic myelodysplastic syndrome (hMDS) or a BMFS with marrow hypoplasia/aplasia not able to be definitively categorised. Patients initially underwent 90-gene targeted sequencing (Peter MacCallum Cancer Centre PanHaem and Myeloid Amplicon next generation sequencing [NGS] panels) for rapid turnaround of accredited results for clinical decision-making. In addition, whole exome sequencing (WES), whole genome copy number analysis, NGS T-cell receptor β (TRB) repertoire assessment and longitudinal monitoring of selected mutations by digital droplet PCR (ddPCR) were performed. All patients received pre-test counselling and assessment. Genomic results were reviewed in centralised multidisciplinary case conferences including the treating clinician, molecular haematopathologists, medical scientists, clinical geneticists and genetic counsellors. Results 100 patients were enrolled. Median age was 25 years (range 3 months - 80 years); 39% were under 18 years. Detection of sequence variants or copy number abnormalities led to or confirmed a diagnosis of either an inherited or acquired BMFS in 36 patients. In 17 patients a diagnosis of an inherited BMFS was positively made by detection of pathogenic sequence variants or copy number changes in FANCA(1 patient [pt]), FANCM(1 pt), FANCI(1 pt), RAD51C(1 pt), HAX1(1 pt), SBDS(1 pt), DNAJC21(1 pt), RPS19(5 pts), RPL35A(1 pt), TERT(1 pt), TINF2(1 pt) and SAMD9L(1 pt). In five patients the clinical BMFS was considered undifferentiated without a clear candidate gene suspected on phenotypic features prior to genomic evaluation. Importantly, an established diagnosis of AA was altered to an inherited BMFS by genomic characterisation in two patients (SAMD9L, FANCA). In 19 patients pathogenic sequence variants or copy number changes were detected either leading to or confirming a diagnosis of an acquired BMFS (paroxysmal nocturnal haemoglobinuria, hMDS or AA). Pathogenic sequence variants were detected in TET2(n=5), RUNX1(n=4), ASXL1(n=3), PIGA(n=3), DNMT3A(n=3),CBL(n=2), and BCOR/IDH2/SF3B1/SRSF2/TP53/U2AF1(n=1 each). Sequencing-detected copy number abnormalities included loss of chromosome 7 (n=6), losses on chromosome 5q (n=2) and copy number loss of ETV6(n=2). Longitudinal monitoring of an acquired truncating RUNX1 mutation by ddPCR resulted in one patient undergoing allogeneic bone marrow transplant for a progressively rising allelic burden. There was a trend towards more restricted TRB diversity in patients with genomically-defined acquired BMFS versus inherited BMFS (normalised Shannon index ≤0.85, 36.4% vs 0%, p=0.09). Conclusion We have established and evaluated a model of comprehensive multimodal genomic characterisation and multidisciplinary care for 100 patients with BMFS. Our results demonstrate a significant contribution to diagnostic categorisation and patient care in this area of clinical need. Disclosures Lieschke: CSL Behring Australia: Consultancy. Tam:Janssen: Honoraria, Research Funding; Gilead: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Travel funding; Pharmacyclics: Honoraria; Beigene: Honoraria, Other: Travel funding; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding; Gilead: Honoraria; Roche: Honoraria; AbbVie: Honoraria, Research Funding.

Description: Proteoglycans within the extracellular matrix of human bone marrow have been implicated in the process of hematopoiesis, but little is known about the structure and composition of these macromolecules in this tissue. Hematopoietically active human long-term bone marrow cultures were incubated with medium containing 35S-sulfate and 3H-glucosamine as labeling precursors. Proteoglycans present in the medium and cell layer were extracted with 4 mol/L guanidine HCI and purified by diethylaminoethyl (DEAE)-Sephacel ion exchange and molecular sieve chromatography. Both culture compartments contain a large chondroitin sulfate proteoglycan (MI, CI) that eluted in the void volume of a Sepharose CL-4B column and contained glycosaminoglycan chains of molecular weight (mol wt) approximately 38,000. A second population of sulfate-labeled material was identified as a broad heterogenous peak (MII, CII) that was included on Sepharose CL-4B at Kav = 0.31. This material when chromatographed on Sepharose CL-6B could be further separated into a void peak (MIIa, CIIa) and an included peak eluting at Kav = 0.39 (MIIb, CIIb). The void peaks (MIIa, CIIa) were susceptible to chondroitinase ABC digestion (99%) but slightly less susceptible to chondroitinase AC digestion (90%). Papain digestion of these peaks revealed them to be proteoglycans with glycosaminoglycan chains of mol wt approximately 38,000. The included peaks on Sepharose CL-6B (MIIb, CIIb) from both medium and cell layer compartments resisted digestion with papain, indicating the presence of glycosaminoglycan chains of mol wt approximately 38,000 either free or attached to a small peptide. Although this material was susceptible to chondroitinase ABC (98%), it was considerably less susceptible to chondrotinase AC (approximately 60%), indicating that it contained dermatan sulfate. A small amount of heparan sulfate proteoglycan was also identified but constituted only approximately 10% of the total sulfated proteoglycan extracted from these cultures. Additionally, approximately 40% of the incorporated 3H- activity radioactivity was present as hyaluronic acid. Electron microscopy revealed a layer of adherent cells covered by a mat containing ruthenium red-positive granules that were connected by thin filaments. The extracellular matrix layer above the adherent cells contained a mixture of hematopoietic cells. Chondroitinase ABC treatment of the cultures completely removed the ruthenium red-positive granules overlying the cells and resulted in a loss of approximately 70% of the 35S-sulfate-labeled material from the cell layer.(ABSTRACT TRUNCATED AT 400 WORDS)

Description: Introduction: The optimal treatment approach for newly diagnosed patients with AML remains uncertain. HiDAC is widely considered to increase the proportion of patients cured compared to standard-dose cytarabine. However, it remains uncertain whether HiDAC is best given during induction or consolidation, and how many cycles of HiDAC are optimal. Many centres in Australia treat younger patients (age ≤60 yrs) with newly diagnosed AML with one of two approaches: either 7+3 induction followed by HiDAC-2 consolidation for 2 cycles; or a single course of HiDAC-3±7 induction followed by 2 cycles of lower dose cytarabine-based therapy (eg 5+2±5). Our retrospective study compared the outcomes of these 2 approaches in a large cohort of Australian patients treated at 5 centres. Methods: Consecutive patients aged ≤60 yrs with a new diagnosis of AML (de novo or secondary) were included in the study if they were planned for treatment with either: 1) cytarabine 100 mg/m2 for 7 days plus idarubicin 12 mg/m2 for 3 days (7+3) induction followed by 2 cycles of HiDAC 3 g/m2 days 1,3,5,7 plus idarubicin 12 mg/m2 for 2 days (HiDAC consolidation cohort); or 2) HiDAC 3 g/m2 days 1,3,5,7 plus idarubicin 9-12 mg/m2 for 3 days ± etoposide 75-100 mg/m2 for 7 days as induction followed mostly by cytarabine 100 mg/m2 for 5 days plus idarubicin 9-12 mg/m2 for 2 days ± etoposide 75-100 mg/m2 for 5 days as consolidation (HiDAC induction cohort). Patients were diagnosed from 1999 to June 2013, and were followed for at least 12 months with data cut off June 2014. Results: 486 patients were included: HiDAC consolidation cohort n=251; HiDAC induction cohort n=235. The HiDAC consolidation cohort had a greater median age (49 vs 47 yrs, p=0.02) and more patients with good risk cytogenetics (16% vs 8%, p=

Description: Background: Whilst up to 60% of DLBCL patients (pts) are cured with frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), outcomes remain poor for those with relapsed or refractory disease. 1 New strategies to improve frontline cure rates are needed. Tumour cells exploit immune checkpoint pathways, including the PD1/PDL1 axis, to evade the host immune system. PD1/PDL1 over-expression and cytogenetic 9p24 alterations in some DLBCL subtypes provide additional rationale for immune checkpoint inhibition (ICI) in this disease. Although single agent PD1 inhibition yields an overall response rate (ORR) of only 10%-30% in heavily pre-treated unselected DLBCL, many responses are durable.2 Immunosuppressive effects of prior therapy may contribute to the modest response to ICI in relapsed disease. A number of considerations influence the incorporation of ICI into upfront DLBCL treatment. Although concurrent PD1/PDL1 inhibition and R-CHOP is safe,3 corticosteroid-related immunosuppression may negate PDL1-inhibitor efficacy. Evidence supporting host immune priming with ICI prior to chemotherapy is promising,4 and maintenance ICI post chemotherapy may assist with immune reconstitution and enhance the anti-tumour immune response. Additionally, avelumab (Av, an anti-PDL1 monoclonal antibody with antibody dependent cellular cytotoxicity activity) acts synergistically with rituximab (R) in vitro (unpublished data, Pfizer 2016). Thus, we present our phase II study assessing the safety of sequential Av+R induction, R-CHOP and Av maintenance as upfront therapy for DLBCL. Methods: AvR-CHOP (NCT03244176) is a phase II multicentre single-arm trial of Av induction + maintenance with R-CHOP in newly-diagnosed adult pts with DLBCL. Pts aged 〉18 years, ECOG 0-2, stage II-IV and with no active autoimmune disease are eligible. Exclusion criteria include the necessity for urgent cytoreduction, grade 3B or transformed follicular lymphoma, CNS involvement, chronic steroid use, prior transplantation or pneumonitis. Treatment (Fig 1) comprises R (375mg/m2 IV) + Av (10mg/kg IV) x 2 cycles q2-weekly, followed by R-CHOP21 x 6 cycles. Maintenance Av x 6 cycles q2-weekly is given to patients achieving a complete metabolic response by PET/CT at the end of R-CHOP. PET/CT is performed after R+Av 2 cycles, cycle 2 R-CHOP, end of R-CHOP and end of Av maintenance. The primary endpoint is immune-related toxicity within 30 days post-treatment. Secondary endpoints include ORR, failure free survival (FFS), overall survival (OS) and toxicity of treatment. Complete metabolic response rates by PET-CT after R-Av induction and after C2 R-CHOP are exploratory endpoints. Biomarker sample collection is synchronised with PET response assessment. A comprehensive translational substudy will apply high throughput technologies to tissue and sequential blood samples to characterise the tumour-immune system interaction and correlate novel host, tumour and tumour microenvironment factors with treatment responses and toxicity. Planned enrolment is 28 pts across 3 sites in Australia. The study follows a Simon 1 stage design, with an 80% power and a 1-sided alpha of 0.05 to rule out an Av-related toxicity rate of 30% (p0=70%), assuming an expected immune related toxicity rate of 10% [p1=90%]. 23 pts are enrolled to date. Acknowledgements: Merck KgA (avelumab and funding) References: 1. Cunningham D et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet (London, England). 2013;381(9880):1817-26. 2. Ansell SM et al. Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm, Phase II Study. J Clin Oncol. 2019;37(6):481-9. 3. Nowakowski GS et al. Safety and efficacy of PD-L1 inhibitor durvalumab with R-CHOP or R2-CHOP in subjects with previously untreated, high-risk DLBCL. Journal of Clinical Oncology. 2019;37(15_suppl):7520-. 4. Park SE et al. Increased Response Rates to Salvage Chemotherapy Administered after PD-1/PD-L1 Inhibitors in Patients with Non-Small Cell Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2018;13(1):106-11. Disclosures Hawkes: Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mundi pharma: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Takeda: Speakers Bureau; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees. Manos:NovoNordisk Pharmaceuticals: Other: Travel; Janssen: Honoraria. Renwick:Celgene: Consultancy; Roche: Honoraria. Grigg:MSD: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel. Scott:Medimmune: Consultancy; Abbvie: Consultancy, Patents & Royalties; IBA: Consultancy; Avipep: Consultancy; Life Science Pharmaceuticals: Equity Ownership; Paracrine Therapeutics: Equity Ownership, Patents & Royalties; NHMRC: Research Funding; Cancer Australia: Research Funding; Cancer Council Victoria: Research Funding; Cure Brain Cancer: Research Funding; Humanigen: Patents & Royalties. Lee:Australian Nuclear Science and Technology Organisation: Membership on an entity's Board of Directors or advisory committees. Fong:Astellas: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Rooney:GenesisCare: Employment. Wight:Janssen: Honoraria; Takeda: Honoraria; Abbvie: Honoraria; BMS: Other: Travel; Amgen: Other: Travel. Chong:BMS: Research Funding; Merck Serono: Research Funding; Bayer: Research Funding; Novartis: Research Funding; Hutchison Medipharma: Research Funding; Pharmacyclics: Research Funding. OffLabel Disclosure: Avelumab is an anti-PDL1 monoclonal antibody.