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- Label: BACKGROUND NlmCategory: BACKGROUND content: "Sub-Saharan Africa and south Asia contributed 81% of 5\xC2\xB79 million under-5 deaths and 77% of 2\xC2\xB76 million stillbirths worldwide in 2015. Vital registration and verbal autopsy data are mainstays for the estimation of leading causes of death, but both are non-specific and focus on a single underlying cause. We aimed to provide granular data on the contributory causes of death in stillborn fetuses and in deceased neonates and children younger than 5 years, to inform child mortality prevention efforts." - Label: METHODS NlmCategory: METHODS content: "The Child Health and Mortality Prevention Surveillance (CHAMPS) Network was established at sites in seven countries (Baliakandi, Bangladesh; Harar and Kersa, Ethiopia; Siaya and Kisumu, Kenya; Bamako, Mali; Manhi\xC3\xA7a, Mozambique; Bombali, Sierra Leone; and Soweto, South Africa) to collect standardised, population-based, longitudinal data on under-5 mortality and stillbirths in sub-Saharan Africa and south Asia, to improve the accuracy of determining causes of death. Here, we analysed data obtained in the first 2 years after the implementation of CHAMPS at the first five operational sites, during which surveillance and post-mortem diagnostics, including minimally invasive tissue sampling (MITS), were used. Data were abstracted from all available clinical records of deceased children, and relevant maternal health records were also extracted for stillbirths and neonatal deaths, to incorporate reported pregnancy or delivery complications. Expert panels followed standardised procedures to characterise causal chains leading to death, including underlying, intermediate (comorbid or antecedent causes), and immediate causes of death for stillbirths, neonatal deaths, and child (age 1-59 months) deaths." - Label: FINDINGS NlmCategory: RESULTS content: Between Dec 10, 2016, and Dec 31, 2018, MITS procedures were implemented at five sites in Mozambique, South Africa, Kenya, Mali, and Bangladesh. We screened 2385 death notifications for inclusion eligibility, following which 1295 families were approached for consent; consent was provided for MITS by 963 (74%) of 1295 eligible cases approached. At least one cause of death was identified in 912 (98%) of 933 cases (180 stillbirths, 449 neonatal deaths, and 304 child deaths); two or more conditions were identified in the causal chain for 585 (63%) of 933 cases. The most common underlying causes of stillbirth were perinatal asphyxia or hypoxia (130 [72%] of 180 stillbirths) and congenital infection or sepsis (27 [15%]). The most common underlying causes of neonatal death were preterm birth complications (187 [42%] of 449 neonatal deaths), perinatal asphyxia or hypoxia (98 [22%]), and neonatal sepsis (50 [11%]). The most common underlying causes of child deaths were congenital birth defects (39 [13%] of 304 deaths), lower respiratory infection (37 [12%]), and HIV (35 [12%]). In 503 (54%) of 933 cases, at least one contributory pathogen was identified. Cytomegalovirus, Escherichia coli, group B Streptococcus, and other infections contributed to 30 (17%) of 180 stillbirths. Among neonatal deaths with underlying prematurity, 60% were precipitated by other infectious causes. Of the 275 child deaths with infectious causes, the most common contributory pathogens were Klebsiella pneumoniae (86 [31%]), Streptococcus pneumoniae (54 [20%]), HIV (40 [15%]), and cytomegalovirus (34 [12%]), and multiple infections were common. Lower respiratory tract infection contributed to 174 (57%) of 304 child deaths. - Label: INTERPRETATION NlmCategory: CONCLUSIONS content: Cause of death determination using MITS enabled detailed characterisation of contributing conditions. Global estimates of child mortality aetiologies, which are currently based on a single syndromic cause for each death, will be strengthened by findings from CHAMPS. This approach adds specificity and provides a more complete overview of the chain of events leading to death, highlighting multiple potential interventions to prevent under-5 mortality and stillbirths. - Label: FUNDING NlmCategory: BACKGROUND content: Bill & Melinda Gates Foundation.

Acute myeloid leukemia (AML) represents a heterogeneous disease entity that is continuously moving to a more genetically defined classification. The classification of AML with recurrent chromosomal translocations, including those involving core binding factor subunits, plays a critical role in diagnosis, prognosis, treatment stratification, and residual disease evaluation. Accurate classification of variant cytogenetic rearrangements in AML contributes to effective clinical management. We report here the identification of four variant t(8;V;21) translocations in newly diagnosed AML patients. Two patients showed a t(8;14) and a t(8;10) variation, respectively, with a morphologically normal-appearing chromosome 21 in each initial karyotype. Subsequent fluorescence in situ hybridization (FISH) on metaphase cells revealed cryptic three-way translocations t(8;14;21) and t(8;10;21). Each resulted in RUNX1::RUNX1T1 fusion. The other two patients showed karyotypically visible three-way translocations t(8;16;21) and t(8;20;21), respectively. Each resulted in RUNX1::RUNX1T1 fusion. Our findings demonstrate the importance of recognizing variant forms of t(8;21) translocations and emphasize the value of applying RUNX1::RUNX1T1 FISH for the detection of cryptic and complex rearrangements when abnormalities involving chromosome band 8q22 are observed in patients with AML.

Context.— Inappropriate laboratory testing and the threat it poses to patient care and rising health care costs has become an important focus in the medical literature. Pathology residents, as physicians with an intimate knowledge of laboratory testing, may be uniquely equipped with the tools to intervene in situations of inappropriate testing and also benefit from lab use experience as part of their clinical pathology training. Objective.— To employ a resident-driven initiative aimed at incorporating pathology residents as consultants for appropriate ordering of high-volume, send-out myeloid mutation panel testing. Design.— During a 6-month study period, all myeloid mutation panel send-out tests were screened by senior pathology residents on their clinical chemistry rotation prior to approval at an academic medical center. A retrospective review of myeloid mutation panels from the prior 6 months was conducted with the same criteria to determine effectiveness of the intervention. Results.— Of the 234 tests ordered during the study period, screening resulted in cancellation of 17% (n = 39), with proportional cost savings. The number of inappropriate orders successfully cancelled was significant compared with the preintervention period (control, 0%; intervention, 76.5%; P < .001, Fisher exact test). There was no significant difference in the proportion of inappropriate tests before and after intervention. Conclusions.— Although test ordering patterns did not substantially change during the intervention period, pathology residents effectively reduced inappropriate myeloid mutation panel testing through prospective send-out auditing, leading to significant cost savings. Moreover, assessment of test use and appropriateness provided critical clinical pathology training within the areas of hematology, molecular genetics, and laboratory management.

Outcomes and life expectancy for patients with multiple myeloma (MM) have improved substantially over the last two decades with advancements in therapy, including autologous stem cell transplantati...

Intraosseous (IO) devices are used for vascular access in settings where venous access is initially unobtainable, such as prehospital trauma care or cardiac arrest. While IO devices are effective for infusion of blood, fluids, and medications, there is limited data on the analytical equivalence of specimens taken out of IO devices and peripheral venous blood. Despite this, IO device manufacturers and clinical resources state that IO specimens can be submitted for laboratory analysis. As reported in this case, IO specimens may be drawn and labeled as ‘peripheral blood’. IO specimens are not always caught by automated sample quality testing and may proceed through analysis without any warning signal to the laboratory. There are potential regulatory risks in accepting IO samples for analysis without validation. IO infusion is a valuable technique for vascular access in critically ill patients, but clinical laboratories will need to determine their own policies for identifying and handling IO specimens.

A 76-year-old man with acute myelogenous leukemia presented to the hospital with 1 week of left-sided jaw pain and swelling and subjective fevers. The patient had been severely neutropenic (i.e., with an absolute neutrophil count of

Answer: Mucormycosis caused by Rhizopus species. A feared opportunistic invasive fungal infection of the immunocompromised host, mucormycosis typically presents as rhinocerebral, pulmonary, or cutaneous disease in patients with diabetes or hematological malignancies. Rhizopus and Mucor are the most

We describe two patients with acute promyelocytic leukemia (APL) with an unusual immunophenotype with co-expression of myeloperoxidase (MPO) with cytoplasmic CD3 (cCD3) representing myeloid and T-lineage differentiation. Both harbored FLT3-ITD mutations. One additionally had a deletion in the PML gene affecting the primer binding site, thus limiting measurable residual disease (MRD) analysis during follow-up. Both patients achieved durable remission with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO)-based therapy, thus mitigating the need for repetitive conventional chemotherapy cycles and allogeneic stem cell transplantation. Our report highlights the complexity and challenge of diagnosis and management of APL due to the variant immunophenotype and genetics, and underscores the importance of synthesizing information from all testing modalities. The association of the unusual immunophenotype and FLT3-ITD mutation illustrates the plasticity of the hematopoietic stem cell and the pathobiology of leukemia with mixed lineage or lineage infidelity.

Bispecific antibodies (BsAbs) are an emerging class of novel immunotherapy agents that have led to major breakthroughs in the treatment of hematologic malignancies. By targeting two separate antigens at the same time, BsAbs can bridge tumor cells to cytotoxic immune cells and bypass several limitations of conventional monoclonal antibody treatment (Wang et al., 2019). In 2020, the Association of Community Cancer Centers (ACCC) launched an ongoing education program to identify and address barriers to awareness, preparedness, adoption, and use of BsAbs to treat cancer. As part of this program, ACCC developed a survey with an expert Advisory Committee to gain an understanding of multidisciplinary cancer providers' experiences with BsAbs. The survey primarily assessed experiences with blinatumomab, the first FDA-approved bispecific antibody for the treatment of malignancy (Newman & Benani, 2016). One hundred and twenty-nine individuals responded to the survey. Sixty percent of these respondents reported prescribing, dispensing, and administering blinatumomab and/or caring for patients being treated with blinatumomab. Of those respondents, 44% were medical oncologists/hematologists, 8% were advanced practice providers (APPs), 17% were nurses, 23% were pharmacists, and 9% fell into an 'Other' category of various other disciplines. Interestingly, the provider experience with blinatumomab varied greatly. Ninety-two percent of oncologists indicated having experience with blinatumomab while only 35% of nurses reported so. Regarding how blinatumomab is used in the community, respondents indicated that 59% of their institutions use it to treat relapsed or refractory acute lymphoblastic leukemia (ALL) while 41% use it to treat ALL with MRD positivity. Additionally, 74% of oncologists use blinatumomab before CAR-T therapy when considering both therapies for patients with ALL. Survey results also showed that although 79% of providers felt comfortable caring for patients being treated with blinatumomab, 59% identified barriers when caring for these patients. Some of the common challenges include transitioning patients from the inpatient to outpatient setting (41%), managing patients in remote areas (33%), securing insurance coverage (28%), managing side effects (27%), assisting patients with costs (24%), and lacking in-house expertise with the drug (22%). Another reported obstacle was the management neurotoxicity and cytokine release syndrome (CRS). In the survey, less than half of oncologists reported experience with managing neurotoxicity or CRS and only 6-9% of APPs reported the same. In general, more oncologists described feeling comfortable with using blinatumomab compared to APPs or nurses. Notably, 23% of nurses did not feel they had all the information needed to safely administer blinatumomab. In terms of opportunities to promote smooth adoption of blinatumomab, 86% of respondents indicated that written guidelines, best practices, and care recommendations would be helpful when caring for patients. Specific desired resources include a list of home health pharmacies and agencies familiar with the drug, care coordinators or navigators, best practices on transitioning from inpatient to outpatient administration, information on how to address problems that may occur with outpatient administration, and in-house or onsite expertise from either the drug manufacturer or someone within the organization. Respondents noted direct patient education as another significant area of need. Eighty-two percent felt that educational resources for patients and caregivers on transitioning from inpatient to outpatient care would be beneficial, and 70% thought that peer support services for patients would also be helpful. Multiple BsAbs are in various stages of development for hematologic malignancies. Using blinatumomab as an example, this survey highlighted challenges to the use of BsAbs and identified opportunities to overcome these obstacles. Translation of best practices for use in the community must be established to reach all eligible patients with cancer who may benefit from these therapies. With this survey data, ACCC is positioned to offer this support. Through its education program, ACCC will build on the survey results to develop content and resources that prepare multidisciplinary providers to welcome BsAbs into the community to treat cancer. Disclosures Atembina: Amgen: Research Funding. Boehmer: Pfizer, Inc: Other: paid consultant within the past 12 months; Amgen: Research Funding. Terrell: Amgen: Honoraria. Koka: Amgen: Honoraria. Janakiram: Amgen: Honoraria. Grothey: Amgen: Honoraria. Morris: Amgen: Honoraria. Rogers: Coherus BioSciences: Speakers Bureau; Astra Zeneca: Speakers Bureau. Kelly: Amgen: Honoraria. Berdeja: Poseida: Research Funding; Acetylon: Research Funding; Lilly: Research Funding; Kite Pharma: Consultancy; Genentech: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Celularity: Research Funding; Celgene: Consultancy, Research Funding; Teva: Research Funding; EMD Serono: Research Funding; GlaxoSmithKline: Research Funding; SecuraBio: Consultancy; Legend Biotech: Consultancy; Janssen: Consultancy, Research Funding; Novartis: Research Funding; Incyte: Research Funding; Ichnos Sciences: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; Astex Pharmaceuticals: Research Funding; Bluebird bio: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Research Funding. El Chaer: Amgen: Honoraria, Research Funding.

Key Clinical Message Promyelocytic leukemia is a known medical emergency and requires rapid diagnosis and expedient therapy with differentiating agents. We present an unusual case in which the diagnosis is based on a fine needle aspirate of a humeral mass. Despite lack of systemic involvement, the sarcoma responded to traditional differentiation agents.

Mycosis fungoides (MF) accounts for approximately 50% of all primary cutaneous lymphomas. MF occurrence in the oral cavity is extremely rare with approximately 45 cases reported to date. We present a case of a 68 year-old man with a raised nodular lesion of the ventral tongue with clinical impression of irritational fibroma. Histopathologic and immunohistochemical (IHC) examination revealed a phenotype consistent with MF with large cell transformation in the context of Sezary syndrome. The histological diagnosis of oral MF requires a high index of suspicion and IHC panel to rule out large cell transformation. To our knowledge, only four cases of large cell transformation of oral MF have been reported in the English literature. The clinical and histopathologic features of a rare case of intra-oral MF with large cell transformation are exemplified in this article.

The day 14 bone marrow aspirate and biopsy (D14BM) is regularly used to predict achievement of complete remission (CR) with induction chemotherapy in acute myeloid leukemia (AML), however its utility has been questioned. Clearance of peripheral blood blasts (PBB) may serve as an early measure of chemosensitivity. PBB rate of clearance (PBB-RC) was calculated for treatment-naive AML patients (n = 164) undergoing induction with an anthracycline and cytarabine (7+3) and with detectable PBB at diagnosis. PBB-RC was defined as the percentage of the absolute PBB count on the day of diagnosis that was cleared with each day of therapy, on average, until D14 or day of PBB clearance. Each 5% increase in PBB-RC approximately doubled the likelihood of D14BM clearance (OR = 1·81; 95% CI: 1·24-2·64, P < 0·005). PBB-RC was also associated with improved CR rates (OR per 5% = 1·97; 95% CI: 1·27-3·01, P < 0·005) and overall survival (OS) [hazard ratio (HR) per 5% = 0·67; 95% CI: 0·52-0·87]. African American patients had poorer OS adjusted for PBB-RC (HR = 2·18; 95% CI: 1·13-4·23), while race was not associated with D14BM or CR rate. PBB-RC during induction chemotherapy is predictive of D14BM clearance, CR, and OS, and can therefore serve as a prognostic marker for clinical outcomes in AML.

Gene amplification is one mechanism by which oncogenes are overexpressed. Although MLL (KMT2A) gene rearrangements (or 11q23 rearrangements) are well known in acute myeloid leukemia (AML), MLL gene...

Adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with conventional chemotherapy have dismal outcomes. Novel immunotherapies targeting CD19, including the bispecific T-cell engager blinatumomab and chimeric antigen-receptor T (CAR-T) cells, have revolutionized the treatment of R/R B-ALL. Robust response rates to CAR-T cell therapy after blinatumomab have recently been reported, but it is unknown whether blinatumomab can be effective following failure of anti-CD19 CAR-T cell therapy. Herein, we describe a patient with Philadelphia chromosome-positive B-ALL who relapsed after CD19-directed CAR-T therapy, but subsequently responded to the combination of blinatumomab and the tyrosine kinase inhibitor ponatinib, with the achievement of a complete remission lasting 12 months.

Breast cancer is the most common women cancer and is the second leading cause of cancer-related mortality in women. While the last two decades revolutionized breast cancer treatment with the development and use of therapies targeting steroid receptors and HER2/neu, there are limits to the risk estimation provided by traditional clinicopathologic parameters and IHC. Therefore, there is continued potential for inaccurate risk stratification of breast cancer patients which may lead to over- or under-treatment. In this review, we discuss the latest developments in the area of breast cancer research which have lead to better understanding of the breast cancer mechanisms, provided more accurate risk stratification, and identified potential new treatment targets. Specifically, we review the new dualistic model of breast carcinogenesis, which can inform pathologic diagnosis and tumor grading; we also discuss the intrinsic molecular classification of breast cancer and its impact on diagnosis and treatment; lastly, we compare the most common commercial molecular prognostic and predictive assays, with their respective strengths and weaknesses, and their clinical utility.

Introduction Despite recent advances in treatment, acute myeloid leukemia (AML) remains difficult to cure with high rates of relapse. Relapsed/refractory AML patients who are elderly or unfit for cytotoxic chemotherapy and whose disease fails to respond to hypomethylating agents represent an unmet need, and new safe and effective treatment options are needed for this patient population. Aspartate β-hydroxylase (ASPH) is a transmembrane protein that hydroxylates aspartyl and asparaginyl residues of epidermal growth factor (EGF)-like protein domains, and promotes cellular motility, migration, and adhesion. ASPH is highly expressed during fetal development and in placental trophoblasts, but not in any other healthy adult human tissue. ASPH is uniquely upregulated in cancer cells and is reported to be overexpressed in over 20 different solid neoplasms, in which it propagates a malignant phenotype, and is associated with increased cell proliferation, invasiveness, and poor prognosis. ASPH is therapeutically targetable via a fully human monoclonal antibody against ASPH, SNS-622. Subsequently, SNS-622 antibody-drug conjugates (ADCs) and a vaccine have been developed and are under current preclinical and clinical testing, respectively. We have previously demonstrated ASPH overexpression on the MOLM-14 AML cell line and effective in vitro killing of these cells using SNS-622 ADCs. In an effort to further characterize ASPH as a therapeutic target in AML, we report here the first study of ASPH expression patterns in AML patient samples. Methods Bone marrow (BM) aspirate and peripheral blood (PB) samples were collected from AML patients during 2014-2018 on a University of Maryland Greenebaum Comprehensive Cancer Center (UMGCCC) tissue banking protocol. Mononuclear cells were isolated by density centrifugation and were viably cryopreserved at -80ᵒC. Samples were analyzed using 8-color multiparameter flow cytometry to assess cell surface expression of ASPH, using fluorescein isothiocyanate (FITC)-conjugated SNS-622. The remainder of the fluorophores were labeled with standard lineage-specific markers. Expression of ASPH was measured via FITC fluorescence for each cell population and analyzed by two blinded, independent reviewers using FlowLogicTM software. Statistical analysis of ASPH expression was conducted using IBM® SPSS® Statistics for Windows, release 25.0.0 (IBM Corp., Armonk, N.Y., USA). Cohen's kappa (κ) was used to quantify the inter-observer agreement between two independent observers. Visual inspection of the expression data for the whole patient population showed a bimodal distribution, which was used to identify a robust cut-point separating high (i.e. positive) from low (i.e. negative) ASPH expression. Results Forty-two AML patient samples were evaluated (32 BM, 10 PB). Median patient age was 66 years, 48% (n=20) were female, 69% Caucasian and 21% African American. Disease status was 52% untreated de novo, 19% untreated secondary from antecedent MDS or MPN, and 29% relapsed/refractory. Samples were cytogenetically and molecularly diverse - with 50% exhibiting normal and 14% complex karyotype; 38% FLT3-ITD or FLT3-TKD, 29% NPM1, 19% IDH1/2, and 10% TP53 mutations. Full patient characteristics are shown in Table 1. Myeloblast expression of ASPH was found in 38% of samples (n=16; 14 BM, 2 PB) with a mean fluorescent intensity (MFI) of 10 as a cutoff for ASPH surface expression positivity. ASPH expression was not seen on other non-neoplastic cells including CD34+ hematopoietic stem cells, B- or T-lymphocytes, and monocytes. A blinded, independent review of the data revealed a Cohen's kappa (κ) of 0.74 with standard error of the estimate of ± 0.11. Patients with AML with ASPH expression were clinically heterogeneous, with no correlation between ASPH expression and AML subtype, karyotype or mutation status (Table 1). Conclusion ASPH is overexpressed in approximately 40% of patients with AML and serves as a promising therapeutic target. An ASPH nanoparticle vaccine is currently under clinical investigation and has shown promising results in solid tumors. We plan to expand clinical testing of targeting ASPH to AML. The ASPH positivity cutoff established via this work will serve as the eligibility criterion for the planned phase Ib/IIa of anti-ASPH vaccination in AML. . Disclosures Lebowitz: Sensei Biotherapeutics: Employment. Malhotra:Sensei Biotherapeutics: Employment. Fuller:Sensei Biotherapeutics: Employment. Shahlaee:Sensei Biotherapeutics: Equity Ownership; Sensei Biotherapeutics: Consultancy. Ghanbari:Sensei Biotherapeutics: Employment; Sensei Biotherapeutics: Equity Ownership. Emadi:NewLink Genetics: Research Funding.

Background Successful allogeneic stem cell transplantation (HSCT) in treatment of patients (pts) with acute myeloid leukemia (AML) is dependent upon graft-versus-leukemia, suggesting that intact immune surveillance is essential for eradicating minimal residual disease. Myeloblast-induced T-cell tolerance through overexpression of indoleamine 2,3-dioxygenase (IDO) is thought to play a significant role in immune evasion through upregulation of tryptophan (Trp) catabolism and kynurenine production, resulting in a Trp-poor environment that leads to immune system suppression. Indoximod is a small-molecule inhibitor of the IDO pathway that acts directly on immune cells to reverse IDO pathway-mediated suppression. We are assessing the safety and preliminary efficacy of indoximod in combination with standard induction chemotherapy in patients (pts) with newly diagnosed AML. Methods In this open-label, multicenter, phase 1 study (NCT02835729), eligible pts with newly diagnosed AML were treated with indoximod in combination with induction chemotherapy (idarubicin 12 mg/m2/d x3 days with cytarabine 100 mg/m2/d x7 days). Using a "3+3" design, indoximod (600 mg [dose level 0], 1000 mg [dose level 1], 1200 mg [dose level 2]) was given orally every 8 hours (Q8h) starting on day 9 of induction. Regimen limiting toxicity (RLT) was defined as any ≥ grade 3 non-hematologic adverse event (AE) that was not incontrovertibly related to the underlying AML or cytarabine or idarubicin. After induction, pts received up to 4 cycles of high dose cytarabine (HiDAC) consolidation while continuing indoximod. Patients continued on maintenance indoximod for up to 6 months from completion of consolidation therapy. Indoximod was discontinued 4 weeks prior to HSCT in eligible patients and not restarted as maintenance post-HSCT. Results As of July 15, 2018, 31 pts were enrolled (median age 55 years, range 18-78; 77% male). Six patients did not proceed with study therapy due to a diagnosis of acute promyelocytic leukemia, issues with medical insurance coverage, consent withdrawal, critical illness, and intestinal myeloid sarcoma preventing oral intake. Pts who received ≥1 dose of indoximod were included in the intention-to-treat (ITT) analysis (n=25), and pts who received ≥80% of their scheduled indoximod doses were included in the per-protocol (PP) analysis (n=19). Reasons for not completing ≥80% of indoximod doses were: consent withdrawal (n=3), inability to swallow (n=2) and physician decision (n=1). Of the 19 PP patients, 16 (84%) had either unfavorable karyotype or adverse mutation profile and 3 (16%) had secondary AML (s-AML). Indoximod combined with induction chemotherapy was well tolerated; no RLT was observed. The most frequent grade ≥3 non-hematologic treatment-emergent AEs in the ITT population, regardless of attribution, were febrile neutropenia (60%), hypoxia (16%), atrial fibrillation (12%), pneumonia (12%), hypocalcemia (12%), and hypotension (12%). Among 25 ITT pts, 21 (84%) achieved a remission (CR/CRh/CRi/CRp), and 15 of 19 (79%) in the PP analysis achieved remission. Among 12 pts with measurable residual disease (MRD) available in remission, 10 (83%) had MRD Conclusions Indoximod is well tolerated in combination with standard AML induction therapy. Rates of morphologic response and of MRD-neg status are very promising. The recommended phase 2 dose (RP2D) was 1200 mg oral Q8h and a placebo-controlled randomized phase 2 study is under development. Disclosures Emadi: NewLink Genetics: Research Funding. Loken:Hematologics, Inc: Employment, Equity Ownership. Kennedy:NewLink Genetics: Employment, Equity Ownership. Link:NewLink Genetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Munn:NewLink Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

The high affinity interleukin (IL)-15 receptor, IL-15Ralpha, is essential for supporting lymphoid homeostasis. To assess whether IL-15Ralpha's role in vivo is to trans present IL-15, we generated mixed bone marrow chimera from IL-15Ralpha- and IL-2/15Rbeta-deficient mice. We find that IL-15Ralpha-competent, IL-2/15Rbeta-deficient cells are able to support IL-15Ralpha-deficient natural killer (NK) and memory CD8+ T cells, thus ruling out secondary signals on these cells and demonstrating that IL-15Ralpha-mediated presentation of IL-15 in trans is the primary mechanism by which IL-15Ralpha functions in vivo. Surprisingly, using IL-15- and IL-15Ralpha-deficient mixed chimera, we also find that IL-15 and IL-15Ralpha must be expressed by the same cells to present IL-15 in trans, indicating that IL-15Ralpha is required on a cellular level for the elaboration of IL-15. These studies indicate that IL-15Ralpha defines homeostatic niches for NK and memory CD8+ T cells by controlling both the production and the presentation of IL-15 in trans to NK and CD8+ memory T cells.

Detection of the functional CD8+ CTL response usually requires in vitro restimulation. The differences between the CD8+ CTL repertoire in freshly isolated precursor cells and CD8+ CTL after short-term in vitro expansion have been generally assumed to be minimal, but have never been defined experimentally. Using staining with P18-I10/H-2Dd tetramers and monoclonal antibodies (mAb) against Vβ, we show the surprising result that there was significant skewing of the CD8+ CTL repertoire after just 7 days of stimulation. In contrast, we found that overnight incubation of precursor cells with peptide allows the functional assessment of CD8+ CTL (which cannot be detected ex vivo from freshly isolatedcells) without changing the absolute number of antigen-specific CTL as measured by tetramer staining or the repertoire of TCR analyzed with mAb. This study affords a better understanding of the differences between the ex vivo and in vitro stimulated CTL repertoire, and provides an approach to reveal a more faithful representation of the functional in vivo CTL response without skewing of the repertoire of T cells detected.

Adhesion of microcrystals that nucleate in tubular fluid to the apical surface of renal tubular cells could be a critical step in the formation of kidney stones, 12% of which contain uric acid (UA) either alone or admixed with calcium oxalates or calcium phosphates. UA crystals bind rapidly to monolayer cultures of monkey kidney epithelial cells (BSC-1 line), used to model the surface of the nephron, in a concentration-dependent manner. The urinary glycoproteins osteopontin, nephrocalcin, and Tamm-Horsfall glycoprotein had no effect on binding of UA crystals to the cell surface, whereas other polyanions including specific glycosaminoglycans blocked UA crystal adhesion. Specific polycations also inhibited adhesion of UA crystals and appeared to exert their inhibitory effect by coating cells. However, removal of anionic cell surface molecules with neuraminidase, heparitinase I, or chondroitinase ABC each increased UA crystal binding, and sialic acid-binding lectins had no effect. These observations suggest that hydrogen bonding and hydrophobic interactions play a major role in adhesion of electrostatically neutral UA crystals to renal cells, unlike the interaction of calcium-containing crystals with negatively charged molecules on the apical cell surface via ionic forces. After adhesion to the plasma membrane, subsequent cellular events could contribute to UA crystal retention in the kidney and the development of UA or mixed calcium and UA calculi.

Splenic angiosarcoma is a rare and aggressive malignancy with an incidence of less than one per million and a fatality rate over 90%. Early diagnosis is of great importance for optimal management. Here, we report the case of a patient with splenic angiosarcoma who presented with prominent schistocytes, echinocytes, thrombocytopenia, and iron deficiency anemia, which in combination with radiographic evidence of a splenic mass, raised the suspicion for angiosarcoma and resulted in a prompt surgical intervention with curative intent. Resolution of the hematologic findings following splenectomy suggests that patients with this malignancy should be monitored for recurrent hematologic abnormalities as they may herald recurrence of the disease. We present a literature review on the hematologic manifestations that is associated with this malignant disease.

NK cells vigorously proliferate during viral infections. During the course of murine CMV infection, this response becomes dominated by the preferential proliferation of NK cells that express the activation receptor Ly49H. The factors driving such selective NK cell proliferation have not been characterized. In this study, we demonstrate that preferential NK cell proliferation is dependent on DAP12-mediated signaling following the binding of Ly49H to its virally encoded ligand, m157. Ly49H signaling through DAP12 appears to directly augment NK cell sensitivity to low concentrations of proproliferative cytokines such as IL-15. The impact of Ly49H-mediated signaling on NK cell proliferation is masked in the presence of high concentrations of proproliferative cytokines that nonselectively drive all NK cells to proliferate.

IL-2, IL-15, and IL-7 are cytokines that are critical for regulating lymphoid homeostasis. These cytokines stimulate similar responses from lymphocytes in vitro, but play markedly divergent roles in lymphoid biology in vivo. Their distinct physiological functions can be ascribed to distinct signaling pathways initiated by proprietary cytokine receptor chains, differential expression patterns of the cytokines or their receptor chains, and/or signals occurring in distinct physiological contexts. Recently, the discovery of a novel mechanism of cytokine signaling, trans-presentation, has provided further insights into the different ways these cytokines function. Trans-presentation also raises several novel cell biological and cellular implications concerning how cytokines support lymphoid homeostasis.

NK cells protect hosts against viral pathogens and transformed cells, and dendritic cells (DCs) play important roles in activating NK cells. We now find that murine IL-15Rα-deficient DCs fail to support NK cell cytolytic activity and elaboration of IFN-γ, despite the fact that these DCs express normal levels of costimulatory molecules and IL-12. By contrast, IL-15Rα expression on NK cells is entirely dispensable for their activation by DCs. In addition, blockade with anti-IL-15Rα and anti-IL-2Rβ but not anti-IL-2Rα-specific Abs prevents NK cell activation by wild-type DCs. Finally, presentation of IL-15 by purified IL-15Rα/Fc in trans synergizes with IL-12 to support NK cell priming. These findings suggest that murine DCs require IL-15Rα to present IL-15 in trans to NK cells during NK cell priming.

Publisher Summary Edward Jenner's recognition of immune memory represents one of the oldest and most significant of immunological observations. However, it has also proved to be one of the most difficult to understand on both cellular and molecular level. Recently, significant advances have been made in understanding where memory T cells, particularly CD8 + T cells, come from, what they can do, and what maintains them. While the factors that control this unique phenotype are unknown, they may be dependent to some extent on IL-7 and/or IL-15 for their expression, given these cytokines' critical role in the long-term maintenance of memory CD8 + T cells.