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About 2% of mothers with Sjögren’s syndrome and about 1% of mothers with systemic lupus erythematosus deliver a baby with a congenital heart block (CHB). This is thought to be as a result of the maternal autoantibodies that cross the placenta and cause congenital lupus in the fetus/neonate. Among patients with a 2nd or 3rd degree atrioventricular block, the mortality rate in the neonatal period is about 10%, and most neonates who survive require a pacemaker into adulthood. Despite the compelling mortality and morbidity, the data on the optimal preventive treatments are meager and not well-established. In addition to pharmaceutical therapy, one potentially effective therapy is plasmapheresis. Plasmapheresis is safe in pregnancy, well tolerated, and is effective in removing the offending substances in the serum which may cause disease. We review this literature, in order to educate the reader and to motivate interest in studying this condition in the future.

Mesothelioma is a rare malignant tumor of the serosal membranes that can be challenging to diagnose, especially on small biopsy specimens. There are updated guidelines on the diagnosis and classification of mesothelioma, which incorporate advancements in understanding mesothelioma biology published in the literature over recent years. This review will discuss marked developments and/or improvements that have been made, including: (1) to the histologic classifications of mesothelioma; (2) the use of such classifications and nuclear grading in prognosis; (3) the indispensability of ancillary studies in the diagnosis of mesothelioma; (4) the application of these pleural based classifications and diagnostic schemes in peritoneal mesothelioma; and (5) the potential for diagnosis of mesothelioma in situ.

Acute myeloid leukemia (AML) is a highly heterogeneous cancer of the bone marrow. To better understand leukemogenesis and improve predictors of patient response to chemotherapy and overall survival (OS), we recently examined the role of inositol polyphosphate-4-phosphatase, type-II (INPP4B) in AML. Normally, INPP4B plays a role in PI3K/Akt signaling by regulating phosphorylation of phosphoinositides (PIs), critical membrane-bound second messenger molecules, by dephosphorylating the 4'-position of PI(3,4)P2 to generate PI(3)P. Because PI(3,4)P2, like PI(3,4,5)P3, is necessary for the activation Akt, INPP4B was first hypothesized and demonstrated to be a tumor suppressor protein, akin to PTEN, in several cancers including breast, prostate and ovarian. Recent work however, including our own study, has demonstrated a paradoxical tumor-promoting role of INPP4B in AML and estrogen receptor positive (ER+) breast cancer. Specifically, we demonstrated that INPP4Bhigh AML patients (25% of patients) had significantly shorter OS, lower response to induction therapy, and shorter event-free survival. Furthermore, INPP4B expression was found to be an independent prognostic marker for OS in AML outperforming FLT3-ITD and NPM1 mutation status. Overexpression of INPP4B in several AML cell lines results in enhanced colony formation potential, chemotherapy drug resistance, and increased proliferation. Though this previous work has shown that INPP4B plays a significant role in AML, it remains unclear why INPP4Bhigh AML differs from INPP4Blow AML, and what causes its upregulation. To address this question, we interrogated gene expression data from three independent datasets (n=942) to identify genes with differential expression between INPP4Bhigh and INPP4Blow AML. Gene expression analysis revealed that INPP4Bhigh AML was associated with differential expression of 233 genes. High INPP4B expression was associated with higher expression of genes related to the hematopoietic lineage, PI3K-Akt signaling, Jak-STAT signaling and ECM-receptor interaction pathways. Specifically, INPP4Bhigh AML has significantly higher expression of leukemic stem cell signature (LSC) genes CD34, RBPMS, GUCY1A3, KIAA0125, SOCS2, SPINK2, HTR1F, PPP1R16B, EVI1 (MECOM), DAPK1, BAALC, ABCB1, and PRKCH. Furthermore, INPP4B was found to be co-expressed with anti-apoptotic genes of the BCL2 family, namely BCL2 and BCL2L1. Further analysis revealed that INPP4B was co-expressed with the transcription factors EVI1, GATA2, NFATC2, ZEB1, GATA3 and ETS1, all of which having predicted binding sites within the INPP4B promoter region. Due to the observed enrichment of hematopoietic lineage/LSC genes in INPP4Bhigh AML, we wanted to validate the potential role of the EVI1 transcription factor in regulating INPP4B expression. Chromatin immunoprecipitation was used to demonstrate that EVI1 binding was enriched in the INPP4B promoter region of both EVI1high OCI/AML-4 and OCI/AML-6 cell lines. In addition, retroviral overexpression of EVI1 in EVI1low U937 cells resulted in subsequent upregulation of INPP4B transcript levels. Moreover, shRNA mediated knockdown of EVI1 in EVI1highOCI/AML-4 and UCSD-1 cells resulted in downregulation of INPP4B expression. Overall, our analysis reveals that INPP4Bhigh AML is characterized by upregulation of genes related to the hemotopoietic lineage, and LSC signature - consistent with the in vitro colony formation phenotype seen in INPP4B overexpressing AML cell lines. Furthermore, we demonstrate that one of the hematopoietic stem cell genes, EVI1 is a potentially key regulator of INPP4B expression in AML. Disclosures Jain: Roche Canada: Research Funding.

Our studies have focused on characterizing a role for the lipid phosphatase inositol polyphosphate 4-phosphate Type II (INPP4B) in Acute Myeloid Leukemia (AML). Although INPP4B has been reported to antagonize the oncogenic PI3K pathway, and is frequently disrupted in several epithelial cancers, our recent studies provide new evidence for a paradoxical oncogenic role for INPP4B in AML. Our analysis of several AML patient databases led to the discovery that high levels of INPP4B expression were associated with poor clinical outcome, including significantly decreased survival metrics and poor response to chemotherapy. Frequency distribution analysis utilizing a fit of mixture model identified a population of high INPP4B expressers comprising 25% of patients across all the datasets. INPP4Bhigh patients had lower rates of CR compared with their INPP4Blow counterparts (57% vs 74%, respectively; P = 0.01). Accordingly, the mean expression of INPP4B was significantly lower in CR vs NR samples (61.8 ± 2.0 vs 84.9 ± 10.7, P = 0.003). Thus, we have characterized INPP4B as a useful clinical prognostic factor associating with unfavourable outcome in AML. We have since established that INPP4B expression is significantly enriched in human and mouse hematopoietic stem cells (HSC), with an approximate 3-fold higher relative-expression in HSC and MPP compared to common myeloid precursors (CMP), granulocyte-macrophage progenitors (GMP) and multilymphoid progenitor (MLP). We demonstrate compelling evidence that INPP4B protein plays a critical functional role in both human and murine HSC maintenance, using in vivo models of leukemia and Inpp4b-knockout. Inpp4b-knockout mice show a disrupted bone-marrow stem-niche with reduced long-term HSC, HSC and GMP (49.1%, 32.4% and 19.7% lower than wild-type, respectively). To further test the role of INPP4B in HSC we conducted functional assays in vivo. Competitive transplant of bone marrow into lethally-irradiated host mice shows that Inpp4b-knockout cells preferentially reconstitute myeloid blood lineages in the short term, with 78.5% of myeloid cells being Inpp4b-knockout at 16 weeks post-transplant of 1:1 ratio of Inpp4b-knockout to wild-type cells. Targeting proliferating cells with chemotherapeutic agents induces HSC cycling and differentiation to replenish the blood system, and has been used as an indirect measure of HSC functionality in vivo. We then injected mice weekly with 5'-fluorouracil, a non-mutagenic myelosuppressive agent that kills cycling hematopoietic cells, (150mg/kg every 7 days, i.p.) to model repeated hematopoietic injury. We observed a reduced overall survival in Inpp4b-knockout mice compared to wild-type controls, indicating an impaired ability of Inpp4b-knockout HSCs to repopulate the hematopoietic system post-insult. We generated MLL-AF9 leukemic mouse models in Inpp4b-wild type and Inpp4b -knockout bone marrow and determined that Inpp4b is not an absolute requirement for formation of leukemia. In order to better understand the mechanism underlying the role of Inpp4b in hematopoiesis and leukemia we have an undertaken an unbiased -omics approach to identify key changes associated with Inpp4b-loss in stem and progenitor cells. We have performed quantitative-proteomics and next-generation sequencing on HSC, CMP, GMP and MEP populations. We have also investigated altered signalling dynamics associated with Inpp4b-loss- quantifying phospho-signalling changes in stem-enriched cell populations by means of high-dimensional single-cell mas-cytometry. Based on our current data, we hypothesize that INPP4B plays a critical role in HSC maintenance and contributes to worse leukemia. We further hypothesise it is this stem-related function of INPP4B that is responsible for the poor therapy response observed in patients with elevated INPP4B. Given the aging population, and the association of AML and age on prognosis, our success has the potential to have an impact on an ever-growing number of patients. Disclosures No relevant conflicts of interest to declare.

Introduction: Gliomas are neoplasms of the central nervous system (CNS). Despite aggressive treatment, median survival of malignant tumors remains poor at 12 - 18 months. Newer treatments allow delivery of therapeutic substances across the selectively permeable blood-brain barrier (BBB). This allows for chemotherapeutics to more easily reach their target location in the CNS. Drug eluting wafers made up of carmustine can be placed in the surgical resection cavity of a tumor and clinical trials to date have demonstrated their utility. Hypothesis: Bypassing the BBB to allow greater accumulation of chemotherapeutics in the CNS will improve clinical outcomes in glioma patients. Methods: Studies from medical literature databases describing trials using carmustine wafers implanted after glioma resection were obtained. To test our hypothesis, the available data using this therapy was compared to current first line treatment data for glioma as described by Stupp and colleagues. The inclusion criterion for efficacy analysis was histopathologically confirmed primary glioma. Exclusion criteria included presence of metastasis or pediatric tumors. Results: 10 studies describing wafer therapy use were initially gathered, encompassing over 500 patients. 6 studies met criteria for treatment efficacy analysis. 4 of 6 (75%) trials exhibited significant survival advantage as compared to control treatment. Furthermore, 3 of the 4 (75%) studies showing significance also demonstrated equal or higher percent increase in overall survival from control as compared to data generated from current first line therapy. Conclusion: Treatments bypassing the BBB are not currently standard-of-care for patients with glioma. We uncovered that most trials using carmustine implants post tumor resection describe increased overall survival, however in specific cohorts. Diverting the BBB in general may also have fewer side effects in contrast to classical routes of therapy. Future work is needed to develop similar therapeutics that improve outcomes in all age, gender, and prognostic risk factor populations.