Oncogenic EML4-ALK assemblies suppress growth factor perception and modulate drug tolerance.

Drug resistance remains a challenge for targeted therapy of cancers driven by EML4-ALK and related fusion oncogenes. EML4-ALK forms cytoplasmic protein condensates, which result from networks of interactions between oncogene and adapter protein multimers. While these assemblies are associated with oncogenic signaling, their role in drug response is unclear.

Pediatric Leukemia Roadmaps Are a Guide for Positive Metastatic Bone Sarcoma Trials.

ALL cures require many MRD therapies. This strategy should drive experiments and trials in metastatic bone sarcomas.

FET fusion oncoproteins disrupt physiologic DNA repair networks and induce ATR synthetic lethality in cancer.

The genetic principle of synthetic lethality is clinically validated in cancers with loss of specific DNA damage response (DDR) pathway genes (i.e. BRCA1/2 tumor suppressor mutations).

FET fusion oncoproteins disrupt physiologic DNA repair networks in cancer.

While oncogenes promote cancer cell growth, unrestrained proliferation represents a significant stressor to cellular homeostasis networks such as the DNA damage response (DDR). To enable oncogene tolerance, many cancers disable tumor suppressive DDR signaling through genetic loss of DDR pathways and downstream effectors (e.g.

Clinical characteristics and outcomes of infants compared with children diagnosed with rhabdomyosarcoma: Analysis of surveillance, epidemiology and end results data from 2000 to 2016.

Background: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood, but occurs infrequently in infants (<1 year). Historically, infants with RMS have worse overall survival compared to other pediatric age groups.

Aim: This study aims to assess the clinical features and treatment factors associated with survival comparing infants to children aged 1-9 years diagnosed with RMS.

Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules.

Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that actively signal.

Multicenter Evaluation of the BD Phoenix CPO Detect Test for Detection and Classification of Carbapenemase-Producing Organisms in Clinical Isolates.

Limited treatment options contribute to high morbidity/mortality rates with carbapenem-resistant, Gram-negative bacterial infections. New approaches for carbapenemase-producing organism (CPO) detection may help inform clinician decision-making on patient treatment and infection control. BD Phoenix CPO detect (CPO detect) detects and classifies carbapenemases in , , and during susceptibility testing.

A dual-center evaluation of platelet culture vials to detect the presence of microorganisms in platelets.

Background: Microorganism contamination of platelets results in a high risk of transfusion-related sepsis. Here, the ability of culture vials (BD BACTEC Platelet Aerobic/F and Platelet Anaerobic/F vials, Becton, Dickinson and Company) to detect microorganisms in leukoreduced apheresis platelets (LRAPs) and leukoreduced whole blood platelet concentrates (LRWBPCs) was assessed.

Methods: LRAPs or LRWBPCs were inoculated into Aerobic/F and Anaerobic/F vials and placed in a blood culturing system (BD BACTEC FX System, Becton, Dickinson and Company) for growth/monitoring over 7 days to detect preexisting contamination during false-positive testing.

Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor and bi-functional lipid and protein phosphatase. We report that the metabolic regulator pyruvate dehydrogenase kinase1 (PDHK1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The PTEN protein phosphatase dephosphorylates nuclear factor κB (NF-κB)-activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NF-κB target gene.

Outcomes for Relapsed and Refractory Peripheral T-Cell Lymphoma Patients after Front-Line Therapy from the COMPLETE Registry.

Background: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data.

Objectives: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease.

The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study.

Background: The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T-cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1.

Methods: Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis.

Surveillance Screening in Li-Fraumeni Syndrome: Raising Awareness of False Positives.

Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome inherited in an autosomal dominant fashion that involves a germline mutation of tumor protein 53 (TP53). With the advent of more accessible and accurate genetic testing methods, along with more widespread knowledge of LFS, asymptomatic carriers can now be more easily identified. No general surveillance protocols were previously recommended other than routine physical exams and breast and colon cancer screening at younger ages, primarily due to questions involving efficacy, cost, and clinical benefits.

Cardiac birth defects in a twin infant born to a woman with chronic myeloid leukemia on dasatinib.

Preclinical animal studies have demonstrated an association between maternal use of tyrosine kinase inhibitors and embryofetal toxicity; yet, multiple clinical case series have reported normal pregnancy outcomes and healthy infants in women on these medications during the course of their pregnancy. We describe a case of a woman with chronic myeloid leukemia who had taken the second-generation tyrosine kinase inhibitor dasatinib during the first 12 weeks of her dichorionic diamniotic twin pregnancy and subsequently delivered two low-birth weight infants, one with severe cardiac malformations and the other without apparent birth abnormalities. To our knowledge, this is the first reported case of fetal cardiovascular defects in an infant born to a woman on dasatinib during a twin pregnancy and supports current recommendations to avoid this medication during pregnancy.

Randomized Phase II Study of R-CHOP With or Without Bortezomib in Previously Untreated Patients With Non-Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma.

Purpose To evaluate the impact of the addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on outcomes in previously untreated patients with non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL). Patients and Methods After real-time determination of non-GCB DLBCL using the Hans immunohistochemistry algorithm, 206 patients were randomly assigned (1:1; stratified by International Prognostic Index [IPI] score) to six 21-day cycles of standard R-CHOP alone or R-CHOP plus bortezomib 1.3 mg/m intravenously on days 1 and 4 (VR-CHOP).

Analysis of Peripheral T-cell Lymphoma Diagnostic Workup in the United States.

Background: With increased understanding of the unique entities, subtype-specific approaches for peripheral T-cell lymphoma (PTCL) are emerging, and more precise diagnoses are becoming increasingly important. PATIENTS AND METHODS: We analyzed the approach to the histopathologic diagnosis of PTCL using data from the comprehensive oncology measures of peripheral T-cell lymphoma (COMPLETE) study. The COMPLETE trial is a large prospective cohort study of patients with newly diagnosed PTCL in the United States.

A prospective cohort study of patients with peripheral T-cell lymphoma in the United States.

Background: Long-term survival in patients with aggressive peripheral T-cell lymphoma (PTCL) is generally poor, and there currently is no clear consensus regarding the initial therapy used for these diseases. Herein, the authors analyzed treatment patterns and outcomes in a prospectively collected cohort of patients with a new diagnosis of nodal PTCL in the United States.

Methods: Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a prospective multicenter cohort study designed to identify the most common prevailing treatment patterns used for patients newly diagnosed with PTCL in the United States.

Inactivation of Capicua drives cancer metastasis.

Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4, driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis.

RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer.

One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4.

p53 expression is a strong marker of inferior survival in de novo diffuse large B-cell lymphoma and may have enhanced negative effect with MYC coexpression: a single institutional clinicopathologic study.

Objectives: To examine interactions among clinical factors and pathologic biomarkers in predicting the outcome of patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab-based immunochemotherapy.

Methods: In 85 patients treated at a single institution, clinicopathologic variables were analyzed, including the International Prognostic Index (IPI); germinal/nongerminal center phenotype; MYC, p53, BCL2, Ki-67, and Epstein-Barr virus (EBV) expression; and MYC translocation status.

Results: In univariate analysis, overall survival (OS) was worse for patients with high IPI scores, nongerminal center phenotype, high MYC and p53 expression by immunohistochemistry, and EBV positivity.

Pluripotent stem cell models of Shwachman-Diamond syndrome reveal a common mechanism for pancreatic and hematopoietic dysfunction.

Shwachman-Diamond syndrome (SDS), a rare autosomal-recessive disorder characterized by exocrine pancreatic insufficiency and hematopoietic dysfunction, is caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. We created human pluripotent stem cell models of SDS through knockdown of SBDS in human embryonic stem cells (hESCs) and generation of induced pluripotent stem cell (iPSC) lines from two patients with SDS. SBDS-deficient hESCs and iPSCs manifest deficits in exocrine pancreatic and hematopoietic differentiation in vitro, enhanced apoptosis, and elevated protease levels in culture supernatants, which could be reversed by restoring SBDS protein expression through transgene rescue or by supplementing culture media with protease inhibitors.

Pegylated liposomal doxorubicin, rituximab, cyclophosphamide, vincristine, and prednisone in AIDS-related lymphoma: AIDS Malignancy Consortium Study 047.

Purpose: Infusional chemotherapy is efficacious in patients with AIDS-related lymphoma, but it may be difficult to administer. We studied standard agents with rituximab plus pegylated liposomal doxorubicin (DR-COP) in an attempt to provide a more practical approach to therapy while ascertaining rates of response, potential infectious complications, and prognostic role of biologic markers.

Patients And Methods: We conducted a prospective, multi-institutional phase II trial, employing (day 1) pegylated liposomal doxorubicin 40 mg/m(2), rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), vincristine 1.

Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity.

Background: Proteins of the BCL-2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas. Navitoclax is a targeted high-affinity small molecule that inhibits the anti-apoptotic activity of BCL-2 and BCL-XL. We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours, and establish the drug's pharmacokinetic and pharmacodynamic profiles.

Randomized trial of paclitaxel versus pegylated liposomal doxorubicin for advanced human immunodeficiency virus-associated Kaposi sarcoma: evidence of symptom palliation from chemotherapy.

Background: Paclitaxel and pegylated liposomal doxorubicin (PLD) are active cytotoxic agents for the treatment of human immunodeficiency virus (HIV)-associated Kaposi sarcoma (KS). A randomized trial comparing the efficacy and toxicity of paclitaxel and PLD was performed, and the effects of therapy on symptom palliation and quality of life were determined.

Methods: Patients with advanced HIV-associated KS were randomly assigned to receive paclitaxel at a dose of 100 mg/m2 intravenously (iv) every 2 weeks or PLD at a dose of 20 mg/m2 iv every 3 weeks.

Induction, regulation, and biologic function of Axl receptor tyrosine kinase in Kaposi sarcoma.

Axl is an oncogenic receptor tyrosine kinase that plays multiple roles in tumorigenesis and metastasis of many cancers. This study is the first to demonstrate that Axl is induced in Kaposi sarcoma and Kaposi sarcoma herpesvirus (KSHV) transformed endothelial cells. Conditionally, expression of one KSHV latency protein vFLIP induces Axl expression in endothelial cells.