Joseph L. Lasky

Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation

Cancer stem cells, which share many common properties and regulatory machineries with normal stem cells, have recently been proposed to be responsible for tumorigenesis and to contribute to cancer resistance. The main challenges in cancer biology are to identify cancer stem cells and to define the molecular events required for transforming normal cells to cancer stem cells. Here we show that Pten deletion in mouse haematopoietic stem cells leads to a myeloproliferative disorder, followed by acute T-lymphoblastic leukaemia (T-ALL). Self-renewable leukaemia stem cells (LSCs) are enriched in the c-KitmidCD3+Lin- compartment, where unphosphorylated β-catenin is significantly increased. Conditional ablation of one allele of the β-catenin gene substantially decreases the incidence and delays the occurrence of T-ALL caused by Pten loss, indicating that activation of the β-catenin pathway may contribute to the formation or expansion of the LSC population. Moreover, a recurring chromosomal translocation, T(14;15), results in aberrant overexpression of the c-myc oncogene in c-KitmidCD3+Lin- LSCs and CD3+ leukaemic blasts, recapitulating a subset of human T-ALL. No alterations in Notch1 signalling are detected in this model, suggesting that Pten inactivation and c-myc overexpression may substitute functionally for Notch1 abnormalities, leading to T-ALL development. Our study indicates that multiple genetic or molecular alterations contribute cooperatively to LSC transformation.

Notch Signaling, Brain Development, and Human Disease

The Notch signaling pathway is central to a wide array of developmental processes in a number of organ systems, including hematopoiesis, somitogenesis, vasculogenesis, and neurogenesis. These processes involve maintenance of stem cell self-renewal, proliferation, specification of cell fate or differentiation, and apoptosis. Recent studies have led to the recognition of the role of the Notch pathway in early neurodevelopment, learning, and memory, as well as late-life neurodegeneration. This review summarizes what is currently known about the role of the Notch pathway in neural stem cells, gliogenesis, learning and memory, and neurologic disease.

Cancer Stem Cells

Cancer stem cells (CSC) are recently proposed to be the cancer initiating cells responsible for tumorigenesis and contribute to cancer resistance. Advances have been made in identifying and enriching CSC in leukemia and several solid tumors, including breast, brain and lung cancers. These studies suggest that, like normal stem cells, CSCs should be rare, quiescent, and capable of self-renewing and maintaining tumor growth and heterogeneity. Although the concept of CSC originates from that of normal stem cells, CSCs are not necessarily aberrant counterparts of normal stem cells. In fact, they may arise from stem cells or committed progenitors of corresponding tissues, and even cells from other tissues. At the molecular level, the alteration of stem cell self-renewal pathway(s) has been recognized as an essential step for CSC transformation. Better understanding of CSC will no doubt lead to a new era of both basic and clinical cancer research, re-classification of human tumors and development of novel therapeutic strategies specifically targeting CSC.

Abducens nerve ocular neuromyotonia following non-sellar or parasellar tumors.

Ocular neuromyotonia is an uncommon disorder resulting from episodic involuntary discharge of ocular motor nerves producing sustained contraction of their respective ocular muscles. Ocular neuromyotonia manifests in brief spells of diplopia occurring spontaneously or after eccentric gaze holding. In most cases, ocular neuromyotonia follows months or years after radiotherapy to the sellar and parasellar region and involves the oculomotor nerve. We report two unusual cases of abducens nerve ocular neuromyotonia that followed radiation therapy of tumors in areas other than the sellar or parasellar region.

Congenital brain tumors: case series and review of the literature.

Congenital brain tumors are rare and make up only 2% of all pediatric central nervous system tumors. We present 12 cases of congenital brain tumors of various histopathologies. Most of these tumors were of astrocytic lineage. One patient was diagnosed before birth with prenatal ultrasound, but the rest were diagnosed after birth owing to increased head circumference. Four patients received adjuvant chemotherapy after surgery. None received radiation therapy. Seven out of 12 (58%) are long-term survivors. Four of these survivors (57%) have significant neurocognitive or psychomotor impairment. Although rare, congenital brain tumors are one of the more common tumors presenting in the perinatal period and generally carry a poor prognosis. Novel therapies are needed to improve efficacy and decrease the devastating side effects of treatment in this age group.

Targeting stem cells in brain tumors

Stem cells are commonly defined as undifferentiated cells capable of self-renewing and giving rise to a large number of differentiated progeny. It is becoming increasingly apparent that there exist cancer stem cells (CSCs) from which the cells of any given malignancy arise, whereby only a few cells out of a population of cancer cells are able to initiate tumor formation. These CSCs, like their normal counterparts, are characterized by self-renewal and the ability to “differentiate” into all of the cell types in the original tumor. Current chemotherapeutic strategies involve using non-specific cytotoxic agents that target rapidly cycling cells. Although this may reduce disease burden in many cases, these therapies may miss the rare, self-renewing population that truly gives rise to the malignancy (the CSC). This review will focus on the recent discovery of stem cell-like cells in human brain tumors, putative “brain cancer stem cells,” which exhibit the properties of self-renewal and the ability to recapitulate the original tumor heterogeneity. Dissecting the molecular mechanisms that underlie the ability of these cells to self-renew and maintain quiescence may allow the development of novel therapeutic strategies that will allow for more efficacious and less toxic therapies for these devastating malignancies.

Primary leptomeningeal medulloblastoma ☆

We report the case of an 8-year-old boy who presented with a 2-month history of headaches and mild visual impairment and was found to have a medulloblastoma with primary leptomeningeal involvement. No mass lesion was found on imaging studies, during subsequent intraoperative surgical inspection or at autopsy. The pathologic findings were first documented on cerebrospinal fluid cytologic examination and biopsy of the cerebellum and were later confirmed at necropsy. To our knowledge, this is the third reported case of medulloblastoma identified with primary leptomeningeal involvement without a cerebellar mass and the first such case with documented autopsy findings.

The surgical management of a stage III Wilms tumor presenting with perforated appendicitis.

The majority of the cases of nephroblastoma do not present with abdominal pain. We present a patient with an acute surgical abdomen due to perforated appendicitis and an incidental abdominal mass. He underwent an urgent appendectomy after which tumor specific therapy was successfully initiated.

A phase 3 trial of l-glutamine in sickle cell disease

BACKGROUND Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical‐grade l‐glutamine (USAN, glutamine) has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell–related pain. METHODS In a multicenter, randomized, placebo‐controlled, double‐blind, phase 3 trial, we tested the efficacy of pharmaceutical‐grade l‐glutamine (0.3 g per kilogram of body weight per dose) administered twice daily by mouth, as compared with placebo, in reducing the incidence of pain crises among patients with sickle cell anemia or sickle β0‐thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48‐week treatment period. RESULTS A total of 230 patients (age range, 5 to 58 years; 53.9% female) were randomly assigned, in a 2:1 ratio, to receive l‐glutamine (152 patients) or placebo (78 patients). The patients in the l‐glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the l‐glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the l‐glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the l‐glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low‐grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l‐glutamine group than in the placebo group. CONCLUSIONS Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l‐glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217.)