Studies on monozygotic twins with concordant leukemia and retrospective scrutiny of neonatal blood spots of patients with leukemia indicate that chromosomal translocations characteristic of pediatric leukemia often arise prenatally, probably as initiating events. The modest concordance rate for leukemia in identical twins (Ϸ5%), protracted latency, and transgenic modeling all suggest that additional postnatal exposure and͞or genetic events are required for clinically overt leukemia development. This notion leads to the prediction that chromosome translocations, functional fusion genes, and preleukemic clones should be present in the blood of healthy newborns at a rate that is significantly greater than the cumulative risk of the corresponding leukemia. Using parallel reverse transcriptase-PCR and real-time PCR (Taqman) screening, we find that the common leukemia fusion genes, TEL-AML1 or AML1-ETO, are present in cord bloods at a frequency that is 100-fold greater than the risk of the corresponding leukemia. Single-cell analysis by cell enrichment and immunophenotype͞ fluorescence in situ hybridization multicolor staining confirmed the presence of translocations in restricted cell types corresponding to the B lymphoid or myeloid lineage of the leukemias that normally harbor these fusion genes. The frequency of positive cells (10 ؊4 to 10 ؊3 ) indicates substantial clonal expansion of a progenitor population. These data have significant implications for the pathogenesis, natural history, and etiology of childhood leukemia.C himeric fusion genes generated by chromosomal translocations are consistent genetic abnormalities in pediatric acute leukemia (1-3). DNA breaks and fusions occur in introns, and each patient's leukemic cells have a unique or clonotypic breakpoint, providing a specific, sensitive, and stable marker for tracking leukemic clones (4). Using this approach in identical twins with concordant leukemia (5-7) and, retrospectively, with neonatal blood spots (8-10), it was demonstrated that common fusion genes-MLL fusions in infants with acute lymphoblastic leukemia (ALL) and TEL-AML1 and AML1-ETO in children with ALL or acute myeloblastic leukaemia (AML), respectively-arise predominantly in utero, probably as initiating events, and are present before and at birth in circulating blood.The evolutionary, clonal development of pediatric cancers involves a sequence of two or more independent genetic events (11), and it therefore is unlikely that fusion genes, initiating the disease, would be sufficient. This supposition is supported by the modest concordance rate for ALL in monozygotic twin children, 5-10% (12), by protracted postnatal latency (up to 14 years) (7) and by the absence of overt signs of leukemia in mice transgenic for AML1-ETO (13) or TEL-AML1 (14). This finding leads to the prediction that chromosomal translocations, functional fusion genes, and preleukemic clones should be generated in stem cells during fetal hemopoiesis, and present in blood at birth, at a rate that substantially exceeds the k...

Summary. In postnatal life, mesenchymal stem cells (MSC) self-replicate, proliferate and differentiate into mesenchymal tissues, including bone, fat, tendon, muscle and bone marrow (BM) stroma. Possible clinical applications for MSC in stem cell transplantation have been proposed. We have evaluated the frequency, phenotype and differentiation potential of MSC in adult BM, cord blood (CB) and peripheral blood stem cell collections (PBSC). During culture, BM MSC proliferated to confluence in 10-14 d, maintaining a stable non-haemopoietic phenotype, HLA class-1 + , CD29 + , CD44 + , CD90 + , CD45 -, CD34 -and CD14 through subsequent passages. Using the colony forming unit fibroblasts assay, the estimated frequency of MSC in the BM nucleated cell population was 1 in 3AE4 · 10 4 cells. Both adipogenic and osteogenic differentiation of BM MSC was demonstrated. In contrast, CB and PBSC mononuclear cells cultured in MSC conditions for two passages produced a population of adherent, non-confluent fibroblast-like cells with a haemopoietic phenotype, CD45 + , CD14 + , CD34 -, CD44 -, CD90 -and CD29 -. In paired experiments, cultured BM MSC and mature BM stroma were seeded with CB cells enriched for CD34 + . Similar numbers of colony-forming units of granulocytes-macrophages were produced by MSC-based and standard stroma cultures over 10 weeks. We conclude that adult BM is a reliable source of functional cultured MSC, but CB and PBSC are not.

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Global Retinoblastoma Study Group IMPORTANCE Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale.OBJECTIVES To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. DESIGN, SETTING, AND PARTICIPANTSA total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. MAIN OUTCOMES AND MEASURESAge at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. RESULTSThe cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low-and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI,, and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI,). CONCLUSIONS AND RELEVANCEThis study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Human mesenchymal stem cells (MSCs) contribute to the regeneration of mesenchymal tissues, and are essential in providing support for the growth and differentiation of primitive hemopoietic cells within the bone marrow microenvironment. Techniques are now available to isolate human MSCs and manipulate their expansion in vitro under defined culture conditions without change of phenotype or loss of function. Mesenchymal stem cells have generated a great deal of interest in many clinical settings, including that of regenerative medicine, immune modulation and tissue engineering. Studies have already demonstrated the feasibility of transplanted MSCs providing crucial new cellular therapy. In this review, many aspects of the MSC will be discussed, with the main focus being on clinical studies that describe the potential of MSCs to treat patients with hematological malignancies who are undergoing chemotherapy and/or radiotherapy.

Secondary glaucoma is an important sequela in patients who undergo surgery for congenital cataracts. It is imperative that these patients get lifelong surveillance, as glaucoma can occur years after the initial operation.

Summary. Recent reports have shown that low nucleated cell dose signi®cantly decreases survival after cord blood transplantation. Prior to starting clinical cord blood banking we investigated the impact of obstetric factors on cell dose and volume of cord blood donations. Cord blood was obtained from 114 normal full-term deliveries. Mean volume collected was 93´5 ml, mean total nucleated cell count (TNC) was 13´1´10 8 . Statistical analysis was by backwards stepwise regression. Signi®cant factors affecting nucleated cell yield were volume of blood collected (P < 0´001), length of gestation (P < 0´0001), time from delivery of the infant to cord clamping (P 0´018) and total length of labour (P 0´002). In clinical cord blood banking we have successfully used these ®ndings for pre-collection assessment of placentae. Out of 476 cord blood donations subsequently collected for banking, only 29 (6´1%) have been discarded due to low volume. The mean TNC of the 409 banked units following volume reduction was 10´1´10 8 . Despite careful optimization of collection, processing and storage techniques, cell dose still limits cord blood transplantation to smaller recipients.

IMPORTANCE Microphthalmia, anophthalmia, and coloboma form an interrelated spectrum of congenital eye abnormalities. OBJECTIVE To document the ocular and systemic findings and inheritance patterns in patients with microphthalmia, anophthalmia, and coloboma disease to gain insight into the underlying developmental etiologies. DESIGN, SETTING, AND PARTICIPANTS This retrospective consecutive case series was conducted at a tertiary referral center. Included in the study were 141 patients with microphthalmia, anophthalmia, and coloboma disease without a recognized syndromic etiology who attended the Westmead Children's Hospital, Sydney, from 1981-2012. EXPOSURE Cases were grouped on the basis of the presence or absence of an optic fissure closure defect (OFCD); those with OFCD were further subdivided into microphthalmic and nonmicrophthalmic cases. Anophthalmic cases were considered as a separate group. MAIN OUTCOMES AND MEASURES Associated ocular and systemic abnormalities and inheritance patterns were assessed. RESULTS Of 141 cases, 61 (43%) were microphthalmic non-OFCD (NOFCD), 34 (24%) microphthalmic OFCD, 32 (23%) nonmicrophthalmic coloboma (OFCD), 9 (6%) anophthalmic, and 5 (4%) were unclassified. Sixty-three (45%) had bilateral disease. Eighty-four patients (60%) had an associated ocular abnormality; of these, cataract (P < .001) and posterior segment anomalies (P < .001) were most common in the NOFCD group. Forty-eight (34%) had an associated systemic abnormality, most commonly neurological, musculoskeletal and facial, urological and genital, or cardiac. Neurological abnormalities were most common in the anophthalmic group (P = .003), while urological abnormalities were particularly seen in the OFCD groups (P = .009). Familial cases were identified in both the OFCD and NOFCD groups, with a likely autosomal dominant inheritance pattern in 9 of 10 families. CONCLUSIONS AND RELEVANCE This series indicated that the OFCD/NOFCD distinction may be useful in guiding evaluation for ocular and systemic associations, as well as the direction and analysis of genetic investigation.