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Gray zone lymphoma is an aggressive disease for which appropriate management is still debated. We report a 15-year-old girl with a cervical mass, an enlarged ipsilateral tonsil, and anemia. Both sites showed hypermetabolism on F18-FG positron emission tomography/CT. Surgical resection was diagnostic of Epstein-Barr virus-negative gray zone lymphoma cervical and tonsillar involvement. No abnormality was found in cytogenetic analysis on tumor cells. However, exome sequencing in peripheral blood DNA revealed a germline mutation in TP53. Complete response was achieved after surgery and 6 cycles of rituximab with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin regimen.

Importance Little progress in pediatric cancer treatment has been noted in the past decade, urging the development of novel therapeutic strategies for adolescents and children with hard-to-treat cancers. Use of comprehensive molecular profiling in the clinical management of children and adolescents with cancer appears a suitable approach to improve patient care and outcomes, particularly for hard-to-treat cases. Objective To assess the feasibility of identifying potentially actionable mutations using next-generation sequencing–based assays in a clinically relevant time frame. Design, Setting, and Participants This diagnostic study reports the results of the TRICEPS study, a prospective genome sequencing study conducted in Quebec, Canada. Participants, aged 18 years or younger at diagnosis, with refractory or relapsed childhood and adolescent cancers were enrolled from April 2014 through January 2018. Whole-exome sequencing (WES) of matched tumor normal samples and RNA sequencing of tumor were performed to identify single-nucleotide variants, fusion transcripts, differential gene expression, and copy number alterations. Results reviewed by a team of experts were further annotated, synthesized into a report, and subsequently discussed in a multidisciplinary molecular tumor board. Main Outcomes and Measures Molecular profiling of pediatric patients with hard-to-treat cancer, identification of actionable and targetable alteration needed for the management of these patients, and proposition of targeted and personalized novel therapeutic strategies. Results A total of 84 patients with hard-to-treat cancers were included in the analysis. These patients had a mean (range) age of 10.1 (1-21) years and a similar proportion of male (45 [54%]) and female (39 [46%]). Sixty-two patients (74%) had suitable tissues for multimodal molecular profiling (WES and RNA sequencing). The process from DNA or RNA isolation to genomic sequencing and data analysis steps took a median (range) of 24 (4-41) days. Potentially actionable alterations were identified in 54 of 62 patients (87%). Actions were taken in 22 of 54 patients (41%), and 18 (33%) either were on a second or third line of treatment, were in remission, or had stable disease and thus no actions were taken. Conclusions and Relevance Incorporating genomic sequencing into the management of hard-to-treat childhood and adolescent cancers appeared feasible; molecular profiling may enable the identification of potentially actionable alterations with clinical implications for most patients, including targeted therapy and clinically relevant information of diagnostic, prognostic, and monitoring significance.

OBJECTIVE. Unclassified inherited bone marrow failure syndromes are a heterogeneous group of genetic disorders that represent either new syndromes or atypical clinical courses of known inherited bone marrow failure syndromes. The relative prevalence of the unclassified inherited bone marrow failure syndromes and their characteristics and the clinical and economic challenges that they create have never been studied. METHODS. We analyzed cases of inherited bone marrow failure syndrome in the Canadian Inherited Marrow Failure Registry that were deemed unclassifiable at study entry. RESULTS. From October 2001 to March 2006, 39 of the 162 patients enrolled in the Canadian Inherited Marrow Failure Registry were registered as having unclassified inherited bone marrow failure syndromes. These patients presented at a significantly older age (median: 9 months) than the patients with classified inherited bone marrow failure syndrome (median: 1 month) and had substantial variation in the clinical presentations. The hematologic phenotype, however, was similar to the classified inherited bone marrow failure syndromes and included single- or multiple-lineage cytopenia, severe aplastic anemia, myelodysplasia, and malignancy. Grouping patients according to the affected blood cell lineage(s) and to the presence of associated physical malformations was not always sufficient to characterize a condition, because affected members from several families fit into different phenotypic groups. Compared with the classified inherited bone marrow failure syndromes, the patients with unclassified inherited bone marrow failure syndromes had 3.2 more specific diagnostic tests at 4.5 times higher cost per evaluated patient to attempt to categorize their syndrome. At last follow-up, only 20% of the unclassified inherited bone marrow failure syndromes were ultimately diagnosed with a specific syndrome on the basis of the development of new clinical findings or positive genetic tests. CONCLUSIONS. Unclassified inherited bone marrow failure syndromes are relatively common among the inherited bone marrow failure syndromes and present a major diagnostic and therapeutic dilemma.

Progressive transformation of germinal center (PTGC) is a pattern of lymph node reactive hyperplasia. It can also be the predominant pattern in a hyperplastic lymph node known as florid PTGC. It is characterized histologically by the expansion of the mantle zone lymphocytes into both the adjacent sinusoids and germinal centers. The lymphocytes destroying the germinal centers are predominantly B cells, with a minor population of T cells. Morphologically, it can be confused with nodular lymphocyte-predominant Hodgkin disease (NLPHD) because of its nodular pattern and because of the presence of large cells that can be incorrectly identified as lymphocytic and histiocytic cells. A relationship between PTGC and NLPHD remains unclear, and many authors have suggested that PTGC can represent a precursor lesion of NLPHD. Here we report the first karyotype obtained in PTGC, in a 12-year-old boy. It shows a t(3;22)(q27;q11) translocation, probably involving the BCL6 gene. This translocation has previously been described in diffuse large B-cell lymphomas and in NLPHD with BCL6 rearrangement. This finding offers an insight into a possible tumorigenic pathway from PTGC to NLPHD. Further studies will be required to confirm this hypothesis.

Childhood cancer is a group of heterogeneous complex diseases. Although 80% of these children are cured with conventional therapies, it remains the first cause of death among children in Western countries. A significant number of refractory/relapse patients will eventually succumb to their disease and the lack of therapeutic advances for these patients is even more worrisome. Indeed, no significant progress has been noted over the last decade for these patients, urging the need for new and more effective therapeutic approaches. Precision medicine and more effective personalized targeted therapies (PTT) are a major breakthrough leading to increased cure rates and decreased treatment-related morbidity and mortality for the patients with refractory or relapsed tumors. To address this challenge, the TRICEPS study was initiated on April 2014 at the Sainte-Justine UHC (Montreal, Canada) with an overreaching goal to explore the feasibility of performing genomic-driven targeted therapy in pediatric and adolescent (aged 0-21 years) patients with relapsed or refractory childhood cancer. This study offers in-depth genomic and transcriptomic investigation of patient’s tumoral material to identify patient-specific alterations and actionable driver mutation(s) that can be targeted with approved targeted drug and within a reasonable clinically relevant timeframe to assess the feasibility of going from biopsy to a detailed tumor analysis report. Over a period of 30 months, 44 relapsed/refractory cancer patients were recruited. Twenty-two of them underwent extensive genomic investigation (exomic and transcriptomic sequencing) within a median timeframe of 9.7 weeks from patient enrolment to return of results. Patient screen failures occurred due to benign/necrotic tumor biopsies or low tumor purity resulting in suboptimal DNA/RNA quantity or quality for genomic analysis. In all 22 patients, we have identified clinically relevant genomic alterations (SNVs, indels, fusions, CNAs) and relapse-specific mutations influencing patient management and providing options for personalized interventions. We assessed the functional impact of some of these cancer-specific alterations. This was the case of a novel relapse-specific rearrangement, identified on relapsed childhood ETP-ALL, and leading to asparagine synthetase (ASNS) up-regulation through a promoter exchange. The expression of this fusion was associated with reduced apoptosis following l-asparaginase treatment. This study shows that PPT based on next generation sequencing technology is a powerful approach that could be implemented in the clinic within a foreseeable future to guide treatment of hard-to-treat childhood cancers and to further improve patient care and outcomes. Citation Format: Fida Khater, Stephanie Vairy, Sylvie Langlois, Jasmine Healy, Sophie Dumoucel, Mathieu Lajoie, Thomas Sontag, Pascal St-Onge, Henrique Bittencourt, Dorothée Dal Soglio, Anne-Sophie Carret, Sonia Cellot, Josette Champagne, Michel Duval, Maja Krajinovic, Jean-Marie Leclerc, Valerie Larouche, Natalie Patey, Sébastien Perreault, Nelson Piché, Yvan Samson, Pierre Teira, Monia Marzouki, Daniel Sinnett. Identification of actionable targets for refractory/relapsed childhood cancer leading to personalized targeted therapy (TRICEPS Study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4885. doi:10.1158/1538-7445.AM2017-4885

Background: The authors reviewed retrospectively their experience in 30 children with hepatoblastoma (HB). Despite an increased trend in the incidence of HB during the last 2 decades, an encouraging cure rate has been achieved with complete resection of the tumor and chemotherapy before or after surgery with cisplatin plus doxorubicin (Adriamycin) or cisplatin plus vincristine plus 5-Fluorouracil. Results: There were 10 female and 20 male patients. For the period from 1963 to 1980 there were 8 patients, and for the period from 1981 to 1998 there were 22 patients. Their mean age at surgery was 16 months (range, 3.5 months to 5.5 years). Tumors were localized to the right lobe in 10 (42%), to the left lobe in 7 (29%), and in both lobes in 7 (29%) of the resected patients. Tumors were greater than 10 cm in size in 16 (67%) of these patients. Twenty-four patients (80%), underwent liver resection before or after chemotherapy. One patient (3%) with an unresectable tumor received chemotherapy and a liver transplant. In 5 patients (17%) the hepatic involvement was too extensive for resection. The types of resection performed were right lobectomy in 7, left lobectomy in 6, right trisegmentectomy in 8, left trisegmentectomy in 2, and middle hepatectomy in 1. The overall survival rate for 35 years of the study was 60% (18 of 30). With the association of surgery and chemotherapy (1981 through 1998) survival rate is 82% (14 of 17). Overall median follow-up in our study is 8 years (range, 2.5 to 24 years). Conclusions: There has been a dramatic improvement in the results of treatment of hepatoblastoma. Formerly, only 25% to 30% of patients were cured, whereas today, with combination of chemotherapy and surgery, 75% to 80% may be cured. J Pediatr Surg 36:755-759. Copyright © 2001 by W.B. Saunders Company.

Objective To report two cases of severe reactive hemophagocytic syndrome (RHS), to discuss their impact, and to present evidence that RHS may be a constitutive part of multiple organ dysfunction syndrome (MODS). Design Case-report. Setting Pediatric intensive care unit (PICU). Patients Two patients with RHS and MODS. Interventions None. Measurements and main results Case #1: A 3 yr-old boy with Mucha-Haberman syndrome (pityriasis lichenoides) was admitted to the PICU for septic shock, acute respiratory distress syndrome, capillary leak, acute renal failure, liver dysfunction, and RHS (pancytopenia and hemophagocytosis on bone marrow aspirate). The pancytopenia was severe (white blood cell count, 0.9 x 10(9)/L; hemoglobin, 59 g/L; platelets, 36 x 10(9)/L), required many transfusions, and resolved 2 months later. The patient needed mechanical ventilation for 6 wks. Length of stay in PICU was 2 months. Case #2: A previously healthy 4 yr-old girl was admitted to the PICU for respiratory failure. She developed acute respiratory distress syndrome, cardiomyopathy with complete atrioventricular block, shock, capillary leak, liver dysfunction, and RHS (pancytopenia and hemophagocytosis on bone marrow aspirate). The pancytopenia was severe (white blood cell count, 1.92 x 10(9)/L; hemoglobin, 65 g/L; platelets, 58 x 10(9)/L) and necessitated transfusional support. Serology for respiratory syncytial virus was positive. RHS duration was 20 days; the patient recovered completely. Length of mechanical ventilation was 16 days and length of stay in PICU was 3 wks. Conclusions These cases show that RHS may be a significant cause of pancytopenia in the PICU. It needs to be recognized as a clinical entity because it can be reversible and nonneoplastic. RHS and MODS share some pathophysiologic elements and could be related to each other.

In Canada, about 1500 pediatric cancers are diagnosed each year. Despite improvements in risk-stratified treatments, around 20% of childhood cancer patients do not respond to current therapies and ultimately succumb to their disease, urging the need for new and more effective therapeutic approaches. Personalized targeted therapy (PTT) based on next generation sequencing (NGS) may be a key component to increase cure rates and decrease treatment-related morbidity and mortality. To assess the feasibility of performing PTT clinical trials in the context of childhood cancers, a pilot study is currently underway at the Sainte-Justine UHC, Montreal, where 30 relapsed or refractory cancer patients (aged 0-21 years) are being recruited over a 2 year period and offered in-depth genomic and transcriptomic investigation to identify patient-specific alterations. This pilot study will allow us to determine the number of children with cancer who are suitable candidates for targeted therapy, to determine the number and type of driver mutation(s) found in the recurrent or refractory childhood cancers, to determine the number of cancer patients who harbor actionable driver mutation(s) that can be targeted with a Health Canada/FDA approved targeted drug and to assess the feasibility of going from biopsy to a detailed tumour analysis report within a clinically-relevant timeframe. Thus far, sixteen patients have been recruited in this study between April 2014 and July 2015. Study subject accrual has been successful with 100% compliance. Eight patients have undergone extensive genomic investigation in a real-time manner. We identified clinically relevant genomic alterations (singe nucleotide variants or structural variations) that can be used to inform clinical management for 8/8 of these patients. Patient screen failures occurred due to benign tumor biopsies, necrotic tumor tissue or low tumor purity, resulting in suboptimal DNA/RNA quantity or quality for NGS. Identified relapse-specific mutations allowed follow up of minimal residual disease, particularly post-transplant for relapsed leukemia cases, influenced patient management and revealed alternative therapeutic options for future personalized targeted therapy. This feasibility study shows that PTT based on NGS technology is a useful approach that could be implemented in the clinic within a foreseeable future to guide treatment of relapsed or refractory childhood cancer patients. The following step toward translating our results into novel personalized therapeutic approaches will be the development of phase II clinical trials to evaluate the efficacy of these targeted therapies in terms of therapeutic response, survival, and overall quality of life. Our overreaching goal is to be able to offer personalized targeted therapy options to all patients upon primary diagnosis of their cancer. Citation Format: Sylvie Langlois, Jasmine Healy, Mathieu Lajoie, Sophie Dumoucel, Fida Khater, Thomas Sontag, Pascal St-Onge, Patrick Beaulieu, Henrique Bittencourt, Dorothée Dal Soglio, Anne-Sophie Carret, Sonia Cellot, Josette Champagne, Michel Duval, Maja Krajinovic, Jean-Marie Leclerc, Natalie Patey, Nelson Piché, Yvan Samson, Pierre Teira, Monia Marzouki, Daniel Sinnett. TRICEPS: A feasibility study of personalized targeted therapy in relapsed/refractory childhood cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A41.

Our knowledge of the phenotypes of inherited bone marrow failure syndromes (IBMFSs) derives from case reports or case series in which only one IBMFS was studied. However, the substantial phenotypic overlap necessitates comparative analysis between the IBMFSs. Shwachman-Diamond syndrome (SDS) is an IBMFS that the appreciation of what comprises its clinical phenotype is still evolving. In this analysis we used data on 125 patients from the Canadian Inherited Marrow Failure Study (CIMFS), which is a prospective multicenter population-based study. Thirty-four cases of SDS patients were analyzed and compared to other patients with the four most common IBMFSs on the CIMFS: Diamond Blackfan anemia, Fanconi anemia (FA), Kostmann/severe congenital neutropenia and dyskeratosis congenita (DC). The diagnosis of SDS, FA and DC was often delayed relative to symptoms onset; indicating a major need for improving tools to establish a rapid diagnosis. We identified multiple phenotypic differences between SDS and other IBMFSs, including several novel differences. SBDS biallelic mutations were less frequent than in previous reports (81%). Importantly, compared to patients with biallelic mutations, patients with wild type SBDS had more severe hematological disease but milder pancreatic disease. In conclusion, comprehensive study of the IBMFSs can provide useful comparative data between the disorders. SBDS-negative SDS patients may have more severe hematological failure and milder pancreatic disease.

Objective To estimate the frequency and volume of fetomaternal hemorrhage during external cephalic version for term breech singleton fetuses and to identify risk factors involved with this complication. Methods A prospective observational study was performed including all patients undergoing a trial of external cephalic version for a breech presentation of at least 36 weeks of gestation between 1987 and 2001 in our center. A search for fetal erythrocytes using the standard Kleihauer-Betke test was obtained before and after each external cephalic version. The frequency and volume of fetomaternal hemorrhage were calculated. Putative risk factors for fetomaternal hemorrhage were evaluated by chi(2) test and Mann-Whitney U test. Results A Kleihauer-Betke test result was available before and after 1,311 trials of external cephalic version. The Kleihauer-Betke test was positive in 67 (5.1%) before the procedure. Of the 1,244 women with a negative Kleihauer-Betke test before external cephalic version, 30 (2.4%) had a positive Kleihauer-Betke test after the procedure. Ten (0.8%) had an estimated fetomaternal hemorrhage greater than 1 mL, and one (0.08%) had an estimated fetomaternal hemorrhage greater than 30 mL. The risk of fetomaternal hemorrhage was not influenced by parity, gestational age, body mass index, number of attempts at version, placental location, or amniotic fluid index. Conclusion The risk of detectable fetomaternal hemorrhage during external cephalic version was 2.4%, with fetomaternal hemorrhage more than 30 mL in less than 0.1% of cases. These data suggest that the performance of a Kleihauer-Betke test is unwarranted in uneventful external cephalic version and that in Rh-negative women, no further Rh immune globulin is necessary other than the routine 300-microgram dose at 28 weeks of gestation and postpartum. Level of evidence II.

BACKGROUND: Although the frequency of complications in adults undergoing therapeutic apheresis is low, there are little data in children. STUDY DESIGN AND METHODS: A retrospective study of 186 children who had undergone a total of 1632 apheresis procedures between 1994 and 2002 was conducted. Adverse reactions were prospectively documented. The procedures were plasma exchange (67%), hematopoietic progenitor cell collection (18%), red blood cell exchange (6.9%), leukodepletion (0.7%), and plasma exchange with immunoadsorption (6.7%). RESULTS: Adverse reactions, most minor, were reported in 55 percent of procedures in 82 percent of patients. The most frequent complications, per procedure and per patient during an entire course of therapy, were hypotension (14 and 48.4%), hypotension requiring fluid bolus (4.8 and 26.9%), symptomatic hypocalcemia (9.7 and 28.5%), allergic reactions (4.4 and 5.9%), catheter-related thrombosis (1.7 and 12.4%), catheter-related infection (2.1 and 16.1%), and severe anemia (hemoglobin [Hb] level

An 18-month-old Oldenbourg filly was presented with a bleeding diathesis. Laboratory testing included platelet count, gingival bleeding time, prothrombin time (PT), activated partial thromboplastin time (aPTT), von Willebrand factor (vWf) antigen, clottable fibrinogen, clot retraction time, PFA-100 closure time, platelet aggregometry (on platelet-rich plasma), and thrombelastography (TEG). TEG was performed by using kaolin and tissue factor as coagulation activators. Expression of the platelet receptor for fibrinogen was assessed by flow cytometry by using anti CD41 (alpha(IIb) or glycoprotein IIb)/CD61 (beta(III) or glycoprotein IIIa) and anti-CD41 antibodies. Abnormal laboratory findings included prolonged oral mucosal bleeding time (>12 hours), prolonged closure time with collagen/ADP (>300 seconds), and absence of clot retraction after 60 minutes. TEG reaction times were similar with kaolin and tissue factor in the patient and a control horse. However, maximum amplitudes in the patient were decreased with both kaolin (43.7 mm; control, 63.9 mm) and tissue factor (37.7 mm; control, 57.8 mm). Platelet aggregation responses to ADP and collagen were profoundly reduced in the affected horse compared with a control. Flow cytometry showed an absence of CD41 and decreased expression of CD41/CD61-reacting antigen on the patient's platelets compared with those from a control horse. The laboratory findings supported a diagnosis of Glanzmann thrombasthenia, likely caused by a mutation in the gene encoding the GPIIb subunit.

BACKGROUND: Selection of a cord blood (CB) unit for allogeneic transplantation relies on graft characterization results provided by cord blood banks (CBBs). The goal was to compare the graft characterization results obtained upon thawing and washing to those provided by CBBs at selection. STUDY DESIGN AND METHODS: With tests that assess CB graft characteristics known to impact engraftment, CB units have been analyzed after thaw and before infusion. Our results were compared to data provided by CBBs to determine the impact on engraftment and assess how CBB-supplied information can affect future CB unit selection. RESULTS: Variability was noted as to the type of information provided by the different CBBs. Also, variability was found between the information provided by CBBs and the graft characterization results obtained upon thawing and washing. In some cases, CB measures known to be predictive of engraftment were found much lower than reported by CBBs. Only the total nucleated cell count, which is the main CB graft selection criterion besides HLA matching, correlated favorably. CONCLUSIONS: Our data reveal a high degree of variability in graft characteristics provided by CBBs and often poor correlation with results obtained on thawed and washed CB units. We suggest that standardized laboratory procedures aimed at graft characterization should be used by both CBBs and transplant centers to avoid unacceptable discrepancies.

Background:. Inherited bone marrow failure syndromes (IMFSs) are genetic disorders characterized by defective single-lineage or multi-lineage hematopoiesis. IMFS patients are at risk for severe cytopenias, development of marrow cytogenetic abnormalities (MCA), myelodysplasia (MDS), and malignancy. The rate of disease progression and proportion of patients at risk for these complications is currently unclear. We examined recently diagnosed IMFS patients to determine distribution of diagnoses, disease progression and development of significant outcomes. Methods:. The CIMFR is a prospective multi-center study established in 2001 to register all IMFS patients in Canada. Analysis was restricted to patients diagnosed after November 30, 1997. Summary statistics were used to depict the study population while survival was described using the Kaplan‐Meier method. Results:. 74 CIMFR patients were considered recently diagnosed. Median age at diagnosis was 2.7 years (range, birth to 40.6). Annual follow-up data were available for 53 (72%) patients. The five most prevalent diagnoses were Fanconi anemia (FA), Shwachman‐Diamond syndrome (SDS), Diamond‐Blackfan anemia (DBA), dyskeratosis congenita (DKC), and Kostmann’s neutropenia (KS). Eighteen (24%) patients were unclassifiable. Twenty-eight (53%) follow-up patients had disease progression as indicated by new or worsening cytopenias, new marrow changes, or initiation of transfusion support and/or medical therapy. Fourteen (19%) fulfilled minimal diagnostic criteria for myelodysplasia. Eleven patients had hematopoietic stem cell transplantation (HSCT) by first follow-up. Five patients have died. Survival at 36 months is 89.8 � 5.7%. Conclusions:. IMFS patients are often diagnosed at a young age. The relative distribution of diagnoses is similar to previous reviews of published cases; however, 25% of patients are currently unclassifiable. Disease progression has occurred in approximately 50% of follow-up patients. Early mortality is noted. Continued prospective observation of these patients is warranted. Pediatr Blood Cancer 2006;47:918‐925. 2006 Wiley-Liss, Inc.

The role of natural killer (NK) cells in hematopoietic stem cell transplantation and in the control of neonatal infections is not yet clear. Donor-versus-recipient NK cell alloreactivity was found to improve outcome in some settings of hematopoietic stem cell transplantation. We hypothesized that the role of NK cells in cord blood (CB) transplantation and neonatal infections may depend on CB NK cell maturation stage. We therefore analyzed the expression of NK cell differentiation/phenotypic markers in human CB, as well as functional properties of purified CB NK cells. CD8 and CD57 expression was lower in CB than in adult NK cells. However, the expression of other differentiation markers was similar, as was cell surface density of CD56, the percentage of late NK cell precursors, interferon-gamma production, and the proliferative response of purified NK cells to IL-2. Spontaneous cytotoxic activity of purified CB NK cells against NK-sensitive targets was low but reached adult levels after treatment with IL-15. Expression of perforin and granzyme B was higher in CB NK cells (90 versus 58% and 86 versus 69%, respectively). intercellular adhesion molecule-1 and CD161 expression was lower in CB. Surprising, fewer CB NK cells expressed L-selectin, a marker of immature NK cells. Taken together, our results suggest that CB NK cells are phenotypically and functionally mature.

Summary: Between 15% and 30% of children with acute lymphoblastic leukemia (ALL) experience disease recurrence. With the possible exception of patients presenting with late isolated extramedullary relapse, induction of second complete remission (CR) is employed as a stepping stone to allogeneic hematopoietic stem cell transplantation (HSCT). The authors report their institutional experience in the management of children with recurrent ALL using the Dana Farber Cancer Institute (DFCI) ALL protocol in patients treated initially with that same protocol. Successful reinduction was followed by allogeneic HSCT when possible. Between April 1986 and May 2003, 34 patients with recurrent ALL, treated at initial diagnosis with DFCI-ALL protocol therapy, were given the same protocol as repeat induction chemotherapy. The median age was 4.6 years at diagnosis and 7.1 years at recurrence. Median duration of CR1 was 30.3 months. Second CR was obtained in 29 (85%) patients. Twenty went on to allogeneic HSCT; 10 of them currently remain in CR. Two additional patients treated with chemotherapy without HSCT are also in continuous CR2. Overall, 13 (38%) of the 34 patients are alive with a median follow-up of 105 months. There were no toxic deaths due to the reinduction therapy. One child died of cardiac failure after autologous HSCT. The treatment of children with recurrent ALL using the DFCI-ALL protocol induction regimen after initial use of the same protocol is associated with a high rate of second CR with no excess toxicity. However, the overall prognosis in these patients remains unsatisfactory and needs to be improved.

The most common childhood malignancy, acute lymphoblastic leukemia (ALL), remains the leading cause of cancer-related death in children because of resistant cases in which underlying predisposing factors are poorly understood. The interindividual variation in the activity of xenobiotic metabolizing enzymes that modify individual somatic mutation burden in the context of environmental exposure was shown to modify susceptibility to childhood ALL. Variable DNA repair capacity may further modulate induced DNA lesions. Similarly, differential capacity of ALL patients to process carcinogens and chemotherapeutic drugs could both modify an individual's risk of recurrent malignancy and response to therapy.We investigated the relationship between the risk of relapse in ALL patients and functional polymorphisms in genes encoding carcinogen-metabolizing enzymes, including CYP1A1, CYP2D6, CYP2E1, MPO, GSTM1, GSTT1, GSTP1, NAT1, NAT2, NQO1, as well as DNA-repair enzymes hMLH1, hMSH3, XRCC1, XPF, and APE. Our study included 320 children with ALL, of which 68 relapsed or died because of this disease within 5 years of follow-up.Among children of the latter group, we found that carriers of CYP1A1*2A and NQO1*2 variants had worse disease prognosis according to Kaplan-Meier (P = 0.003) and Cox regression (Por= 0.03) analyses. hMLH1 Ile219 contributed to the increased risk of relapse when combined with the CYP1A1*2A variant.Our findings suggest that determining individual genotypes can become important in predicting disease outcome. Genotyping could also guide the therapeutic protocol.

Abstract 1266 Introduction: Inherited bone marrow failure syndromes (IBMFSs) are a group of rare, genetic disorders with a risk of clonal and malignant myeloid transformation including clonal marrow cytogenetic abnormalities, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The clinical characteristics and outcome of IBMFS-related clonal and malignant myeloid transformation are unclear, particularly in cases of early transformation such as isolated clonal marrow cytogenetic abnormalities. Objectives: The aims of this study were to determine the risk and clinical outcome of IBMFS-related clonal and malignant myeloid transformation using data from the Canadian Inherited Marrow Failure Registry (CIMFR). Methods: The CIMFR is a multicenter collaborative study which is intended to enroll all patients with IBMFSs in Canada. The registry was approved by the Institutional Ethics Board of all the participating institutions, and includes 15 of 16 pediatric tertiary care centers across all provinces in Canada. We estimate that these centers care for >95% of the eligible pediatric IBMFS population in Canada. The CIMFR is population-based as >90% of the patients in this study are from centers who enrolled >80% of the patients in their institutions. Clonal and malignant myeloid transformation was defined as having either clonal marrow cytogenetic abnormalities or prominent bi-lineage morphologic dysplasia or increased percentage of marrow blasts (≥5%) or a combination of the above. Results: Among 327 IBMFS patients enrolled on the CIMFR, 45 (13.8%) developed clonal and malignant myeloid transformation. In these 45 patients, the three most common IBMFS diagnoses were Fanconi anemia (31.1%), Shwachman-Diamond syndrome (20.0%) and unclassifiable IBMFSs (28.9%). Clonal marrow cytogenetic abnormalities were identified in 38/45 (84.4%) patients, while 5/45 (11.1%) patients had constitutional cytogenetic changes, 1/45 patients had AML with no cytogenetic abnormalities and 1/45 patients had no cytogenetic abnormalities. Two out of the 5 patients with constitutional cytogenetic abnormalities developed a clonal marrow cytogenetic abnormality later in their disease course. The most common clonal marrow cytogenetic abnormality was monosomy 7, which was found in 14/38 (36.8%) patients. Cytology in the majority of patients 20/45 (44.4%) was consistent with refractory cytopenia. Eight out of the 45 patients developed AML and 2 of these patients had monosomy 7. Twenty-two out of 45 (48.9%) patients with clonal and malignant myeloid transformation underwent hematopoietic stem cell transplantation due to severe cytopenia, excess blasts or leukemia. Fourteen out of the 22 (63.6%) transplanted patients are alive at last follow-up. Out of 8 patients who had AML, 3 received transplant and are alive at last follow-up. The 5 remaining AML patients died; 3 while awaiting transplant, 1 did not achieve remission and 1 refused transplant. Overall mortality in the group of patients with clonal and malignant myeloid transformation was 15/45 (33.3%) at a median follow-up of 10 months from diagnosis with clonal and malignant myeloid transformation. Overall mortality in those 282 patients on CIMFR without clonal and malignant myeloid transformation is 6.4%. Conclusion: Despite short-term follow-up of patients on the CIMFR, a relatively high prevalence of clonal and malignant myeloid transformation was found. Clonal marrow cytogenetic abnormalities are associated with a high risk of progression into advanced MDS or AML and death. Disclosures: No relevant conflicts of interest to declare.

The evolution of 118 children treated for acute lymphoblastic leukemia between 1976 and 1984, and followed until 1991, was reviewed. Maintenance chemotherapy consisted of daily 6-mercaptopurine (6-MP), weekly methotrexate (MTX), and monthly vincristine and prednisone. Eighty-two children took 6-MP and MTX in the morning, and 36 took them in the evening. Disease-free survival, as determined by Kaplan-Meier analysis, was better for children on evening chemotherapy. Regression analysis (Cox proportional hazards model, with evening versus morning schedule as exposure variable, and age at diagnosis, leucocytosis at diagnosis, and sex as covariates) showed that for those surviving free of disease for longer than 78 weeks, the risk of relapse was 2.56 times greater for the morning schedule than for the evening one.

Chronic graft versus host disease (GVHD) has many clinical and histopathological features that are similar to human autoimmune diseases including pulmonary fibrosis, sclerodermatous skin changes, esophageal dysmotility, and an increased frequency of autoantibodies.[1–3] It has been difficult, however, to study chronic GHVD in animal models because most models of GVHD lead to the early death of the animals or the surviving animals do not have the histopathological features seen in human chronic GVHD.[4,5]

One hundred ninety episodes of septicemia were surveyed from 1973 to 1983 in chlldrens treated for leukemia at Childrens Hospital of Los Angeles. The mean number of episodes documented each year was 18 ± 5 (range 10-29) and significant changes in the type of organisms involved were observed, with an increased incidence of Candida (from 0 to 9%) and gram positive septicemia over the last 5 years. Gram positive sepsis had a low mortality rate (8%) compared with gram negative sepsis (54%) or septicemia caused by multiple organisms (72%). Factors of risk included (1) absolute granulocyte count less than 500 (78%), (2) presence of relapse (62%), and (3) prolonged previous administration of broad spectrum antibiotics (35%). Over the last 3 years an increased incidence of gram positive septicemia in non-neutropenic patient was observed. 9 staphylococcus epidermidis septicemia were seen in the last 2 years compared to none in the 8 previous years. 3 of those 9 patients had a central venous line. These data have provided helpful informations in our therapeutic approach of febrile episodes in neutropenic patients.