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Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P

Background: Children who are treated for myeloid leukemia associated with Down syndrome (DS) experience superior survival compared with children who have myeloid leukemia without DS. To maintain excellent outcomes while avoiding toxicity, the Children's Oncology Group (COG) conducted the phase 3 trial COG A2971, the first trial solely designed to provide uniform treatment of myeloid leukemia in North American children with DS. A2971 eliminated 2 induction drugs and 3 months of maintenance therapy from the standard-timing regimen of dexamethasone, cytarabine, 6-thioguanine, etoposide, and rubidomycin/daunomycin (DCTER) used in the previous study (Children's Cancer Group [CCG] 2891).Methods: COG A2971 was a multi-institutional, nonrandomized, clinical trial that enrolled 132 patients who had DS with either acute myeloid leukemia (n = 91) or myelodysplastic syndrome (n = 41).Results: The median follow-up was 4.8 years (range, 0.8-8.6 years), the median age at diagnosis was 1.7 years (range, 0.3-13.6 years), and the median white blood cell count was 6200/μL (range, 900-164,900/μL). The remission rate (92.7% ± 6%) was similar to that reported in the CCG 2891 study (91.3% ± 5%; P = .679). The 5-year event free survival (EFS) rate was 79% ± 7% (vs 77% ± 7% in CCG 2891; P = .589), the disease-free survival (DFS) rate was 89% ± 6% (vs 85% ± 6% in CCG 2891; P = .337), and the overall survival rate was 84% ± 6% (vs 79% ± 7% in CCG 2891; P = .302). Induction day-14 bone marrow response trended toward a more favorable outcome (EFS: P = .12). Age >4 years was an adverse risk factor (5-year EFS rate: 33% ± 38% for children aged >4 years [median, 8.5 years; n = 6] vs 81% ± 7% for children ages 0-4 years [median, 1.7 years; n = 126]; P = .001).Conclusions: The COG A2971 trial reduced the chemotherapy dose and maintained survival to that achieved by the CCG 2891 trial in children who had myeloid leukemia associated with DS. [ABSTRACT FROM AUTHOR]

Background: The development of antigen-targeted therapies may provide additional options to improve outcomes in children with acute myeloid leukemia (AML). The Children's Oncology Group AAML03P1 trial sought to determine the safety of adding 2 doses of gemtuzumab ozogamicin, a humanized anti-CD33 antibody-targeted agent, to intensive chemotherapy during remission induction and postremission intensification for children with de novo AML.Methods: AAML03P1 enrolled 350 children with previously untreated AML. Patients with a matched family donor received 3 courses of chemotherapy followed by hematopoietic stem cell transplantation; those without a matched family donor received 5 courses of chemotherapy. Gemtuzumab ozogamicin 3 mg/m(2)/dose was administered on Day 6 of Course 1 and Day 7 of Course 4.Results: Toxicities observed in all courses of therapy were typical of AML chemotherapy regimens, with infection being most common. Patients achieved a complete remission rate of 83% after 1 course and 87% after 2 courses. The mortality rate was 1.5% after the first gemtuzumab ozogamicin-containing induction course and 2.6% after 2 induction courses. The 3-year event-free survival and overall survival rates were 53 ± 6% and 66 ± 5%, respectively.Conclusions: This trial determined that it is safe and feasible to include gemtuzumab ozogamicin in combination with intensive chemotherapy. The survival rates compare favorably with the recently published results of clinical trials worldwide. [ABSTRACT FROM AUTHOR]

As a result of recent media coverage of cord blood transplantation, expectant parents increasingly ask perinatal caregivers about the possibility of collecting and saving their newborn child's umbilical cord blood. Umbilical cord blood has been used as a source of hematopoeitic stem cells for the treatment of human disease since 1988. As a result of these initial successes, cord blood collection, banking, and transplantation has become increasingly used worldwide, giving rise to several controversies. We have reviewed the current status of the indications for cord blood collection, the methods of collection, and safety issues related to the cyropreservation of cord blood units. In addition, the clinical success of cord blood transplants from related and unrelated donors is detailed. We have examined the major issues concerning cord blood transplantation as it exists in the year 2000 to provide insight into this exciting area of clinical investigation. [ABSTRACT FROM AUTHOR]

BackgroundWeb-based patient access to personal health information is limited but increasing in Canada and internationally. ObjectiveThis exploratory study aimed to increase understanding of how Web-based access to laboratory test results in British Columbia (Canada), which has been broadly available since 2010, affects patients’ experiences. MethodsIn November 2013, we surveyed adults in British Columbia who had had a laboratory test in the previous 12 months. Using a retrospective cohort design, we compared reported wait-time for results, test result comprehension, and anxiety levels of “service users” who had Web-based access to their test results (n=2047) with those of a general population panel that did not have Web-based access (n=1245). ResultsThe vast majority of service users (83.99%, 95% CI 82.31-85.67) said they received their results within “a few days”, compared to just over a third of the comparison group (37.84%, 95% CI 34.96-40.73). Most in both groups said they understood their test results, but the rate was lower for service users than the comparison group (75.55%, 95% CI 73.58-77.49 vs 84.69%, 95% CI 82.59-86.81). There was no significant difference between groups in levels of reported anxiety after receiving test results. ConclusionsWhile most patients who received their laboratory test results online reported little anxiety after receiving their results and were satisfied with the service, there may be opportunities to improve comprehension of results.

Background: The importance of matching at the HLA C locus has not been well defined for unrelated umbilical-cord blood transplantation. The selection algorithm for umbilical-cord blood units generally considers intermediate resolution HLA typing at A and B and allele-level typing at DRB1. We aimed to establish the relative importance of additional matching at HLA C.Methods: We used Cox regression to assess retrospectively the effect of donor-recipient HLA matching on outcomes of single umbilical-cord blood transplantations for leukaemia and myelodysplastic syndrome. Our primary endpoint was transplant-related mortality. HLA typing was done with molecular techniques with a minimum of intermediate resolution for HLA A, B, and C, and at the allele-level for DRB1.Findings: The median age of our study population was 10 years (range <1-62) and 552 (69%) of 803 patients were aged 16 years or younger at transplantation. Compared with transplantations matched at HLA A, B, C, and DRB1 (n=69), transplant-related mortality risk was higher after transplantations matched at HLA A, B, and DRB1 and mismatched at HLA C (n=23; HR 3·97, 95% CI 1·27-12·40; p=0·018). Transplant-related mortality risk was also higher after transplantations with a single mismatch at HLA A, B, or DRB1 and mismatched at HLA C (n=234; 1·70, 1·06-2·74; p=0·029) compared with transplantations matched at HLA C with a single mismatch at HLA A, B, or DRB1 (n=127). Assessing the overall effect of HLA disparity on transplant-related mortality, risks were higher with units mismatched at two (n=259; 3·27, 1·42-7·54; p=0·006), three (n=253; 3·34, 1·45-7·71; p=0·005), or four (n=75; 3·51, 1·44-8·58; p=0·006) loci compared with matched units (n=69).Interpretation: Our data suggest that the present strategy for umbilical-cord blood unit selection should be reassessed; matching at HLA C for units that are matched at HLA A, B, or DRB1 or in the presence of a single locus mismatch at HLA A, B, or DRB1 should be included to minimise mortality risks.Funding: National Cancer Institute, National Heart Lung and Blood Institute, National Institute for Allergy and Infectious Diseases, Leukemia and Lymphoma Society, US Department of the Navy, Children's Leukemia Research Association, and INSERM. [ABSTRACT FROM AUTHOR]

Introduction: The incidence and risk factors associated with upstaging from initial biopsy to definitive excision in cutaneous melanoma have not been established. The aim of this study was to determine the incidence of tumor stage upstaging and associated risk factors using the National Cancer Database., Methods: A retrospective study of the National Cancer Database between 2012 and 2016 was performed. The cohort of patients undergoing excision of melanoma with available data comprised 133,592 patients. Differences in characteristics for upstaging were determined using Wilcox rank-sum, chi-square, or Fisher's exact tests. Multivariable analysis was performed using logistic regression to determine factors associated with upstaging., Results: Incidence of upstaging was 5.2%. Upstaged patients were older, male, of non-White race, and of lower education level (P < 0.001). Lesions of the head/neck and lower extremity had increased incidence of upstaging compared to the trunk (P < 0.001). Nodular and acral lentiginous melanoma was associated with higher incidence of upstaging compared to superficial spreading melanoma (P < 0.001). Patients with lymphovascular invasion had increased risk of upstaging (P < 0.001)., Conclusions: Upstaging of melanoma is infrequent but is significantly more prevalent in non-White patients and those with lower educational status. Provider and patient education should include the higher risk of upstaging in these groups and the possible need for further surgical intervention, such as re-excision of margins and sentinel lymph node biopsy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

National guidelines recommend sentinel lymph node biopsy (SLNB) be offered to patients with > 10% likelihood of sentinel lymph node (SLN) positivity. On the other hand, guidelines do not recommend SLNB for patients with T1a tumors without high-risk features who have < 5% likelihood of a positive SLN. However, the decision to perform SLNB is less certain for patients with higher-risk T1 melanomas in which a positive node is expected 5%-10% of the time. We hypothesized that integrating clinicopathologic features with the 31-gene expression profile (31-GEP) score using advanced artificial intelligence techniques would provide more precise SLN risk prediction., Methods: An integrated 31-GEP (i31-GEP) neural network algorithm incorporating clinicopathologic features with the continuous 31-GEP score was developed using a previously reported patient cohort (n = 1,398) and validated using an independent cohort (n = 1,674)., Results: Compared with other covariates in the i31-GEP, the continuous 31-GEP score had the largest likelihood ratio (G 2 = 91.3, P < .001) for predicting SLN positivity. The i31-GEP demonstrated high concordance between predicted and observed SLN positivity rates (linear regression slope = 0.999). The i31-GEP increased the percentage of patients with T1-T4 tumors predicted to have < 5% SLN-positive likelihood from 8.5% to 27.7% with a negative predictive value of 98%. Importantly, for patients with T1 tumors originally classified with a likelihood of SLN positivity of 5%-10%, the i31-GEP reclassified 63% of cases as having < 5% or > 10% likelihood of positive SLN, for a more precise, personalized, and clinically actionable SLN-positive likelihood estimate., Conclusion: These data suggest the i31-GEP could reduce the number of SLNBs performed by identifying patients with likelihood under the 5% threshold for performance of SLNB and improve the yield of positive SLNBs by identifying patients more likely to have a positive SLNB., Competing Interests: John T. Vetto Employment: Gilead Sciences (I) Stock and Other Ownership Interests: Gilead Sciences (I), Roche/Genentech (I) Speakers' Bureau: Castle Biosciences Travel, Accommodations, Expenses: Castle Biosciences No other potential conflicts of interest were reported. John T. Vetto Employment: Gilead Sciences (I) Stock and Other Ownership Interests: Gilead Sciences (I), Roche/Genentech (I) Speakers' Bureau: Castle Biosciences Travel, Accommodations, Expenses: Castle Biosciences No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

>1.2 million people in the United States have a personal history of melanoma skin cancer and are at increased risk for disease recurrence and second primary melanomas. Many of these individuals do not follow recommendations to conduct regular, thorough skin self-examinations that facilitate early disease detection and do not sufficiently engage in sun protection behaviors. In this project, we are conducting a randomized controlled trial of an innovative, tailored, theory-driven Internet intervention-called mySmartSkin-to promote these behaviors among melanoma patients. This paper outlines the study design and characteristics of the study sample. A total of 441 patients were recruited (40.9% response rate) and randomized to the mySmartSkin or a Usual Care condition. Participants complete surveys at baseline and 8 weeks, 24 weeks, and 48 weeks later. The primary aim of the project is to examine the impact of mySmartSkin versus Usual Care on skin self-examination and sun protection behaviors. The secondary aim focuses on identifying mediators of the intervention's effects. In an exploratory aim, we will examine potential moderators of the impact of the intervention. At baseline, the recruited participants had a mean age of 61 years, 49% were female, 7.5% met criteria for having conducted a recent, thorough skin self-examination, and the mean score on the index of sun protection behaviors was 3.3 (on a scale from 1 to 5). The results of the project will determine whether the mySmartSkin intervention is efficacious in promoting skin self-examination and sun protection behaviors among individuals diagnosed with melanoma. Trial registration: ClinicalTrials.govNCT03028948., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Malignant melanoma accounts for 75% of all skin cancer deaths and is potentially curable if identified early. Although melanoma is rare in African-Americans (AA), it is associated with a worse prognosis than in Caucasians. This study examines the demographic, pathologic, and clinical factors impacting AA melanoma outcomes.Data for 1106 AA and 212,721 Caucasian cutaneous melanoma patients were abstracted from the Surveillance, Epidemiology, and End Result (SEER) database (1988-2011). Data were grouped on the basis of histological subtypes: "Superficial Spreading" (SS), "Nodular" (NM), "Lentigo Maligna" (LM), "Acral Lentiginous" (AL), and "Not otherwise specified" (NOS).Cutaneous malignant melanoma occurs most commonly in the sixth and seventh decade of life. Caucasian patients presented most commonly with trunk melanomas (34.5%), while lower extremity melanomas were more common in AAs (56.1%), P < 0.001. AAs presented with deeper tumors, more advanced stage of disease, and higher rates of ulceration and lymph node positivity than Caucasians. Cancer-specific mortality was significantly higher, while 5-year cancer-specific survival was significantly lower among AAs for NM and AL subtypes. Multivariate analysis identified male gender, regional and distant stage, NM and AL subtypes as independently associated with increased mortality among both ethnic groups.AAs present most often with AL melanoma on the lower extremities, and with deeper and more advanced stage lesions. AAs have higher cancer-specific mortality for NM and LM than Caucasians. Melanoma education for AA patients and health care providers is needed to increase disease awareness, facilitate early detection, and promote access to effective treatment.

Background: Following wide excision of Merkel cell carcinoma (MCC), postoperative radiation therapy (RT) is typically recommended. Controversy remains as to whether RT can be avoided in selected cases, such as those with negative margins. Additionally, there is evidence that RT can influence survival., Methods: We included 171 patients treated for non-metastatic MCC from 1994 through 2012 at a single institution. Patients without pathologic nodal evaluation (clinical N0 disease) were excluded to reflect modern treatment practice. The endpoints included local control (LC), locoregional control (LRC), disease-free survival (DFS), overall survival (OS), and disease-specific survival (DSS)., Results: Median follow-up was 33 months. Treatment with RT was associated with improved 3-year LC (91.2 vs. 76.9 %, respectively; p = 0.01), LRC (79.5 vs. 59.1 %; p = 0.004), DFS (57.0 vs. 30.2 %; p < 0.001), and OS (73 vs. 66 %; p = 0.02), and was associated with improved 3-year DSS among node-positive patients (76.2 vs. 48.1 %; p = 0.035), but not node-negative patients (90.1 vs. 80.8 %; p = 0.79). On multivariate analysis, RT was associated with improved LC [hazard ratio (HR) 0.18, 95 % confidence interval (CI) 0.07-0.46; p < 0.001], LRC (HR 0.28, 95 % CI 0.14-0.56; p < 0.001), DFS (HR 0.42, 95 % CI 0.26-0.70; p = 0.001), OS (HR 0.53, 95 % CI 0.31-0.93; p = 0.03), and DSS (HR 0.42, 95 % CI 0.26-0.70; p = 0.001). Patients with negative margins had significant improvements in 3-year LC (90.1 vs. 75.4 %; p < 0.001) with RT. Deaths not attributable to MCC were relatively evenly distributed between the RT and no RT groups (28.5 and 29.3 % of patients, respectively)., Conclusions: RT for MCC was associated with improved LRC and survival. RT appeared to be beneficial regardless of margin status.

Background: The purposes of this study were 1) to determine the impact of primary tumor-related factors on the prediction of the sentinel lymph node (SLN) status and 2) to identify clinical and pathologic factors associated with survival in Merkel cell carcinoma (MCC)., Methods: An institutional review board-approved, retrospective review of patients with MCC treated between 1988 and 2011 at a single center was performed. Patients were categorized into 5 groups: 1) negative SLN, 2) positive SLN, 3) clinically node-negative but SLN biopsy not performed, 4) regional nodal disease without a known primary tumor, and 5) primary MCC with synchronous clinically evident regional nodal disease. Factors predictive of the SLN status were analyzed with logistic regressions, and overall survival (OS) and disease-specific survival (DSS) were analyzed with Cox models and competing risk models assuming proportional hazards, respectively., Results: Three hundred seventy-five patients were analyzed, and 70% were male; the median age was 75 years. The median tumor diameter was 1.5 cm (range, 0.2-12.5 cm), and the median tumor depth was 4.8 mm (range, 0.3-45.0 mm). One hundred ninety-one patients underwent SLN biopsy, and 59 (31%) were SLN-positive. Increasing primary tumor diameter and increasing tumor depth were associated with SLN positivity (P = .007 and P = .017, respectively). Age and sex were not associated with the SLN status. Immunosuppression, increasing tumor diameter, and increasing tumor depth were associated with worse OS (P = .007, P = .003, and P = .025, respectively). DSS differed significantly by group and was best for patients with a negative SLN and worst for those with primary MCC and synchronous clinically evident nodal disease (P = .018)., Conclusion: For patients with MCC, increasing primary tumor diameter and increasing tumor depth are independently predictive of a positive SLN, worse OS, and worse DSS. Tumor depth should be routinely reported when primary MCC specimens are being evaluated histopathologically., (© 2015 American Cancer Society.)

Background: This Phase 2 study tested the tolerability and efficacy of bortezomib combined with reinduction chemotherapy for pediatric patients with relapsed, refractory or secondary acute myeloid leukemia (AML). Correlative studies measured putative AML leukemia initiating cells (AML-LIC) before and after treatment., Procedure: Patients with <400 mg/m(2) prior anthracycline received bortezomib combined with idarubicin (12 mg/m(2) days 1-3) and low-dose cytarabine (100 mg/m(2) days 1-7) (Arm A). Patients with ≥400 mg/m(2) prior anthracycline received bortezomib with etoposide (100 mg/m(2) on days 1-5) and high-dose cytarabine (1 g/m(2) every 12 hours for 10 doses) (Arm B)., Results: Forty-six patients were treated with 58 bortezomib-containing cycles. The dose finding phase of Arm B established the recommended Phase 2 dose of bortezomib at 1.3 mg/m(2) on days 1, 4, and 8 with Arm B chemotherapy. Both arms were closed after failure to meet predetermined efficacy thresholds during the first stage of the two-stage design. The complete response (CR + CRp) rates were 29% for Arm A and 43% for Arm B. Counting additional CRi responses (CR with incomplete neutrophil recovery), the overall CR rates were 57% for Arm A and 48% for Arm B. The 2-year overall survival (OS) was 39 ± 15%. Correlative studies showed that LIC depletion after the first cycle was associated with clinical response., Conclusion: Bortezomib is tolerable when added to chemotherapy regimens for relapsed pediatric AML, but the regimens did not exceed preset minimum response criteria to allow continued accrual. This study also suggests that AML-LIC depletion has prognostic value., (© 2014 Wiley Periodicals, Inc.)

Purpose: To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification., Patients and Methods: Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children’s Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three)., Results: There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v. 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P.04) but not OS (3 years: 69.4% v. 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v. 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v. 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v. 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v. 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07)., Conclusion: GO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML.

We report on 27 patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) who received allogeneic hematopoietic cell transplantation (HCT) between 2000 and 2009. Seventy-eight percent of patients received myeloablative conditioning and 52% underwent transplantation in second remission. Disease-free survival (DFS) was 24% at a median of 3 years. Post-transplant leukemic relapse was more frequent than expected for children with DS-ALL (54%) than for non-DS ALL. These data suggest leukemic relapse rather than transplant toxicity is the most important cause of treatment failure. Advancements in leukemia control are especially needed for improvement in HCT outcomes for DS-ALL., (© 2014 Wiley Periodicals, Inc.)

Background: A majority of Fanconi anemia (FA) patients will experience bone marrow failure (BMF) and androgen therapy (most often oxymetholone) may be utilized as a treatment to improve BMF-related cytopenias. However, oxymetholone is associated with toxicities making identification of other agents of interest. In this study we aimed to evaluate the toxicity profile and hematologic response in patients with FA who are treated with low-dose oxandrolone, a synthetic non-fluorinated anabolic steroid, similar to oxymetholone, with known dosing thresholds for virilization., Procedure: A single arm, Phase I/II study was designed to treat patients on low-dose oxandrolone. If no toxicity or hematologic response was noted at 16 weeks, a single dose escalation was offered. Subjects were regularly assessed for toxicity, including determinations of virilization, behavioral changes, and liver and kidney function. At 32 weeks, those who demonstrated hematologic response were allowed to continue study treatment, and those without improvement were deemed non-responsive., Results: Nine subjects completed the study and were followed for a median of 99 weeks (46-136 weeks). Three (33.3%) subjects developed mild sub-clinical virilization and continued treatment with a dose reduction. None (0%) had adverse behavioral changes. Two (22.2%) developed elevated liver function tests at 42 and 105 weeks. Seven (77.8%) subjects had a hematologic response., Conclusion: Oxandrolone appears to be well-tolerated, has limited toxicities at the administered doses in FA with patients, and may be an alternative androgen for the treatment of BMF in FA., (© 2013 Wiley Periodicals, Inc.)

A formal Mentorship Program within the Children's Oncology Group (COG) was established to pair young investigators (mentees) with established COG members (mentors). Despite the American Academy of Pediatrics policy statement promoting mentorship programs, there are no publications describing and evaluating national mentorship programs in pediatric subspecialties. In this study, a series of internal program evaluations were performed using surveys of both mentors and mentees. Responses were deidentified and analyzed to determine the utility of the program by both participant satisfaction and self-reported academic productivity. Results indicated that mentees were generally satisfied with the program. Mentor-mentee pairs that met at least quarterly demonstrated greater academic productivity than pairings that met less frequently. This formal mentorship program appeared to have subjective and objective utility for the development of academic pediatric subspecialists.

Data on outcomes of allogeneic transplantation in children with Down syndrome and acute myelogenous leukemia (DS-AML) are scarce and conflicting. Early reports stress treatment-related mortality as the main barrier; a recent case series points to posttransplantation relapse. We reviewed outcome data for 28 patients with DS-AML reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2009 and performed a first matched-pair analysis of 21 patients with DS-AML and 80 non-DS AML controls. The median age at transplantation for DS-AML was 3 years, and almost half of the cohort was in second remission. The 3-year probability of overall survival was only 19%. In multivariate analysis, adjusting for interval from diagnosis to transplantation, risks of relapse (hazard ratio [HR], 2.84; P < .001; 62% versus 37%) and transplant-related mortality (HR, 2.52; P = .04; 24% versus 15%) were significantly higher for DS-AML compared to non-DS AML. Overall mortality risk (HR, 2.86; P < .001; 21% versus 52%) was significantly higher for DS-AML. Both transplant-related mortality and relapse contribute to higher mortality. Excess mortality in DS-AML patients can only effectively be addressed through an international multicenter effort to pilot strategies aimed at lowering both transplant-related mortality and relapse risks., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Children with trisomy 21 have a unique predisposition to develop a megakaryoblastic proliferative disease of varying severity during their first 3 months of life. This disorder exists in no other children or adults without the presence of trisomy 21 and only occurs in the fetal or neonatal period of life. Its spontaneous resolution in most cases further delineates it from otherwise indistinguishable neonatal leukaemias. The identification that GATA1 mutations are the leukaemogenic source along with three recently reported prospective clinical trials now provide a clearer understanding of this haematopoietic disorder. These recent advances in this enigmatic disorder, now known as Transient Myeloproliferative Disorder, are reviewed here in order to bring clarity to the breadth of organ involvement, the range of severity, the risk factors for mortality, the therapeutic options for severe manifestations, the natural course of spontaneous resolution regardless of therapy, and the elucidation of the subsequent risk for myeloid leukaemia., (© 2012 Blackwell Publishing Ltd.)

The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Invasive aspergillosis (IA) can cause significant morbidity and mortality in immunocompromised children. The galactomannan (GM) enzyme immunoassay (EIA) has been shown in adult studies to be a useful adjunct in diagnosing IA. Data on this assay in children are limited by small sample sizes and conflicting results; false-positive assays were a concern in historical studies. We sought to evaluate the GM EIA in a large cohort of children who received intensive chemotherapy and/or hematopoietic stem cell transplant. A focus was placed on evaluating the assay specificity, and the potential of measuring GM antigen in urine., Methods: A multicenter prospective observational study in children with anticipated prolonged neutropenia was performed. Serum specimens were collected twice weekly, and urine was collected once weekly during neutropenic periods. Operating characteristics were calculated using the GM EIA optical density index cutoffs of 0.5 and 1.0 for both serum and urine specimens., Results: At least one serum or urine specimen was tested from 198 patients. Ten patients had one or more repeatedly positive serum specimens, while 37 patients had one or more repeatedly positive urine specimens. The specificity of serum and urine testing was 95% and 80%, respectively. Although the urine test resulted in a higher false positivity rate, it successfully identified the only case of probable IA., Conclusions: Data suggest that the serum GM EIA does not provide frequent false-positive results as previously reported. Screening for galactomannan, or a related antigen in urine, needs to be further evaluated as it may be amenable to development of surveillance strategies., (© The Author 2012. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Clinicians in private practice, specialty practice, and emergency clinic settings are likely to be presented with bitches and queens with parturition emergencies. Parameters for the identification of dystocia include prolonged parturition, collapse of the dam, abnormal vaginal discharge, prolonged labor, prolonged interval between delivery of neonates, uterine inertia, malpresentation of the fetus, and large litter sizes. Methods for the diagnosis of dystocia are discussed. Resolution of parturition emergencies may be achieved through manipulative, medical, or surgical methods, although the great percentage of dystocia will require surgical intervention. Techniques for medical and surgical interception are discussed.

Transient myeloproliferative disorder (TMD), restricted to newborns with trisomy 21, is a megakaryocytic leukemia that although lethal in some is distinguished by its spontaneous resolution. Later development of acute myeloid leukemia (AML) occurs in some. Prospective enrollment (n = 135) elucidated the natural history in Down syndrome (DS) patients diagnosed with TMD via the use of uniform monitoring and intervention guidelines. Prevalent at diagnosis were leukocytosis, peripheral blast exceeding marrow blast percentage, and hepatomegaly. Among those with life-threatening symptoms, most (n = 29/38; 76%) received intervention therapy until symptoms abated and then were monitored similarly. Organomegaly with cardiopulmonary compromise most frequently led to intervention (43%). Death occurred in 21% but only 10% were attributable to TMD (intervention vs observation patients: 13/14 vs 1/15 because of TMD). Among those solely observed, peripheral blasts and all other TMD symptoms cleared at a median of 36 and 49 days from diagnosis, respectively. On the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms, 3 groups were identified with differing survival: low risk with neither finding (38%), intermediate risk with hepatomegaly alone (40%), and high risk with both (21%; overall survival: 92% ± 8%, 77% ± 12%, and 51% ± 19%, respectively; P ≤ .001). Among all, AML subsequently occurred in 16% at a median of 441 days (range, 118-1085 days). The trial is registered at http://www.clinicaltrials.gov as NCT00003593.

Based on its potential role in adult myelodysplastic syndrome (MDS), the Children's Oncology Group (COG) embarked on a phase II study using amifostine in pediatric MDS (WHO 2001 criteria) patients. Responses were evaluated after two cycles. Ten patients were enrolled; five were deemed ineligible, and four withdrew after the first course. Only one patient completed two courses, and was found to be in complete remission. The study was closed after being open for 2 years due to slow accrual. Studying a rare disease like MDS may pose insurmountable obstacles even in a large clinical trials group such as COG, in part because of the changing definitions of MDS and the rarity of adult type MDS in children. The role of amifostine in pediatric MDS was not known at the time of study., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Conflicting data exist regarding whether low bone mineral density (BMD) is associated with Fanconi anemia (FA). The current study identified the frequency of low BMD in FA, expecting low BMD even in childhood and before HCT., Procedure: Thirty-seven FA patients (18 prior HCT, 19 no prior HCT), participating in an IRB-approved database, had clinical assessment of DXA of lumbar spine BMD. Four had used androgens, one later underwent HCT. Most had used glucocorticoids after HCT (prolonged in five), and one more with no HCT. BMD [in standard deviation units from mean for age (SD), gender, and ethnicity (BMD Z-score)] was then adjusted for height age, and separately for bone maturation (BA). Data were collected for height SD, pubertal stage, and duration since HCT., Results: BMD Z-score (without adjustment) was <-1 SD in half of FA children. BA-adjusted BMD Z-score was similar. (BA was not usually delayed, although most patients were short.) In contrast, height age-adjusted BMD Z-score was normal in most with FA (only below -2.0 in one child after prolonged glucocorticoids). Mean duration after HCT until DXA test was 6.2 years (median 4.2 years, range 1-18 years)., Conclusions: Children and adolescents with FA have normal BMD prior to and after HCT, when DXA results are adjusted for bone size/height age. In contrast, BA-adjustment of BMD was not useful in this population. Individual BMD results may be influenced by gonadal function, transplantation status, and prolonged glucocorticoid therapy., (Copyright © 2011 Wiley-Liss, Inc.)

Purpose: To determine the efficacy of imatinib in children with newly diagnosed chronic phase (CP) chronic myelogenous leukemia (CML)., Methods: This was an open label, multi-center phase II clinical trial. Courses were defined as consecutive 28-day intervals. Oral imatinib was administered daily at 340 mg/m² without interruption in the absence of toxicity., Results: Fifty-one children received 978 28-day courses of imatinib. The most common toxicities encountered were hematologic. Forty-one patients (80%) achieved a complete hematologic response by the end of course 2. Nineteen children (38%) obtained a complete cytogenetic response (CCyR) at the end of course 3. Overall, 72% achieved CCyR at a median time of 5.6 months. The rate of complete molecular response (>3 log reduction) was 27%. Progression-free and overall survival at 3 years were 72%  ± 6.4% and 92%  ± 3.9%, respectively., Conclusions: Daily oral imatinib at a dose of 340 mg/m² is well tolerated in children. In addition, imatinib therapy is effective in inducing a high percent of hematologic, cytogenetic and molecular responses, comparable to adults with CML. (This study was registered at ClinicalTrials.gov under identifier NCT00030394.)., Competing Interests: Nothing to declare., (Copyright © 2011 Wiley-Liss, Inc.)