The American Society of Pediatric Hematology/Oncology workforce assessment: Part 2-Implications for fellowship training.

The American Society of Pediatric Hematology/Oncology (ASPHO) solicited information from division directors and fellowship training program directors to capture pediatric hematology/oncology (PHO) specific workforce data of 6 years (2010-2015), in response to an increase in graduating fellows during that time. Observations included a stable number of physicians and advanced practice providers (APPs) in clinical PHO, an increased proportion of APPs hired compared to physicians, and an increase in training-level first career positions. Rapid changes in the models of PHO care have significant implications to current and future trainees and require continued analysis to understand the evolving discipline of PHO.

Children as hematopoietic cell donors in research: when is it approvable?

With increasing frequency, allogeneic hematopoietic cell transplantation involving children is being performed in the research setting. Allogeneic hematopoietic cell transplantation, however, cannot be performed without a hematopoietic stem cell (HSC) donor. This donor is often a sibling of the recipient and may also be a child. In such circumstances, it is unclear whether or how the federal regulations for pediatric research apply to the minor donors. This introductory paper reviews the issues to be considered while evaluating studies that use HSCs obtained from minor donors and identifies areas where further research is needed. In the era of increasing applicability for donor-derived cellular therapies, we provide a suggested framework for determining when minor donors qualify as human research subjects and when their participation can be approved under the federal regulations.

New frontiers in pediatric Allo-SCT: novel approaches for children and adolescents with ALL.

Although most children with ALL can be cured by chemotherapy approaches, allogeneic hematopoietic cell transplant (HCT) therapy offers a better chance of cure to selected high-risk patients in first remission and most children who relapse. Although transplant-related mortality has decreased significantly in the past decade, relapse remains high after HCT for ALL; developing strategies to decrease relapse and improve survival are vital. Recent studies have shown that relapse risk can be accurately defined using measurements of minimal residual disease (MRD) both pre- and post-HCT and by knowing whether patients get GVHD in the first 2 months after transplant. With these risk definitions in hand, investigators are now applying novel agents and immunotherapeutic methods in attempt to lower MRD before transplant and modulate the GVL effect after transplant. With powerful new immunological approaches coming on line, the transplant process itself will likely expand to include pre and/or post-HCT interventions aimed at reducing relapse.

High frequencies of leukemia stem cells in poor-outcome childhood precursor-B acute lymphoblastic leukemias.

In order to develop a xenograft model to determine the efficacy of new therapies against primary human precursor-B acute lymphoblastic leukemia (ALL) stem cells (LSCs), we used the highly immunodeficient non-obese diabetic (NOD).Cg-Prkdc(scid)IL2rg(tmlWjl)/SzJ (NOD-severe combined immune deficient (scid) IL2rg(-/-)) mouse strain. Intravenous transplantation of 2 of 2 ALL cell lines and 9 of 14 primary ALL cases generated leukemia-like proliferations in recipient mice by 1-7 months after transplant. Leukemias were retransplantable, and the immunophenotypes, gene rearrangements and expression profiles were identical or similar to those of the original primary samples. NOD-scid mice transplanted with the same primary samples developed similar leukemias with only a slightly longer latency than did NOD-scid-IL2Rg(-/-) mice. In this highly sensitive NOD-scid-IL2Rg(-/-)-based assay, 1-100 unsorted primary human ALL cells from five of five tested patients, four of whom eventually experienced leukemia relapse, generated leukemias in recipient mice. This very high frequency of LSCs suggests that a hierarchical LSC model is not valuable for poor-outcome ALL.

Elevation of soluble CD307 (IRTA2/FcRH5) protein in the blood and expression on malignant cells of patients with multiple myeloma, chronic lymphocytic leukemia, and mantle cell lymphoma.

CD307 is a differentiation antigen expressed in B-lineage cells. One soluble and two membrane-bound forms have been predicted and an enzyme-linked immunosorbent assay (ELISA) for soluble CD307 established. Our goal was to determine if CD307 is expressed on the surface of cells from patients with multiple myeloma (MM), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and other B-cell malignancies and if soluble CD307 levels are elevated in the blood of patients with these B-cell malignancies. Cells and blood were collected from patients. Expression of CD307 was measured by flow cytometry and blood levels of soluble CD307 by ELISA. High soluble CD307 levels were detected in 21/43 (49%) of patients with MM, 36/46 (78%) with CLL and 9/24 (38%) with MCL. Soluble CD307 levels correlated with plasma cell percentages in bone marrow aspirates in MM and total white blood cells in CLL. CD307 on the cell membrane was detected by flow cytometry in 8/8 MM, 23/29 CLL and 4/5 MCL samples. Because CD307 is present on malignant cells from patients with MM, CLL and MCL, CD307 may be a useful therapeutic target for the treatment of these diseases.

Topical corticosteroid therapy for cicatricial conjunctivitis associated with chronic graft-versus-host disease.

A retrospective chart review was performed on seven patients treated with topical ocular corticosteroid therapy for progressive cicatricial conjunctivitis associated with chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. A clinical grading criteria for conjunctival GVHD based on the degree of cicatrization was developed and patients graded prior to therapy. During the treatment course, the dose and frequency of topical corticosteroids and clinical outcomes were recorded. A complete response was defined as a complete resolution of the conjunctival hyperemia with either total resolution of the conjunctival fibrovascularization or presence of inactive conjunctival scarring. Prednisolone acetate 1% eye drops were used in a total of eight courses of therapy in seven patients. A complete response was documented in all seven patients with a total treatment duration of 7 weeks (median, range: 3-16 weeks). Additional studies are required to determine the long-term safety and efficacy of topical corticosteroids for cicatricial conjunctivitis associated with ocular GVHD in the context of a randomized, prospective clinical trial.

Catastrophic failures of freezing bags for cellular therapy products: description, cause, and consequences.

BACKGROUND: Container integrity is critical for maintaining sterility of cryopreserved cellular therapy products. We investigated a series of catastrophic bag failures, first noticed in early 2001. METHODS: Process records were reviewed for all PBPC and lymphocyte products cryopreserved in bags from January 2000 through April 2002. Patient charts were also reviewed. RESULTS: One thousand two hundred and four bags were removed from storage for infusion to 261 patients. All products had been cryopreserved in Cryocyte poly(ethylene co-vinyl acetate) (EVA) bags in either 10% DMSO or 5% DMSO and 6% pentastarch. Product volumes were 25-75 mL, and bags were stored with overwrap bags in a liquid nitrogen tank. From January 2000 to April 2001, failure occurred in 10 of 599 (1.7%) bags. From May 2001 to April 2002, 58 of 605 (9.6%) bags failed, typically with extensive fractures that were visible before thaw. Of the 58 that failed, 24 were salvaged by aseptic methods and infused to patients under antibiotic coverage; 10 of those 24 (42%) had positive bacterial cultures. Bag failures were not related to product type, cryoprotectant solution, liquid versus vapor storage, or freezer location. Failures were linked to use of four Cryocyte bag lots manufactured in 2000 and 2001. After replacing these lots with a 1999 Cryocyte lot and with KryoSafe polyfluoroethylene polyfluoropropylene (FEP) bags, no more failures occurred in 75 and 102 bags, respectively, thawed through April 2002. DISCUSSION: High rates of bag failure were associated with four Cryocyte bag lots. No serious adverse patient effects occurred, but bag failures led to microbial contamination, increased product preparation time, increased antibiotic use, and increased resource expenditure to replace products.

Lymphocytic interstitial pneumonitis, elevated IgM concentration, and hepatosplenomegaly in ataxia-telangiectasia.

An 8-year-old girl developed ataxia-telangiectasia. Western blotting of lysate revealed absence of the ATM protein, and 2 mutations in the ATM gene were found. Subsequently, the patient developed increased respiratory symptoms. Open lung biopsy revealed lymphocytic interstitial pneumonitis, which is not characteristic of ataxia-telangiectasia. There was a therapeutic response to glucocorticosteroid treatment.

Financial analysis of chronic transfusion for stroke prevention in sickle cell disease.

Chronic red blood cell transfusion can prevent many of the manifestations of sickle cell disease. The medical costs of chronic transfusion and management of associated side effects, especially iron overload, are considerable. This study was undertaken to evaluate the financial impact of chronic transfusion for stroke prevention in patients with sickle cell anemia. Outpatient charges pertaining to hospital-based Medicare uniform bill (UB-92) codes, professional fees, and iron chelation were evaluated. Data were collected on 21 patients for a total of 296 patient months (mean, 14; median, 14 months/patient). Charges ranged from $9828 to $50 852 per patient per year. UB-92, chelation, and physician-related charges accounted for 53%, 42%, and 5% of total charges, respectively. Of UB-92 charges, 58% were associated with laboratory fees and 16% were related to the processing and administration of blood. Charges for patients who required chelation therapy ranged from $31 143 to $50 852 per patient per year (mean, $39 779; median, $38 607). Deferoxamine accounted for 71% of chelation-related charges, which ranged from $12 719 to $24 845 per patient per year (mean, $20 514; median, $21 381). The financial impact of chronic transfusion therapy for sickle cell disease is substantial with charges approaching $400 000 per patient decade for patients who require deferoxamine chelation. These data should be considered in reference to cost and efficacy analyses of alternative therapies for sickle cell disease, such as allogeneic bone marrow transplantation.

Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease.

Fifty children who had symptomatic sickle cell disease received matched sibling marrow allografts between September 1991 and March 1999, with Kaplan-Meier probabilities of survival and event-free survival of 94% and 84%, respectively. Twenty-six patients (16 male, 10 female) had at least 2 years of follow-up after transplantation and were evaluated for late effects of transplantation and for its impact on sickle cell-related central nervous system (CNS) and pulmonary disease. Patients ranged between 3.3 and 14.0 (median, 9. 4) years of age and had a median follow-up of 57.9 (range 38-95) months after transplantation. Among 22 of 26 patients who had stable donor engraftment, complications related to sickle cell disease resolved, and none experienced further episodes of pain, stroke, or acute chest syndrome. All 10 engrafted patients with a prior history of stroke had stable or improved cerebral magnetic resonance imaging results. Pulmonary function tests were stable in 22 of the 26 patients, worse in two, and not studied in two. Seven of eight patients transplanted for recurrent acute chest syndrome had stable pulmonary function. Linear growth measured by median height standard deviation score improved from -0.7 before transplantation to -0.2 after transplantation. An adverse effect of busulfan conditioning on ovarian function was demonstrated in five of seven evaluable females who are currently at least 13 years of age. None of the four males tested had elevated serum gonadotropin levels. These data confirm that allogenic bone marrow transplantation establishes normal erythropoiesis and is associated with improved growth and stable CNS imaging and pulmonary function in most patients. (Blood. 2000;95:1918-1924)

Nucleoside analogues in the therapy of Langerhans cell histiocytosis: a survey of members of the histiocyte society and review of the literature.

BACKGROUND: Previous reports have suggested activity of the nucleoside analogues 2-chlorodeoxyadenosine (2-CdA) and 2'-deoxycoformycin (2'-DCF) in Langerhans cell histiocytosis (LCH). PROCEDURE: To assess the efficacy of 2-CdA and 2'-DCF as salvage therapy for LCH, a survey of members of the Histiocyte Society and a literature review were undertaken. Twenty-three patients treated with 2-CdA and 4 treated with 2'-DCF were found, age range 2 months to 49 years. RESULTS: All 15 survey patients had multiorgan involvement, and 14 were heavily pretreated. Doses of 2-CdA ranged from 0.1 mg/kg/day continuous infusion for 5-7 days (majority of patients) to 13 mg/m(2)/day for 5 days, for 1-6 courses. One of the 15 patients had an early death, 5 had no response (NR), 3 had partial response (PR), and 6 achieved complete response (CR). Among 8 published patients, 7 achieved stable CR and 1 NR. Among 4 patients treated with 2'-DCF (4 mg/m(2)/week for 8 weeks then q 2 weekly), 2 achieved CR for 16+ and 18+ months and 2 PR for 2 and 5 months. Toxicity consisted mainly of combined myelo- and immunosuppression but no significant infections occurred and there were no toxic deaths. A cumulative thrombocytopenia was noted, which in 1 case took up to 6 months to resolve. Transient gastrointestinal toxicity and elevation of liver enzymes was seen, and 2 patients developed renal tubular acidosis. The peripheral neuropathy reported in adult patients receiving high doses was not seen. CONCLUSIONS: 2-CdA and 2'-DCF appear to have a useful role in LCH and are worthy of prospective trial in patients unresponsive to routine therapy.

Collaborative multicenter investigation of marrow transplantation for sickle cell disease: current results and future directions.

We present updated results of a multicenter collaborative investigation of bone marrow transplantation for sickle cell disease. Between September 1991 and April 1997, thirty-four children less than 16 years of age with severe sickle cell disease received marrow allografts from HLA-identical siblings. Indications for transplantation included a history of stroke (n = 17), recurrent acute chest syndrome or sickle pulmonary disease (n = 10), and recurrent vaso-occlusive crises (n = 7). Twenty-one patients received regular red blood cell (RBC) transfusions to prevent complications of sickle cell disease. Patients were prepared for transplantation with busulfan, cyclophosphamide, and antithymocyte globulin or CAMPATH (Cambridge Pathology) antibody. Thirty-two of the 34 patients survived, with a median follow-up of 26.5 months (range, 0.2-66.9 months); and 28 patients demonstrated stable engraftment of donor hematopoietic cells. Graft rejection or recurrence of sickle cell disease occurred in four patients, and two patients died of intracranial hemorrhage or graft-vs.-host disease. In the group of 34 children with symptoms of advanced sickle cell disease, current Kaplan-Meier estimates of survival and event-free survival are 93% and 79%, respectively.

Clonality in juvenile chronic myelogenous leukemia.

Juvenile chronic myelogenous leukemia (JCML) is a myeloproliferative disease in which morbidity and mortality are primarily caused by nonhematopoietic organ failure from myelomonocytic infiltration or by failure of the normal bone marrow. Morphologic evidence of maturation arrest, karyotypic abnormalities, and progression to blast crisis are infrequent events. Viral infections and other reactive processes can initially mimic the clinical course of JCML, creating diagnostic problems. Because of the rarity of JCML and technical limitations, formal clonality studies have not been reported previously. Nine female JCML patients were identified by clinical criteria, characteristic 'spontaneous' in vitro cell growth, and negative cultures and titers for various viral agents. Peripheral blood and bone marrow samples were obtained at the time of diagnosis for cell separation and RNA and DNA isolation. To assess clonality, X-chromosome inactivation patterns were evaluated using three different, recently developed polymerase chain reaction-based clonality assays. All nine female JCML patients showed evidence for monoclonal origin of mononuclear cells at the time of diagnosis. Cell separation studies further traced the monoclonal origin back to at least the most primitive myeloid progenitor cell. Reversion to a polyclonal state was demonstrated after bone marrow transplant and also in one patient following treatment with 13-cis retinoic acid. This demonstration of clonality in JCML delineates it from the reactive processes and provides a basis for molecular genetic strategies to identify causally associated mutations.

Survival in medically treated patients with homozygous beta-thalassemia.

BACKGROUND: The prognosis of patients with homozygous beta-thalassemia (thalassemia major) has been improved by transfusion and iron-chelation therapy. We analyzed outcome and prognostic factors among patients receiving transfusions and chelation therapy who had reached the age at which iron-induced cardiac disease, the most common cause of death, usually occurs. METHODS: Using the duration of life without the need for either inotropic or antiarrhythmic drugs as a measure of survival without cardiac disease, we studied 97 patients born before 1976 who were treated with regular transfusions and chelation therapy. We used Cox proportional-hazards analysis to assess the effect of prognostic factors and life-table analysis to estimate freedom from cardiac disease over time. RESULTS: Of the 97 patients, 59 (61 percent) had no cardiac disease; 36 (37 percent) had cardiac disease, and 18 of them had died. Univariate analysis demonstrated that factors affecting cardiac disease-free survival were age at the start of chelation therapy (P < 0.001), the natural log of the serum ferritin concentration before chelation therapy began (P = 0.01), the mean ferritin concentration (P < 0.001), and the proportion of ferritin measurements exceeding 2500 ng per milliliter (P < 0.001). With stepwise Cox modeling, only the proportion of ferritin measurements exceeding 2500 ng per milliliter affected cardiac disease-free survival (P < 0.001). Patients in whom less than 33 percent of the serum ferritin values exceeded 2500 ng per milliliter had estimated rates of survival without cardiac disease of 100 percent after 10 years of chelation therapy and 91 percent after 15 years. CONCLUSIONS: The prognosis for survival without cardiac disease is excellent for patients with thalassemia major who receive regular transfusions and whose serum ferritin concentrations remain below 2500 ng per milliliter with chelation therapy.

Total hip arthroplasty in beta-thalassemia. Case report and review of the literature.

A 60-year-old man with beta-thalassemia intermedia and degenerative joint disease was successfully treated by total hip arthroplasty. The operation was complicated by severe bleeding associated with marked bone marrow hyperplasia. Despite autologous cell salvage, massive homologous transfusion was required. Special orthopaedic and perioperative complications stem from beta-thalassemia syndromes. Management may be complicated by anemia, medullary hyperplasia, organ dysfunction associated with iron overload, and susceptibility to infection. The orthopaedic manifestations of beta-thalassemia may be mitigated by chronic transfusions.

Stage III neuroblastoma over 1 year of age at diagnosis: improved survival with intensive multimodality therapy including multiple alkylating agents.

PURPOSE: A nonrandomized, single-arm trial was conducted to assess the efficacy of multimodality therapy including intensive chemotherapy with multiple alkylating agents in the treatment of children with Evans stage III neuroblastoma older than 1 year at diagnosis. PATIENTS AND METHODS: Twenty-five patients with a median age of 18 months at diagnosis were treated with multimodality therapy including surgery and chemotherapy using either nitrogen mustard (mechlorethamine), doxorubicin, cisplatin, dacarbazine (DTIC), vincristine, and cyclophosphamide (MADDOC) or cisplatin and cyclophosphamide induction followed by maintenance MADDOC (induction MADDOC) protocols. Sixteen of 25 patients also received radiotherapy to the tumor bed and primary lymph nodes. Event-free survival (EFS) was compared with that reported previously in the literature. N-myc amplification was evaluated prospectively and the Shimada classification was evaluated retrospectively as potential prognostic factors. RESULTS: We report a 72% EFS (95% confidence interval +/- 18%) with a median follow-up of 85 months. EFS was significantly worse for patients with tumors demonstrating N-myc amplification (P = .018). Patients classified as favorable according to the Shimada system experienced a significantly better EFS (P = .04), but unfavorable patients still maintained a 60% EFS. CONCLUSION: Intensive multimodality treatment including MADDOC and induction MADDOC chemotherapy provides a very good EFS for children older than 1 year who have stage III neuroblastoma. Children classified as favorable according to the Shimada system have a better prognosis. Patients whose tumors demonstrate N-myc amplification have a poor prognosis despite therapy.

Perioperative management for cholecystectomy in sickle cell disease.

Perioperative complications of surgical procedures are frequently encountered in patients with sickle cell disease. We have reviewed our series of patients with hemoglobinopathies who underwent cholecystectomy from 1978 to 1991 to evaluate their perioperative management and clinical outcome. Twenty-two children with major sickle hemoglobinopathy underwent cholecystectomy for symptomatic cholelithiasis. All 22 were transfused to achieve a hemoglobin (Hgb) level greater than 9 g/dL and hemoglobin S (HbS) less than 37%. Fourteen underwent immediate preoperative automated red cell exchange (ARCE). The median preexchange Hgb of these patients was 8.1 g/dL (range, 6.8 to 10.5). Their median HbS was 84% (range, 53% to 97%). These patients underwent placement of an apheresis catheter under local anesthesia followed by red cell exchange. The median volume of packed red blood cells (PRBC) exchanged was 28.1 mL/kg (range, 13.8 to 58.7). The median HbS after exchange was 21% (range, 16% to 37%) and the median Hgb was 10.6 g/dL (range, 6.5 to 16.7). Eight other patients underwent sequential transfusion (3 after an exchange for an acute pulmonary vasoocclusive crisis). These patients had been prepared over an interval of 2 to 8 weeks preoperatively and had received a median of 26.9 mL PRBC/kg (range, 12.8 to 95). Following sequential transfusion the median Hgb was 11.8 g/dL (range, 9 to 15.7) and the median HbS was 19% (range, 5% to 32%) at the time of surgery. All patients received extended antigen matched blood. Complications of preoperative transfusion were minor and included two febrile-/allergic reactions and one mild superficial catheter-induced phlebitis.(ABSTRACT TRUNCATED AT 250 WORDS)