Transbronchial biopsy in the management of pulmonary complications of hematopoietic stem cell transplantation.

The utility of transbronchial biopsy in the management of pulmonary complications following hematopoietic stem cell transplantation (HSCT) has shown variable results. Herein, we examine the largest case series of patients undergoing transbronchial biopsy following HSCT. We performed a retrospective analysis of 130 transbronchial biopsy cases performed in patients with pulmonary complications post HSCT. Logistic regression models were applied to examine diagnostic yield, odds of therapy change and complications. The most common histologic finding on transbronchial biopsy was a nonspecific interstitial pneumonitis (n=24 cases, 18%). Pathogens identified by transbronchial biopsy were rare, occurring in <5% of cases. A positive transbronchial biopsy significantly increased the odds of a subsequent change in corticosteroid therapy (odds ratio (OR)=3.12; 95% confidence interval (CI) 1.18-8.23; P=0.02) but was not associated with a change in antibiotic therapy (OR=1.01; 95% CI 0.40-2.54; P=0.98) or changes in overall therapy (OR=1.92; 95% CI 0.79-4.70; P=0.15). Patients who underwent a transbronchial biopsy had increased odds of complications related to the bronchoscopy (OR=3.33, 95% CI 1.63-6.79; P=0.001). In conclusion, transbronchial biopsy may contribute to the diagnostic management of noninfectious lung injury post HSCT, whereas its utility in the management of infectious pulmonary complications of HSCT remains low.

Functional-metabolic imaging of neuroblastoma.

Neuroblastoma is the third most common malignant solid tumor of childhood. It originates from primitive neural crest cells of the sympathetic nervous system. Many imaging procedures help guide therapy and predict outcomes. Anatomic imaging methods, such as CT and MRI, are most useful for evaluation of the primary tumor mass and nearby involved lymph nodes. Functional imaging tracers, such as [123I]MIBG, [18F]FDG, and [99mTc]MDP, are used to assess the extent of disease and to search for distant metastases. [123I]MIBG is the principal functional imaging tracer for the detection and monitoring of neuroblastoma. [18F]FDG PET/CT is an alternative that is valuable in tumors with poor or no MIBG-uptake. [99mTc]MDP bone scans may be useful to assess cortical bone metastases. This article will review the use of [123I]MIBG and other functional imaging agents for the management of patients with neuroblastoma.

Acanthamoeba infection in a patient with chronic graft-versus-host disease occurring during treatment with voriconazole.

We report a case of disseminated infection with Acanthamoeba in a patient with graft-versus-host disease after hematopoietic stem cell transplant (HSCT) for acute lymphocytic leukemia. The infection involved the brain, skin, and lungs and occurred despite treatment with voriconazole for mold prophylaxis, and did not respond to treatment with multiple other agents reported to have activity against Acanthamoeba. To our knowledge, infection with Acanthamoeba has been reported in 4 other patients after HSCT or bone marrow transplant, and our case is the first to be diagnosed ante-mortem.

Stem cell transplantation in patients with severe congenital neutropenia with evidence of leukemic transformation.

Severe congenital neutropenia (SCN) is a hematologic condition characterized by arrested maturation of myelopoiesis at the promyelocyte stage of development. With appropriate treatment using recombinant human granulocyte-colony-stimulating factor (r-HuG-CSF), SCN patients are now surviving longer, but are at increased risk of developing myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but transplantation outcomes after malignant transformation are not well established. We report results for six patients with SCN who underwent HSCT for MDS or AML between 1997 and 2001 at two transplant centers. Two patients transplanted for MDS survived. Both of these patients were transplanted without being given induction chemotherapy. Four patients, who all received induction chemotherapy for AML prior to HSCT, died. Administering induction chemotherapy prior to HSCT resulted in significant morbidity. Rapid transplantation should be the goal for the SCN patient once the diagnosis of MDS/AML is established. SCN patients should be monitored carefully for progression to MDS in order to be treated with HSCT as soon as they have progressed and before developing AML. For SCN patients who progress to AML, HSCT should still be considered, even though the risks appear to be greater.

Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression.

Dendritic cells (DCs) have been shown to be a promising adjuvant for inducing immunity to cancer. We evaluated tumor lysate-pulsed DC in a Phase I trial of pediatric patients with solid tumors. Children with relapsed solid malignancies who had failed standard therapies were eligible. The vaccine used immature DC (CD14-, CD80+, CD86+, CD83-, and HLA-DR+) generated from peripheral blood monocytes in the presence of granulocyte/monocyte colony-stimulating factor and interleukin-4. These DC were then pulsed separately with tumor cell lysates and the immunogenic protein keyhole limpet hemocyanin (KLH) for 24 h and then combined. A total of 1 x 10(6) to 1 x 10(7) DC are administered intradermally every 2 weeks for a total of three vaccinations. Fifteen patients (ages 3-17 years) were enrolled with 10 patients completing all vaccinations. Leukapheresis yields averaged 2.8 x 10(8) peripheral blood mononuclear cells (PBMC)/kg, and DC yields averaged 10.9% of starting PBMC. Patients with neuroblastoma, sarcoma, and renal malignancies were treated without obvious toxicity. Delayed-type hypersensitivity (DTH) response was detected in 7 of 10 patients for KLH and 3 of 6 patients for tumor lysates. Priming of T cells to KLH was seen in 6 of 10 patients and to tumor in 3 of 7 patients as demonstrated by specific IFN-gamma-secreting T cells in unstimulated PBMCs. Significant regression of multiple metastatic sites was seen in 1 patient. Five patients showed stable disease, including 3 who had minimal disease at time of vaccine therapy and remain free of tumor with 16-30 months follow-up. Our results demonstrate that it is feasible to generate large numbers of functional DC from pediatric patients even in those highly pretreated and with a large tumor burden. The DC can be administered in an outpatient setting without any observable toxicity. Most importantly, we have demonstrated the ability of the tumor lysate/KLH-pulsed DC to generate specific T-cell responses and to elicit regression of metastatic disease.

Successful bone marrow transplantation in a patient with Schimke immuno-osseous dysplasia.

Early death in Schimke immuno-osseous dysplasia often results from renal failure and/or cell-mediated immunodeficiency. Kidney transplants have improved renal function, but effective therapy for the immunodeficiency has not yet been reported. We describe markedly improved marrow function 2 years after bone marrow transplantation in a boy with Schimke immunoosseous dysplasia.

Continuous octreotide infusion for the treatment of secretory diarrhea caused by acute intestinal graft-versus-host disease in a child.

This report describes the use of octreotide, a synthetic somatostatin analogue, for severe diarrhea caused by acute intestinal graft-versus-host disease (GVHD) after bone marrow transplantation. A 22-month-old boy suffered grade 4 intestinal GVHD, with profuse diarrhea, intestinal inflammation, and grossly bloody stools after matched, unrelated donor transplant for biphenotypic leukemia. He required intensive blood product support. In addition to aggressive anti-GVHD therapy, octreotide acetate was initiated at 30 microg (2 microg/kg) intravenously 3 times per day and escalated to continuous infusion at 15 microg/hr (1 microg/kg per hour). The diarrhea did not improve with anti-GVHD treatment. However, moderate dose octreotide therapy resulted in prompt control of the bloody diarrhea, which rebounded on cessation of octreotide therapy. Rebound diarrhea responded promptly when the dose of octreotide was escalated. Octreotide was associated with an exacerbation of preexisting hypertension, but it appeared to be effective for control of severe, bloody diarrhea caused by acute GVHD in a child, with manageable side effects. Further studies of this application in infants and children are warranted.

Identification of the molecular genetic defect of patients with methemoglobin M-Kankakee (M-Iwate), alpha87 (F8) His --> Tyr: evidence for an electrostatic model of alphaM hemoglobin assembly.

We determined that the molecular defect of 2 patients with hemoglobin (Hb) M-Kankakee [Hb M-Iwate, alpha87 (F8) His --> Tyr] resides in the alpha1-globin gene. The proportion of Hb M observed is higher than that predicted for an alpha1-globin variant. Our evidence suggests that the greater-than-expected proportion of Hb M-Kankakee results from preferential association of the electronegative beta-globin chains with the alpha(M)-globin chains that are more electropositive than normal alpha-globin chains.

CT demonstration of periorbital graft-versus-host disease.

A 13-year-old boy who had undergone allogenic bone marrow transplantation for treatment of acute lymphocytic leukemia presented with bilateral periorbital rash and swelling. A CT scan showed bilateral symmetric periorbital swelling, subconjunctival fluid collections, and lacrimal gland enlargement. The patient was initially treated for presumed cellulitis. However, persistently negative regional cultures (eye, nasopharynx), a rapid response to immunosuppressive therapy after several days of nonresponse to intravenous antibiotic therapy, and ultimately, results of a skin biopsy confirmed the diagnosis of acute graft-versus-host disease.

Neuroblastoma: positron emission tomography with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose compared with metaiodobenzylguanidine scintigraphy.

PURPOSE: To assess the uptake in neuroblastoma of 2-[fluorine-18] -fluoro-2-deoxy-D-glucose (FDG) versus metaiodobenzylguanidine (MIBG). MATERIALS AND METHODS: Seventeen patients with known or suspected neuroblastoma underwent FDG positron emission tomography (PET) (20 scans) and MIBG scintigraphy. Tumor uptake of FDG was quantified on positive PET scans. RESULTS: Tumor uptake of FDG was detected in 16 of 17 patients (18 of 20 scans). Neuroblastomas and their metastases avidly concentrated FDG prior to chemotherapy or radiation therapy. Uptake after therapy was variable. Uptake of FDG was intense in one patient with neuroblastoma that failed to accumulate MIBG. In 13 of the 20 scans, however, MIBG was rated superior to FDG for delineation of tumor compared with background and normal organs. CONCLUSION: Most neuroblastomas accumulate FDG. The mechanism of MIBG uptake is more intense prior to therapy. Concentration of FDG is not dependent on type 1 catecholamine uptake. FDG PET helps define the distribution of neuroblastomas that fail to concentrate MIBG.

Comparison of two double labeling techniques to measure cell cycle kinetics in myeloid leukemias.

Five patients with acute myeloid leukemia (AML) received a one hour infusion of iododeoxyuridine (IUdR) 100 mg/M2 to label S-phase cells in vivo. The aspirate was labeled in vitro either with tritiated thymidine (3HTdr) or bromodeoxyuridine (BrdU) to measure the duration of S-phase (Ts). The mean Ts using 3HTdr (Ts1) was 15.9h (13.1-19.8h) and using BrdU (Ts2) was 17.1h (14.5-20.6h). Total cell cycle time (Tc) ranged between 44.7h to 158.8h using Ts1 and 54.0h to 170.5h using Ts2. Based on this close approximation between the results, we confirm the reliability of the newly developed method that relies purely on immunohistochemical reaction.

Simultaneous immunohistochemical detection of IUdR and BrdU infused intravenously to cancer patients.

Cell cycle kinetics of solid tumors in the past have been restricted to an in vitro labeling index (LI) measurement. Two thymidine analogues, bromodeoxyuridine (BrdU) and iododeoxyuridine (IUdR), can be used to label S-phase cells in vivo because they can be detected in situ by use of monoclonal antibodies (MAb) against BrdU (Br-3) or IUdR (3D9). Patients with a variety of solid tumors (lymphoma, brain, colon cancers) received sequential intravenous IUdR and BrdU. Tumor tissue removed at the end of infusion was embedded in plastic and treated with MAb Br-3 and 3D9 sequentially, using a modification of a previously described method. Clearly single and double labeled cells were visible, which enabled us to determine the duration of S-phase (Ts) and the total cell cycle time (Tc), in addition to the LI in these tumors. Detailed control experiments using tissue culture cell lines as well as bone marrow cells from leukemic patients are described, including the comparison of this double label technique with our previously described BrdU-tritiated thymidine technique. We conclude that the two methods are comparable and that the IUdR/BrdU method permits rapid and reliable cell cycle measurements in solid tumors.