Mature and immature extracranial teratomas in children: the UK Children's Cancer Study Group Experience.

PURPOSE: The purpose of this article is to describe the features, treatment, and risk factors for relapse of children with mature teratoma (MT) and immature teratoma (IT) to assist future treatment plans. PATIENTS AND METHODS: Patients were younger than 16 years of age and referred to the UK Children's Cancer Study Group centers with biopsy-proven extracranial MT and IT and no prior chemotherapy. Complete excision, with the coccyx in sacrococcygeal patients, and follow-up, including serum alpha-fetoprotein monitoring for early detection of malignant yolk sac tumor (YST) recurrence, were recommended. Carboplatin, etoposide, and bleomycin (JEB) were given for YST relapse, whereas relapsed MT and IT were treated at clinicians' discretion, usually surgically. Pathology was reviewed and treatments, outcome, and prognostic features assessed. RESULTS: There were 351 patients, 227 with MT, 124 with IT. Tumor sites were: testis (n = 53), ovary (n = 130), sacrococcygeal region (n = 98), thorax (n = 23), and other (n = 47). Surgical resection was incomplete in 26% of MT and 40% of IT patients; 5-year event-free survival was 92.2% and 85.9%, respectively, and 5-year overall survival was 99% and 95.1%. Poorer outcome occurred with incomplete resection, tumor rupture, nongonadal site (particularly sacrococcygeal), young age, higher stage and grade, and gliomatosis peritonei, but not with cyst fluid aspiration/spillage, tumor enucleation, nodal gliomatosis, or microfoci of YST in the tumor (Heifetz lesions). JEB was effective for YST recurrence, but not for MT or IT. CONCLUSION: Treatment remains primarily surgical, with JEB chemotherapy for YST relapse. No definite response followed JEB for pure MT and IT. Adjuvant chemotherapy after surgery for sacrococcygeal patients is not advocated.

Immunotherapeutic strategies in acute lymphoblastic leukaemia relapsing after stem cell transplantation.

Acute lymphoblastic leukaemia (ALL) responds well to chemotherapy and the majority of children and a significant proportion of adults are cured of their disease after primary therapy. However, a number of patients relapse and allogeneic transplantation following conditioning with chemotherapy and radiotherapy offers the possibility of long-term survival in a proportion of these patients. A significant number of patients with ALL develop disease that is refractory to further therapy. The infusion of unmodified donor lymphocytes (DLI) following relapse after allogeneic transplantation has been shown to be curative in patients with chronic myeloid leukaemia (CML). However, in ALL the success rate is much lower. The results of in vitro and limited in vivo studies suggest that it may be possible to manipulate lymphocytes from the transplant donor to produce cytotoxic T-lymphocytes (CTL) with increased effectiveness in killing patients' ALL cells. This may be done in a number of ways. For example, some strategies utilise the patients dendritic cells (DC) to present tumour antigens to donor lymphocytes and convert them into CTL either by pulsing DC taken in remission with ALL cells or lysate, fusing such 'normal' DC with ALL cells or using DC cultured from the patient's ALL cells. Other approaches include exploiting the expression of leukaemia-specific antigens such as the proteinase PR-3 or the zinc finger transcription factor Wilms tumour-1 protein (WT-1) to stimulate CTL responses. Alternatively, immunotherapeutic strategies might exploit differences in minor histocompatibility antigens such as HA-1 and HA-2 between donor and recipient. These are expressed solely on haemopoietic cells making them suitable targets for donor derived anti-leukaemic cells. In vivo studies to date suggest that educated T-cells may have a role to play in the treatment of relapsed and refractory ALL in the future.

Characterization of acute lymphoblastic leukemia progenitor cells.

Only some acute lymphoblastic leukemia (ALL) cells are thought to be capable of proliferating to maintain the leukemic clone, and these cells may be the most relevant to target with treatment regimens. We have developed a serum-free suspension culture (SC) system that supported growth of B-ALL cells from 33 patients for up to 6 weeks. ALL cells from 28 cases (85%) were expanded in this system, and growth was superior in SC than in long-term bone marrow culture. To characterize ALL progenitors, cells were sorted for expression of CD34 and CD10 or CD19 and the subfractions assayed in SC and in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Cells capable of long-term proliferation in vitro and NOD/SCID repopulation were derived only from the CD34(+)/CD10(-) and CD34(+)/CD19(-) subfractions, and these cells could engraft secondary recipients. The engrafted cells had the same immunophenotype and karyotype as was seen at diagnosis, suggesting they had differentiated in vivo. These results demonstrate that ALL cells capable of long-term proliferation in vitro and in vivo are CD34(+)/CD10(-)/CD19(-). This suggests that cells with a more immature phenotype, rather than committed B-lymphoid cells, may be the targets for transformation in B-ALL.

Outcome of single fraction total body irradiation-conditioned stem cell transplantation in younger children with malignant disease--comparison with a busulphan-cyclophosphamide regimen.

The logistic difficulties of using fractionated total body irradiation (TBI) in the youngest children often limit the choice to single fraction TBI (sfTBI) or non-TBI-based regimens. We retrospectively evaluated 44 such children ( < 7 years) conditioned with either sfTBI (n = 26) or busulphan-cyclophosphamide (Bu-Cy) (n = 18), transplanted for hematological malignancies between 1988 and 2001. Both neutrophil and platelet engraftment were faster in the sfTBI group with a similar incidence of graft failure (6.8%). Acute GVHD (graft versus host disease) grade 2-4 occurred in 38.4% and 38.8% and chronic GVHD in 20% and 15.4% of the patients in the sfTBI and Bu-Cy groups, respectively Grade 2-4 GVHD was associated with reduced risk of relapse (p = 0.03). This finding was more pronounced in high-risk patients with 2/10 relapses in patients with GVHD grade 2-4, compared with 13/18 relapses among those with GVHD 0-1 (p = 0.05). The probability of overall survival was 43.3% in the sfTBI group and 33.3% in the Bu-Cy group (p = 0.6). However, the outcomes for high-risk patients and those with acute lymphoblastic leukemia were better in the sfTBI group. While hypothyroidism, growth hormone deficiency, learning problems and cataract formation were observed only in the sfTBI group, early cardiac toxicity, behavioral problems and seizures were more common in the Bu-Cy group. Thus, where fractionated TBI is not feasible, sfTBI offers improved survival in high-risk children with acute lymphoblastic leukemia compared with Bu-Cy, without an unacceptable increase in early or late toxicity.

The use of stimulated granulocyte transfusions to prevent recurrence of past severe infections after allogeneic stem cell transplantation.

The predictable neutropenia that follows allogeneic stem cell transplantation (ASCT) may be associated with recurrence of previous life-threatening infection. We describe nine patients with either previous invasive aspergillosis (IA) or considered to be at high risk of developing IA who underwent ASCT with prophylactic granulocyte transfusions. The study group, when compared with a control group, had a significant reduction in the incidence and duration of fevers (P < 0.05) and maximum C-reactive protein (P < 0.05). There were significantly fewer days of neutropenia (P < 0.05). There was also radiological improvement of pulmonary infiltrates in four out of seven assessable patients. No serious toxicity was encountered in donors or recipients. We conclude that prophylactic granulocyte donations can be given safely, and that they significantly reduce the number of days of neutropenia. Further investigation is warranted to determine whether granulocyte donations can prevent the recurrence of IA in patients at risk of fungal infection.

The impact of transfusion of leucodepleted platelet concentrates on cytomegalovirus disease after allogeneic stem cell transplantation.

The impact of transfusion of leucodepleted platelet concentrates (PCs) on cytomegalovirus (CMV) disease was assessed in 215 allogeneic (145 unrelated and 70 related donor) transplants over 3 years. In 43%, both donor and patient were CMV seronegative (CMV-/-). All received CMV-seronegative red cells and random leucodepleted PCs. No CMV disease occurred in any CMV-/- (low risk) transplant. CMV infection occurred in 31 seropositive patients (26%); 13 died and five deaths were attributable to CMV disease. When compared with historical controls, who received CMV-seronegative PCs, we found no difference in transfusion-acquired CMV in the current cohort.