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Biomedical subjects

G Heller

Publications and source records attributed to G Heller.

At least 91 records · Page 5Linked to original sources
PubMed1996

Growth and final height after treatment for childhood Hodgkin disease.

PURPOSE: To evaluate in children the impact of contemporary treatment for Hodgkin disease on the pattern of growth and final height. PATIENTS AND METHODS: We studied 80 patients (54 males) aged <14 years at diagnosis, with newly diagnosed, pathologically confirmed Hodgkin disease, treated at a single institution. Forty six patients received chemotherapy (CT) + radiotherapy (RT), 23 patients received RT alone, and 11 patients received CT alone. Heights were obtained at diagnosis, at the end of treatment, 1, 2, and 3 years after the end of treatment and at attainment of final height. Heights were converted to age- and sex-adjusted SD scores (SDS). RESULTS: There was a significant change in height SDS at the end of treatment compared to height SDS at diagnosis for all three groups (CT + RT: -0.33, p<0.001; RT: +0.09, p=0.027; CT: -0.24, p=0.012). Over the 3 years following treatment, the rate of change of height SDS was not statistically different between the three treatment groups. Final height SDS was decreased for patients receiving RT + CT (-0.41 SDS, p=0.02; n=31). The change in final height SDS for patients receiving RT or CT only was -0.36 (n=14) and +0.42 (n=4), respectively. Loss of final height SDS correlated with younger age at diagnosis (p=0.005). Patients receiving higher RT doses tended to fare worse (p=0.08). CONCLUSIONS: Pediatric patients treated for Hodgkin disease with the combination of RT and CT suffer a small but significant decrease in their final height SDS. Younger patients and those treated with higher RT doses appear to experience the greatest loss of height potential.

Adolescent↗
PubMed1996

Chemotherapy without irradiation--a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. The First International Central Nervous System Germ Cell Tumor Study.

PURPOSE: Radiation therapy for CNS germ cell tumors (GCT) is commonly associated with neurologic sequelae. We designed a therapeutic trial to determine whether irradiation could be avoided. PATIENTS AND METHODS: Patients received four cycles of carboplatin, etoposide, and bleomycin. Those with a complete response (CR) received two further cycles; others received two cycles intensified by cyclophosphamide. RESULTS: Seventy-one patients were enrolled (45 with germinoma and 26 with nongerminomatous GCT [NGGCT]). Sixty-eight were assessable for response. Thirty-nine of 68 (57%) achieved a CR within four cycles. Of 29 patients with less than a CR, 16 achieved CR with intensified chemotherapy or second surgery. Overall, 55 of 71 (78%) achieved a CR without irradiation. The CR rate was 84% for germinomas and 78% for NGGCT. With a median follow-up duration of 31 months, 28 of 71 patients were alive without relapse or progression. Thirty-five showed tumor recurrence (n = 28) or progression (n = 7) at a median of 13 months. Twenty-six of 28 patients (93%) who recurred following remission underwent successful salvage therapy. Pathology was the only variable predictive of survival. The probability of surviving 2 years was .84 for germinoma patients and .62 for NGGCT. Seven of 71 patients died of toxicity associated with study chemotherapy. CONCLUSION: Forty-one percent of surviving patients and 50% of all patients were treated successfully with chemotherapy only without irradiation. Chemotherapy-only regimens for CNS GCT, although encouraging, should continue to be used only in the setting of formal clinical trials.

Adolescent↗
PubMed1996

High-dose chemotherapy with autologous marrow rescue for malignant brain tumors: analysis of the impact of prior chemotherapy and cranio-spinal irradiation on hematopoietic recovery.

The relative impact of age, sex, nucleated cell dose, prior chemotherapy, prior cranio-spinal irradiation (CSI) and bone marrow harvest (BMH) site on hematological recovery after ABMT were analyzed in a multivariate model. The study population comprised 100 patients with a median age of 9 years who underwent ABMT for malignant brain tumors. Two engraftment parameters were evaluated: number of days post ABMT before (1) an absolute neutrophil count (ANC) > or = 0.5 x 10(9)/l and (2) a platelet count > or = 50 x 10(9)/I were achieved for the third consecutive day without transfusions. Increasing cell dose correlated significantly with a more prompt recovery of platelet counts and ANC. Previous chemotherapy significantly delayed both neutrophil and platelet engraftment. The group of patients who also received CSI had a very delayed platelet recovery with a median time to engraftment of 72 days. Neutrophil engraftment was also significantly delayed and occurred at a median of 23 days. This effect of CSI was independent of cell dose or prior chemotherapy. In 20 of these patients, marrow was harvested at least partially from the posterior iliac crests, which might have received significant doses of irradiation. We conclude that engraftment is significantly faster if bone marrow is harvested prior to any chemotherapy administration, and that patients who receive prior CSI may have significant engraftment delay, particularly of the platelet lineage. In this latter group of patients, marrow should not be harvested from the posterior iliac crests. Strategies that might enhance both neutrophil and platelet count recovery should be considered in patients with irradiation damage to a substantial proportion of the total hematopoietic tissue.

Adolescent↗
PubMed1996

Polymerase chain reaction is highly predictive of relapse in patients following T cell-depleted allogeneic bone marrow transplantation for chronic myeloid leukemia.

In chronic myeloid leukemia (CML) the polymerase chain reaction (PCR) can be used to detect minimal residual disease after bone marrow transplantation (BMT). Previous studies have shown that PCR positivity is common following BMT. However, the clinical significance of this finding for any given individual who is PCR positive remains unclear, as many of these patients remain long-term disease-free survivors after allogeneic BMT. In the present study, we used PCR to detect BCR-ABL mRNA in 144 blood or marrow samples from 36 patients who received a T cell-depleted BMT for CML in first chronic phase. Six patients had no evidence of PCR-detectable residual disease at any time following transplant. The other 30 patients had at least one positive PCR result post-BMT. Once PCR positivity was found, it was usually sustained, with only four patients having a subsequent PCR negative assay. No patient who had two consecutive PCR-positive assays had a return to PCR negativity. None of the six patients with exclusively PCR-negative assays have developed either cytogenetic or hematologic relapse at a median follow-up of 42 months. Of the 30 patients with at least one PCR-positive assay post-BMT, 28 were PCR positive at last follow-up, and 22 have progressed to cytogenetic or hematologic relapse. If the PCR-positive assay occurred within 24 months of the transplant then the estimated probability of progression to cytogenetic or hematologic relapse was 65% at 24 months. Twenty of the 26 patients who were studied early (< or = 6 months) after BMT had at least one positive PCR assay. Fifteen of the 20 patients who were PCR positive < or = 6 months following transplant have progressed to either cytogenetic or hematologic relapse resulting in an estimated probability of relapse of 84% at 24 months. These results indicate that following T cell-depleted BMT for CML in first chronic phase, PCR is highly predictive of relapse and may identify a cohort of patients in need of therapeutic intervention before the onset of overt clinical relapse.

Biomarkers, Tumor↗
PubMed1995

Second malignant neoplasms in long-term survivors of childhood rhabdomyosarcoma.

BACKGROUND: The occurrence of second malignant neoplasms (SMNs) in successfully treated pediatric patients with cancer has been an area of increasing concern because survival of these patients has improved with intensification of therapy. Therefore, the incidence of SMNs in long term survivors of childhood rhabdomyosarcoma (RMS) was studied. METHODS: From 1970 to 1989, 210 newly diagnosed patients (median age, 9.7 years; range, 1 month to 27 years) with RMS were treated at Memorial Sloan-Kettering Cancer Center (New York, NY). Multimodality treatment included chemotherapy, surgery, and radiotherapy, when indicated. There were 130 long term survivors (> 2 years off therapy) with a median follow-up of 9 years (range, 2-20 years). The cumulative dose of each chemotherapeutic agent and the radiation doses each patient received were reviewed. Statistical analysis was performed by comparison with the Connecticut Tumor Registry data. RESULTS: Seven patients developed a SMN, including three with acute nonlymphoblastic leukemia (ANLL) and four with solid tumors. Acute nonlymphoblastic leukemia developed a median of 4.5 years after diagnosis. Of the solid tumors, 3 developed within the radiation field at a median of 10 years after diagnosis, whereas the fourth occurred 9.3 years after initial diagnosis in a patient who did not receive radiotherapy. All seven patients with SMNs received total dactinomycin doses higher than the median (9.6 mg/M2) for the group. All three patients with ANLL received total cyclophosphamide doses higher than the median (16.8 g/M2). Moreover, six of the seven patients received a dose of radiotherapy greater than 4000 cGy. The standardized incidence ratio was: 17.07 (95% confidence interval, 6.68-35.18; P < 0.0001). CONCLUSIONS: Multimodality therapy has improved long term survival for patients with childhood RMS. The combination of high dose radiotherapy and chemotherapy appears to increase the risk for developing a second malignancy.

Adolescent↗
PubMed1995

Growth in children after bone marrow transplantation for acute leukemia.

We evaluated the growth of children with acute leukemia who received a bone marrow transplant (BMT) after preparation with hyperfractionated total body irradiation (TBI). Seventy-two patients (27 female and 45 male patients) with acute lymphoblastic leukemia (ALL; n = 39) or acute myelogenous leukemia (AML; n = 33) who were less than 14 years of age at BMT were studied. Before BMT all had received multiagent chemotherapy and 31 had received cranial irradiation (RT). Preparation for BMT included total body irradiation (1,375 cGy [n = 37] or 1,500 cGy [n = 35]). Heights, expressed as standard deviation scores (SDS), were studied up to 4 years post-BMT. The estimated height SDS for the entire group at the time of BMT was -0.28 +/- 0.05 and decreased to -1.11 +/- 0.22 at 4 years post-BMT (P < .0001). Using a growth curve model to compare covariate groups over the period of study, we found that the loss in height SDS was most significant in those patients who received cranial RT before BMT (P = .005). The estimated height SDS for patients treated with cranial RT went from -0.52 +/- 0.20 at transplantation to -1.83 +/- 0.23 4 years later. In contrast, patients who did not receive cranial RT before BMT showed a smaller decrease in height SDS over the 4-year observation period, ie, -0.11 +/- 0.20 decreasing to -0.73 +/- 0.21. Similarly, patients with a diagnosis of ALL had a greater loss of height SDS than those with AML (P = .033). Fifteen of 18 patients tested were found to be growth hormone (GH) deficient; 9 patients were treated with GH and all showed an improvement in growth velocity (P < .0001). We conclude that (1) children with acute leukemia who have received cranial RT and subsequently undergo BMT, primarily those with ALL, are at high risk for growth failure and GH deficiency, and (2) that fractionation of TBI may have a relative sparing effect on growth.

Acute Disease↗
PubMed1995

Validation of a technique of computer-aided tumor volume determination.

Tumor volume at diagnosis is an important prognostic factor and volume change may predict therapeutic response. However, the accuracy of in vivo tumor volume measurement has not been established. The purpose of this study was validation of a personal computer-based technique of in vivo volume determination. CT scans of 8 radiological phantoms and 25 neuroblastoma patients were digitized using three-dimensional reconstruction and volume determination software. Phantom volumes were calculated from known dimensions or direct measurement while tumor volumes were determined by water displacement at the time of complete gross resection. Comparison to tumor volume determination was performed using an ellipsoid geometric model. The standard deviation for computer-generated triplicate volume determinations varied from 0.1 to 5.6 cc (median = 0.6 cc). Linear regression analysis demonstrated a close correlation between computer-derived volumes and the volume measured at surgery (r = 0.99) with small variability. In contrast, the correlation coefficient between ellipsoid formula-derived and water displacement volumes was 0.93. Computer-generated tumor volume determination is reproducible, accurate, and easily obtained from hard copy scans. This technique provides a quantitative in vivo measurement for use as a prognostic or therapeutic response variable.

Adolescent↗
PubMed1995

Very-high-dose short-term chemotherapy for poor-risk peripheral primitive neuroectodermal tumors, including Ewing's sarcoma, in children and young adults.

PURPOSE: To improve the prognosis of patients with poor-risk peripheral primitive neuroectodermal tumors (pPNETs; including peripheral neuroepithelioma and Ewing's sarcoma), while testing the feasibility of intensive use in adolescents and young adults of high-dose cyclophosphamide, doxorubicin, and vincristine (HD-CAV). PATIENTS AND METHODS: This report concerns previously untreated patients with newly diagnosed pPNET deemed poor-risk because of a tumor volume more than 100 cm3 or metastases to bone or bone marrow. The P6 protocol consists of seven courses of chemotherapy. Courses 1, 2, 3, and 6 include 6-hour infusions of cyclophosphamide on days 1 and 2 for a total of 4,200 mg/m2 per course (140 mg/kg per course for patients < 10 years old), plus 72-hour infusions of doxorubicin 75 mg/m2 and vincristine 2.0 mg/m2 beginning on day 1 (HD-CAV). Courses 4, 5, and 7 consist of 1-hour infusions of ifosfamide 1.8 g/m2/d and etoposide (VP-16) 100 mg/m2/d, for 5 days. Granulocyte colony-stimulating factor (G-CSF) and mesna are used. Courses start after neutrophil counts reach 500/microL and platelet counts reach 100,000/uL. Surgical resection follows course 3 and radiotherapy follows completion of all chemotherapy. RESULTS: Among the first 36 consecutive assessable patients (median age, 17 years), HD-CAV achieved excellent histopathologic or clinical responses in 34 patients and partial responses (PRs) in two patients. For 24 patients with locoregional disease, the 2-year event-free survival rate was 77%; adverse events were two locoregional relapses, one distant relapse, and one secondary leukemia. All six patients with metastatic disease limited to lungs achieved a complete response (CR) and did not relapse; one is in remission 36+ months from diagnosis, but the other patients are not assessable in terms of long-term efficacy of the P6 protocol because of short follow-up time (n = 3), additional systemic therapy (bone marrow transplantation), or septic death (autopsy showed no residual pPNET). All six patients with widespread metastases had major responses, including eradication of extensive bone marrow involvement, but distant relapses ensued. Myelosuppression was severe, but most patients received the first three courses of HD-CAV within 6 to 7 weeks. Major nonhematologic toxicities were mucositis and peripheral neuropathy. CONCLUSION: Excellent antitumor efficacy and manageable toxicity support the dose-intensive use of HD-CAV for pPNET in children, as well as in young adults. Consolidation of remissions of pPNET metastatic to bone and bone marrow remains a therapeutic challenge.

Adolescent↗
PubMed1995

Pediatric desmoid tumor: retrospective analysis of 63 cases.

PURPOSE: This study was conducted to evaluate clinical prognostic factors predictive of the probability of recurrence of desmoid tumor (DT). PATIENTS AND METHODS: Sixty-three patients with histologically confirmed diagnosis of DT were retrospectively studied. Median age at diagnosis was 13 years. Patient distribution by site was as follows: 61% extremities, 18% head and neck, 13% trunk (including 5% intraabdominal), and 8% multicentric lesions. All patients had partial or complete resections; 20 patients also received radiotherapy and/or chemotherapy. RESULTS: At a median follow-up time of 6 years since first treatment, the overall actuarial probability of having one or more recurrences was 75%. Age, sex, site, size, or number of previous recurrences had no significant impact on the likelihood of recurrence. The only factor associated with an increased proportion of recurrence-free patients was a negative margin of resection (70% v 15% with positive margins; P = .006). Of the four patients with more than 3 years follow-up since chemotherapy, two recurred, and of the 11 patients with the same follow-up after radiotherapy, four recurred, including two of five patients who received a dose of 50 Gy or more. No deaths directly related to tumor invasion were observed. CONCLUSION: A surgical approach aiming at clear margins is presently the best treatment option. When this cannot be accomplished without severe disfigurement or function impairment, partial resection is an acceptable alternative, but one associated with a high risk of regrowth. Whether adjuvant strategies should be used in this situation remains to be addressed.

Adolescent↗
PubMed1995

Serum granulocyte colony-stimulating factor (G-CSF) levels after allogeneic T cell-depleted marrow transplantation.

Endogenously produced and exogenously administered granulocyte colony-stimulating factor (G-CSF) has correlated with myeloid engraftment in a number of hematopoietic progenitor cell transplantation settings. Given the increased susceptibility of T cell-depleted (TCD) bone marrow transplants (BMT) to graft failure, a cohort of 36 (21 male and 15 female) recipients of TCD BMT was evaluated prospectively during the first month post-transplant for circulating serum G-CSF levels, to examine the correlation between myeloid engraftment and G-CSF levels. All recipients of TCD BM had measurable G-CSF levels, with a median peak level of 1750 pg/ml (range 540-26,250 pg/ml) occurring at a median of 5 days (range 1-18 days) after BM infusion. There was no association between G-CSF kinetics within 1 month post-transplant and the development of primary non-engraftment or secondary graft failure. One patient with primary non-engraftment and 6 patients with secondary graft failure exhibited median G-CSF peak levels of 1600 pg/ml and 1850 pg/ml (range 600-16,250 pg/ml) occurring 5 and 5.5 days (range 4-7 days) after BM infusion, respectively. Additionally, the patient with primary non-engraftment demonstrated a high G-CSF level in response to a low absolute neutrophil count (ANC). An inverse relationship between serial G-CSF levels and concomitant ANC was documented (log G-CSF = 6.19-0.009 ANC, P < 0.001). Higher peak G-CSF levels were associated with older recipient age (P = 0.01) and lower BM cell dose (P = 0.02), while administration of anti-thymocyte globulin post-transplant did not alter G-CSF levels.

Adolescent↗
PubMed1995

Thyroid dysfunction following bone marrow transplantation using hyperfractionated radiation.

Thyroid dysfunction has been reported following single dose and fractionated radiation in the context of bone marrow transplantation (BMT). Limited data are available regarding this complication following hyperfractionated radiation. We undertook a retrospective analysis of thyroid function in 150 patients who received BMT at our institution, and who were alive and disease-free for at least 1 year after transplant. There were 100 pediatric patients and 50 adult patients, with a median follow-up of 6.2 years for the whole group. These patients had acute (n = 91) or chronic leukemias (n = 36), severe aplastic anemia (n = 18) or immunodeficiency disorders (n = 5). The majority of the patients received radiation-based cytoreductive regimens including 129 patients who received hyperfractionated total body irradiation (TBI) to a total dose of 1375 cGy or 1500 cGy and 10 patients who received total lymphoid irradiation (TLI) to a total dose of 600 cGy. Twenty two patients of the cohort of 150 patients (14.7%) and 21 of the 139 patients (15.1%) who received hyperfractionated radiation were found to have developed hypothyroidism, 11-88 months after transplant (median 49 months). Eight patients had received 1375 cGy and 12 patients 1500 cGy TBI, while one patient was treated with 600 cGy TLI and one patient was treated with chemotherapy only (busulfan and cyclophosphamide). Three patients had primary thyroid failure with an elevated TSH and a low T4 index, while 19 patients had compensated hypothyroidism with an elevated TSH but a normal T4 index. Six of eight patients with untreated compensated hypothyroidism recovered spontaneously.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

In vitro sensitivity of post-bone marrow transplantation CFU-GM and BFU-E to TNF-alpha and IFN-gamma.

Graft failure remains one of the limitations of successful marrow transplantation. T cell-depleted (TCD) bone marrow transplantation (BMT) is reported to have a higher incidence of graft failure than unmodified (UM) BMT. In most cases of secondary graft failure, no cellular immune mechanism has been identified and etiology remains unclear. In an effort to delineate a cytokine-mediated mechanism of secondary graft failure, we investigated colony-forming unit-granulocyte/macrophage (CFU-GM) and burst-forming unit-erythroid (BFU-E) growth and pattern of inhibition by tumor necrosis factor-alpha (TNF-alpha) and gamma-interferon (IFN-gamma) in the early posttransplant period (day 28). Gradient-separated bone marrow mononuclear cells (BMMNC) from 38 recipients of TCD BMT, 15 recipients of UM BMT, and 23 normal donors (NLD) were plated in cultures of semisolid, serum-containing medium with the addition of stem cell factor (SCF), erythropoietin (Epo), and granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Three to seven times more CFU-GM and BFU-E colonies were cultures from NLD BM-derived BMMNC than from BMMNC of recipients of TCD or UM BMT (p = 0.0001). There was no difference in colony number between recipients of UM and TCD BMT on day 28 posttransplant, however. Under G-CSF culture conditions, CFU-GM colonies from recipients of UM and TCD BMT were more susceptible (p < or = 0.05) to suppression by IFN-gamma at concentrations of 1 and 100 U/mL than NLD BMMNC-derived colonies. No other difference in IFN-gamma inhibition was detected among the three groups. Under G-CSF and GM-CSF culture conditions, maximal inhibition was obtained at TNF-alpha concentrations > 10 ng/mL. Although early posttransplant BMMNC was more sensitive to inhibition than NLD-derived BMMNC, overall, no difference in colony growth or percent of inhibition induced by TNF-alpha or IFN-gamma was observed between recipients of unmodified and T. cell-depleted transplants. In this series, two recipients of TCD BM and one recipient of UM BMT developed graft failure; no distinct pattern of colony growth or colony inhibition was evident for those patients. The optimized in vitro conditions and specific cytokines used in this study do not indicate any quantitative or qualitative differences in the hematopoietic progenitors present in recipients of unmodified and T cell-depleted bone marrow early posttransplant to explain an increased risk of graft failure following a T cell-depleted BMT compared to an unmodified BMT.

Adolescent↗
PubMed1994

Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid.

All-trans retinoic acid (RA) has proven a major advance in the treatment of acute promyelocytic leukemia (APL). However, the proper management of patients who present with or develop leukocytosis during remission induction with all-trans RA is not established, nor is there a clear relation between leukocytosis and the development of the retinoic acid syndrome. We reviewed the course of our patients who underwent induction with all-trans RA to identify potential factors that might predict for the development of this syndrome and to identify which patients, if any, might specifically benefit from additional treatment with cytotoxic chemotherapy. Seventy-eight courses of all-trans RA therapy were administered to patients with a molecular diagnosis of APL. Initial and peak leukocyte counts, their rate of rise, leukocyte count criteria developed in Europe, and cell surface marker expression were all analyzed relative to subsequent development of both the RA syndrome as well as all causes of early mortality. The outcome of patients who received specific treatment for retinoid-induced leukocytosis was also examined. No factor was found to consistently predict for the development of the RA syndrome. Although the occurrence of the syndrome was positively associated with the peak value of the peripheral blood leukocyte count (P = .001), neither the initial leukocyte count nor the rate of rise in leukocyte counts on days preceding onset of the syndrome were sufficiently well-correlated to be clinically useful (P = .21). The leukocyte count criteria developed in Europe had a sensitivity of 62%, a specificity of 69%, and a positive predictive value that ranged from only 44% to 72%. However, we unexpectedly found that basal expression of CD13 (aminopeptidase N), a cell surface enzyme previously linked to tumor cell invasion and an inferior outcome in patients with acute myeloid leukemia, was highly associated with both development of the syndrome (P < .05) as well as an elevated leukocyte count (P = .006). Neither low-dose chemotherapy nor leukapheresis prevented development of the syndrome nor ameliorated its effects. In fact, 9 of 11 patients who received these interventions sustained fatal or near-fatal events, most of which were due to hemorrhage. However, early treatment with a short-course of high-dose corticosteroids halted progression of the syndrome in most cases. Finally, we found that expression of the type "A" isoform of PML/RAR-alpha (also known as bcr3 or "short") was associated with a significantly shorter duration of relapse-free and overall survival (P = .005).(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex Hormones↗
PubMed1994

Minimal residual disease is more common in patients who have mixed T-cell chimerism after bone marrow transplantation for chronic myelogenous leukemia.

Determining both lymphoid chimerism and the presence of minimal residual disease after allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukemia (CML) could be helpful to the understanding of the biology of leukemic relapse in this disease. We prospectively investigated 32 patients with CML post-BMT by assessing T-cell chimerism and minimal residual disease using sensitive polymerase chain reaction (PCR) methodologies. Patients were studied between 1 and 24 months post-BMT. Thirty patients received a T-cell-depleted marrow grafts and 2 received unmanipulated marrow. All but 1 patient were conditioned with total body irradiation (TBI)+thiotepa+cyclophosphamide (Cy). The other patient received TBI+Cy as conditioning. The T cells were exclusively of donor origin in 12 of 16 patients who were tested at 1 month post-BMT, but were mixed chimeric in 11 of these patients by > or = 3 months. Once mixed T-cell chimerism was documented, no patient returned to having all donor T-cells. At a median follow-up of 12 months, minimal residual disease was present in 18 of 22 patients with mixed T-cell chimerism and in 3 of 10 patients with full donor chimerism. The actuarial molecular relapse rate at 24 months for the two groups is 91% and 33%, respectively (P < .02). The finding of BCR-ABL mRNA within the first 6 months of transplant or on two consecutive assays was highly predictive of subsequent cytogenetic or hematologic relapse (P = .032 and P < .02, respectively). Ten patients, 9 with mixed T-cell chimerism, have relapsed (4 clinical, 6 cytogenetic) at a median of 12 months post-BMT. These data suggest that mixed T-cell chimerism may be a marker for abrogation of graft-versus-leukemia activity that is thought to be pivotal in eradicating minimal residual disease after BMT for CML.

Bone Marrow Transplantation↗
PubMed1994

Antibody response to murine anti-GD2 monoclonal antibodies: correlation with patient survival.

Clinical strategies which modulate the human anti-mouse antibody response (HAMA) in patients may have a profound influence on the idiotype network inducible by murine monoclonal antibodies (MoAb). Prior to myeloablative chemotherapy (ABMT), 9 patients with Stage IV neuroblastoma were imaged with 131I-3F8, a MoAb specific for the ganglioside GD2. Their serum HAMA, anti-idiotypic, anti-GD2, and anti-anti-idiotypic antibodies were assayed by enzyme-linked immunosorbent assay prior to, and at 3 and 6 months postimaging. HAMA and anti-idiotypic levels remained low, in contrast to the high levels in 10 patients imaged with 131I-3F8 without ABMT. Five of the 9 patients are long-term survivors; all had elevated anti-GD2 and anti-anti-idiotypic levels, significantly higher than those who died of disease. Although 131I-3F8 imaging prior to ABMT detected abnormal sites in 4 of 9 patients, 3 of the 4 patients have continued in remission for 24-63 months after ABMT, and all 3 mounted anti-GD2 and anti-anti-idiotypic antibody responses. We conclude that myeloablative therapy strongly suppressed the HAMA/anti-idiotypic response to murine MoAb and that the prognostic significance of host immune response to ganglioside GD2 MoAb deserves further investigation.

Animals↗
PubMed1994

All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York Study.

OBJECTIVE: To evaluate the safety and efficacy of all-trans retinoic acid to induce complete remission and to examine its effects on duration of remission and survival in patients with acute promyelocytic leukemia. DESIGN: Phase II evaluation and comparison with historical control patients. SETTING: Tertiary care cancer referral center. PATIENTS: Consecutive patients with morphologic diagnoses of acute promyelocytic leukemia were treated during a 2-year period with all-trans retinoic acid (daily oral dose, 45 mg/m2). Newly diagnosed patients discontinued the drug approximately 30 days after they achieved complete remission, at which time they received three courses of combination chemotherapy. Patients treated with previous cytotoxic chemotherapy who then relapsed were continued on all-trans retinoic acid as "maintenance" therapy until they relapsed again. RESULTS: 56 patients entered the study: 34 were newly diagnosed and 22 had relapsed from previous treatment. Fifty-one patients subsequently were found to have the PML/RAR-alpha gene rearrangement indicative of acute promyelocytic leukemia, and 44 of these patients achieved complete remission (86%; 95% Cl, 76% to 96%). A distinctive respiratory distress syndrome developed in 13 patients (23%) during treatment, and 5 patients (9%; Cl, 3% to 20%) died of this complication. The 5 patients who lacked PML/RAR-alpha rearrangements were withdrawn and given chemotherapy. The 13 patients given all-trans retinoic acid alone as maintenance therapy (10 of whom had relapsed from a chemotherapy-induced remission) had a median duration of remission of only 3.5 months (range, 1 to 23 months). Only 3 of 19 patients who relapsed from a remission induced by all-trans retinoic acid could be brought into remission again using this drug. The median survival time of all newly diagnosed patients has not been reached, but it now exceeds 31 months (range, 0.4 to 36+ months). No decrease in the early mortality rate was observed compared with a historical control group composed of 80 consecutive, newly diagnosed patients treated only with chemotherapy at this center; however, overall survival was superior. CONCLUSIONS: All-trans retinoic acid is an effective agent to induce remission in patients with a molecular diagnosis of acute promyelocytic leukemia, but remissions are short and resistance develops rapidly. Although the incidence of early death was not reduced, the use of all-trans retinoic acid to induce remission, followed by cytotoxic chemotherapy for "consolidation," was associated with longer survival times when compared with historical controls treated only with chemotherapy. Additional studies to prevent or mitigate consequences of the "retinoic acid syndrome" and to identify specific patients who might benefit from earlier intervention with chemotherapy are needed to maximize the advantages of this approach.

Adolescent↗
PubMed1994

The effect of age at diagnosis on outcome in rhabdomyosarcoma.

BACKGROUND: Survival for rhabdomyosarcoma appears to be more favorable in children and adolescents compared with adults. To determine the significance of age at diagnosis as a prognostic indicator in rhabdomyosarcoma, we performed a retrospective analysis of a combined pediatric and adult rhabdomyosarcoma data base. METHODS: Pertinent prognostic variables, including age, TNM stage, histopathologic subtype, anatomic site, resectability, radiation to the primary site, and dose intensity of chemotherapy, were compared in a Cox proportional hazards model with mortality as the outcome variable. RESULTS: Age at diagnosis (P = 0.0001) and local tumor invasiveness (P < 0.0001), distant parenchymal metastases (P < 0.0001), regional lymph node involvement (P = 0.0027), and histopathologic subtype (P = 0.0446) contributed information to the proportional hazards model. CONCLUSIONS: Age at diagnosis is an independent predictor of outcome in patients with rhabdomyosarcoma along with tumor invasiveness, metastases, regional lymph node involvement, and histopathologic subtype.

Adolescent↗