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H J Laws

Publications and source records attributed to H J Laws.

At least 19 recordsLinked to original sources
PubMed2004

Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention.

Veno-occlusive disease (VOD) of the liver is a complication observed particularly in patients undergoing hematopoietic stem cell transplantation (HSCT). Defibrotide (DF) is a polydeoxyribonucleotide with aptameric activity on endothelium. We evaluated in a retrospective analysis the efficacy of DF in pediatric patients developing hepatic VOD after HSCT.A total of 45 patients between 0.2 and 20 years (median age: 8.2 years) with hepatic VOD were treated with DF: 22 patients (49%) met risk criteria for severe or progressive disease and 23 (51%) for moderately severe and mild disease. The median duration of DF treatment was 17 days. In all, 34 patients (76%) achieved complete response (CR) with a survival rate of 64% at day 100. CR rate in patients with severe disease was 50% with long-term survival of 36%. The average DF dose in the CR group was 45 mg/kg/day and in the no responder (NR) group 27 mg/kg/day. The use of additional drugs besides DF to treat VOD made no difference in the outcome compared to DF alone. The average interval from diagnosis to start of DF was 1 day in the CR and 5.5 days in NR group. In multivariate analysis, early intervention remained the only significant factor for a CR.

Adolescent↗
PubMed2003

High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: results of two consecutive regimens assessing the role of total-body irradiation.

PURPOSE: Risk stratification of metastatic and relapsed Ewing's tumors (ETs) has been a matter of debate during the last decade. Patients with bone or bone marrow metastases or early or multiple relapses constitute the worst risk group in ET and have a poorer prognosis than patients with primary lung metastases or late relapses. In this article, the results of the present Meta European Intergroup Cooperative Ewing Sarcoma Study (MetaEICESS) (tandem melphalan/etoposide [TandemME]) were compared with the result of the previous study (hyper melphalan/etoposide [HyperME]), both at 5 years, in a patient population within the same high-risk stratum to determine toxicity. PATIENTS AND METHODS: Among 54 eligible patients, 26 were treated according to the HyperME protocol, and 28 were treated according to TandemME protocol. Patients received six cycles of the Cooperative Ewing Sarcoma Study treatment in HyperME and six cycles of the EICESS treatment in TandemME as induction chemotherapy. Patients also received involved-compartment irradiation for local intensification and myeloablative systemic intensification consolidation with hyperfractionated total-body irradiation (TBI) combined with melphalan/etoposide in HyperME or two times the melphalan/etoposide in TandemME followed by autologous stem-cell transplantation. RESULTS: The event-free survival (EFS) rate +/- SD in HyperME and TandemME was 22% +/- 8% and 29% +/- 9%, respectively. The dead of complication rate was 23% in HyperME and 4% in TandemME. CONCLUSION: TandemME offers a decent, albeit still not satisfactory, rate of long-term remissions in most advanced ETs (AETs), with short-term treatment and acceptable toxicity. TBI was not required to maintain EFS level in this setting but was associated with a high rate of toxic death. Future prospective studies in unselected patients are warranted to evaluate high-dose therapy in an unselected group of patients with AET.

Adolescent↗
PubMed2003

Relapse after high-dose therapy in relapsed Ewing's tumor patients: effects of maintenance chemotherapy in two selected patients?

BACKGROUND: The prognosis for patients with high-risk Ewing's tumor, i.e. primarily multifocal or early relapsed disease, is extremely poor with conventional relapse therapy. High-dose radio/chemotherapy (HDC) with subsequent stem cell transplantation seems to improve outcome in this patient cohort. In spite of this intensified therapy however, relapse remains the most frequent cause of death. In the majority of patients the time to second relapse after HDC is shorter than the time to first relapse after conventional therapy (3.4 vs. 18 months). Event-free survival in Ewing's tumor patients who suffer a second relapse after first-line therapy (EICESS 92) is 2% after 18 months. CASE REPORT: The present report describes the clinical course of two girls who relapsed after HDC and subsequently received low-dose oral trofosfamide and etoposide. The patient with very late multifocal relapse after first-line treatment and a second localized relapse 30 months after HDC remains disease-free for 5 years after the last relapse. However, the other patient with 2 early relapses after first-line treatment and HDC, respectively, did not benefit from this regime. CONCLUSION: We propose that low-dose maintenance therapy may be beneficial in the subgroup of Ewing's tumor patients with late relapse after HDC.

Adolescent↗
PubMed2002

Serial evaluation of the oncological pediatric risk of mortality (O-PRISM) score following allogeneic bone marrow transplantation in children.

The O-PRISM score was introduced for risk assessment in children transferred to intensive care following BMT. The aim of this study is to determine the prognostic value of a serial evaluation of the O-PRISM score. Ninety-three children, 58 allogeneic-related and 35 unrelated BMT, were evaluated. At weekly intervals, the O-PRISM was calculated based on the standard PRISM score and the three additional variables CRP, GVHD and hemorrhage. Overall survival was 0.51 +/- 0.05 (48/93 patients). Seventeen children died of recurrent disease and 28 of BMT-related complications. High O-PRISM scores significantly correlated with adverse outcome. The relative risks of DOC of patients with scores > or =10 compared to patients with lower scores were: day 0: 3.9 (95% confidence-interval: 1.1-13.7, P = 0.02), day 7: 2.0 (0.7-6.2, P = 0.20), day 14: 5.2 (1.9-14.0, P = 0.001), day 21: 5.6 (1.9-16.5, P = 0.001), day 28: 11.5 (3.8-100.9, P < 0.001), day 35: 7.3 (1.9-27.7, P = 0.001). As early as day 0, children with scores > or =10 points showed a higher cumulative incidence of DOC than patients with lower scores (0.69 +/- 0.15 vs 0.27 +/- 0.05, P = 0.02). The O-PRISM score represents a useful clinical parameter for serial risk assessment following BMT. As it indicates fatal events early, it may be helpful for parent information and even more for the early establishment of intensified supportive treatment. The O-PRISM score may therefore be a valuable parameter for the evaluation of different strategies for BMT and supportive treatment.

Adolescent↗
PubMed2000

Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Düsseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria.

BACKGROUND: An update of results from the High Risk Protocol of the Meta-EICESS Study, conducted at the Pediatric Stem-Cell Transplant Centers of Düsseldorf and Vienna. In order to evaluate a possible therapeutic benefit after allogeneic SCT in patients with advanced Ewing tumors (AET), we compared outcome after autologous and allogeneic stem-cell transplantation (SCT). PATIENTS AND METHODS: We analyzed 36 patients treated with the myeloablative Hyper-ME protocol (hyperfractionated total body irradiation, melphalan, etoposide +/- carboplatin) between November 1986 and December 1994. Minimal follow-up for all patients was five years. All patients underwent remission induction chemotherapy and local treatment before myeloablative therapy. Seventeen of thirty-six patients had multifocal primary Ewing's tumor, eighteen of thirty-six had early, multiple or multifocal relapse, one of thirty-six patients had unifocal late relapse. Twenty-six of thirty-six were treated with autologous and ten of thirty-six with allogeneic hematopoietic stem cells. We analyzed the following risk factors, that could possibly influence the event-free survival (EFS): number of involved bones, degree of remission at time of SCT, type of graft, indication for SCT, bone marrow infiltration, bone with concomitant lung disease, age at time of diagnosis, pelvic involvement, involved compartment radiation, histopathological diagnosis. RESULTS: EFS for the 36 patients was 0.24 (0.21) +/- 0.07. Eighteen of thirty-six patients suffered relapse or died of disease, nine of thirty-six died of treatment related toxicity (DOC). Nine of thirty-six patients are alive in CR. Age > or = 17 years at initial diagnosis (P < 0.005) significantly deteriorated outcome. According to the type of graft, EFS was 0.25 +/- 0.08 after autologous and 0.20 +/- 0.13 after allogeneic SCT. Incidence of DOC was more than twice as high after allogeneic (40%) compared to autologous (19%) SCT, even though the difference did not reach significance (P = 0.08, Fisher's exact test). CONCLUSIONS: Because of the rather short observation period. secondary malignant neoplasms (SMN) may complicate the future clinical course of some of our patients who are currently viewed as event-free survivors. EFS in AET is not improved by allogeneic SCT due to a higher complication rate. The patient group was to small to analyze for a possible graft-versus-tumor effect.

Adolescent↗
PubMed2000

Successful treatment of relapsed CML after cord blood transplantation with donor leukocyte infusion IL-2 and IFNalpha.

A 3-year-old girl with BCR/ABL-positive CML relapsed after related HLA-identical cord blood transplantation. She was treated with three cycles of donor lymphocyte (DLI) infusion from her 15-month-old brother. Interferon alpha was added after the second DLI, whereas a trial of IL-2 had to be discontinued because of increasing immature myeloid cells in the blood smear. No signs of GVHD were observed, but she developed myelosuppression and needed one platelet and one red blood cell transfusion. She achieved a molecular remission after 6 months with transient molecular relapse followed by sustained remission for 15 months. Thus, DLI with or without interferon alpha might prove to be a promising treatment option with tolerable side-effects in relapsed CML after cord blood transplantation. Bone Marrow Transplantation (2000) 25, 219-222.

Blood Component Transfusion↗
PubMed2000

In vivo cytokine responses to interleukin-2 immunotherapy after autologous stem cell transplantation in children with solid tumors.

The potent immunostimulatory cytokine interleukin-2 (IL-2) has been extensively investigated for its potential to induce anti-tumor immunity in a number of tumor models. Only recently the complex interplay of mutually suppressive or supportive cytokines of the IL-2-induced network of cytokines has been better characterized. The aim of this study was to assess which of these in vitro findings are reproducible in vivo in recipients of stem cell transplants (SCT), since in these patients long- lasting impairments in cytokine inducibility have been described. We have therefore studied the kinetics of putative modulators and mediators of IL-2-induced immune activation, namely IL-1beta, IL-4, IL-5, IL-10, IL-12, soluble Fas ligand (sFasL), and GM-CSF during IL-2 therapy. All patients were children or adolescents suffering from solid tumors with poor prognosis who received three 5-day courses of high-dose intravenous IL-2 as an adjuvant to their radio-chemotherapy and autologous SCT. While IL-1beta, IL-4 and IL-12 were not, and sFasL was only mildly affected by the IL-2 therapy, we observed a consistent and early rise of IL-10, IL-5, and GM-CSF. These increases were rapidly reversible after discontinuation of IL-2 therapy. The inducibility of IL-10, IL-5 and GM-CSF was more pronounced with increasing time from the SCT, and in the third cycle reached an order of magnitude as in high-dose IL-2 patients without SCT. Together with the abundant in vitro data, these findings may help devise a combination immunotherapy permitting stronger anti-tumor effects, but lesser adverse effects.

Adolescent↗
PubMed1999

Radiotherapy and high-dose chemotherapy in advanced Ewing's tumors.

BACKGROUND: Ewing's tumors are sensitive to radio- and chemotherapy. Patients with multifocal disease suffer a poor prognosis. Patients presenting primary bone marrow involvement or bone metastases at diagnosis herald a 3-year disease-free survival below 15%. The European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) has established the following indications for high-dose therapy in advanced Ewing's tumors: Patients with primary multifocal bone disease, patients with early (< 2 years after diagnosis) or multifocal relapse. PATIENTS AND METHOD: As of 1987, 83 patients have been treated in the EICESS group, 39 of them at the transplant center in Düsseldorf, who have been analyzed here. All individuals received 4 courses of induction chemotherapy with EVAJA and stem cell collection after course 3 and 4. Consolidation radiotherapy of the involved bone compartments was administered in a hyperfractionated regimen 2 times 1.6 Gy per day, up to 22.4 Gy simultaneously to course 5 and 22.4 Gy to course 6 of chemotherapy. The myeloablative chemotherapy consisted of melphalan and etoposide (ME) in combination with 12 Gy TBI (Hyper-ME) or Double-ME with whole lung irradiation up to 18 Gy (without TBI). RESULTS: The survival probability at 40 months was 31% (44% DOD; 15% DOC). Pelvic infiltration did not reach prognostic relevance in this cohort. Radiotherapy encompassed 75% of the bone marrow at maximum (average 20%). Engraftment was not affected by radiotherapy. CONCLUSION: High-dose chemotherapy can improve outcome in poor prognostic advanced Ewing's tumors. The disease itself remains the main problem. The expected engraftment problems after intensive radiotherapy in large volumes of bone marrow can be overcome by stem cell reinfusion.

Adolescent↗
PubMed1999

Multimodality diagnostics and megatherapy in poor prognosis Ewing's tumor patients. A single-center report.

BACKGROUND: The prognosis of Ewing's tumor patients has been improved gradually through cooperative therapy studies, so that meanwhile 55 to 65% of the patients survive relapse-free in the long term. Patients with multifocal primary, early or multiply-relapsed Ewing's tumors have a dismal prognosis. Megatherapy with subsequent stem cell transplantation seems to improve outcome in this patient cohort. Feasibility of this intense megatherapy regimen is crucially dependent on collaboration and multidisciplinary coordination of radiologists, radiotherapists, surgeons and oncologists. PATIENTS AND METHODS: Since 1988, 25 patients were treated with megatherapy consisting of melphalan, etoposide and total-body irradiation followed by stem cell transplantation. All patients received 6 courses of an induction therapy. Before the fourth therapy block, tumors that were bulky at initial diagnosis (> 200 ml) were excised, as well as lung metastases which could still be detected after the third chemotherapy block. During the fifth and sixth chemotherapy block, patients received local irradiation on all infiltrated sites. Persisting immunosuppression after high-dose treatment may facilitate the incidence of relapse. To improve proliferation and cytotoxic activity of early regenerating NK-cells, adoptive immunotherapy with systemic IL-2 therapy after megatherapy is part of the treatment protocol. RESULTS: Of 25 patients treated with megatherapy, 10 patients are still alive with a follow-up time of 6 months to 9 years after megatherapy. The time up to engraftment was decreased from 15 +/- 6 days down to 9 +/- 2 days through the use of G-CSF and CD34+ selected stem cells. At the same time, erythrocyte and platelet replacement was shortened. Frequently occurring complications were mucositis and infections. One patient died after developing septicemia and multi-organ failure, another patient developed a myelodysplastic syndrome 4.5 years after megatherapy. However, relapse is still the major cause of death. The influence of IL-2 on event-free survival cannot valued because 21 of 25 patients were treated with adoptive immunotherapy. CONCLUSION: The complex diagnostic and therapeutic strategy renders and EFS of 34% for a patient group with otherwise dismal prognosis. To clarify the efficiency of megatherapy in patients with advanced Ewing's tumors, a standardized treatment strategy is necessary to accumulate a sufficient number of patients for large cooperative studies in this subject.

Adolescent↗
PubMed1998

Induction of a CD3+/CD56+ lymphocyte population following gene therapy with transgenic IL-2 secreting fibroblasts in a child with peripheral neuroectodermal malignancy.

BACKGROUND: Adjuvant interleukin-2 (IL-2) therapy after stem cell transplantation can improve the prognosis of patients with Ewing tumors. This has been attributed to stimulation of the immune system and its antineoplastic activity, thus eliminating minimal residual disease. As the side effects of systemic IL-2 limit the dosage, attempts have been made to locally augment the concentration of IL-2 in the proximity of the tumor. To achieve this, fibroblasts and/or tumor cells can be genetically modified to secrete IL-2 and then be injected to generate tumor immunogen. PROCEDURE: In a preliminary clinical trial we assessed whether the administration of transgenic IL-2-secreting fibroblasts was feasible without major toxicity and whether it had any effect regarding the activation of the immune system. We treated an 11-year-old boy with a peripheral neuroectodermal tumor of the left neck in fourth relapse, who was refractory to all available therapy. We transfected fibroblasts of the patient with an IL-2 gene expression vector using a cationic liposome reagent. In 51Cr cytotoxicity assays we obtained lysis of this patient's tumor cells by IL-2-stimulated mononuclear cells (MNCs). Under CT-guidance we intratumorally injected IL-2 transgenic autologous fibroblasts. RESULTS: We observed no local or systemic toxicity. In addition, we found a rise in the CD3+CD56+ lymphocyte population, previously described as cytokine-induced killer cells. No other hematological parameter changed significantly. CONCLUSIONS: Our data suggest that the intratumoral injection of transgenic IL-2-secreting fibroblasts is feasible without major toxicity and may lead to an increase in CD3+CD56+ cells.

CD3 Complex↗
PubMed1995

Treatment of acute renal failure with urodilatin after unrelated bone marrow transplantation in an 18-month-old boy.

Acute renal failure was imminent in an 18-month-old male infant 20 days after unrelated BMT. The infant was treated with urodilatin (URO), a natriuretic vasorelaxant peptide. Diuresis increased 2 h after the commencement of URO infusion and the furosemide infusion was reduced from 5 mg/h to 2.5 mg/h. After seven days of URO treatment diuresis was normal, the serum creatinine level had decreased, and furosemide was reduced from 12 mg/kg bw/d to 1.8 mg/kg bw/d. No side effects were observed either during or following URO therapy. We consider URO to be a promising drug for the treatment, without any apparent side effects, of imminent or manifest acute renal failure in infants following BMT.

Acute Kidney Injury↗
PubMed1995

Time course of interferon-gamma production deficiency after autologous and allogeneic stem cell transplantation for malignancies.

While success of autologous bone marrow transplantation (BMT) for malignancies largely depends on the cytotoxicity of the ablative regimen, achievement of relapse-free survival after allogeneic BMT is thought to be enhanced by immunologic effects. We therefore investigated in vivo and in vitro production of interferon-gamma (IFN-gamma), soluble interleukin-2 (IL-2) receptor alpha-chain (sCD25), tumor necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients before and during various time periods up to 2 years after autologous and allogeneic BMT. Cytokine levels were assessed in patient plasma and in supernatants of patient-derived peripheral blood mononuclear cells (PBMNC) cultured for 3 days in the presence of T cell-specific stimulation via CD3 plus IL-2. Our studies show that IFN-gamma plasma levels are decreased in autologous graft recipients before and during the first 30 days posttransplant. In allogeneic graft recipients, IFN-gamma plasma levels are also decreased during the first 30 days posttransplant, but otherwise are comparable to normal control (NC) values. In vitro stimulated PBMNC from autologous graft recipients also exhibit an IFN-gamma production defect before and during the first 30 days posttransplant. In contrast, before and up to 30 days after allogeneic BMT, stimulated IFN-gamma production is comparable to NC values but then gradually decreases, reaching its trough levels at between 61 and 180 days post-BMT. The IFN-gamma production defects in both patient groups seem to be specific, as sCD25, TNF-alpha, and GM-CSF production in stimulated PBMNC is normal or even enhanced at any time after autologous or allogeneic BMT. Deficient IFN-gamma production in patient-derived PBMNC does not correlate with variation in monocyte, T cell, or natural killer (NK) cell numbers during the posttransplantation course.

Adolescent↗
PubMed1994

Induction of two distinct natural killer-cell populations, activated T cells and antineoplastic cytokines, by interleukin-2 therapy in children with solid tumors.

Children with poor prognoses regarding solid tumors have benefited from autologous bone marrow transplantation as a treatment modality. Posttransplantation adjuvant interleukin-2 (IL-2) therapy has previously been shown to improve prognosis in adults with neoplastic disease. The improved survival probability has been attributed to IL-2-mediated stimulation of the immune system and its antineoplastic activity. In this study, 10 pediatric patients with solid tumors in complete remission after autologous stem cell transplantation were treated with recombinant IL-2, which was administered in three 5-day cycles of continuous intravenous infusions with a 2-week rest in between cycles. We demonstrated that IL-2 therapy enhanced transplantation-related stimulation of the immune system, on both the cellular and humoral levels. Peripheral blood T and natural killer (NK) cells increased by the factors four and 14, respectively. Activation of the immune system was demonstrated by significantly elevated levels of soluble IL-2 receptor (IL-2R) and increased CD25 surface expression on T lymphocytes. IL-2 also induced significant proliferation of the CD56bright NK-cell subpopulation that appears post-bone marrow transplant (BMT) and is found only in minimal amounts in normal controls. In vivo and in vitro production of tumor cytotoxic cytokines tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) was significantly stimulated following IL-2 therapy, further indicating IL-2-mediated stimulation of the antineoplastic activity of the immune system.

Adolescent↗
PubMed1993

[Hemoglobin SD disease].

A 7 year old Kurdish girl presented with a cerebral infarction and a resulting hemiparesis following a blood transfusion. Examination of the blood film suggested sickle cell anaemia. However a simultaneously carried out haemoglobin electrophoresis showed haemoglobin S and haemoglobin D. The diagnosis of haemoglobin SD disease was thereby established. This kind of haemoglobin disorder usually shows a mild clinical manifestation. According to our knowledge such serious cases have not been published before. With this disease the main emphasis is on the prevention of recurrent cerebral infarctions bay a long-term transfusion programme whereas the effects of the cerebral infarction are treated in the usual way.

Anemia, Sickle Cell↗
PubMedDate not supplied

[Immune stimulation with interleukin-2 after autologous stem cell transplantation in children and adolescents with solid tumors].

Children with solid tumors of poor prognosis have benefitted from autologous bone marrow transplantation as a treatment modality. Adjuvant interleukin-2 (IL2) therapy has previously been shown to improve prognosis in adults with some solid tumors. In this setting improved survival probability has been attributed to IL2-mediated augmentation of antineoplastic activity of the immune system. In this study 8 pediatric patients in complete remission after autologous stem cell transplantation were treated with recombinant IL2 administered in 3 cycles of 5 days continuous intravenous infusions and a two week rest in between. We demonstrated that IL2 therapy increased transplantation-related activation of the immune system both on cellular and humoral levels. Peripheral blood T and NK cell number increased by the factors 1.7 and 6.0 respectively. NK and T cell activation were further enhanced as indicated by elevated levels of soluble IL2 receptor. The production of tumor cytotoxic cytokines like alpha TNF and gamma INF was stimulated. The elevated aTNF and gamma INF cytokine synthesis seemed to be mainly related to the activation and proliferation of NK cells, as T cells obtained from patients after IL2 therapy showed a definite cytokine production deficiency after T cell specific stimulation.

Adolescent↗
PubMedDate not supplied

[Hereditary heterozygote factor VII deficiency].

Hereditary Factor VII deficiency is one of the rare congenital coagulopathies. Prolonged prothrombin time (PT) with normal partial prothrombin time (PTT) may be an indicator for Factor VII deficiency. A family with hereditary heterozygous Factor VII deficiency is presented in whom no symptoms of a bleeding disorder were clinically detectable. A discussion of the therapeutic options follows.

Blood Coagulation Tests↗