Heribert Jürgens

Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group's protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs

BACKGROUND In an effort to intensify osteosarcoma therapy, systemic ifosfamide was added pre- and postoperatively to an already aggressive three-drug regimen. In a subgroup of patients, loco-regional treatment intensification was attempted by using the intraarterial route to give cisplatin. PATIENTS AND METHODS Patients < or = 40 years at diagnosis of a localised, de novo high-grade central extremity osteosarcoma were eligible for inclusion into study COSS-86 if registered within three weeks from biopsy. Doxorubicin, high-dose methotrexate, and cisplatin were given to all patients. Patients who fulfilled one or more of three defined high-risk criteria received early systemic treatment intensification by adding ifosfamide as the fourth agent. Preoperatively, these high-risk patients received cisplatin either intraarterially or intravenously. RESULTS 171 eligible patients were entered, of which 128 were stratified into the high-risk group. When all 171 were analysed by intention-to-treat, actuarial overall and event-free survival rates at ten years were 72% and 66%, respectively. No benefit of intraarterial cisplatin application was detected. Cumulative treatment toxicity was considerable. CONCLUSIONS In a multicenter setting, intensive treatment of osteosarcoma according to protocol COSS-86 led to long-term disease-free survival for two thirds of patients. We saw no benefit of using the intraarterial route to administer cisplatin.

In Childhood Acute Lymphoblastic Leukemia, Blasts at Different Stages of Immunophenotypic Maturation Have Stem Cell Properties

We examined the leukemic stem cell potential of blasts at different stages of maturation in childhood acute lymphoblastic leukemia (ALL). Human leukemic bone marrow was transplanted intrafemorally into NOD/scid mice. Cells sorted using the B precursor differentiation markers CD19, CD20, and CD34 were isolated from patient samples and engrafted mice before serial transplantation into primary or subsequent (up to quaternary) recipients. Surprisingly, blasts representative of all of the different maturational stages were able to reconstitute and reestablish the complete leukemic phenotype in vivo. Sorted blast populations mirrored normal B precursor cells with transcription of a number of stage-appropriate genes. These observations inform a model for leukemia-propagating stem cells in childhood ALL.

Evaluation of prognostic factors in a tumor volume‐adapted treatment strategy for localized Ewing sarcoma of bone: The CESS 86 experience

Background. The Cooperative Ewing Sarcoma Study (CESS 86), conducted by the German Society of Pediatric Oncology and Hematology (GPOH), was planned on the basis of the results of the preceding CESS 81 study. The prognostic significance of tumor volume in localized Ewing sarcoma of bone was well documented in the CESS 81 trial. As a consequence, the treatment intensity was adapted to volume in the follow-up CESS 86 trial: the four-drug combination used in CESS 81 was amended for patients with large tumor volume (≥ 100 ml), where ifosfamide was substituted for cyclophosphamide. Procedure. From January 1986 to June 1991, 177 protocol patients with localized Ewing sarcoma of bone were registered in CESS 86. The prognostic implication of tumor volume and several covariates was evaluated using Kaplan-Meier life table analysis and Coxs proportional hazard model. Results. The estimated 5- and 8-year event-free survival (EFS) rates were both 59%. Age, gender, tumor site, and a tumor volume of 100 ml did not distinguish groups of patients with different prognosis. However, the prognosis of patients with tumors >200 ml (8-year EFS rate: 42%) was significantly inferior compared to patients with tumors both of 100 to 200 ml (70%) and of <100 ml (63%). In contrast to CESS 81, the histological response to chemotherapy was no longer a significant prognostic factor (EFS: 64% for good and 50% for poor responders, respectively). Conclusions. Despite risk-adapted treatment intensity, tumor volume retained its prognostic significance; the cut point, however, was shifted toward larger volumes.

Important Aspects of Nutrition in Children with Cancer

Adequate nutrition during cancer plays a decisive role in several clinical outcome measures, such as treatment response, quality of life, and cost of care. However, the importance of nutrition in children and young adults with malignancies is still an underestimated topic within pediatric oncology. The importance of our work is to reinforce and indicate that malnutrition in children with cancer should not be accepted at any stage of the disease or tolerated as an inevitable process. Unique to our manuscript is the close collaboration, the exchange of knowledge and expertise between pediatric oncologists and a nutritional specialist, as well as the comprehension of the mechanisms during cancer cachexia and malnutrition. We provide a critical review of the current state of research and new knowledge related to nutritional management in childhood cancer.

Ewing Sarcoma: Clinical State-of-the-Art

Ewing sarcoma, a rare malignancy of childhood and adolescence, has become a model of advances in diagnosis, treatment, and outcome through long-standing research efforts in multinational clinical trials. With modern multimodal regimens consisting of local surgery and/or radiotherapy plus intensive systemic chemotherapy, survival can be achieved for ∼70% of patients with localized disease. However, in the last decade, improvement in survival curves has slowed down. Also, a relapse rate of ∼30% remains unacceptable, since salvage strategies for Ewing sarcoma recurrence are discouraging and prognosis is unfavorable in most cases. Metastatic disease at diagnosis poses a similar challenge, since even if remission is achieved, relapse frequently occurs despite the most intensive treatment. Urgently needed, novel biology-driven treatment options are now beginning to emerge on the horizon, but have not yet reached the standard of care. An overview of the current clinical state-of-the-art is provided in this article.

Human γδ T cells as mediators of chimaeric‐receptor redirected anti‐tumour immunity

Human peripheral blood γδ T cells (Vγ9+ Vδ2+) can be selectively expanded in vivo by the systemic administration of aminobisphosphonates without prior antigen priming. To assess the potential of human γδ T cells to serve as effector cells of specific anti‐tumour immunity, we expanded peripheral blood‐derived γδ T cells and transduced them with recombinant retrovirus encoding GD2‐ or CD19‐specific chimaeric receptors. Flow cytometric analysis of T cells from four individual donors cultured in the presence of zoledronate at day 14 of culture showed selective enrichment of the γδ T cell population (Vγ9+ Vδ2+ CD3+ CD4− CD8−) to 73–96% of total CD3+ T cells. Retroviral gene transfer resulted in chimaeric receptor surface expression in 73 ± 12% of the population. Transduced γδ T cells efficiently recognized antigen‐expressing tumour cell targets, as demonstrated by target‐specific upregulation of CD69 and secretion of interferon‐α. Moreover, transduced γδ T cells efficiently and specifically lysed the antigen‐expressing tumour targets. They could be efficiently expanded in vitro and maintained in culture for prolonged periods. Zoledronate‐activated human γδ T cells expressing chimaeric receptors may thus serve as potent and specific anti‐tumour effector cells. Their responsiveness to stimulation with aminobisphosphonates may enable the selective re‐expansion of adoptively transferred T cells in vivo, permitting long lasting anti‐tumour immune control.

Synthetic Lethality Screens Reveal RPS6 and MST1R as Modifiers of Insulin-like Growth Factor-1 Receptor Inhibitor Activity in Childhood Sarcomas

The insulin-like growth factor-1 receptor (IGF1R) is emerging as a promising therapeutic target in human cancers. In the high-risk childhood sarcomas Ewing family tumor and rhabdomyosarcoma, IGF1R-blocking antibodies show impressive antitumor activity in some but not all patients, and acquired resistance is observed. Because tumor IGF1R mutations are not described, the basis of IGF1R inhibitor resistance remains unknown. We hypothesized that compensatory signaling cascades bypassing targeted IGF1R inhibition might be involved. To test this systematically, we performed small interfering RNA (siRNA) screens in sarcoma cell lines to identify IGF1R pathway components or related protein tyrosine kinase (PTK) networks that modulate the antitumor efficacy of the BMS-536924 IGF1R kinase inhibitor. This strategy revealed (a) that sarcoma cells are exquisitely sensitive to loss of distal rather than proximal IGF1R signaling components, such as ribosomal protein S6 (RPS6); (b) that BMS-536924 fails to block RPS6 activation in resistant sarcoma cell lines; and (c) that siRNA knockdown of the macrophage-stimulating 1 receptor tyrosine kinase (MST1R; also known as RON) restores BMS-536924 efficacy, even in highly drug-resistant cell lines. We confirmed MST1R expression across a broad panel of childhood sarcomas, and found that loss of MST1R by RNA interference blocks downstream RPS6 activation when combined with BMS-536924 in vitro. These findings underscore the importance of fully understanding PTK networks for successful clinical implementation of kinase inhibitor strategies.

Non-linkage of familial rhabdoid tumors to SMARCB1 implies a second locus for the rhabdoid tumor predisposition syndrome.

Rhabdoid tumors represent an independent entity among embryonal neoplasms. These tumors affect the kidney (RTK, rhabdoid tumor of kidney) and central nervous system (AT/RT, atypical teratoid, rhabdoid tumor), but may also be found in peripheral soft tissue. Unifying features include immunohistochemical characteristics and inactivation of the putative tumor suppressor gene SMARCB1 (hSNF5/INI1) in chromosome 22q11.2. Several familial cases have been published and summarized under the term rhabdoid tumor predisposition syndrome. In all of the published familial cases, inactivation of SMARCB1 was detected in tumor tissues.

High-dose ifosfamide with mesna uroprotection in Ewing's sarcoma

SummaryThe German Society of Pediatric Oncology (GPO) has studied the efficacy of high-dose ifosfamide with mesna uroprotection in patients with Ewings sarcoma. A phase II trial of ifosfamide (IFO) (2 g/m2 per day, days 1–5) in eight patients with recurrent evaluable disease resulted in three partial and two complete responses lasting from 3 to 12 months (median, 6 months). In a second phase II trial in 15 patients, the combination of IFO and cisplatin (20 mg/m2 per day, days 1–5) resulted in 7 partial and 2 complete responses lasting from 3 to 32 months (median, 6 months). Consequently, in 1985 IFO was incorporated into first-line chemotherapy for newly diagnosed patients (replacing cyclophosphamide) and given in combination with vincristine, actinomycin D, and Adriamycin (VAIA) in patients considered to be at high risk for relapse. IFO was given at a dose of 3 g/m per day on days 1 and 2 as a 48-h continuous infusion, in combination with actinomycin D (0.5 mg/m2 per day on days 1–3) or Adriamycin (30 mg/m2 per day on days 1 and 2). The study was piloted from March to December 1985 and has been open since January 1986; 37 patients were entered during the pilot phase and 65 have been entered in the ongoing main trial since January 1986. At present, Kaplan-Meier disease-free survival projects that disease-free survival in patients with large primary tumors has improved compared with that reported for the previous CESS 81 trial. The toxicity of the VAIA regimen was comparable with that of the conventional vincristine, actinomycin D, cyclophosphamide, and Adriamycin (VACA) regimen used in the previous CESS 81 trial.

Osteosarcoma of the Hand and Forearm: Experience of the Cooperative Osteosarcoma Study Group

BackgroundOsteosarcoma is extremely rare in the hand and forearm. Therefore, only limited data are available for planning treatment or predicting the outcome and prognosis of osteosarcoma in the peripheral upper extremity.MethodsEpidemiological, clinical, and histopathologic data were analyzed in 39 patients with osteosarcoma of the forearm or hand who were enrolled in studies of the Cooperative German-Austrian-Swiss Osteosarcoma Study Group from 1977 to December 2000. In patients with high-grade osteosarcoma, the treatment entailed surgical resection in combination with chemotherapy, whereas patients with low-grade osteosarcoma underwent only surgery.ResultsThe 5-year overall survival rate among the 33 patients with high-grade central osteosarcoma of the distal upper extremity was 86.2% ± 6.4%. The 5-year event-free survival rate was 65.4% ± 9.6%. Five of the eight patients with secondary metastases were in remission at the time of analysis. Four patients died of their disease, and two patients died of chemotherapy-related complications. The mean overall survival rate was 88.0% ± 6.5% in patients treated by wide or radical tumor resection and was 75.0% ± 21.7% in patients with nonwide margins of resection. Whether amputation or local resection was performed had no significant influence on the prognosis. All six patients whose osteosarcoma was not classified as high-grade central osteosarcoma were in remission at the time of analysis.ConclusionsThe results demonstrate a remarkably high survival rate for patients with high-grade osteosarcoma of the hand and forearm and confirm that multiagent chemotherapy in combination with wide excision is a highly effective treatment for this malignant tumor.