Ulrich Goebel

Mesoblastic nephroma—A report from the Gesellschaft fur Pädiatrische Onkologie und Hämatologie (GPOH)†

Surgery alone is the appropriate first‐line treatment for patients with mesoblastic nephroma (MN). Nevertheless, there are reports of local recurrences and metastasis, especially in the cellular subtype. The authors evaluated the outcome of patients with MN who were enrolled in either the International Society of Pediatric Oncology (SIOP) 93‐01/GPOH or the SIOP 2001/GPOH Nephroblastoma Study and Trial.

Therapeutic Management of Rare Malignant Pancreatic Tumors in Children

Abstract. Malignant pancreatic tumors in children are rare. The major problem for the clinician is a lack of experience and of accepted therapeutic strategies. Malignant pancreatic tumors in children show a pattern different from that in adults. In infants, especially pancreatoblastomas, solid cystic tumors of females, and endocrine carcinomas of the pancreas must be expected. We report our experience in three patients with malignant pancreatic tumors (one pancreatoblastoma and two malignant endocrine pancreatic carcinomas) and review the present literature with a focus on the typical clinical and biologic features and the presently recommended therapeutic strategies. Pancreatoblastomas and solid cystic tumors are mainly found in the head of the pancreas. Fibrotic capsules with rare, late metastases are characteristic of these tumors, indicating total resection to be an important therapeutic procedure. Pancreatoblastomas should additionally be treated with chemotherapy (ADM, IFO, cis-PL, VP16). Endocrine carcinomas of the pancreas (malignant gastrinomas and malignant insulinomas) should also primarily be treated with radical surgery, including extensive lymph node dissection. In case of distant metastasis, local resection (liver) or somatostatin in combination with chemotherapy (streptozocin in the case of malignant insulinomas) may be used.

The CD70/CD27 Pathway Is Critical for Stimulation of an Effective Cytotoxic T Cell Response against B Cell Precursor Acute Lymphoblastic Leukemia

For effective immunotherapy, maintaining the frequency and cytotoxic potential of effector cells is critical. In this context costimulation via the CD70/CD27 pathway has been proven essential. CD70 has been reported to be expressed to varying degrees on malignant B cells. However, in B cell precursor acute lymphboblastic leukemia, the most common childhood malignancy, the role of CD70 in stimulation of antileukemic T cell responses has so far not been delineated. Herein we demonstrate that in B cell precursor acute lymphboblastic leukemia expression of CD70 is low but can be induced upon blast activation via CD40. Both CD70 and CD80/CD86 up-regulated on CD40-stimulated blasts contribute to primary stimulation of T cell proliferation and cytokine production in an additive manner. These two signals also cooperate in the prevention of T cell anergy. In contrast to blockade of CD70 during the effector phase, inhibition of CD70-mediated costimulation during generation of antileukemic T cells prevents effector cell proliferation and reduces their cytotoxic capacity. Modulation of the CD70/CD27 pathway may thus represent a novel therapeutic approach for augmenting magnitude and quality of the antileukemic response in B cell precursor acute lymphboblastic leukemia.

High expression of CD40 on B-cell precursor acute lymphoblastic leukemia blasts is an independent risk factor associated with improved survival and enhanced capacity to up-regulate the death receptor CD95

CD40 and CD27, members of the tumor necrosis factor receptor (TNFR) family, are critical regulators of lymphocyte growth and differentiation. In B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we prospectively assessed the impact of CD40 and CD27 on outcome in 121 children treated according to the CoALL06-97 protocol. Expression of both CD40 and CD27 was found to be significantly higher in low- than in high-risk patients as defined by standard clinical risk parameters such as age and white blood cell count. In addition, in multivariable analysis, a very high percentage of CD40(+) blasts at diagnosis was identified as an independent favorable prognostic factor for relapse-free survival. Of note, high CD40 expression particularly protected against late relapse. In B cells, CD40 is known to enhance both antigen-presenting capacity and sensitivity to proapoptotic signals. Yet, although CD40 ligation does result in significant up-regulation of CD80/CD86 in our cohort, it is up-regulation of the death receptor CD95 that significantly correlates with the percentage of CD40(+) blasts. Thus very high expression of CD40 on BCP-ALL blasts is an independent prognostic marker indicative of superior relapse-free survival that may in part be due to CD40-dependent death receptor up-regulation.

High nerve growth factor receptor (p75NTR) expression is a favourable prognostic factor in paediatric B cell precursor-acute lymphoblastic leukaemia

Nerve growth factor (NGF) plays a pivotal role in cellular survival/death decisions with the low affinity receptor p75NTR predominately transmitting anti‐proliferative signals. In spite of its established role in B‐cell function and identification as a prognostically favourable marker in a number of malignancies, little is known about the expression pattern and prognostic significance of p75NTR in B cell precursor‐acute lymphoblastic leukaemia (BCP‐ALL). p75NTR expression was prospectively studied on primary ALL‐blasts in a cohort of paediatric patients with common ALL (n = 86) and preB‐ALL (n = 34) treated within the Co‐operative study group for childhood acute lymphoblastic leukaemia (CoALL) protocol, CoALL06‐97. Flow cytometric analysis showed that almost half of the patients expressed no or negligible amounts of p75NTR (<10%). The median expression in patients expressing p75NTR beyond that threshold was 49% (range 11–100%). In patients classified as low‐risk at diagnosis, p75NTR expression was significantly higher than in high‐risk patients (P = 0·001). Of note, p75NTR expression was lower in the 21 patients who subsequently developed relapse compared with those remaining in remission (P = 0·038). Accordingly, relapse‐free survival was significantly better in patients expressing high surface p75NTR (P = 0·041). Thus, in this prospective analysis, high p75NTR expression was a strong prognostic marker that identified a group of paediatric ALL patients with favourable outcome.

POOR RESPONSE TO PULSED HIGH-DOSE DEXAMETHASONE THERAPY IN CHILDREN WITH RESISTANT IMMUNE THROMBOCYTOPENIC PURPURA

Sir: Corticosteroids and intravenous immunoglobulins are the mainstay in treatment of resistant immune thrombocytopenic purpura (ITP) in children. However, the effect of these treatments is often transitory. Recently a pulsed high-dose dexamethasone therapy was evaluated in ten adult patients with resistant ITP [ 1 ]. Results showed a sustained remission with few side-effects. To evaluate this treatment for paediatric purposes we performed a pulsed high-dose dexamethasone therapy in five children with refractory ITP. Five children, three girls and two boys, with chronic ITP confirmed by bone marrow aspiration were enrolled into the trial. Median age was 12.8 years (range 9-15 years), median duration of disease was 5 years (range 3-8 years). The children were previously treated with steroids, intravenous immunoglobulins, anti-D-immunoglobulins and anabolic steroids and all children failed to achieve sustained remission. Splenectomy was not performed because of the risk of postsplenectomy sepsis. All children were symptomatic for ITP at time of enrollment. Four children had not received any therapy for thrombocytopenia within the last 4 weeks before the trial; in one child with a severe bleeding episode immediately before enrollment, anti-D= treatment was administered without sustained response. Therefore this child was also included in this trial. All children had normal haematological, virological and endocrinological laboratory results apart from thrombocytopenia. Children were given 25 mg/m 2 of oral dexamethasone daily for 4 consecutive days. This treatment was repeated every 28 days for a total of six cycles. Dosage corresponded to the recommendation for the adult treatment schedule of 40 rag/day (considering an average body surface of 1.73m 2 for adults). During the follow ups children did not receive any other therapy. Results (see Fig. 1) show an increase of platelets after the first cycle of treatment in four children. In three children platelet counts rose over > 50 000/gl, in two of them platelets decreased again to 10 000-30 000/gl. Two children are continuing the trial at present (11 and 12 months, respectively) with platelet counts _< 50 000/~tl. Side-effects were observed in four children. In two children they were severe enough to discontinue treatment. These children suffered from psychotic alteration with aggressive behaviour, loss of hair and dyspnoea. Two children had tolerable sideeffects including nausea, dizziness and hyperglycaemia (150-200 mg%). One patient had a weight increase of 11 kg. None of the observed side-effects persisted after treatment was intenupted or completed. High-dose methylprednisolone therapy our children was less effective compared to results in adults. The increase of platelets was transitory and both frequency and extent of side-effects were remarkably higher. This may be caused by a different pathomechanism of ITP in children compared to adults. As no therapeutic gold standard for resistant ITP is available at present, further evaluation of pulsed highdose methylprednisolone therapy in children may be considered. Regarding toleability and long-term efficacy it might be useful to evaluate different schedules in dosage, frequency and duration to reduce side-effects and increase therapeutic efficacy.