Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma.

PURPOSE: Overall survival is poor in children with primary unresectable hepatocellular carcinoma. Sorafenib has been shown to significantly improve progression-free survival in adult hepatocellular carcinoma (HCC) patients. We evaluated the experience of PLADO (cisplatin 80 mg/m(2) /day, doxorubicin 2 × 30 mg/m(2) /day) in combination with sorafenib in pediatric HCC patients. PATIENTS AND METHODS: Clinical data of 12 patients (7-16 years), 7 with unresectable tumor, were retrospectively assessed. RESULTS: In total 6/12 (50%) patients are in complete remission after a median follow-up of 20 months (4 with PLADO/sorafenib/resection, 2 with liver transplantation after local relapse). Of the seven patients with unresectable tumor, PLADO/sorafenib resulted in partial response (PR) in four, stable disease (SD) in two, and progression in one. Three are alive in CR after complete resection after 12 (alternative therapy after two cycles PLADO/sorafenib), 12 and 18 months (six cycles PLADO/sorafenib), respectively. All four patients with elevated alpha-fetoprotein levels had a marked drop after two cycles. Of the five patients with primary complete tumor resection one is alive disease-free at 27 months. Four had local or metastatic relapses (13, 7, 12, and 13 months), two of whom were rescued by liver transplantation (CR after 25 and 32 months). The main toxicity attributable to sorafenib was a hand-foot skin reaction (HFSR) in seven patients. CONCLUSION: Sorafenib in combination with PLADO may be a promising approach in pediatric HCC; HFSR was the most important toxicity. Data based on prospective studies are needed to evaluate pharmacokinetics, resectability rates, and survival in pediatric HCC treated with sorafenib.

Long-term remission after first-line single-agent treatment with arsenic trioxide of relapsed acute promyelocytic leukemia in an 8-year-old boy.

Arsenic trioxide (ATO) has been proven to be highly effective in adults with newly diagnosed or relapsed acute promyelocytic leukemia (APL). Only very limited data are published on the use of ATO as a single agent for first-line therapy of relapsed APL. The authors present a case of a 8-year-old boy with a bone marrow relapse of APL 7 years after first diagnosis, who achieved durable molecular remission with ATO as single agent: induction therapy for 12 weeks, consolidation for 4 weeks, then 6 cycles of 10 days over a period of 6 months. In total, 140 doses of ATO (0.15 mg/kg/day) were given (21 mg/kg). Consecutive promyelocytic leukemia-retinoic acid receptor α (PML-RARα) RT-PCR analyses were negative with a follow-up of 48 months. Acute or late side effects of arsenic were not observed. At present, the boy is in complete remission 4 years after the diagnosis of the relapse.

High proportion of leukemic stem cells at diagnosis is correlated with unfavorable prognosis in childhood acute myeloid leukemia.

In acute myeloid leukemia (AML), the leukemia-initiating cell is found within the CD34(+)/CD38(-) cell compartment. Over the last years evidence grew that AML is initiated and propagated by leukemic stem cells (LSCs). Conceivably, these most immature leukemia cells are more resistant to therapy and subsequently initiate relapse. The authors studied 17 patients with childhood AML treated according to the AML-BFM 98/04 protocol. At diagnosis, the authors determined the characteristic immunophenotype of the leukemic cells by flow cytometry and investigated the expression of CD34, CD38, and CD45 to define a population of immunophenotypically immature cells (CD34(+)/CD38(-)/CD45(-/low)) enriched for LSCs in many cases of AML. The authors compared the fraction of this population of all myeloid cells at diagnosis with event-free survival. Kaplan-Meier analysis revealed significant higher event free survival of patients with low CD34(+)/CD38(-)/CD45(-/low) cell proportion (<0.68%) compared to patients with high burden of this population (>0.83%; log-rank P < .04). This correlation was not found for the total number of CD34(+) cells. This is the first study to show that a higher proportion of immature CD34(+)/CD38(-)/CD45(-/low) blasts at diagnosis correlates with unfavorable prognosis in childhood AML. The results suggest that a large CD34(+)/CD38(-)/CD45(-/low) population reflects a higher fraction of LSCs, leading to increased chemotherapy resistance and elevated relapse rate. Thus the initial frequency of CD34(+)/CD38(-)/CD45(-/low) cells may serve as a prognostic marker in pediatric AML. Future treatment in childhood AML should specifically target this immature population as well as the mature blast population.

Vascular encasement as element of risk stratification in abdominal neuroblastoma.

BACKGROUND: Vascular encasement of major vessels has been introduced as element of image defined risk factors (IDRF) for stratification of abdominal neuroblastoma. Some subgroups of this tumor entity are still subject of discussion regarding surgical approach and radicality. Aim of this study was to analyse a cohort of related patients. PATIENTS AND METHODS: Children operated on for neuroblastoma with encasement of major abdominal vessels (April 2002-April 2009) were retrospectively evaluated regarding surgical procedures, intra- and postoperative complications, and outcome. RESULTS: There were 18 patients with abdominal NB and encasement of major vessels. Mean age at operation was 43.5 months (2.5-113), mean operation time was 228 minutes (157-428). Complete macroscopic tumor resection was realised in 14 children. Vascular reconstruction was necessary in 5 patients. Tumor progression/relapses requiring further operation occurred in 3 patients. Major postoperative complications were 1 loss of unilateral renal function with subsequent nephrectomy, 1 renal vein thrombosis (operative revision), 1 renal artery embolism (operative revision), and 1 ureteral obstruction (stenting). Mean follow up was 34.8 months (2-78). CONCLUSIONS: Vascular encasement as part of IDRF is a valuable tool for stratification of abdominal NB. Surgery of NB with vascular encasement includes divers and complex procedures. Children seem to benefit from complete tumor resection or at least relevant tumor reduction although operations can mean a relevant strain for the patients.

High frequency of immature cells at diagnosis predicts high minimal residual disease level in childhood acute lymphoblastic leukemia.

Prognosis for children with acute lymphoblastic leukemia (ALL) has considerably improved, yet relapse still occurs in a significant proportion of patients. Conceivably, the most immature leukemia cells may be more resistant to therapy and initiate relapse. We studied 42 patients with childhood ALL treated according to the ALL-BFM 2000 protocol. At diagnosis, we determined the characteristic immunophenotype of the leukemic cells by flow cytometry and also investigated the expression of CD34 and CD38 to define a population of immunophenotypically immature cells (CD34(+)/CD38(-)). We then studied levels of minimal residual disease (MRD) after induction therapy (day 33) and after consolidation therapy (week 12). We found a significant, increasing correlation between the prevalence of CD34(+)/CD38(-) cells at diagnosis and MRD levels at day 33 and week 12. Our results suggest that the initial frequency of CD34(+)/CD38(-) cells may serve as a prognostic marker in pediatric ALL.

Cooperative trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults.

PURPOSE: To improve risk-adapted therapy for localized childhood soft tissue sarcoma within an international multicenter setting. PATIENTS AND METHODS: Four hundred forty-one patients younger than 21 years with localized rhabdomyosarcoma and rhabdomyosarcoma-like tumors (ie, extraosseous tumors of the Ewing family, synovial sarcoma, and undifferentiated sarcoma) were eligible. Therapy was stratified according to postsurgical stage, histology, and tumor site. In unresectable tumors, treatment was further adapted depending on response to induction chemotherapy, TN classification, tumor size and second-look surgery. A novel five-drug combination of etoposide, vincristine, dactinomycin, ifosfamide, and doxorubicin (EVAIA) was evaluated for high-risk patients, but cumulative chemotherapy dosage and treatment duration were reduced for the remaining individuals as compared with that of the previous trial CWS-86. Hyperfractionated accelerated radiotherapy (HART) was recommended at doses of either 32 or 48 Gy. RESULTS: At a median follow-up of 8 years, 5-year event-free survival (EFS) and overall (OS) survival for the entire cohort was 63% +/- 4% and 73% +/- 4%, respectively (all survival rates in this abstract are calculated and displayed with +/-95% CI). EFS/OS rates by histology were 60% +/- 5%/72% +/- 5% in rhabdomyosarcoma, 62% +/- 10%/69% +/- 10% for Ewing tumors of soft tissues, 84% +/- 12%/90% +/- 10% for synovial sarcoma, and 67% +/- 38%/83% +/- 30% for undifferentiated sarcoma, respectively. Response to one cycle of the five-drug combination EVAIA was similar to that of the four-drug combination VAIA used in CWS-86. Two hundred twelve patients with rhabdomyosarcoma underwent radiation (EFS, 66% +/- 6%); 53 of those patients had a favorable risk profile and received 32 Gy of HART (EFS, 73% +/- 12%). TN classification, tumor site, tumor size, histology, and age were prognostic in univariate analysis. CONCLUSION: Improved risk stratification enabled decreased therapy intensity for selected patients without compromising survival. Intensified chemotherapy with EVAIA did not improve outcome of localized high-risk rhabdomyosarcoma.

Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97.

PURPOSE: The excellent prognosis of localized neuroblastoma in infants, the overdiagnosis observed in neuroblastoma screening studies, and several case reports of regression of localized neuroblastoma prompted us to initiate a prospective cooperative trial on observation of localized neuroblastoma without cytotoxic treatment. PATIENTS AND METHODS: For infants with localized neuroblastoma without MYCN amplification, chemotherapy was scheduled only in cases with threatening symptoms; otherwise, the tumor was either resected or observed by ultrasound and magnetic resonance imaging (MRI). RESULTS: Of 340 eligible participants, 190 underwent resection, 57 were treated with chemotherapy, and 93 were observed with gross residual tumor. Of those 93 patients with unresected tumors, spontaneous regression was seen in 44, local progression in 28, progression to stage 4S in seven, and progression to stage 4 in four. Time to regression was quite variable, with first signs of regression noted 1 to 18 months after diagnosis and in 15 of 44 patients even after the first year of life. So far, complete regression was observed in 17 of 44 patients 4 to 20 months after diagnosis. Known clinical risk factors were not able to differentiate between patients with regression and regional or metastatic progression. Overall survival (OS; 3-year OS, 0.99 +/- 0.01) and metastases-free survival (rate at 3 years, 0.94 +/- 0.03) for patients with unresected tumors was excellent and was not different from patients treated with surgery or chemotherapy. CONCLUSION: Spontaneous regression is regularly seen in infants with localized neuroblastoma and is not limited to the first year of life. A wait-and-see strategy is justified in those patients.

Long-term survival in patients with acute leukemia and chronic disseminated candidiasis despite minimal antileukemic therapy.

Infections may require discontinuation of antineoplastic chemotherapy, which, in turn, renders patients vulnerable to disease progression or relapse. We identified six patients with acute leukemia in whom antineoplastic treatment had to be discontinued because of chronic disseminated candidiasis (CDC). However, despite minimal antileukemic treatment, all patients remained in complete remission. Immunologic mechanisms associated with CDC might have had an antileukemic effect.

Giant mullerian duct cyst with malignant transformation in 15-year-old boy.

We present a case of a giant mullerian duct cyst with components of clear cell adenocarcinoma in a 15-year-old boy. Complete tumor resection was achieved in two steps. The presented case with a combination that has never been described before may change the perspective of treatment approaches for this rare entity.

A complicated case of bilateral cystic nephroma in a 16-month-old boy.

We describe a case of a progressive bilateral cystic nephroma (BCN) in a child undergoing a multistaged surgical procedure. After partial resection of the left sided tumor, a progress occurred on that side and the left kidney had to be removed 10 weeks later. After 35 months a tumor progression was observed on the right side together with an ureteral obstruction leading to a decreased renal function. In a third operation a complete tumor resection on the right side was achieved through longitudinal partial nephrectomy, reconstruction of the renal pelvis, and reanastomosis of the reconstructed pelvis and ureter. The patient showed no evidence of the disease at 28 months of follow-up. The presented case provides an evidence that in BCN a tumor progress may occur after multistaged surgical approaches. A single-staged complete tumor resection with renal salvage techniques seems indicated.

Salvage therapy of progressive and recurrent Hodgkin's disease: results from a multicenter study of the pediatric DAL/GPOH-HD study group.

PURPOSE: To evaluate a salvage therapy (ST-HD-86) for patients with progressive and relapsed Hodgkin's disease after primary treatment in the pediatric DAL/GPOH studies. The essential chemotherapeutic regimens were ifosfamide, etoposide, and prednisone (IEP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS: One hundred seventy-six patients with progression (n = 51) or first relapse (n = 125) were enrolled by 67 centers. The median time from initial diagnosis to progression/relapse was 1.1 year (range, 0.1 to 15.3 years), and the patients' median age was 14.7 years (range, 4.3 to 24.5 years). Salvage chemotherapy consisted of two to three cycles of IEP alternating with one to two cycles of ABVD supplemented in part by one to two cycles of cyclophosphamide, vincristine, procarbazine, and prednisone or lomustine (CCNU), etoposide, and prednimustine. Radiotherapy was given to involved areas using individualized doses. In the 1990s, additional high-dose chemotherapy with autologous stem-cell transplantation (SCT) was introduced for patients with unfavorable prognosis. RESULTS: Disease-free survival (DFS) and overall survival (OS) after 10 years are 62% and 75%, respectively (SE, 4% each). Of 176 patients, 73 suffered second events. The risk-factor analysis revealed the time to progression/relapse as the strongest prognostic factor (P = .0001). Patients with progression have an inferior outcome (DFS, 41%; OS, 51%), whereas patients with late relapse (> 12 months after end of therapy) do well (DFS, 86%; OS, 90%), although none of them received SCT in second remission. CONCLUSION: The result can be considered favorable. Whereas the salvage strategy for progressive disease has to be optimized further, it is possible to reduce intensity and avoid SCT in late relapses after Hodgkin's disease in childhood/adolescence.

Three-dimensional visualization and virtual simulation of resections in pediatric solid tumors.

PURPOSE: Three-dimensional visualization of solid tumors is possible because of high-resolution computed tomography and magnetic resonance imaging scans. However, additional preoperative information is often desirable in complex malignancies. For the first time, the authors present a model of preoperative 3-dimensional visualization and virtual resections in pediatric solid tumors. METHODS: Image analysis of various pediatric tumors was performed using the research software HepaVision2 (MeVis, Bremen). Organs, tumors, and the vascular system were extracted from multislice computed tomography scans. After hierarchical analysis of the vascular system, territories supplied or drained by the major vascular branches were calculated. Results were explored and virtual resections of organs were carried out using the research software InterventionPlanner (MeVis, Bremen). Data were correlated to intraoperative findings. RESULTS: Four hepatic malignancies, 4 renal tumors, and 3 other neoplasms were analyzed. The technique of 3-dimensional visualization was feasible for all investigated children (mean age 5 years and 9 months). Spatial relations between physiological and pathological structures were identified, and anatomical structures (vessels, tumor tissue, and organ parenchyma) were determined using colorimetric encoding. Virtual simulations of tumor resection were used successfully for planning of surgical procedures in the hepatic and renal tumors. CONCLUSIONS: The technique of 3-dimensional tumor visualization and virtual simulation of tumor resections provides the basis for a successful planning of complex tumor resections in children. The efficiency of these techniques should be further analyzed in series with higher numbers and differentiations of tumors.

Long-term outcome after haploidentical stem cell transplantation in children.

We present an update of our results with transplantation of highly purified stem cells from one to three loci mismatched parental donors. Sixty-three pediatric patients with acute lymphoblastic leukemias (n = 32), acute myeloid, chronic myeloid and myelomonocytic leukemias (n = 13), myelodysplastic syndromes (n = 4), lymphomas (n = 4), and various nonmalignant diseases (n = 10) underwent transplantation. Mobilized peripheral-blood stem cells were selected with either anti-CD34- or anti-CD133-coated microbeads. Patients received a median of 19.5 x 10(6) purified cells and <25,000 CD3+ T lymphocytes per kilogram, with no regular posttransplant pharmacological immunosuppression. Engraftment occurred in 98% of patients (primary sustained engraftment, 83%; engraftment after reconditioning/stem cell boosts, 15%). Moreover, all survivors but one had a stable three-lineage engraftment with a median follow up of 4.1 years (range 0.6-8 years). Primary acute graft-versus-host disease (GvHD) grade II was seen in only 7% of patients. No severe primary acute GvHD grades III-IV occurred. Thirteen percent of the patients developed transient chronic GvHD. Probability of disease-free survival (DFS) at 3 years was 60% for patients with nonmalignant diseases and 48% for patients with acute lymphatic leukemia (ALL)/non-Hodgkin lymphoma (NHL) in complete remission (CR)1-3. None of the ALL/NHL patients with active disease survived. Children with acute and chronic myeloid leukemias had a poorer outcome (3-year DFS = 18%), whereas two of four patients with myelodysplastic syndrome (MDS) are alive. Relapse probability of the whole group was not significantly increased when compared to a historical control group. The incidence of lethal viral infections was 18% between 1995 and 2002 and has since been reduced to 8% by the introduction of new therapeutic strategies. In summary, the use of stem cells from haploidentical parental donors should be strongly considered in all children who need transplantation but lack an identical donor.

Transplantation of highly purified CD34+ progenitor cells from unrelated donors in pediatric leukemia.

Unrelated donors are commonly used for hematopoietic stem cell transplants, but graft-versus-host disease (GVHD) is a major problem. We investigated whether transplantation of purified mobilized peripheral-blood CD34(+) stem cells from unrelated donors would prevent acute and chronic GVHD in pediatric patients with leukemia and avert the need for pharmacologic immunosuppression. Thirty-one pediatric patients with acute lymphoblastic leukemia (ALL, n = 16), acute myeloid (n = 7), chronic myeloid (n = 6), or juvenile myelomonocytic leukemia (n = 2) underwent transplantation. The median purity of CD34(+) cells after positive magnet-activated cell sorting was 98.5%. Patients received a median of 8.0 x 10(6) CD34(+) cells and 6 x 10(3) CD3(+) T lymphocytes per kilogram, with no posttransplantation pharmacologic immunosuppression. Primary acute GVHD > or = grade II was seen in only 10% of patients (n = 3) and occurred only after human herpesvirus 6 (HHV 6) infection. Two patients had limited chronic GVHD. Engraftment occurred in all patients (primary engraftment, n = 26; engraftment after reconditioning, n = 5). The 2-year survival estimate was 38% for all patients and 63% for patients with ALL in complete remission. Patients with myeloid malignancies had a poor outcome. In comparison to a historical control group who received unmanipulated bone marrow, our patients had a lower incidence of GVHD (P <.001). No difference was observed in the probability of relapse or survival. Study patients with ALL in remission showed a trend toward better survival (P =.07). Transplantation of purified peripheral-blood CD34(+) cells from unrelated donors effectively minimizes GVHD and may be a good therapeutic option for patients with relapsed ALL.

Enhanced erythrocyte apoptosis in sickle cell anemia, thalassemia and glucose-6-phosphate dehydrogenase deficiency.

Erythrocyte diseases such as sickle cell anemia, thalassemia and glucose-6-phosphate dehydrogenase deficiency decrease the erythrocyte life span, an effect contributing to anemia. Most recently, erythro-cytes have been shown to undergo apoptosis upon increase of cytosolic Ca(2+) activity. The present study has been performed to explore whether sickle cell anemia, thalassemia and glucose-6-phosphate dehydrogenase deficiency enhance the sensitivity of erythrocytes to osmotic shock, oxidative stress or energy depletion, all maneuvers known to increase cytosolic Ca(2+) activity. To this end, annexin binding as an indicator of apoptosis has been determined by FACS analysis. Erythrocytes from healthy individuals, from patients with sickle cell anemia, thalassemia or glucose-6-phosphate dehydrogenase deficiency all responded to osmotic shock (up to 950 mOsm by addition of sucrose for 24 hours), to oxidative stress (up to 1.0 mM tetra-butyl-hydroxyperoxide tBOOH) and to energy depletion (up to 48 hours glucose deprivation) with enhanced annexin binding. However, the sensitivity of sickle cells and of glucose-6-phosphate dehydrogenase deficient cells to osmotic shock and of sickle cells, thalassemic cells and glucose-6-phosphate dehydrogenase deficient cells to oxidative stress and to glucose depletion was significantly higher than that of control cells. Annexin binding was further stimulated by Ca(2+) ionophore ionomycin with significantly higher sensitivity of sickle cells and glucose-6-phosphate dehydrogenase deficient cells as compared to intact cells. In conclusion, sickle cells, thalassemic cells and glucose-6-phosphate dehydrogenase deficient erythrocytes are more sensitive to osmotic shock, oxidative stress and/or energy depletion, thus leading to enhanced apoptosis of those cells. The accelerated apoptosis then contributes to the shortened life span of the defective erythrocytes.