Optimizing the process of fertility preservation in pediatric female cancer patients - a multidisciplinary program.

BACKGROUND: Current evidence indicates sub-optimal incidence of fertility preservation (FP) in eligible patients. We present herein our designated multidisciplinary program for FP in pediatric and adolescent population and present our data on FP in female patients. METHODS: Pediatric patients (age 0-18) who were candidate for highly gonadotoxic treatments were referred to FP program for a multidisciplinary discussion and gonadal risk-assessment followed by either oocyte cryopreservation or ovarian cryopreservation (OCP) for female patients, and sperm banking for male patients. The OCP protocol consists of aspiration of oocytes from small antral follicles and in-vitro maturation followed by cryopreservation, as well as ovarian tissue cryopreservation. RESULTS: The establishment of a designated FP program resulted in a significant increase in referral and subsequent FP procedures of all eligible patients. Sixty-two female patients were referred for FP discussion during a period of 36 months; 41 underwent OCP; 11 underwent oocyte cryopreservation and six were declined due to parental decision. The median age was 13.2y (range 18 months-18y). Thirty-two (51.6 %) were chemotherapy-naïve. Seventeen patients (27 %) had sarcoma, 16 patients (26 %) had acute leukemia. The mean number of mature oocytes that were eventually vitrified was significantly higher in chemotherapy-naïve patients compared with chemotherapy-exposed patients (mean 12 oocytes (1-42) versus 2 (0-7)). CONCLUSION: Multidisciplinary programs that encompass experts of all relevant fields, skilled laboratory resources and a facilitated path appear to maximize the yield. We observed a considerable higher referral rates following launching a designated program and earlier OCP in chemo-naïve patients that culminated in a better fertility preservation procedure.

Does aggressive local treatment have an impact on survival in children with metastatic rhabdomyosarcoma?

PURPOSE: Due to the extensive initial distant tumour spread in metastatic rhabdomyosarcoma, the importance of local treatment is sometimes underestimated. A retrospective study was conducted to identify the prognostic value of aggressive local treatment in paediatric metastatic rhabdomyosarcoma. PATIENTS: Patients with metastatic rhabdomyosarcoma aged 1-21 years treated in France from 1998 to 2011 according to European protocols MMT-4-89, 4-91, 98 and recent national guidelines were selected. Survival comparison were performed between patients with 'aggressive local treatment' (surgery and radiotherapy) and exclusive surgery or radiotherapy, after exclusion of patients with early progression. End-points were event-free and overall survival (OS). RESULTS: A total of 101 children, median age 9 years, with majority of primaries in unfavourable sites (73 patients, pts), T2 tumours (66 pts), alveolar subtypes (65 pts) and large tumours (>5 cm, 83 pts) received various chemotherapy regimens. On univariate and multivariate analyses, OS was better after 'aggressive local treatment' (49 pts; 44.3 ± 8%), than after exclusive surgery (10 pts; 18.8% ± 15.5%) or exclusive radiotherapy (29 pts; 16.1 ± 7.2%, P < 0.006). Moreover, OS was better in the case of surgery with complete resection (41.1 ± 10.2%) or microscopic residue (56.4 ± 14.9%) than macroscopic residue (20.0 ± 12.6%; P < 0.03). CONCLUSIONS: In this large retrospective analysis, OS appeared to be better for patients receiving 'aggressive local treatment' even after adjustment for the initial patient and tumour characteristics. Isolated debulking surgery is associated with a very poor outcome and should be avoided. Aggressive local treatment in patients with rhabdomyosarcoma, even with metastasis, should be seriously considered.

Synovial sarcoma in children and adolescents: the European Pediatric Soft Tissue Sarcoma Study Group prospective trial (EpSSG NRSTS 2005).

BACKGROUND: To report the results of the first European prospective nonrandomized trial dedicated to pediatric synovial sarcoma. PATIENTS AND METHODS: From August 2005 to August 2012, 138 patients <21 years old with nonmetastatic synovial sarcoma were registered in 9 different countries (and 60 centers). Patients were treated with a multimodal therapy including ifosfamide-doxorubicin chemotherapy and radiotherapy, according to a risk stratification based on surgical stage, tumor size and site, and nodal involvement. RESULTS: With a median follow-up of 52.1 months (range 13.8-104.4 months), event-free survival (EFS) was 81.9% and 80.7%, and overall survival (OS) was 97.2% and 90.7%, at 3 and 5 years, respectively. The only significant prognostic variable at univariate analysis was the risk group: 3-year EFS was 91.7% for low-risk, 91.2% for intermediate-risk, and 74.4% for high-risk cases. In 24 low-risk patients (completely resected tumor ≤5 cm in size) treated with surgery alone, there were two local relapses and no metastatic recurrences. Among 67 high-risk patients (unresected, or axial tumor or nodal involvement), 66 underwent surgery after neoadjuvant chemotherapy. Response to chemotherapy was 55.2%, including 22.4% cases with complete or major partial remissions, and 32.8% with minor partial remissions. CONCLUSION: This study demonstrates that collaborative prospective studies on rare pediatric sarcomas are feasible even on a European scale, with excellent treatment compliance. The overall results of treatment were satisfactory, with higher survival rates than those previously published by pediatric groups. Nonetheless, larger, international projects are needed, based on a cooperative effort of pediatric and adult oncologists. CLINICAL TRIALS NUMBER: European Union Drug Regulating Authorities Clinical Trials No. 2005-001139-31.

Serum VEGF as a significant marker of treatment response in hodgkin lymphoma.

This pilot study aimed at determining serum VEGF levels (S-VEGF) at diagnosis and at restaging in children with Hodgkin lymphoma, and investigating whether this parameter provides prognostic information for remission after 2 courses of chemotherapy. PET-CT fusion was performed to assess response to treatment. Changes in S-VEGF levels were found to correlate with response to treatment for most of the children. This provides a rationale for exploring clinical interest in S-VEGF measurements in a larger group of children with Hodgkin lymphoma, and using the test for clinical trials of anti-angiogenic therapies.

Serum vascular endothelial growth factor as a significant marker of treatment response in pediatric malignancies.

The aim of this pilot study was to determine VEGF serum levels (S-VEGF) at diagnosis and at restaging in children diagnosed with cancer, and to investigate whether this parameter provides prognostic information for remission after induction therapy and response to treatment. S-VEGF levels of 35 consecutive pediatric patients with various types of cancer were assayed at diagnosis and at restaging. Levels of VEGF were determined using a commercially available ELISA anti-human VEGF immunoassay kit. Thirty-one children went into complete remission or had a very good partial response to first-line therapy; 4 patients developed tumor progression. At diagnosis average S-VEGF level was 495 pg/mL (range, 0.89--2220 pg/mL) and at restaging it decreased to 118.36 pg/mL (range, 7.44--487 pg/mL). (p=.0039). The 4 patients with tumor progression had increased S-VEGF levels at restaging. The comparison between the levels of S-VEGF at diagnosis and at restaging showed a significant difference for the patients who responded to treatment with decreased S-VEGF and the patients who developed tumor progression with increased S-VEGF (p=.0019). One child with metastatic Ewing sarcoma developed progressive disease after several weeks, with significantly progressively higher S-VEGF levels. One child with Hodgkin disease, who had a higher level at first restaging and developed progressive disease, responded to reinduction therapy and had a significantly lower level at the second restaging. The child with metastatic hepatoblastoma responded to first-line chemotherapy with concomitant decrease in S-VEGF and alpha-fetoprotein levels, but developed local recurrence with elevation in both parameters. Changes in S-VEGF levels correlated with response to treatment for most of the children diagnosed with cancer. This provides a rationale for exploring clinical interest in S-VEGF measurements of a larger group of children with malignancies, and using the test for clinical trials of antiangiogenic therapies.

Disappearance of diffuse calcinosis following autologous stem cell transplantation in a child with autoimmune disease.

A 12-year-old girl presented with arthritis, myalgia, anemia and positive ANA. Subsequently, she developed recurrent episodes of pulmonary hemorrhage, thrombocytopenia, CNS abnormalities, skin ulcers and diffuse calcinosis. This was followed by secondary antiphospholipid syndrome. Despite vigorous immunosuppression, the patient became bedridden. A peripheral blood stem cell autograft was offered when she developed pulmonary hypertension and digital ischemia at the age of 16 years. The post-transplantation course was uneventful. Liquefaction of calcinosis nodules with improvement of mobility occurred gradually. She is now 24 months post-transplant with no sign of disease activity and total disappearance of calcinosis nodules.

Delay in diagnosis of children with cancer: a retrospective study of 315 children.

To determine the demographic and systemic parameters in children with solid malignancies and to ascertain which of them affected the delay in diagnosis, a retrospective study was performed on 315 children diagnosed with a solid tumor at our hospital, including epidemiological, social, and medical issues concerning the family, the child, the medical system, and the tumor. Lag time, defined as the interval between onset of symptoms and final diagnosis, including parent delay and physician delay, was estimated for each child. Mean lag time: 15.75 weeks (w), median: 7 w, range: 0-208 w. Lowest mean values appeared in kidney tumors, highest in epithelial, brain and soft tissue sarcomas. Mean parent delay: 4.42 w, median: 1 w, range: 0-130 w. Mean physician delay: 11.17 w, median: 4 w, range: 0-206 w. Among the demographic and personal parameters, the best predictors for diagnosis delay were age of child and father's ethnic origin. Several factors influenced diagnosis delay of childhood solid tumors. Recognizing these factors could minimize the delay, thereby improving the child's chances of survival.

Central nervous system involvement in children with sarcoma.

OBJECTIVES: To summarize and analyze the experience in CNS involvement (CNSI) in children with sarcomas treated in the above-mentioned institutions. PATIENTS AND METHODS: From 1990 to 2001, all medical charts were retrospectively reviewed: 19 sarcoma patients (12 boys and 7 girls) were diagnosed with CNSI (4 osteogenic sarcomas, 11 Ewing sarcomas, 2 rhabdomyosarcomas, 1 alveolar soft part sarcoma and 1 mesenchymal chondrosarcoma). Mean age of all patients at the time of initial diagnosis was 14.9 years (range: 4-24 years), mean age at the time when CNSI was diagnosed was 16.9 years (range: 5.5-27 years). RESULTS: The frequency of CNSI among our patients was 6.17%. The following symptoms and signs (sometimes combined) presented: headache (10 patients), nausea and vomiting (6 patients), seizures (11 patients) and focal neurological signs (9 patients). The mean duration of time elapsed since diagnosis of CNSI till death or last follow-up was 5.2 months (SD: +/-5.7 months). Four patients received chemotherapy (CT) alone, 8 CT and radiotherapy (RT), 2 RT alone, 3 supportive treatment only, 1 CT and surgery and 1 surgery alone. Sixteen patients died; there was no significant difference in the duration of survival between those who were treated with RT or surgery (mean +/- SD: 6.77 +/- 6.56 months) and those who received only CT or supportive treatment (mean +/- SD: 2.60 +/- 2.94 months) (p = 0.07). Brain disease was the main cause of death in all but 1 patient who died 4 days after autologous bone marrow transplantation from uncontrolled sepsis. In 16 patients, CNSI was part of a metastatic disease. CONCLUSIONS: Among children with sarcoma, CNSI is encountered in 6.17% of cases. More effective therapy has to be developed in order to improve their outcome.

Familial severe congenital neutropenia associated with infantile osteoporosis: a new entity.

A new entity manifested by severe congenital neutropenia associated with osteoporosis and recurrent bone fracture is described in a family. A possible role for a new recognized cytokine system involved in bone remodeling, the osteoprotegerin/receptor activator of nuclear factor-kappa B ligand, is suggested.

Prophylactic therapy with enoxaparin during L-asparaginase treatment in children with acute lymphoblastic leukemia.

Forty-one consecutive children with acute lymphoblastic leukemia (ALL) received prophylaxis therapy with the low molecular weight heparin (LMWH) enoxaparin during L-asparaginase treatment. Enoxaparin was given every 24 h subcutaneously at a median dose of 0.84 mg/kg per day (range, 0.45-1.33 mg/kg per day) starting at the first dose of L-asparaginase until 1 week after the last dose. Molecular analysis for thrombophilic polymorphisms documented prothrombin G20210A mutation in 3/27 (11%), homozygosity for MTHFR C677T mutation in 5/27 (18.5%, and heterozygosity for factor V Leiden mutation in 5/27 (18.5%) children. There were no thrombotic events during 76 courses of L-asparaginase in 41 patients who had received enoxaparin. One patient suffered brain infarct 7 days after enoxaparin was stopped. There were no bleeding episodes. In a historical control group of 50 ALL children who had not received prophylactic enoxaparin during L-asparaginase treatment, two had thromboembolisms (one deep vein thrombosis and one pulmonary embolism). Enoxaparin is safe and seems to be effective in prevention of thromboembolism in ALL patients during L-asparaginase therapy. This study provides pilot data for a future randomized trial of the use of LMWH during ALL therapy for the prevention of asparaginase-associated thrombotic events.

Unusual presentation of mastoid eosinophilic granuloma in a young patient.

Eosinophilic granuloma is a well-recognized form of Langerhans cell histiocytosis, most commonly involving the skull bones, usually with an excellent prognosis. Recurrent and difficult to recognize osteolytic lesions of the skull are encountered only rarely. A patient with recurrent eosinophilic granuloma of the skull is reported. In spite of appropriate multimodality treatment, there were several recurrences, most recently with involvement of the mastoid process. Imaging studies revealed extensive involvement of surrounding structures with expansion of the tumor into the middle cranial fossa and slight pressure on the antero-medial portion of the temporal lobe of the brain. Despite extensive involvement, the patient had no complaints. Because of the rarity of such silent and unpredictable lesions, a systematic approach with regular CT and MRI follow-up is suggested.

Detection of isolated distant metastasis in soft tissue sarcoma by fluorodeoxyglucose positron emission tomography: case report.

Fluorodeoxyglucose (FDG), labeled with F-18, is a glucose analog that accumulates in cells in proportion to the rate of glucose metabolism, and increased carbohydrate metabolism has been recognized as a feature of malignant cells versus normal cells. In addition, it permits the detection of metastases not discovered by bone scan. Although detection of the primary site of disease is usually accomplished well with conventional techniques, the performance of FDG positron emission tomography (PET) may be useful to determine metastases that are not clinically evident. The authors describe a case of early detection of distant metastases by FDG-PET in a young patient diagnosed with rhabdomyosarcoma of the hand.

Late recurrence of combined hepatocellular carcinoma and hepatoblastoma in a child: case report and review of the literature.

We report on a case of late relapse of hepatocellular carcinoma in a child suffering from combined hepatoblastoma and hepatocellular carcinoma, stage IV. This is a rare event, as it has been accepted that a 5-year period free of any signs of disease in children suffering from malignant hepatic tumors is sufficient to classify such patients as survivors. In our patient, recurrence of the hepatocellular carcinoma component was diagnosed more than five years after the initial diagnosis. This case illustrates the need for more prolonged follow-ups for such children.

Long-term follow-up of children with retinoblastoma.

Twenty-one pediatric retinoblastoma (RB) patients treated between 1976 and 1994 were evaluated for late treatment-related complications. Median age at diagnosis was 24 months; median age at follow-up was 12 years; median follow-up time was 12 years. Of the 21 patients, 14 had unilateral RB and 7 had bilateral RB. Thirteen patients had received external radiotherapy and 8 children were treated by chemotherapy. Twenty-one patients had undergone enucleation. Radiation-induced cataracts were found in 3 patients, radiation retinopathy in 1, enucleation and postradiotherapy contracted socket in 1, very low visual acuity postradiotherapy in 3, severe hypotelorism in 2, growth hormone deficiency in 2, neurocognitive disorders in 6, and orbital deformation due to radiation bone atrophy was moderate-severe in 12 patients. Azoospermia was found in 1 patient treated by cyclophosphamide and vincristine. The most frequent sequela in this group of RB-cured children were postradiotherapy orbital deformation due to bone atrophy and neurocognitive disabilities. Late radiation effects must be avoided by using modern, innovative, and more sophisticated radiotherapeutic techniques. Late treatment-related complications justify the long-term follow-up of childhood RB survivors.

Large cell lymphoma of bone presented by limp.

We present a rare case of anaplastic large cell lymphoma of the bone in the leg of a child. The patient initially presented with suspected osteomyelitis of the fibula and was treated by antibiotics without apparent success. Thereafter, an open biopsy of the lesion was performed and the correct diagnosis was established. This rare case demonstrates the difficulties that a treating physician meets in establishing the correct diagnosis in a child presenting with limping. A review of the pertinent literature is introduced.

Guidelines for the recognition, prevention, and remediation of burnout in health care professionals participating in the care of children with cancer: report of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology.

This is the eighth official document of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology, instituted in 1991. It deals with a topic discussed and approved by the SIOP Committee; namely, "Recognition, prevention, and remediation of burnout in health care professionals participating in the care of children with cancer." It is addressed to the Pediatric Oncology community and outlines: 1) the general definition of burnout as mental and physical exhaustion, indifference, sense of failure as a professional, and sense of failure as a person; 2) the causes of burnout from the nature of the work itself, the work environment, and the characteristics of the individual; 3) the prevention of burnout, changing the detrimental aspects of one's work environment and modifying one's own behavior; and accepting methods to remediate burnout when it occurs.