DICER1 Hotspot Mutations in Pleuropulmonary Blastoma: A Case Series From a Tertiary Center.

Pleuropulmonary blastoma (PPB) is a potentially aggressive, rare childhood neoplasia. We investigated histopathological features, survival, and DICER1 hotspot mutations among PPB patients. Archive records at our institution were reviewed, covering a 20-year period. Thirteen children (6 males and 7 females) with a mean age of 30.5 (range 6-83) months were included. The tumor subtypes were type I in 6 (46%), type II in 4 (31%), and type III in 3 (23%). Only tumors with type II and type III histology showed anaplasia (4/7, 57%). Median follow-up was 28 (range 9-216) months. Three-year overall survival rate was 83.3% and 3-year progression-free survival rate was 25%. Progression was seen in 60% (3/5) of type I and 66.7% (4/6) of type II and type III cases. Two patients died of disseminated disease at 9 and 44 months. Hotspot missense mutations on DICER1 gene were detected in all 11 patients with available tumor tissue. We found an additional novel germline loss-of-function mutation (c.5436dupT; p.E1813*) in 1 case. To the best of our knowledge, this is the first study to investigate hotspot missense mutations on DICER1 gene among the largest series of Turkish children with PPB.

Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation

To develop an evidence-based guideline for the empiric management of pediatric fever and neutropenia (FN). The International Pediatric Fever and Neutropenia Guideline Panel is a multidisciplinary and multinational group composed of experts in pediatric oncology and infectious disease as well as a patient advocate. The Panel was convened for the purpose of creating this guideline. We followed previously validated procedures for creating evidence-based guidelines. Working groups focused on initial presentation, ongoing management, and empiric antifungal therapy. Each working group developed key clinical questions, conducted systematic reviews of the published literature, and compiled evidence summaries. The Grades of Recommendation Assessment, Development, and Evaluation approach was used to generate summaries, and evidence was classified as high, moderate, low, or very low based on methodologic considerations. Recommendations were made related to initial presentation (risk stratification, initial evaluation, and treatment), ongoing management (modification and cessation of empiric antibiotics), and empiric antifungal treatment (risk stratification, evaluation, and treatment) of pediatric FN. For each recommendation, the strength of the recommendation and level of evidence are presented. This guideline represents an evidence-based approach to FN specific to children with cancer. Although some recommendations are similar to adult-based guidelines, there are key distinctions in multiple areas. Implementation will require adaptation to the local context.

Spontaneous pneumothorax in children with osteosarcoma: report of three cases and review of the literature.

Spontaneous pneumothorax is a rare manifestation of primary lung cancer or metastasis. It is estimated that < 1% of all cases of spontaneous pneumothorax are tumor-associated and metastatic osteogenic or soft-tissue sarcomas are associated most commonly with pneumothorax especially in the setting of cytotoxic chemotherapy or radiotherapy. In this article, we report three pediatric cases with osteosarcoma that developed spontaneous pneumothorax during chemotherapy with a review of the literature. Two of them had lung metastasis at the time of the detection of pneumothorax and the remaining patient was found to have a bronchopleural fistula. SPx is an emergency situation and early diagnosis and management can improve prognosis and quality of life of the patient however the optimal management has yet to be determined.

Survival of retinoblastoma in less-developed countries impact of socioeconomic and health-related indicators.

BACKGROUND: The survival of retinoblastoma in less-developed countries (LDCs) and the impact of socioeconomic variables on survival are not widely available in the literature. METHODS: A systematic review of publications from LDCs was performed. Articles were from multiple databases and written in seven languages. Results were correlated with socioeconomic indicators. Lower-income countries (LICs) and middle-income countries (MICs) were included in our analyses. RESULTS: An analysis of 164 publications including 14,800 patients from 48 LDCs was performed. Twenty-six per cent of the papers were written in languages other than English. Estimated survival in LICs was 40% (range, 23-70%); in lower MICs, 77% (range, 60-92%) and in upper MICs, 79% (range, 54-93%; p = 0.001).Significant differences were also found in the occurrence of metastasis: in LICs, 32% (range, 12-45); in lower MICs, 12% (range, 3-31) and in upper MICs, 9.5% (range, 3-24; p = 0.04). On multivariate analysis, physician density and human development index were significantly associated with survival and metastasis. Maternal mortality rate and per capita health expenditure were significantly associated with treatment refusal. CONCLUSIONS: Important information from LDCs is not always available in English or in major databases. Indicators of socioeconomic development and maternal and infant health were related with outcome.

Clinical, pathological and radiological evaluation of disseminated Langerhans' cell histiocytosis in a 30-month-old boy.

Langerhans' cell histiocytosis is a rare disease characterized histologically by the proliferation of Langerhans' cells. Oral involvement is frequent and the disease simulates severe localized periodontitis. In this report, we present a case of disseminated Langerhans' cell histiocytosis in a 30-month-old boy who had a mass covering the entire maxillopalatine region and suffered severe periodontal destruction in the posterior maxilla and mandible. We discuss the radiological, histopathological and immunohistochemical findings.

Randomized comparison of cefepime versus ceftazidime monotherapy for fever and neutropenia in children with solid tumors.

BACKGROUND: With the availability of new broad-spectrum antibiotics, initial therapy with a single agent has become an alternative to classic combinations, especially beta-lactam antibiotics plus aminoglycosides, in the management of febrile neutropenic cancer patients. PROCEDURE: Since January 1994, monotherapy has been used for empiric initial treatment at our center. The aim of this prospective randomized study is to compare the efficacy of cefepime (CFP), a new fourth-generation cephalosporin, and ceftazidime (CFZ) as empirical monotherapy of febrile neutropenic patients with solid tumors. From January 1998 to November 1998, 63 episodes of fever and neutropenia occurring in 33 children with solid tumors including lymphomas, were randomized to receive treatment with either CFP or CFZ. The patients were analyzed for leukocyte count and absolute neutrophil count (ANC) at entry, days in fever, neutropenia and hospitalization, and side effects of drugs. Success with or without modifications of the initial antibiotic was defined as survival through neutropenia; failure was death due to infection. RESULTS: In our study group, with a median age of 7 [(1/12)-14] years, CFP was administered in 32, and CFZ in 31 episodes. An infection was documented microbiologically in eight episodes (25%) in the CFP arm and in nine episodes (29%) in the CFZ arm. The success rate with initial empiric monotherapy was 62.5% in the CFP arm and 61.3% in the CFZ arm respectively (P > 0.05). The total success rate (success with or without modification) was 100% in both arms. No major adverse effects were observed in either groups. CONCLUSION: CFP is as effective and safe as CFZ for the empirical treatment of febrile episodes in neutropenic patients with solid tumors.

Seroprevalence of hepatitis B, hepatitis C, and human immunodeficiency virus infections in children with cancer at diagnosis and following therapy in Turkey.

BACKGROUND: Children with cancer receiving intensive chemotherapy require multiple transfusions and are at increased risk for blood transmittable diseases such as hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infections. PROCEDURE: Sera from 50 children (24 female, 26 male) admitted between January, 1994, and December, 1995, with solid tumors receiving intensive chemotherapy and multiple transfusions were investigated for HBsAg, anti-HBs, anti-HBc, anti-HCV, and anti-HIV by ELISA at diagnosis and at the end of therapy. RESULTS: HBsAg, HBV, HCV, and HIV seropositivities were 0%, 4%, 2% and 0% at diagnosis and 10%, 20%, 14% and 0% at the end of therapy, respectively. CONCLUSIONS: The high seroprevalence of HCV may be due to the lack of anti-HCV screening of blood products in the blood banks during the study period. Although the HBV seroprevalance of 20% found in this study is much lower than the value of 56% found in a previous study conducted during 1986-1989 in a similar patient population and a similar setting, it is still high. Children infected with HBV during immunosuppressive therapy are at greater risk of becoming chronic carriers and precautions must be taken for immunization of these children.

Prognostic value of proliferating cell nuclear antigen immunostaining in pediatric rhabdomyosarcomas.

BACKGROUND: The levels of proliferating cell nuclear antigen (PCNA) are almost negligible in long-term quiescent cells and increase dramatically during the cell cycle. Recently, the monoclonal antibodies to PCNA have been used to demonstrate the proliferative component of paraffin-embedded tumor tissues. It has been shown to be available as a simple histological marker of proliferative activity and the PCNA labeling index has been correlated with the prognosis of several malignant neoplasms. METHODS: Formalin fixed, paraffin embedded tissue specimens of 29 primary pediatric rhabdomyosarcomas were immunostained by using an anti-PCNA monoclonal antibody (DAKO PCNA PC10). The relationship between the PCNA index and prognosis, clinicopathological features and survival were assessed retrospectively. RESULTS: The mean PCNA index for the whole series was 54%. There was no correlation between PCNA index and any of the clinicopathological characteristics. However, patients having tumors with a high (> 54%) PCNA index demonstrated significantly lower survival rates than tumors with a low (< 54%) PCNA index (P = 0.01). Moreover, there were significantly more patients with relapse or progressive disease in the high PCNA index group (P = 0.005). CONCLUSION: The PCNA labeling index can be a useful prognostic factor and a good indicator of recurrence and/or survival in patients with rhabdomyosarcoma.

Extracranial neuroblastomas and neurological complications.

Between October 1989 and March 1997, 25 pediatric inpatients were treated for primary extracranial neuroblastoma (NB; n=20) or ganglioneuroblastoma (GNB; n=5) at the University of Istanbul, Institute of Pediatric Oncology, and these children were the subjects of this retrospective study. Seventeen (68%) of these patients experienced 19 neurological complications during the course of their disease. Fourteen had nervous system metastases or invasion. Nonmetastatic complications, including CNS infections (n=3) and new onset of seizures (n=2) secondary to metabolic encephalopathy were seen in 5 cases. By the time of the final analysis of the results, 8 of the 17 patients with neurological complications had died, 7 had either been lost to follow-up (n=4) or were in the terminal stage of their disease (n=3), and 2 were in remission. Both of the patients who were in remission had dumbbell neuroblastoma (DNB), and 1 of them, with congenital DNB, also had neurological sequelae, characterized by paraplegia and neurogenic bladder. Neurological complications occurred in 68% of NB and GNB cases. Metastatic complications were more common than nonmetastatic complications and had a poor prognosis. Neurological complications were the primary cause of mortality in this study, mortality being related to neurological complications in 63% of cases, and the final outcome was worse than expected. However, regardless of any differences in social, economic and geographic factors and different treatment protocols for NB in different pediatric oncology institutions, neurological complication rates in pediatric NB are similar in all.

Microscopic local leptomeningeal invasion at diagnosis of medulloblastoma.

PURPOSE: To document the incidence and outcome of patients with microscopic local leptomeningeal invasion at presentation, children with medulloblastoma were reviewed. METHODS AND MATERIALS: Nineteen patients (1-12 years of age), who had surgical resection (14 total, 5 subtotal) and were diagnosed as medulloblastoma, were evaluated for disease extent by pre- and postoperative computerized tomography/magnetic resonance imaging, histopathologic evaluation of leptomeninges adjacent to the resected tumor tissue, myelography/magnetic resonance of the entire spine, and analysis of cerebrospinal fluid cytology. Patients were also reviewed for disease outcome. RESULTS: Staging revealed one T2, nine T3a, eight T3b, and one T4 disease. There were 10 M0, 2 M1, 2 M2, 2 M3, and 3 Mx patients according to Chang's classification. Ten out of 19 patients (52.6%) demonstrated microscopic local leptomeningeal invasion. When only the 10 patients with M0 disease were considered, three out of five patients with microscopic local leptomeningeal invasion was found to have one or more relapses. The five other M0 patients without microscopic local invasion were in complete remission at the time of analysis. CONCLUSION: The incidence of microscopic local leptomeningeal invasion in patients with medulloblastoma is high. Whereas the impact on survival remains to be determined in larger series, data suggests prognostic role for isolated microscopic local leptomeningeal invasion, thus validity for inclusion in the future staging system.

Hypertrophic osteoarthropathy and intrathoracic Hodgkin disease of childhood.

BACKGROUND: Hypertrophic osteoarthropathy (HOA), well known in adults, is rarely encountered in children. The clinical features include clubbing of the fingers and toes, arthritis, and painful periosteal new bone formation of the tubular bones. The association of malignant disorders with HOA is more common in adults than in children. CASE: In this paper, a 12-year-old boy with intrathoracic Hodgkin disease and HOA is presented and four other children with HOA and Hodgkin disease in the literature reviewed. DISCUSSION: The presence of HOA has been thought to be a bad prognostic sign, but complete remission of Hodgkin disease and regression of clinical signs and symptoms of HOA were attained in our patient after chemotherapy and radiotherapy, and continue during 9 months post-therapy follow-up. CONCLUSIONS: HOA accompanying a malignant tumor in children is very rare. Only 5 cases have been associated with Hodgkin disease, including the present boy. It is important that patients with symptoms of HOA and an intrathoracic mass be examined carefully to rule out a malignancy.

Renal dysfunctions secondary to ifosfamide treatment in children.

With the increasing use of ifosfamide in pediatric tumors, nephrotoxicity became the point of interest since it may cause chronic morbidity. In this study, the renal glomerular and tubular functions of 25 cases with solid tumors aged between 2-17 years (median 9) who were treated with ifosfamide, were investigated. For this purpose, routine blood urea, creatinine, calcium, phosphorus, electrolytes, urinary creatinine, phosphorus, glucose, protein and urinary retinol binding protein as well as microglobulin were evaluated. Except for two patients who had hypophosphatemia, phosphaturia, and proteinuria, all the cases had normal blood biochemistry, creatinine clearance, tubular phosphate reabsorption; and none had proteinuria, hematuria, or glycosuria. In spite of these findings, urine beta 2 microglobulin and retinol binding protein were found to be high in 11 patients and this elevation persisted during the following one year in 8 cases whose treatments were stopped and their levels increased in three patients who continued to receive fosfamide therapy. In correlation with the increasing cumulative dose of ifosfamide (32-126 g/m2), urinary retinol binding protein or beta 2 microglobulin of patients who are treated with ifosfamide may predict the existence of renal toxicity even if other routine renal function tests are normal. Thus, the periodic evaluation of urinary beta 2 microglobulin and retinol binding protein in patients receiving chemotherapy containing ifosfamide is recommended.

Immunohistochemical detection of p53 protein in rhabdomyosarcoma: association with clinicopathological features and outcome.

PURPOSE: Alteration in the p53 tumor suppressor gene is the most common tumor specific genetic change identified in most major cancer types including rhabdomyosarcomas. To investigate the overexpression of p53 and its relation to clinical features and outcome in patients with rhabdomyosarcoma (RMS), an immunocytochemical study was performed. METHODS: Formalin-fixed paraffin embedded tissue sections obtained from 42 cases of RMS were immunostained with a mouse monoclonal antibody p53-D07. Staining was assessed by evaluating the percentage of p53 immunopositive cancer cell nuclei. RESULTS: Nuclear accumulation of p53 protein was detected in 8 of 42 (19%) samples. Clinical analyses of patients demonstrated no correlation between positive staining and age, sex, histological subtype, stage and overall survival. This analysis, however, was limited by the small number of patients who demonstrated p53 immunostaining. Nonetheless, a statistically significant association was observed between p53 expression and adverse outcome. Nuclear p53 expression was associated with disease progression or recurrence (p <0.001) and with a worse event free survival (p = 0.0015). CONCLUSION: The nuclear p53 immunoreaction rate is low in RMS, but p53 expression appears to correlate with poor prognosis.

Granulocyte colony-stimulating factor in neutropenic, pediatric solid tumor patients following chemotherapy.

Granulocyte colony-stimulating factor (G-CSF) has been used to reduce the duration and/or degree of neutropenia of different etiologies in recent years. In this study, experience with the use of G-CSF (Neupogen, Roche) after 123 courses of highly myelosuppressive chemotherapy administered to 31 (20 female, 11 male) patients with pediatric solid tumors is reported. G-CSF was initiated at a white blood cell (WBC) count of 918 +/- 452/microL (100-2000), at a dose of 7.6 +/- 2.3 micrograms/kg/d (5-14) subcutaneously for 5.2 +/- 2.4 days (2-18). G-CSF was given for afebrile neutropenia after 82 and for febrile neutropenia after 41 courses. Only in two episodes where G-CSF was given for afebrile neutropenia, fever developed. The average hospitalization period for febrile neutropenia was 9.8 +/- 3.3 days (5-20). Chemotherapy could be given on scheduled time and dosage in 90% of the courses in which G-CSF was used for afebrile neutropenia. G-CSF was well tolerated. Bone pain was observed in two patients and urticaria in one patient. In conclusion, G-CSF increased the WBC count effectively, there were only two febrile episodes in 82 courses in children receiving G-CSF for afebrile neutropenia, it was well tolerated, and it was found to be feasible for use in a developing country.

Evaluation of response to postradiation eight in one chemotherapy in childhood brain tumors.

Ten children, 3 to 15 years of age with high risk primary brain tumors were treated with postradiation 'eight in one' chemotherapy; vincristine, lomustine, procarbazine, hydroxyurea, cisplatin, cytosine arabinoside, cyclophosphamide and methylprednisolone. The tumors comprised of three medulloblastomas, two primitive neuroectodermal tumors, one ependymoblastoma and four anaplastic ependymomas. Treatment involved surgery (two total resection, six subtotal and two biopsy only) followed by conventional radiotherapy (primary tumor: 50-54 Gy, whole brain: 30-45 Gy, and spinal axis: 25-36 Gy). Objective tumor response with radiotherapy was achieved in 7 of 9 patients (78%) (6/8 patients with residual tumor and one patient with complete resection but positive cerebrospinal fluid cytology). Complete response was attained in 4 of 9 patients (44%). 'Eight in one' chemotherapy was initiated four weeks after radiation and repeated at 4 weekly intervals for 5-8 courses. Postradiation 'eight in one' failed to show any additional effect on tumor responses. Median survival was 34 months (range 9-48 months) with five of ten patients alive: four in complete and one in partial remission. All the five survivors were among the patients who had achieved response to initial treatment. This result suggested that degree of response to initial treatment might determine subsequent outcome and thus the choice of modality for initial therapy might be important.

Immunologic status in children with brain tumors and the effect of therapy.

The cellular and humoral immunological parameters (leucocyte, granulocyte, lymphocyte, total T, T4, T8 lymphocyte counts, lymphoproliferative response to PHA [LP-PHA], natural killer cell activity [NKCA], IgG, IgM and IgA levels) of 20 pediatric brain tumor patients were investigated before and after chemo-(CT) and radiotherapy (RT) administered according to the UIOI-PBT-91 protocol. The T4 and T8 cell percentages and the LP-PHA values before therapy were found to be significantly diminished in comparison to values obtained from 12 healthy children (p < 0.05). In patients receiving postoperative CT, all cellular immunity parameters except T8 cell number and NKCA; IgG and IgA levels were significantly decreased after two courses of CT (p < 0.05). In 7 patients given postoperative RT, a depression in all cellular immunity parameters was observed (p < 0.05). In 6 patients treated with 2 courses of postoperative CT followed by RT administered concomitantly with low dose CDDP, there was a decrease in all cellular and humoral immunity parameters, which was not found to be significant. In 5/18 patients infectious episodes in mild to moderate severity were observed, none causing mortality. It was concluded that the UIOI-PBT-91 protocol caused cellular immunosuppression both after CT and after RT and some humoral immunosuppression after CT, but was found to be tolerable in regard to acute immunological side effects.

Epidural metastasis in Wilms' tumor: a case report and review of the literature.

Spinal canal involvement is not a common pattern of metastasis in Wilms' tumor. Although early detection and treatment can achieve improvement of neurological deficit, mortality remains high. We present a 5-year-old girl who had an epidural metastasis while she was receiving chemotherapy for stage IV Wilms' tumor. Within 2 months following laminectomy, total removal of tumor, radiotherapy, and adjuvant chemotherapy some of the neurological signs improved.

Primary osteosarcoma of the cervical spine: a pediatric case report and review of the literature.

A 4 1/2-year-old girl with a primary osteosarcoma of the seventh cervical vertebra, treated by surgery and chemotherapy, and who is off therapy for 24 months with no evidence of disease is presented and the literature reviewed.