Tang Her Jaing

Multivariate analysis of clinical prognostic factors in children with intracranial ependymomas

The optimal postoperative management of pediatric intracranial ependymomas is controversial. We analyzed clinical prognostic factors for their influence on outcome in such children. Our retrospective series included 15 with supratentorial and 28 with infratentorial tumors. Twenty ependymomas were grade II, and 23 were anaplastic. Complete resection was performed in 18 patients, incomplete resection in 19, and stereotactic biopsy in 6. Radiotherapy was done in 31 patients and chemotherapy in 13. The surviving patients have been followed 8–232 months (median: 69 months). The median survival time was 30 months, and 5-year overall survival and progression-free survival rates were 53.9% and 45.9%, respectively. By tumor site: supratentorial, 56.6% and 50.9%; infratentorial, 52.3% and 42.5%. Multivariate analysis identified complete resection (5-year progression-free survival, 71.8%) and age <3 years old as significant favorable and adverse prognostic features (relative risk, 2.59; 95% CI, 1.05–6.38), respectively. Twenty-six children relapsed 1–107 months after diagnosis (median: 12 months). Relapses were local in 22 cases, and combined local and distant in three cases. Only one of 15 patients with supratentorial tumors developed isolated spinal metastasis. Failure at the primary site is the major obstacle to improve cure rates. The extent of surgical resection and age were the only statistically significant prognostic factors.

Cefepime versus ceftazidime as empiric monotherapy for fever and neutropenia in children with cancer

Background. Monotherapy with cefepime or ceftazidime is an effective alternative to combination therapy for the treatment of febrile neutropenic adult cancer patients. We compared the efficacy and safety of cefepime and ceftazidime as empiric monotherapy of febrile neutropenia in children with cancer. Materials and methods. A prospective, open label, randomized, comparative study in pediatric cancer patients was conducted at Chang Gung Children’s Hospital from January 1, 2000, to April 15, 2001. Patients with fever and neutropenia (absolute neutrophil count of ≤500/mm3) were randomized to receive either intravenous cefepime or ceftazidime (50 mg/kg/dose as two or three doses daily). Febrile episodes were classified as microbiologically documented infection, clinically documented infection or unexplained fever. Clinical response to therapy was classified as success and failure. Results. Ninety-five pediatric cancer patients with 120 febrile neutropenic episodes were randomized to receive empiric treatment with cefepime or ceftazidime. After 72 h of treatment, 82.8% (48 of 58) of the eligible patients in the cefepime group continued with unmodified therapy, compared with 87.9% (51 of 58) in the ceftazidime group. The neutrophil count was <100/mm3 at randomization for 76% of the patients in the cefepime group and 83% of those in the ceftazidime group; the median durations of neutropenia (<500/mm3) were 8.5 and 6.5 days, respectively. Of the 96 evaluable episodes the overall success rate with unmodified empiric therapy until the end of the treatment course in the cefepime group was comparable with that in the ceftazidime group (69%vs. 71%, P = 0.95). The response rate after glycopeptides were added to the regimens was 79.2% for the cefepime group and 77.1% for the ceftazidime group. The bacterial eradication rate was 33% for the cefepime group and 20% for the ceftazidime group (P = 0.85), and the rates of new infections were 10.4%vs. 4.2% (P = 0.67), respectively. Both study drugs were well-tolerated. Three (6.4%) patients in the cefepime group and 2 (4.3%) patients in the ceftazidime group died. Conclusion. Cefepime appeared to be as effective and safe as ceftazidime for empiric treatment of febrile episodes in neutropenic pediatric cancer patients.

Metastatic ependymoma: A multi‐institutional retrospective analysis of prognostic factors

Metastatic ependymoma is exceedingly rare at diagnosis with variable prognosis reported in the literature. The purpose of this study was to identify prognostic factors in children with metastatic ependymoma.

Immune defects in active mycobacterial diseases in patients with primary immunodeficiency diseases (PIDs)

Natural human immunity to the mycobacteria group, including Mycobacterium tuberculosis, Bacille Calmette-Guérin (BCG) or nontuberculous mycobacteria (NTM), and/or Salmonella species, relies on the functional IL-12/23-IFN-γ integrity of macrophages (monocyte/dendritic cell) connecting to T lymphocyte/NK cells. Patients with severe forms of primary immunodeficiency diseases (PIDs) have more profound immune defects involving this impaired circuit in patients with severe combined immunodeficiencies (SCID) including complete DiGeorge syndrome, X-linked hyper IgM syndrome (HIGM) (CD40L mutation), CD40 deficiency, immunodeficiency with or without anhidrotic ectodermal dysplasia (NEMO and IKBA mutations), chronic granulomatous disease (CGD) and hyper IgE recurrent infection syndromes (HIES). The patients with severe PIDs have broader diverse infections rather than mycobacterial infections. In contrast, patients with an isolated inborn error of the IL-12/23-IFN-γ pathway are exclusively prone to low-virulence mycobacterial infections and nontyphoid salmonella infections, known as Mendelian susceptibility to the mycobacterial disease (MSMD) phenotype. Restricted defective molecules in the circuit, including IFN-γR1, IFN-γR2, IL-12p40, IL-12R-β1, STAT-1, NEMO, IKBA and the recently discovered CYBB responsible for autophagocytic vacuole and proteolysis, and interferon regulatory factor 8 (IRF8) for dendritic cell immunodeficiency, have been identified in around 60% of patients with the MSMD phenotype. Among all of the patients with PIDs referred for investigation since 1985, we have identified four cases with the specific defect (IFNRG1 for three and IL12RB for one), presenting as both BCG-induced diseases and NTM infections, in addition to some patients with SCID, HIGM, CGD and HIES. Furthermore, manifestations in patients with autoantibodies to IFN-γ (autoAbs-IFN-γ), which is categorized as an anticytokine autoantibody syndrome, can resemble the relatively persistent MSMD phenotype lacking BCG-induced diseases.

Chinese Patients with Defective IL-12/23-Interferon-γ Circuit in Taiwan: Partial Dominant Interferon-γ Receptor 1 Mutation Presenting as Cutaneous Granuloma and IL-12 Receptor β1 Mutation as Pneumatocele

BackgroundIL-12/23-interferon-γ circuit enhances reactive oxygen species (ROS) synthesis in macrophage to attack intracellular pathogens such as mycobacteria and salmonella. Defective ROS in patients with chronic granulomatous disease (CGD) have increased susceptibility to these pathogens. However, patients with defective IL-12/23-interferon-γ circuit rather than CGD are not recognized in Taiwan, endemic for tuberculosis and salmonella.AimThe purpose of this study was to identify Taiwanese patients with defective IL-12/23-IFN-γ circuit.Patients and MethodsIn a long-term molecular study of primary immunodeficiency diseases (PIDD), the tentative CGD patients presenting with Bacille Calmette–Guerin (BCG)-induced infection, refractory atypical mycobacterial cutaneous granuloma and osteomyelitis, recurrent salmonella sepsis, and pneumatocele were studied for the IL-12/23-IFN-γ circuit. ROS was first measured to exclude CGD. Candidate genes of IL12RB1, IFNRG1, IL12p40, IFNRG2, signal transducer and activator of transcription-1, and NF-κB essential modulator and their encoding protein expressions were analyzed.ResultsOf the 175 Taiwanese PIDD patients during a 28-year period, three patients from two unrelated families were identified with the hotspot INFRG1 deletion mutation (818del4) and had CGD features, presenting as cutaneous granuloma, and multiple osteomyelitis infected by non-tuberculosis mycobacteria, Mycobacteria avium complex and Mycobacterium scrofulaceum. Another with mis-sense IL12RB1 mutation (Arg211Pro) was noted as recurrent Salmonella enteritidis D sepsis and pneumatocele.ConclusionPatients with defective IL-12/23-IFN-γ circuit may resemble or overlap CGD manifestations of refractory cutaneous atypical mycobacterial granuloma and salmonella pneumatocele.

Successful unrelated mismatched cord blood transplantation in an infant with severe combined immunodeficiency and Mycobacterium bovis bacillus Calmette-Guèrin disease

Abstract:  The case reported here of an infant who presented with Pneumocystis carinii pneumonia, CD4+ lymphopenia, and hypogammaglobulinemia attributable to severe combined immunodeficiency (SCID). This report discussed treatment of Mycobacterium bovis bacillus Calmette‐Guèrin disease with unrelated cord blood transplantation in addition to antituberculous therapy, by adoptively transferring donor immunity with induction of mixed chimerism. Because of the unique nature of umbilical cord blood hematopoietic cells, engraftment without conditioning may be possible in SCID patients without fully matched donors.

Radiotherapy to primary CNS germinoma: how large an irradiated volume is justified for tumor control?

Between 1990 and 1999, there were 30 primary central nervous system (CNS) germinoma patients who received radiotherapy (RT) as treatment. Of these, 23 are male and 7 are female patients, with a median age of 16 years. The treatment field of RT included whole neuraxis in 10, whole brain in 8 and local tumor site in 12 patients; the median dose delivered to the whole neuraxis being 3060 cGy, with 3060 cGy to the whole brain and 5040 cGy to the tumor site. Chemotherapy was prescribed in 9 patients. The median time on follow-up for survivors is 73 months. There were 7, out of a total of 30 patients, who suffered treatment failure. Five of twelve patients (41.6%) who received partial brain RT failed in the brain, with no difference in the rate between patients with or without chemotherapy, and only 2 of 18 patients (11.1%) who received whole brain or whole neuraxis RT failed in the brain (p = 0.053). None of 5 spinal seeding patients failed in the spine and only one failed in the brain after whole neuraxis RT, one patient without whole neuraxis RT (5%) failed in the spine.In summary, partial brain RT will have higher probability of intracranial relapse, and sparing the spinal RT will not result in more spinal failure, whole brain RT would be sufficient for tumor control on primary CNS germinoma.Between 1990 and 1999, there were 30 primary central nervous system (CNS) germinoma patients who received radiotherapy (RT) as treatment. Of these, 23 are male and 7 are female patients, with a median age of 16 years. The treatment field of RT included whole neuraxis in 10, whole brain in 8 and local tumor site in 12 patients; the median dose delivered to the whole neuraxis being 3060 cGy, with 3060 cGy to the whole brain and 5040 cGy to the tumor site. Chemotherapy was prescribed in 9 patients. The median time on follow-up for survivors is 73 months. There were 7, out of a total of 30 patients, who suffered treatment failure. Five of twelve patients (41.6%) who received partial brain RT failed in the brain, with no difference in the rate between patients with or without chemotherapy, and only 2 of 18 patients (11.1%) who received whole brain or whole neuraxis RT failed in the brain (p = 0.053). None of 5 spinal seeding patients failed in the spine and only one failed in the brain after whole neuraxis RT, one patient without whole neuraxis RT (5%) failed in the spine. In summary, partial brain RT will have higher probability of intracranial relapse, and sparing the spinal RT will not result in more spinal failure, whole brain RT would be sufficient for tumor control on primary CNS germinoma.

Childhood Langerhans cell histiocytosis increased during El Niño 1997-98: A report from the Taiwan Pediatric Oncology Group

From 1995-1999, a nation-wide study of Langerhans cell histiocytosis (LCH) in children less than 15 years old was conducted by the Taiwan Pediatric Oncology Group. The demographic and clinical data of 55 cases were analyzed. Thirty-two cases presented from the beginning of 1997 to the end of 1998, when the most severe El Niño in the century occurred. The incidence was higher than expected during this El Niño period (32 cases versus 22 cases, p = 0.003). During 1997-98, most LCH was diagnosed in summer (n = 15), autumn (n = 8), and winter (n = 8) but rarely in spring (n = 1); coincidentally, rainfall was least in winter but peaked in summer. During 1997-98, the most significant increase occurred in the polyostotic LCH subcategory (p = 0.017), with younger ages at diagnosis (p = 0.039). The incidence of LCH cytopenia, fever, and diseases of the skin, liver, spleen or other organs did not differ significantly. Local treatment modality, disseminated diseases and diagnosis during the El Niño of 1997-98 were independent risk factors predicting the recurrence or progression of LCH. Our findings suggest that particular infections or other environmental factors associated with El Niño might be related to the etiology of childhood LCH.

Clinical Aspects and Genetic Analysis of Taiwanese Patients with Wiskott-Aldrich Syndrome Protein Mutation: The First Identification of X-Linked Thrombocytopenia in the Chinese with Novel Mutations

BackgroundWiskott–Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by microthrombocytopenia, eczema, and recurrent infections. However, the more than 500 patient mutations described are mainly based on Caucasian and Japanese populations. This study investigated Taiwanese patients with WASP mutations since 1985 as part of a long-term comprehensive study in primary immunodeficiency diseases (PIDs) covering 23 million inhabitants.MethodsClinical manifestations, immunologic functions, and WASP gene sequencing and expressions were analyzed in WAS patients. And, those patients with idiopathic thrombocytopenic purpura and “small” thrombocytopenia were enrolled.ResultsOf 16 patients studied in 1993–2009, 12 presented as classic WAS phenotype and four had X-linked thrombocytopenia (XLT). Almost all correlated to the WASP expression level and severity of infections. Causes of mortality in the 12 classic WAS patients were mass bleeding, Staphylococcus aureus sepsis, and cytomegalovirus (CMV) pneumonitis in three non-transplant cases, and EBV-associated lymphoproliferative disorder and CMV pneumonitis in two non-engrafted transplant patients. Splicing mutations of Int 8 (+5) G>A in cousins and insertion of 1023 C in unrelated families presented as both XLT and classic WAS phenotype in the same mutations. Four XLT patients, including two novel mutations of 1023 Ins C (in 2) and “double” missense mutations of 1378 C>T and 1421 T>C had relatively higher CD4+ memory cells and/or activated lymphocytes (CD3+CD69+) compared with those of classic WAS patients.ConclusionsThe lower ratio of XLT to classic WAS patients underestimates the burden of Taiwanese patients with WASP mutations, especially the XLT phenotype. A clustering pattern on exon 1 and five unique mutations (deletion of 45-48 ACCA, IVS 1 (−1) G>C, large deletion of promoter and exon 1 and 2, insertion 1023 C, and 1378 C>T and 1421 T>C) explain the genetic variations in different ethnic groups, despite the possibility of selection and ascertainment bias.

Quality of Life After Hematopoietic Stem Cell Transplantation in Pediatric Survivors: Comparison With Healthy Controls and Risk Factors.

Background: Hematopoietic stem cell transplantation has prolonged life for children with life-threatening diseases. Quality of life is an essential outcome for evaluating the long-term effects of transplantation. Objective: The aims of this study were to compare the quality of life of children posttransplantation to that of healthy peers and explore the variables associated with the quality of life of posttransplant children. Methods: A cross-sectional study was conducted with 43 pediatric transplantation survivors and 43 age- and sex-matched healthy peers. Results: The mean age of the transplant group was 12.06 years. The mean time since transplant was 3.73 years. After covariate adjustment, there was no difference between posttransplant and healthy children in each domain and overall quality of life, except for physical functioning where the posttransplant children had lower scores than did the healthy group. Chronic graft-versus-host disease was found to be the primary factor associated with poor posttransplant overall quality of life and emotional and social functioning. Sociodemographic variables, symptom distress, and caregiver depression were not correlated with posttransplant quality of life. Conclusions: The quality of life of pediatric transplantation survivors was comparable to that of healthy peers. Implications for Practice: The finding that children after transplant may achieve quality of life similar to their healthy peers is important information for parents to consider as they consider treatment options. For those sick children who cannot regularly attend school, their emotional and social functioning should be closely monitored.