Function and size of the residual kidney after treatment of Wilms tumor.

Long-term damage to the residual kidney is of concern in the survivors of Wilms tumor. Our objective was to evaluate the long-term glomerular function and size of the residual kidney in these patients. Twenty-nine survivors of Wilms tumor diagnosed between July 1999 and June 2004 were enrolled. The glomerular function was assessed by creatinine clearance, 99mTc DTPA radionuclide scintigraphy and 24-hour urinary protein. Renal size was evaluated by ultrasonography. Median age at diagnosis and at enrollment were 2.87 ± 1.8 (range: 0.5-7.5) and 7.9 ± 3.8 years (range: 2.5-18). Median duration of follow-up was 4.78 ± 2.6 years (range: 1-8.8). Evidence of renal dysfunction in the form of either function or size was identified in eight (27.6%) children. Six children had subnormal glomerular filtration rate and one had proteinuria. Subnormal size of the residual kidney was observed in one child. Age at diagnosis, stage, and duration elapsed after nephrectomy had no association with renal dysfunction (P >.05). Long-term follow up is crucial to identify clinical nephrotoxicity among survivors of Wilms tumor.

miR-2909-mediated regulation of KLF4: a novel molecular mechanism for differentiating between B-cell and T-cell pediatric acute lymphoblastic leukemias.

BACKGROUND: microRNAs (miRNAs) play both oncogenic and oncostatic roles in leukemia. However, the molecular details underlying miRNA-mediated regulation of their target genes in pediatric B- and T-cell acute lymphoblastic leukemias (ALLs) remain unclear. The present study investigated the relationship between miR-2909 and Kruppel-like factor 4 (KLF4), and its functional relevance to cell cycle progression and immortalization in patients with pediatric ALL. METHODS: Elevated levels of miR-2909 targeted the tumor suppressor gene KLF4 in pediatric B-cell, but not pediatric T-cell ALL, as detected by pMIR-GFP reporter assay. Expression levels of genes including apoptosis-antagonizing transcription factor (AATF), MYC, B-cell lymphoma (BCL3), P21CIP, CCND1 and SP1 in B- and T-cells from patients with pediatric ALL were compared with control levels using real-time quantitative reverse transcription polymerase chain reaction, western blotting, and reporter assays. RESULTS: We identified two novel mutations in KLF4 in pediatric T-ALL. A mutation in the 3' untranslated region of the KLF4 gene resulted in loss of miR-2909-mediated regulation, while mutation in its first or third zinc-finger motif (Zf1/Zf3) rendered KLF4 transcriptionally inactive. This mutation was a frameshift mutation resulting in alteration of the Zf3 motif sequence in the mutant KLF4 protein in all pediatric T-ALL samples. Homology models, docking studies and promoter activity of its target gene P21CIP confirmed the lack of function of the mutant KLF4 protein in pediatric T-ALL. Moreover, the inability of miR-2909 to regulate KLF4 and its downstream genes controlling cell cycle and apoptosis in T-cell but not in B-ALL was verified by antagomiR-2909 transfection. Comprehensive sequence analysis of KLF4 identified the predominance of isoform 1 (~55 kDa) in most patients with pediatric B-ALL, while those with pediatric T-ALL expressed isoform 2 (~51 kDa). CONCLUSIONS: This study identified a novel miR-2909-KLF4 molecular axis able to differentiate between the pathogeneses of pediatric B- and T-cell ALLs, and which may represent a new diagnostic/prognostic marker.

Medication errors on oral chemotherapy in children with acute lymphoblastic leukemia in a developing country.

BACKGROUND: Medication errors occur universally. Inappropriate administration of chemotherapy drugs can have adverse effects in cancer patients. Our objective was to assess the rate and type of medication errors in children with acute lymphoblastic leukemia (ALL) receiving oral chemotherapy in outpatient setting. PROCEDURE: Prescription and administration of oral chemotherapy drugs in children with ALL were evaluated prospectively to determine rate and type of medication errors. Errors were defined as prescription (physician) level or administration (patient) level errors. RESULTS: Two hundred eighty-nine drugs were prescribed to 121 patients. Medication errors occurred in 36 (12.5%) prescriptions; 21(7.3%) were administration errors, 13 (4.5%) were prescribing errors, and two errors occurred at both levels. Mercaptopurine (6-MP) was significantly associated with higher rates of errors (Odds ratio [OR] = 2.1, 95% CI [confidence interval] 1-4.1) whereas lapses were less with dexamethasone (OR = 0.25, 95% CI 0.09-0.67). As a result of medication errors 28 (23.1%) patients received inappropriate doses. Twenty five (21%) patients received sub-optimal doses whereas three got higher doses of chemotherapy. On univariate analysis, socioeconomic status, education status of the caregiver, 6-MP and methotrexate were significantly associated with errors (P ≤ 0.05). On multivariate analysis, ≤ primary school education of the caregiver and prescription of methotrexate were independent predictors of errors. CONCLUSIONS: Medication errors affected nearly one fourth of the children receiving oral chemotherapy. Future studies are needed to look at effective interventions to avoid chemotherapy associated errors especially amongst the lower strata of society.

Significant male preponderance in childhood acute lymphoblastic leukemia in India and regional variation: tertiary care center experience, systematic review, and evaluation of population-based data.

Although, a slight male preponderance has been reported in childhood acute lymphoblastic leukemia (ALL) from several developed nations, several Indian studies suggest a skewed gender ratio in ALL. To assess the gender ratio at presentation in ALL in India, we used a three-prong approach: (i) center audit, (ii) systematic review of published studies on ALL in India, and (iii) assessment of population based registry data. Data on gender at presentation in ALL were extracted from these multiple sources. In our center audit, we observed a significantly higher of male:female (M:F) ratio of 3.16:1 (P = .046) in ALL as compared to world literature. In the systematic review of all ALL studies from India, 367 articles were identified and reviewed. A total of 4230 and 1843 boys and girls in these studies were assessed and the M:F ratio was 2.503:1; much higher than the world ratio but not significantly different (P = .10). Population-based data obtained from the National Cancer Registry Program also depicted a male preponderance, especially from large cities in India in a consistent manner since 1984. There is also significant (P = .025) interregional variation in the gender ratio in India. Our study clearly demonstrates a consistent male preponderance in childhood ALL in India along with significant interregional variations over the last three decades. There is a clear need of prospective nationwide multicenter assessment of high-resolution data to confirm this important observation and assess its implications, especially on the health care system.

Proteus syndrome: Clinical profile of six patients and review of literature.

OBJECTIVE: Proteus syndrome (PS) is characterized by patchy or segmental overgrowth and hyperplasia of multiple tissues and organs, along with susceptibility to development of tumors. Very few cases are reported in literature from developing countries. Due to certain overlapping features with other overgrowth syndromes, diagnosis is usually delayed. Our aim was to describe clinical profile of this rare condition in six patients. MATERIALS AND METHODS: Retrospective case sheet review of patients followed in a Pediatric Genetic and Metabolic clinic at a tertiary care institute of North India with a diagnosis of hemihypertrophy/overgrowth syndrome. RESULTS: Six cases presented with asymmetric overgrowth and peculiar features suggestive of PS were included in this study. Age at presentation was 2 months to 10 years; two were males and four were females. Hemihypertrophy was noticed in only one case at birth, and focal overgrowths in rest of other patients were seen later during childhood. CONCLUSION: Due to certain overlapping features with other overgrowth syndromes, diagnosis of PS is usually delayed. Pediatricians are the first persons who come across such patients and they should be aware about this rare condition.

Relationship of ß-catenin and postchemotherapy histopathologic changes with overall survival in patients with hepatoblastoma.

AIMS: Histopathologic spectrum and expression of ß-catenin were analyzed in patients with hepatoblastoma, diagnosed over a period of 14 years. These were correlated with the survival outcome. The morphologic features subsequent to chemotherapy were also analyzed. METHODS AND RESULTS: Histomorphologic features were studied on paraffin-embedded sections. There were 24 cases with 15 fetal, 4 embryonal, 4 macrotrabecular, and 1 of small cell subtype. Follow-up was available in 20 cases (mean = 16.8 mo). ß-catenin immunostaining performed by indirect immunoperoxidase method revealed 14 cases with nuclear and 10 cases with cytoplasmic positivity. Statistical analysis revealed no significant correlation between morphologic subtype and survival. Significant difference in survival was noted with respect to tumor stage, mitotic index, and ß-catenin staining pattern. Cases with nuclear expression had a mean survival of 71.54 ± 8.1 months in comparison with 14.71 ± 6.5 months in cases with cytoplasmic expression. Besides osteoid and cartilage formation, interesting postchemotherapy findings were the presence of tumoral maturation, hepatocellular carcinoma-like areas, peliotic-like foci, and "glomeruloid clusters." CONCLUSIONS: Nuclear ß-catenin expression is not a poor prognostic factor and this might be indicative of different genetic alterations in hepatoblastoma in the Indian subcontinent. There was no significant correlation between histologic subtype and osteoid differentiation with survival. The histopathologic changes observed were peliotic-like areas, tumoral maturation, hepatocellular carcinoma-like changes, and glomeruloid clusters besides the well-established features of osteoid differentiation after chemotherapy.

Survival outcome of childhood acute lymphoblastic leukemia in India: a resource-limited perspective of more than 40 years.

The outcome of childhood acute lymphoblastic leukemia in India has been inferior to more than 80% cure rates in developed nations. This study was done to analyze the outcome of acute lymphoblastic leukemia in India over 4 decades. There has been a gradual improvement in survival rates of up to >70% in some centers along with a decline in relapse and mortality. However, these results cannot be generalized to the entire nation. There is a crying need to address treatment abandonment, take quality improvement, educational and financial initiatives; cooperative research into risk factors and disease biology, and the implementation of risk stratification along with the assessment of response to therapy.

Antithymocyte globulin-induced acute lung injury during transplantation for aplastic anemia.

A 10-year-old boy with acquired, very severe aplastic anemia developed acute lung injury after the administration of equine antithymocyte globulin, during conditioning for allogenic bone marrow transplantation. Limited cases of antithymocyte globulin-induced acute lung injury have been described in adults. The respiratory worsening was sudden and required mechanical ventilation. The clinical course was complicated by sepsis with Escherichia coli, vancomycin-resistant enterococci, and Stenotrophomonas maltophilia. Implications for treatment are discussed and earlier literature is reviewed.

Childhood acute myeloid leukemia: an Indian perspective.

Cure rates of childhood malignancies are inferior in India as compared to developed nations. There is paucity of data addressing outcome of childhood acute myeloid leukemia (AML) from India. Hence, this study was designed to assess the outcome of childhood AML in India over the last 2 decades, identify shortcomings and suggest remedial measures. A comprehensive search to identify studies addressing outcome of childhood AML from India was carried out. International Society of Paediatric Oncology annual meeting abstracts were searched to identify unpublished data. Clinicodemographic and outcome data were extracted from these abstracts. Outcomes of <500 patients have been published to date, with predominantly small single-center series from 5 cities. Several AML protocols with modifications to suit the logistics in India have been used. Administration of chemotherapy (standard as well as oral and outpatient based) with manageable toxicity has been deemed feasible. Survival outcomes are modest (23% to 53.8%) except for AML M3 (over 80%), with high early-death rates, relapse, along with abandonment. Few series have identified prognostic parameters and disease burden at diagnosis, and used cytogenetics (for risk stratification) or bone marrow transplant (BMT). There is a need for assessment of risk factors in Indian patients; administration of adequate and appropriate therapy, both upfront and after relapse; improvement in supportive care; and national data management infrastructure with updating/monitoring of registries along with better financial and social support initiatives. These multimodal and additive remedial measures could significantly improve outcome of childhood AML in India by reducing mortality, relapse, and abandonment.

Acute lymphoblastic leukemia masquerading as juvenile rheumatoid arthritis: diagnostic pitfall and association with survival.

Acute lymphoblastic leukemia (ALL) often presents with osteoarthritic manifestations which may lead to misdiagnosis with juvenile rheumatoid arthritis (JRA). This study was designed to identify ALL patients with initial diagnosis of JRA, compare their clinicolaboratory characteristics and outcome with other ALL patients treated at our center. Case records of 762 patients with ALL were analyzed. Information regarding the clinical-demographic profile, therapy and outcome were recorded. Of the children, 49 (6.4%) had initial presentation mimicking JRA. Asymmetric oligoarthritis was the most common pattern of joint involvement. Majority presented with fever, pallor, arthritis, night pain, and bone pain. None of the routine prognostic factors including age, gender, lymphadenopathy, hepatosplenomegaly, total leukocytes count (TLC), and platelet count were significantly associated with relapse/death. The mean symptom-presentation interval (SPI), hemoglobin was significantly higher whilst the TLC was significantly lower in these patients compared to other ALL patients. The 5 year overall-survival was better than other patients with ALL (p = 0.06, by logrank test). Significantly longer SPI in these patients underscores the need for prompt and early investigations to rule out ALL in patients of JRA with atypical features and pointers of ALL. Children with ALL-mimicking JRA may belong to a subgroup of ALL with a better prognosis.

Evaluation of the genetic basis of phenotypic heterogeneity in north Indian patients with thalassemia major.

OBJECTIVES: To assess the molecular basis of phenotypic heterogeneity in north Indian patients with thalassemia major (TM). METHODS: To determine the clinical severity, 130 patients of TM were studied for the age of first presentation and frequency of blood transfusion. The type of beta mutations, Xmn-1(G)gamma polymorphism and G6PD Mediterranean mutation was characterized. Analysis of the phenotypic presentation and the genotype was performed. RESULTS: Majority (83.8%) presented before 1 year of age (mean 8.8 months). The caste distribution showed 41.6% were Aroras and 32.3% were migrants from Pakistan. IVS1-5(G-->C) was commonest (32.7%) and the common five Indian mutations comprised of 88.4% of alleles. The mean age of presentation with IVS1-5(G-->C), Fr 8/9, (+G) 619-bp del and IVS1-1(G-->T) homozygosity was 4.3, 6, 3.4 and 9.1 months respectively. Xmn-1(G)gamma status showed -/- in 66.9%, +/- in 26.1% and +/+ in 6.9% patients. Xmn-1(G)gamma-/- presented before 1 year of age. The mean age of presentation with +/+ was 18.3 months. Six hemizygous boys and one heterozygous girl with G6PD Mediterranean were found (prevalence 5.3%). Eight patients could be reclassified as thalassemia intermedia on follow up. CONCLUSIONS: This study showed that majority of TM in north India present before 1 year of age and homozygous 619-bp deletion presents the earliest. The presence of Xmn-1(G)gamma polymorphism delays the presentation, is associated with the IVS 1-1 (G-->T) and shows variable improvement with hydroxyurea therapy. Based on the results of genotyping, reevaluation of patients can improve the outcome in a few patients.

Response to zolendronic acid in children with type III osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a common genetic disorder that manifests with intrauterine or pre- or postnatal fractures, blue sclera, and deafness. Various treatments for the management of OI have been tried, of which bisphosphonates (BPs) seem to have the maximum benefit in reducing fracture rate and improving bone density. Zolendronic acid is a newer BP tried for several bone diseases, mainly in adults. The objective of our analysis was to study the response to zolendronic acid in children with type III OI. The case records of subjects with type III OI receiving zolendronic acid in the past 3 years between February 2006 and March 2009 were analyzed. Relevant details were recorded on a predesigned chart. Subjective improvement, reduction in number of fractures, and the DEXA scan Z-score were used to judge improvement. Five OI type III cases were followed up in the Genetic clinic. Presentation was from neonatal period to 7 years of age; M:F ratio was 3:2. Average duration of therapy given was 20.4 months. Improvement was noted in all patients, in the form of reduction in frequency of fractures (P = 0.002) and increase in bone density on DEXA scan (P = 0.01). Side effects noted were flu-like symptoms and myalgia. No clinical problems due to hypocalcemia were noted in any of the patients. Thus, zolendronic acid is seen as a safe and effective BP in type III OI children. The exact dose for optimal benefit is yet to be determined. The long-term effects of newer BPs need further long-term trials.

Pattern of mortality in childhood acute lymphoblastic leukemia: experience from a single center in northern India.

The outcome of acute lymphoblastic leukemia (ALL) in developing countries is inferior compared with the resource-rich nations. This descriptive study was designed to determine the pattern of deaths in children with ALL treated at a single center and identify the problem areas in management. Case records of 532 patients with ALL were analyzed. Information regarding the clinical-demographic profile, therapy, and course of illness were recorded. One hundred twenty-eight (24.0%) deaths were recorded. Sepsis (53.3%) and bleeding (15.7%) were the most common causes of mortality. The mortality rate fell significantly during the induction and remission phases of the therapy in 2 consecutive time periods between 1990 to 1997 and 1998 to 2006. The factors associated with an increased risk of death were longer symptom diagnosis interval (P=0.049), bulk disease (P=0.008), mediastinal adenopathy (P=0.001), higher total leukocyte count (P=0.001), and lower platelet count (P=0.007) at presentation as compared with the survivors. Multivariate analysis showed that longer symptom diagnosis interval (P=0.001), mediastinal adenopathy (P=0.006), lower platelet count (P=0.001), and higher total leukocyte count significantly influenced death. The estimated median time to death for the induction and remission deaths were 0.5 and 17 months, respectively. A high mortality rate necessitates the reappraisal of our treatment protocols. Many deaths should be avoidable by the provision of adequate supportive care, close supervision during and after chemotherapy, and appropriate antibiotic and antifungal therapy.

Neurofibromatosis type 1 with intracranial hemorrhage and horseshoe kidney.

A 12-year-old boy presented with a history of sudden-onset vomiting, headache, and giddiness. Two members of his family manifested neurofibromatosis type 1. On examination, the child had multiple café-au-lait spots, bilateral axillary freckles, and Lisch nodules in both eyes. A central nervous system examination revealed raised intracranial pressure. Computed tomography of the cranium revealed an intracranial hemorrhage in the right parietal region, without a midline shift. Magnetic resonance imaging of the brain revealed a hemorrhage and a neurofibromatosis bright object. Magnetic resonance angiography and digital subtraction angiography revealed no evidence of arteriovenous malformation or aneurysm. Ultrasonography of the abdomen revealed a horseshoe kidney, as confirmed by a 99m technetium dimercaptosuccinic acid renal cortical scan. He responded to treatment for the raised intracranial pressure, and remained asymptomatic during follow-up.

An autopsy report of a rare pediatric lung tumor: pleuropulmonary blastoma.

An autopsy report of pleuropulmonary blastoma (PPB) is described in a two-and-a-half-year-old male child who died within a few days of starting chemotherapy. Autopsy revealed a large tumor almost occupying the whole of left hemithorax with widespread extension to pleura. The diagnosis was confirmed to be PPB, type III on autopsy.

Multiple constitutional aetiological factors in bone marrow failure syndrome (BMFS) patients from north India.

BACKGROUND AND OBJECTIVES: A large number of patients diagnosed with bone marrow failure syndromes (BMFS), comprising aplastic anaemia (AA) and myelodysplastic syndromes (MDS), remain aetiologically uncharacterized worldover, especially in resource constrained set up. We carried out this study to identify a few constitutional causes in BMFS patients attending a tertiary care hospital in north India. METHODS: Peripheral blood lymphocyte cultures were performed (with and without clastogens) in a cohort of 135 consecutive BMFS patients, in order to detect Fanconi anaemia (FA), Down's syndrome (+21), trisomy 8 (+8) and monosomy 7 (-7). RESULTS: Constitutional factors were detected in 17 (12.6%) patients. FA defect was observed in 24.07 percent (13/54), 16.66 percent (1/6) and 2.85 percent (1/35) paediatric aplastic anaemia, paediatric MDS and adult MDS patients respectively. Down's syndrome was detected in 5.00 percent (2/40) adult aplastic anaemia patients. None of the patients revealed trisomy 8 or monosomy 7. INTERPRETATION AND CONCLUSION: Presence of an underlying factor determines appropriate management, prognostication, family screening and genetic counselling of BMFS patients. Special tests required to confirm or exclude constitutional aetiological factors are not available to majority of the patients in our country. Diepoxybutane (DEB) test yielded better results than mitomycin C (MMC) test in our experience.

Common queries in thalassemia care.

Beta thalassemia is a common genetic disorder in Indians. Around 10,000 thala-ssemia major cases are born every year. The treatment of thalassemia major patients imposes a financial burden on the family. Much progress has been made in last 15 years in understanding of the pathogenesis of thalassemia and development of effective management(1). These include development of a promising new oral iron chelator, intensive preparative regimens for stem cell transplantation and better vectors for gene therapy. In the present article, we highlight the common questions asked by the family and the general practitioners on thalassemia care.

Disseminated herpes simplex infection with cystic fibrosis: a case report.

A 6 months old female infant presented with history of fever, cough and severe respiratory distress. There was past history of recurrent attacks of pneumonia. She succumbed to the illness after a hospital stay of 7 days. Postmortem revealed morphological evidence of cystic fibrosis along with herpes simplex infection of liver and adrenals. The co-existence of disseminated herpes simplex infection and cystic fibrosis is very rare.