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.

Spectrum of diseases diagnosed on bone marrow examination of 285 infants in a single tertiary care center.

OBJECTIVES: Bone marrow (BM) aspiration and trephine biopsy is one of the most valuable procedures in the evaluation of hematological disorders. There is a shortage of published literature regarding the indications, procedure, and outcome of bone marrow examination (BME) in neonates and infants. The aim of the present study is to analyze the common indications of performing BME and to assess the spectrum of disorders diagnosed from BM of neonates and infants. METHODS: A retrospective analysis of BMEs performed in infants over a period of 5 years, between 2009 and 2013 was done. RESULTS AND DISCUSSION: A total of 297 BME were performed on 285 infants, which constitutes 10.3% of pediatric BME procedures during the same period. In our institute, BME is routinely performed by trained pathologists from posterior superior iliac spine in children including infants and neonates with an overall sample adequacy of 97%. Evaluation of cytopenias and suspicion of storage disorder were the most common indications for BME procedure, while acute leukemias and storage disorders were the most common diagnoses offered in infant BM. CONCLUSIONS: Posterior superior iliac spine is a good site of BME in neonates and infants. BM trephine biopsy is a difficult procedure in this age group, however remains indispensable in situations where an infiltrative pathology is suspected. BME not only helps to make specific diagnoses but should also be used as an extremely valuable, quick, and economically viable procedure to exclude major hematological disorders including certain forms of storage disorder and hematological malignancy in this age group.

Bone Marrow Involvement in Neuroblastoma: A Study of Hemato-morphological Features.

Bone marrow involvement in neuroblastoma indicates advanced stage of disease. The recent use of autologous bone marrow "rescue", has provided an additional important reason for accurate assessment of bone marrow status in newly diagnosed patients. In this study, we analyzed 44 cases of neuroblastoma for bone marrow infiltration status and their hematological parameters. Eighty-eight bone marrow aspirate and trephine touch imprint smears and 44 trephine biopsy sections were examined in these 44 patients. Of these, 24 cases (54.5 %) showed marrow infiltration. Leucopenia and bicytopenia were significantly (p < 0.05) associated with marrow infiltration. Both bone marrow aspirate and biopsy were positive for infiltration in 16 out of 24 positive cases. Only aspirate smears were positive in 4 and only trephine biopsy in another 4 cases. The pattern of infiltration consisted of rosette formation in 40.7 % cases on aspirate smears and 22.2 % cases in trephine biopsies. Remaining cases showed diffuse and interstitial presence of tumor cells and cases positive only on trephine biopsy, showed marked stromal reaction. Bilateral trephine biopsies combined with aspirate smears picked up all positive cases compared to when they were assessed alone.

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.

Alloimmunization and autoimmunization in transfusion dependent thalassemia major patients: Study on 319 patients.

BACKGROUND: The development of anti-red blood cell antibodies (both allo-and autoantibodies) remains a major problem in thalassemia major patients. We studied the frequency of red blood cell (RBC) alloimmunization and autoimmunization among thalassemia patients who received regular transfusions at our center and analyzed the factors, which may be responsible for development of these antibodies. MATERIALS AND METHODS: The study was carried out on 319 multiply transfused patients with ß-thalassemia major registered with thalassemia clinic at our institute. Clinical and transfusion records of all the patients were examined for age of patients, age at initiation of transfusion therapy, total number of blood units transfused, transfusion interval, status of splenectomy or other interventions. Alloantibody screening and identification was done using three cell and 11 cell panel (Diapanel, Bio-rad, Switzerland) respectively. To detect autoantibodies, autocontrol was carried out using polyspecific coombs (IgG + C3d) gel cards. RESULTS: Eighteen patients out of total 319 patients (5.64%) developed alloantibodies and 90 (28.2%) developed autoantibodies. Nine out of 18 patients with alloantibodies also had autoantibodies. Age at first transfusion was significantly higher in alloimmunized than non-immunized patients (P = 0.042). Out of 23 alloantibodies, 52.17% belonged to Rh blood group system (Anti-E = 17%, Anti D = 13%, Anti-C = 13%, Anti-C(w) = 9%), 35% belonged to Kell blood group system, 9% of Kidd and 4% of Xg blood group system. CONCLUSION: Alloimmunization was detected in 5.64% of multitransfused thalassemia patients. Rh and Kell blood group system antibodies accounted for more than 80% of alloantibodies. This study re-emphasizes the need for RBC antigen typing before first transfusion and issue of antigen matched blood (at least for Rh and Kell antigen). Early institution of transfusion therapy after diagnosis is another means of decreasing alloimmunization.

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.

(68)Ga-DOTATATE positron emission tomography/computed tomography scan in the detection of bone metastases in pediatric neuroendocrine tumors.

AIM: The aim of this study is to evaluate the role of (68)Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) scan for the detection of bone metastases in pediatric neuroendocrine tumors (NETs) and to compare it with CT scan. MATERIALS AND METHODS: A total of 30 patients (18 were males and 12 were females; age range: 1-18 years; mean age 7.6 years) with histologically confirmed NETs referred to our department were retrospectively analyzed. All patients underwent (68)Ga-DOTATATE PET/CT scan at the time of diagnosis for primary staging. Contrast enhanced CT (CECT) performed at the time of PET scan acquisition was used for comparison with PET data. Imaging results were analyzed on a per-patient and on a per-lesion basis. Clinical follow-up of all patients and repeat PET/CT imaging (n = 10) was taken as the reference standard. RESULTS: Out of the 30 patients, 17 had no evidence of bone metastases on any imaging modality or on clinical follow-up while the rest of 13 patients showed evidence of bone metastases (nine showing positivity both on (68)Ga-DOTATATE PET and CT scan while four showing positivity only on (68)Ga-DOTATATE PET). Compared with CT scan, (68)Ga-DOTATATE PET detected bone metastases at a significantly higher rate (P = 0.0039). On a per lesion analysis, out of a total of 225 lesions detected by (68)Ga-DOTATATE PET, only 84 lesions could be detected by CT scan. CONCLUSION: (68)Ga-DOTATATE PET/CT scan is more useful than CECT scan for the early detection of bone metastases in pediatric NETs.

Zellweger syndrome: prenatal and postnatal growth failure with epiphyseal stippling.

We present a 2-month-old male affected by Zellweger syndrome, a rare peroxisomal disorder. The diagnosis was supported by clinical and radiological findings and established by biochemical tests. The characteristic radiological features included anomalous ossification (epiphyseal stippling). We also discuss main differential diagnoses of epiphyseal stippling and a brief literature review.

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.

Lissencephaly presenting with congenital hypothyroidism.

Lissencephaly is a rare brain malformation characterized by a smooth cerebral surface, thickened cortical mantle and microscopic evidence of incomplete neuronal migration. Association of congenital hypothyroidism with lissencephaly is seldom reported. We report a case of lissencephaly with congenital hypothyroidism.

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.

Outcome of neuroblastoma in India.

OBJECTIVES: To assess the outcome of childhood neuroblastoma in India over the last 2 decades, identify management lacunae and suggest remedial measures. METHODS: A comprehensive search to identify literature addressing outcome of childhood neuroblastoma from India was performed. International Society of Paediatric Oncology and American Society of Clinical Oncology Annual-Meeting abstracts were hand searched to identify unpublished data. Clinico-demographic and outcome data was extracted. RESULTS: Outcome of approximately 700 patients has been published over the last 2 decades with predominantly small to moderate single center series from 6 cities. Primarily non-myeloablative multiagent chemotherapy protocols alongwith surgery, have been used for treatment. A large majority of patients had stage III/IV neuroblastoma. Limited diagnostic facilities were available at most centers. Survival outcome of 8.7 to 80 % has been reported with high death and relapse rates alongwith high incomplete control/disease progression and treatment abandonment. Few series have identified prognostic parameters. Few patients with high-risk disease have been adequately treated and cured. CONCLUSIONS: There is a clear need for replicating neuroblastoma outcomes at centers of excellence in other cancer centers, improving diagnostic and laboratory facilities, administering adequate and appropriate contemporary therapy, assessing disease response and improving supportive care. National data management infrastructure along with better financial and social support initiatives are key factors.

Hepatoblastoma--an attempt of histological subtyping on fine-needle aspiration material.

Hepatoblastoma (HB) is classified into epithelial, mixed (epithelial/mesenchymal), and small-cell (anaplastic) type. Wnt/ß-catenin pathway plays a key role in hepatic development, regeneration, and tumorigenesis, and HB is known to present ß-catenin mutations (50-90%). The present study was undertaken to delineate the cytomorphologic features of HB and to evaluate the feasibility of subtyping of HB on fine-needle aspiration cytology (FNAC). The expression of ß-catenin in these tumors was also evaluated both of histopathologic sections and on the aspirated material. Thirty-three cases with fine-needle aspirates of HB were retrieved over a period of 12 years. Cytologic diagnosis was reviewed in the light of clinicoradiological data, response to therapy, and subsequent histopathology. Immunochemistry for ß-catenin was performed in 19 of 33 cases on histopathologic sections (n = 10)/cell blocks (n = 6)/cytosmears (n = 3). Based on the cytologic features, the cases were divided into fetal HB (n = 17), embryonal HB (n = 4), combined epithelial HB (n = 8), and mixed HB (n = 4). Four cases of histopathologically proven mixed HB were reported as pure epithelial HB on FNAC, as mesenchymal elements were not represented in the cytology smears. Cytoplasmic as well as nuclear staining for ß-catenin was noted in a total of 10 of 19 cases. FNAC can accurately categorize epithelial HB; however, in mixed type, the accuracy depends on number of areas sampled. Cell block can be of help to perform ancillary investigations especially ß-catenin for both diagnostic and therapeutic purposes.

Severe systemic infection masking underlying childhood leukemia.

Severe childhood infections can occasionally be accompanied by bone marrow suppression. It is unusual for infection induced marrow aplasia to evolve into acute leukemia. We share our experience in managing four children with severe sepsis and pancytopenia which in due course evolved into acute leukemia. This report emphasizes that sepsis related pancytopenia can be a harbinger of evolving hematopoietic disorders.

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.

A Study on the Expression of BCR-ABL Transcript in Mixed Phenotype Acute Leukemia (MPAL) Cases Using the Reverse Transcriptase Polymerase Reaction Assay (RT-PCR) and its Correlation with Hematological Remission Status Post Initial Induction Therapy.

INTRODUCTION: The MPAL comprise 2-5% of all acute leukemia. The present WHO 2008 classification has separated two groups in MPAL based on t(9;22) positivity and MLL rearrangement. AIMS #ENTITYSTARTX00026; OBJECTIVES: The aim of the present pilot study is to note the frequency of BCR-ABL transcript in MPAL cases using the RT-PCR assay and to correlate the status with hematological remission post induction. MATERIALS #ENTITYSTARTX00026; METHODS: A total of 10 MPAL cases classified on Flow-cytometry based on the current WHO 2008 criteria were enrolled. In all the cases Bone marrow or peripheral blood sample in EDTA was processed for molecular studies and the RT-PCR reaction carried out using primers specific to the t (9;22) and t(4;11) translocation. The post induction check marrow slides were also reviewed. RESULTS: Out of the total 10 MPAL cases, 7/10 (70%) were adult and 3/10 (30%) pediatric cases. A total of 4/10 (40%) cases showed positivity for the t(9;22) transcript and none for t (4;11). Of the 4 positive cases, 3/10(30%) were adult cases and 1/10(10%) pediatric case. The BCR-ABL transcript type in adult cases was b3a2 (p210) in 2/3 (66%) and e1a2 (p190) in 1/3 (33.3%) case. The single pediatric case was positive for b3a2 transcript. DISCUSSION #ENTITYSTARTX00026; CONCLUSION: All the 4 positive MPAL cases presented with high TLC and low platelet count (p<0.05). The positive cases also showed hematological remission at post induction check marrow (blasts<5%). This could partly be explained due to good response to the imatinib added to the treatment protocol.

Bilateral retinoblastoma presenting as metastases to forearm bones four years after the initial treatment.

Osseous metastases from retinoblastoma, the most common ocular malignant neoplasm of childhood, are reported most commonly in the skull and long bones. However, metastases to forearm bones are very rare. Here we present a case of bilateral retinoblastoma with metastases to right forearm bones four years after the initial treatment.