Jehovah's Witness and consent for blood transfusion in a child: The Indian scenario.

In India, the clinical guidelines and laws governing consent for blood transfusion in a minor are meager and vague. In an elective situation, whether the parents can make a decision for the child on his/her behalf or whether the doctor has the right to make the decision in the best interests of the child is not clear. We present the case scenario of a child belonging to Jehovah's Witness denomination diagnosed with Burkitt lymphoma. His parents were in a dilemma whether to opt for blood transfusion or not. In the absence of laws and guidelines in this context, and considering the complications that he developed during the treatment period, it was very challenging for us to manage the situation both medically and medico-legally. This situation highlights the need for framing consensus guidelines/laws regarding elective blood transfusion in a minor to make health-care delivery, smooth, transparent and flawless.

Comparative diagnostic test evaluation of serum procalcitonin and C-reactive protein in suspected bloodstream infections in children with cancer.

PURPOSE: To compute diagnostic test properties of C-reactive protein (CRP) and serum procalcitonin (PCT) levels in bloodstream infections in children with cancer and suspected sepsis, in comparison with blood culture as the gold standard. METHODOLOGY: Consecutive paediatric cancer patients, aged ≤14 years, with clinically suspected bloodstream infections were evaluated with blood culture and assay of PCT and CRP levels. Blood culture was taken as the gold standard for comparison. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), likelihood ratio (LR) and receiver operating characteristic (ROC) with area under ROC curve (AUC) were calculated to assess the diagnostic test performance for PCT and CRP.Results/Key findings. The ROC curve for PCT was better than that for CRP, with an AUC of 0.751 for PCT at a cut-off of 2.25 ng ml-1. The AUC for CRP was 0.638 at a cut-off of 8.0 mg dl-1. Among the three cut-off values of PCT selected from the ROC curve applicable to the patients under study, the cut-off value of ≥0.49 ng ml-1 had the maximum sensitivity of 81.4 % and an NPV of 94.67 %; ≥2.25 ng ml-1 had a sensitivity and specificity of 65.12 and 71.6 %, respectively, and ≥6.47 ng ml-1 had a maximum specificity of 82.10 %. For CRP, the cut-off value of ≥5.3 mg dl-1 had the maximum sensitivity of 72.09 %; ≥8.0 mg dl-1 had a sensitivity and specificity of 58.14 and 68.09 %, respectively, and ≥8.4 mg dl-1 had the maximum specificity of 70.04 %. CONCLUSION: PCT is a better serological marker for excluding bloodstream infections than CRP. The cut-off value of 0.49 ng ml-1 with a negative predictive value of 94.67 % will be ideal in a clinical setting of immune-compromised children with suspected sepsis.

Computational and mechanistic studies on the effect of galactoxyloglucan: Imatinib nanoconjugate in imatinib resistant K562 cells.

Imatinib mesylate, a BCR/ABL fusion protein inhibitor, is the first-line treatment against chronic myelogenous leukemia. In spite of its advantageous viewpoints, imatinib still has genuine impediments like undesirable side effects and tumor resistance during chemotherapy. Nanoparticles with sustainable release profile will help in targeted delivery of anticancer drugs while minimizing deleterious side effects and drug resistance. The use of biopolymers like galactoxyloglucan (PST001) for the fabrication of imatinib mesylate nanoparticles could impart its use in overcoming multidrug resistance in chronic myelogenous leukemia patients with minimal side effects. This study involved in the synthesis of PST-Imatinib nanoconjugates with appreciable drug payload and excellent cytotoxicity against drug-resistant chronic myelogenous leukemia cell line (K562) in comparison with free drug. The use of bioinformatics tool revealed better binding affinity for the drug-polysaccharide complex than the drug alone with three proteins: 3QX3 (Topoisomerase), 1M17 (EGFR tyrosine kinase domain), and 3QRJ (ABL1 kinase domain). Assessment of the biochemical, hematological, and histopathological parameters in mice upheld the security and adequacy of the nanoconjugate compared to free drug. Although perspective investigations are warranted, in a condition like drug resistance in leukemia, this nanoconjugate would display a productive approach in cancer therapeutics.

Profiling gene mutations, translocations, and multidrug resistance in pediatric acute lymphoblastic leukemia: a step forward to personalizing medicine.

Precise risk stratification and tailored therapy in acute lymphoblastic leukemia (ALL) can lead to enhanced survival rates among children. Translocations and mutations along with multidrug resistance markers are important factors that determine therapeutic efficacy. Gene mutation profiling of patients at the time of diagnosis can offer accurate clinical decision-making. Multiplex PCR was used to screen for various translocations, mutations, and P-glycoprotein (P-gp) status in pediatric ALL samples. The roles of P-gp were analyzed at the transcriptional and translational levels by using real-time PCR and immunoblotting, respectively. ALL specific cell line Jurkat was used to validate the functional role of P-gp in imparting drug resistance by siRNA knockdown studies. Co-occurrence of translocations and mutations contributes to cellular drug resistance. Presence of any translocation in addition to FLT3/ITD hints for overactive P-gp. Co-occurrence of E2A/PBX and TEL/AML has also been positively correlated with P-gp status. Multiplex PCR provides a rapid and cost effective technique for profiling translocations, mutations, and multidrug resistance status that determines what therapy patients could be administered. Mutation profiling in patients for analyzing genetic lesions along with drug resistance profiling will help improve risk stratification and personalized medicine, thereby increasing the treatment success rates among pediatric patients with leukemia.

Synchronous Occurance of Acute Myeloid Leukemia and Rhabdomyosarcoma.

Metachronous primary distinct tumors are frequently and increasingly encountered in oncology clinical practice of recent times, but synchronous tumours are still a rarity. We report an unusual case of a 2 year old male child who had synchronous occurrence of rhabdomyosarcoma of pelvis and acute myeloid leukemia.Our search of literature suggests that this may be the first reported case of simultaneous occurrence of these two malignancies.

Rare presentation of pediatric acute promyelocytic leukemia as multiple lytic bone lesions: case report and review of literature.

Acute promyelocytic leukemia (APL) is an uncommon malignancy in the pediatric population, accounting for only 5-10% of pediatric acute myeloid leukemias, and for this disease to present with bone lesions at diagnosis is extremely unusual. We wish to convey that very rarely, in a pediatric cancer patient presenting with multiple extensive lytic bone lesions, the diagnosis can be APL. The treatment protocol and prognostic implications are vastly different. Histopathology is the gold standard in arriving at a correct diagnosis and delivering proper treatment in such cases. This patient had excellent response to chemotherapy.

Precocious puberty as initial presentation in mediastinal tumour.

Numerous disorders can cause precocious puberty in children, and germ cell tumours (GCT) are one of the rare causes . We report two cases of mediastinal malignant GCTs who presented with precocious puberty. Both patients had bulky and advanced disease, were aggressively treated with neo-adjuvant chemotherapy and surgery, and are surviving and free of disease.

Effectiveness of chemotherapy in melanotic neurectodermal tumor of infancy.

MNTI is an uncommon tumor mainly of infants. Surgery is the primary modality of treatment. Chemotherapy has been tried for recurrent/residual tumors. The chemotherapeutic response of 3 infants treated at a center is discussed here. All 3 infants showed good response to chemotherapy. In 2 of them complete residual tumor resection became possible; 2 of them are alive and tumor regression continues. One child had local recurrence later and was lost for follow-up.

DNA repair gene XRCC1 polymorphisms in childhood acute lymphoblastic leukemia.

Defective DNA repair has been reported to be a risk factor for various malignancies. Genetic polymorphisms of DNA repair genes are thought to result in different phenotypic features compared to the wild type. Genetic polymorphisms in XRCC1 gene could, through alteration of protein structure, lead to defective functioning of DNA Polbeta, PARP and LIG3 enzymes resulting in defective DNA repair and increased risk of childhood acute lymphoblastic leukemia (ALL). The role of DNA repair gene XRCC1 in susceptibility to childhood ALL has, however, not been widely studied and no data exists from Indian children. In this pilot study, through the use of PCR and RFLP, further confirmed by DNA sequencing, we have shown an increased risk of ALL among children with XRCC1 codons 194 and 399 variant genotypes. Among the three variants, only the association between codon 399 variant and risk of ALL appeared to be significant. The risk of ALL was higher in males with codons 194 and 399 polymorphisms than in females. However, no relation was found between the presence of these variant genotypes and treatment outcome.

In vitro drug sensitivity and apoptosis induction in newly diagnosed pediatric acute lymphoblastic leukemia: correlation with overall survival.

The present study looked for any associations between in vitro drug sensitivity and clinical outcome in pediatric acute lymphoblastic leukemia (ALL) with the standard drugs used for leukemia therapy. A total of 72 samples were analyzed. In vitro sensitivity to drugs was tested by a methylthiazol-tetrazolium assay in 6 serial fold dilutions. Apoptosis was determined by TUNEL assay and apoptotic index was calculated for each sample. Patients sensitive to prednisone, asparginase, vincristine, and 6-mercapto purine had higher overall survival compared to patients whose tumor cells were resistant to these drugs (p < .01). For the other drugs tested, overall survival did not vary from that of the resistant patients. For doxorubicin, asparginase, vincristine, prednisone combination sensitivity, there was a significant worsening of prognosis from the extremely sensitive patients through an intermediate sensitive group to a most resistant group. The present study thus shows that in vitro drug-sensitivity testing provides significant prognostic information in childhood ALL.

Genetic polymorphism of CYP1A1, CYP2D6, GSTM1 and GSTT1 and susceptibility to acute lymphoblastic leukaemia in Indian children.

BACKGROUND: Biotransformation plays a crucial role in carcinogen activity and many genetic polymorphisms in xenobiotic metabolising enzymes have been associated with an increased risk of cancer. Such polymorphisms can lead to considerable variation in the activities of these enzymes, which are crucial in carcinogen and drug metabolism. These variations could play a role in the risk of developing paediatric acute lymphoblastic leukaemia (ALL) by their varying action on environmental carcinogens. PROCEDURE: The present study looked for two polymorphisms (m1 and m2) in the CYP1A1, CYP2D6*4 genes and deletions of the glutathione S-transferases (GSTM1 and GSTT1) in 118 paediatric ALL patients and 118 age matched control children. The polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to study gene polymorphisms. RESULTS: In children with ALL, CYP1A1 m1 polymorphism was evident in 42.4% of subjects and CYP1A1 m2 in 37.3%. These were significantly different from the results obtained for control children (20.3% for CYP1A1 m1 and 19.5% for m2). Subjects with CYP1A1 m1 homozygous variant had a sixfold risk and CYP1A1 m2 a fourfold risk. In contrast, CYP2D6*4 was more prevalent in the controls than in the cases. Subjects with GSTM1 deletions had increased risk of ALL (OR = 2.1, P = 0.009). The odds ratios for both CYP1A1 m1 and m2 homozygous polymorphisms being associated with childhood ALL was 5.67 (95% CI = 2.11-15.27). The odds ratios for both GSTM1 and GSTT1 deletions being associated with ALL was 2.78 (95% CI = 0.67-11.56). CONCLUSIONS: These results suggest that genetic polymorphisms of xenobiotic metabolising enzymes appear to influence susceptibility to childhood ALL.

Metastatic osteosarcoma causing intussusception.

Osteosarcoma is the most common malignant bone neoplasm. It has a very high metastatic potential, and lungs are the most common site of metastasis followed by bones. Multiagent chemotherapy has been reported to alter the biological behavior of the disease so that the tumor metastasizes to more rare sites such as brain, bowel, and soft tissues. The authors report a case of jejuno-jejunal intussusception caused by metastases from osteosarcoma.

Expression of folate sensitive and aphidicolin induced chromosomal fragile sites in familial neuroblastoma.

The expression of folate sensitive and aphidicolin induced fragile sites in the blood lymphocyte chromosomes of affected and unaffected members from 2 neuroblastoma families were studied. The subjects included 4 neuroblastoma patients, and 9 of their clinically healthy first degree relatives and corresponding number of age and sex matched controls. Lymphocytes cultured in folate deprived culture medium showed rare fragile sites at band p13.1 of chromosome 1, in a frequency of 3%-5% in all the 4 neuroblastoma patients. In aphidicolin treated cultures, the patients and unaffected members in neuroblastoma families, showed hypersensitivity to aphidicolin, as evidenced by the significant increase in percentage of aberration/cell (ab/c) and damaged cells (dc), over that of controls (P < 0.01). Aphidicolin induced fragile sites were more pronounced in chromosomes 1 and 2. A larger number of subjects have to be studied to prove whether altered fragile site expression may be a cytogenetic evidence for an individual or familial cancer predisposing genetic constitution.

Permanent disabilities in childhood survivors of Langerhans cell histiocytosis.

This study evaluates the permanent disabilities in children treated for Langerhans cell histiocytosis (LCH). From January 1983 to December 1993, 50 patients with newly diagnosed biopsy proven LCH were seen at the Regional Cancer Centre, Trivandrum, India. Disease pattern, treatment, survival, and disabilities of the patients were studied. Patients with localized disease had surgery, irradiation, or steroids. Patients with disseminated disease had combination chemotherapy. Follow-up ranged from 36 to 156 months (median follow-up 85 months). Twelve of the 41 surviving patients (29.2%) had one or more disabilities. Growth retardation was seen in 8 patients, diabetes insipidus in 7, loss of teeth in 6, and mandibular defect, chronic aural discharge, partial hearing loss, facial palsy, and proptosis in 2 each. In short, a significant proportion of survivors of LCH had sequelae, which affected their quality of life. More intensive chemotherapy at the beginning might be helpful in reducing the disabilities.