Effect of socio-economic status & proximity of patient residence to hospital on survival in childhood acute lymphoblastic leukaemia

Background & objectives: Survival in paediatric acute lymphoblastic leukaemia (ALL) in lower/middle income countries continues to lag behind outcomes seen in high-income countries. Socio-economic factors and distance of their residence from the hospital may contribute to this disparity. This study was aimed at identifying the impact of these factors on outcome in childhood ALL. Methods: In this retrospective study, file review of children with ALL was performed. Patients were treated with the modified United Kingdom (UK) ALL-2003 protocol. Details of socio-economic/demographic factors were noted from a web-based patients' database. Modified Kuppuswamy scale was used to classify socio-economic status. Results: A total of 308 patients with a median age of five years (range: 1-13 yr) were studied. Patients belonging to upper, middle and lower SE strata numbered 85 (28%), 68 (22%) and 155 (50%). Nearly one-third of the patients were underweight. There was no treatment abandonment among children whose mothers were graduates. Neutropenic deaths during maintenance therapy were lower in mothers who had passed high school. In patients who survived induction therapy, the five year event-free survival (EFS) of upper SE stratum was significantly better 78.7�9 vs. 59�2 and 58.1�6 per cent in middle and lower strata (P =0.026). Five year overall survival was higher in the higher SE group; being 91.2�5, 78.3�6 and 78.8�9 per cent (P =0.055) in the three strata. Survival was unaffected by a distance of residence from treating centre or rural/urban residence. High-risk and undernourished children had a greater hazard of mortality [1.80 (P =0.015); 1.98 (P =0.027)]. Interpretation & conclusions: Our findings showed that higher socio-economic status contributed to superior EFS in children with ALL who achieved remission. Undernutrition increased the risk of mortality.

Is a diagnostic lumbar puncture indicated in intraocular retinoblastoma?

Background: Lumbar puncture (LP) is frequently performed in patients with advanced intraocular retinoblastoma. However, this may not be necessary in a significant proportion of patients. Materials and Methods: A file review of patients who were diagnosed with retinoblastoma over a 13-year-period was performed. Patients who underwent LP as part of staging were included in the study. Results: The study included 223 patients. One-third had bilateral retinoblastoma. The grouping was C, D, and E in 4 (2.9%), 41 (29.9%), and 92 (67.2%) patients, respectively. The stage was 0, I, II, III, and IV in 14 (6.3), 123 (55.2%), 13 (5.8%), 70 (31.4%), and 3 (1.3%) patients, respectively. Eight (3.6%) patients had a positive cerebrospinal fluid (CSF) cytology. None of the patients with intraocular disease and 7 (10%) patients with extraocular disease had a positive CSF. Conclusions: A diagnostic CSF is not indicated in patients with intraocular retinoblastoma.

Low spontaneous apoptosis index at diagnosis predicts a high-risk phenotype in paediatric acute lymphoblastic leukaemia

Background & objectives: Significance of apoptosis as a prognostic marker is less well studied in paediatric acute lymphoblastic leukaemia (ALL) cases. Hence, a prospective study, involving 30 paediatric ALL cases, was done to assess the clinical relevance of in vivo apoptosis. Methods: Peripheral blood mononuclear cells from all patients were subjected to annexin V/propidium iodide staining to detect the degree of apoptosis [apoptotic index (AI)] at day 0 and day 35 post-induction chemotherapy. In addition, Bax and Bcl2 apoptotic protein expressions were studied at day 0 and their relative fluorescence mean intensity (RFMI) ratios were calculated. Results: Mean age of patients was 5.1 years. Of the 30 cases, 21 (70%) were at standard-risk, five (17%) at intermediate and four (13%) at high risk. Majority (83%) were B-ALL. Day 8 absolute blast count was >1000/?l in seven (23%) and <1000/?l in 23 of 30 (77%) cases. Day 35 marrow was M1 in 23 (92%) and M2 in two of 25 (8%) cases. AI at day 0 and day 35 ranged from 0.9 to16.6 per cent and 1.4 to 62.8 per cent with a mean of 5.90 and 19.64 per cent, respectively. The Bax/Bcl2 ratio ranged from 0.2 to 3.5 with a mean of 0.83. The ratio was predominantly anti-apoptotic, i.e. <1 (77%). A significant association was noted between low AI at day 0 and high total leucocyte count (P=0.02), T-cell phenotype (P=0.043) and high-risk as per NCI category (P=0.025). Significant increase (>30%) in day 35 AI was seen in only six cases. Interpretation & conclusions: Our study showed that low AI at day 0 was associated with a high-risk clinical phenotype in paediatric ALL. However, studies on larger group, especially with longer follow up or study of relapse cases, will help draw conclusions regarding apoptosis assessment in paediatric ALL.

Do traumatic lumbar punctures lead to greater relapses in acute lymphoblastic leukemia: Experience at a university hospital in India.

OBJECTIVE: The aim of the study was to evaluate the impact of traumatic lumbar puncture (TLP) at diagnosis of relapse in childhood acute lymphoblastic leukemia (ALL). Risk factors associated with TLP were assessed. MATERIALS AND METHODS: A retrospective analysis was performed from the records of children with ALL who were treated from January 2010 to December 2012. RESULTS: A total of 311 patients with median age of 5 years (range: 1–13) were treated for ALL. The cerebrospinal fluid analysis obtained from first LP revealed 275: Central nervous system 1 (CNS 1) (no blasts); 8: CNS 3 (blasts positive); and 28: TLP. Twenty‑eight (9%) patients relapsed. Twelve (3.9%) had a CNS relapse. A TLP at diagnosis was not associated with an increased risk of systemic or CNS relapse (P = 0.298, 0.295). Three years event‑free survival of patients with TLP and without atraumatic LP (ATLP) at diagnosis was 56 ± 5.2% and 51.8 ± 12.4%, (P = 0.520). Three years overall survival with TLP and ATLP was 73.3 ± 3.5% and 70.4 ± 12.5%, respectively, (P = 0.963). Median platelet count in patients with TLP was significantly lower than those without TLP (10,000/μL and 28,000/μL, P < 0.001). A receiver operating characteristic curve was constructed for predicting the risk of TLP based on platelet count. Area under the curve was 0.74 ± 0.05 (95% confidence interval 0.64–0.84). Platelet count < 23.5 × 109/L at the time of LP had 75% sensitivity and 64.4% specificity in predicting a TLP. CONCLUSIONS: Low platelet counts are significantly associated with risk of TLP. Traumatic LP at diagnosis was not associated with an increased risk of relapse.

The impact of weight for age on survival in acute lymphoblastic leukemia: Report from a tertiary care center in North India.

BACKGROUND: Undernutrition is considered to have a negative impact on survival in children with malignancies. The objective of this retrospective analysis was to evaluate the morbidity pattern and outcome of therapy in undernourished (UN) children with acute lymphoblastic leukemia. METHODS: A retrospective analysis of impact of weight for age was performed in children treated for ALL. The IAP & CDC criteria for undernutrition were used in the two different time periods of analysis. RESULTS: There were two cohorts in the study: Between 1995 and 2005, 360 children were evaluated where the weight for age was classified using the Indian Academy of Pediatrics criteria for undernourishment (Group A). Group B of the study included 373 children treated from 2007 to 2011, who were graded as per the Centers for Disease Control criteria for weight for age. In Group A, 35% of the children were malnourished at presentation. The morbidity and supportive care needed in the well‑nourished and UN group were similar. The event‑free survival and mortality were similar in both groups. Analysis of Group B showed an overall survival of 62.6% with a greater survival in children with a weight of ≥10th centile for age compared to children at the <10th centile, (P = 0.026) with a higher mortality (P = 0.011) in the UN group. CONCLUSION: Our data have yielded conflicting results. The older cohort did not show a significant difference in survival using malnutrition as a risk factor. However, in the subsequent cohort, a difference in survival was noted. This could be due to the reason that different criteria for classification of undernutrition were applied in the two groups. This analysis lays the foundation for a future prospective analysis to evaluate nutrition as an independent risk factor nutrition as an independent risk factor in the outcome of childhood malignancies.

Invasive bacterial infections in a pediatric oncology unit in a tertiary care center.

BACKGROUND: Multidrug resistant (MDR) pathogens are becoming a major problem worldwide, more so in the immunocompromised hosts resulting in the urgent need of antibiotic stewardship. PURPOSE: To analyze the organisms isolated and the drug resistance pattern in a pediatric oncology unit. RESULTS: Data pertaining to infections with 128 positive cultures in patients with febrile neutropenia over a period of 1-year are presented. The unit antibiotic policy is decided depending on the sensitivity of the prevailing common organisms. We isolated Gram-negative organisms in 56% cases. Escherichia coli and Klebseilla were the most frequent lactose fermenting Gram-negative Bacilli and Pseudomonas and Acinetobacter the nonfermenting Gram-negative Bacilli. Only 20–30% of the Gram-negative organisms cultured were sensitive to a 3rd/4th generation cephalosporin. The combination of a beta-lactam/inhibitor covered 2/3rd of Gram-negative organisms. About 80% of the organisms were sensitive to carbapenems. There was no colistin resistance. About 44% of our cultures grew a Gram-positive bacterial organism and included coagulase negative Staphylococcus. We had an incidence of methicillin resistant Staphylococcus aureus to be 30%. About 30% of the enterococci isolated in our unit were vancomycin-resistant enterococci. About 23% of patients with a positive bacterial culture died. CONCLUSIONS: Infections in pediatric cancer patient’s account for about 15–20% of the deaths in developing countries as these patients are at a high risk for developing MDR infections. Resistance rates among Gram-positive and Gram-negative organisms have increased worldwide. Every unit needs a rational antibiotic policy. Antibiotic de-escalation and judicious decrease in the duration of antibiotics needs to be practiced.

Interleukin-5, interleukin-6, interleukin-8 and tumour necrosis factor-alpha levels obtained within 24-h of admission do not predict high-risk infection in children with febrile neutropenia.

Purpose: Biomarkers that can predict the severity of febrile neutropenia (FN) are potential tools for clinical practice. Objective: The objective of this study is to evaluate the reliability of plasma interleukin (IL) levels as indicators of high-risk FN. Materials and Methods: Children with haematological malignancies and FN were enrolled prospectively. A blood sample was obtained within 24-h of admission for estimation of IL-5, IL-6, IL-8 and tumour necrosis factor-alpha (TNF-α) level by the enzyme-linked immunosorbent assay. Patients were stratified into three groups. Group I (low-risk): No focus of infection; Group II: Clinical/radiological focus of infection; Group III: Microbiologically proven infection or FN related mortality. Groups II and III were analysed as high-risk. The cytokines were assessed at three different cut-off levels. Results: A total of 52 episodes of FN in 48 patients were evaluated. The mean age was 6 years (range: 2-13). Primary diagnosis included acute lymphoblastic leukaemia (82%), non-Hodgkin's lymphoma (13%) and acute myeloid leukaemia (5%). Absolute neutrophil count was < 200 cells/μl in half and 200-500 in 23%. Majority were categorised as Group I (69%), followed by Group II (16%) and III (15%). The range of IL-5 was too narrow and similar in the two risk-groups to be of any relevance. The best sensitivity of TNF-α and IL-6 for high-risk group was 78% and 70%, respectively. The highest specificity observed was 35%. The negative predictive value of IL-6, IL-8 and TNF-α exceeded 80%. Conclusion: IL-5, IL-6, IL-8 and TNF-α failed as predictors of clinically localised or microbiologically documented infection in children with chemotherapy induced FN. However, IL-6, IL-8 and TNF-α could be useful in excluding the possibility of high-risk infection.

Overt testicular disease at diagnosis in childhood acute lymphoblastic leukemia: Prognostic significance and role of testicular irradiation.

Objective. To analyze the prognostic impact of overt testicular disease (OTD) at diagnosis and role of testicular irradiation in the same. Methods. Data of 579 boys treated at our center over 16 years was reviewed. Results. Fourteen (2.4%) males had OTD. 10 (71.4%) of these had high-risk disease. Patients with OTD, had a significantly higher incidence of mediastinal-adenopathy (p=0.001), hyperleucocytosis (p=0.004) and CNS disease at presentation (p<0.0001) compared to patients in continuous complete remission (CCR). 4 of the 11 patients with OTD, who opted for therapy, had relapse; 2 are in CCR. Although, survival in patients with OTD was inferior (p=0.183) compared to patients without OTD, it was not an independent prognostic factor (p=0.47). In the entire study cohort, symptom-diagnosis interval (p=0.006), white cell (p=0.001) and platelet count (p=0.001) at presentation were significantly associated with survival (Cox multivariate regression analysis). Conclusions. OTD was not an independent prognostic factor, despite association with high-risk features. Survival outcome was inferior. The observations indicate the need of revaluation of the present protocol with incorporation of intermediate dose and subsequently high-dose methotrexate (after assessment for toxicity and tolerance), risk-stratified therapy and plausibly omission of testicular irradiation.

Testicular relapse in childhood acute lymphoblastic leukemia: The challenges and lessons.

Background : Relapse of disease is documented in 15-20% of children with acute lymphoblastic leukemia (ALL). Although testicular relapse is rare with modern risk-adapted treatment protocols, earlier, the testes were a frequently encountered site of relapse and were designated as "drug sanctuaries". Purpose : This descriptive study was designed to assess the pattern of testicular relapse and to identify high-risk factors. Materials and Methods : Data obtained from case records of 407 boys with ALL were analyzed. Fine needle aspiration cytology was carried out in children presenting with painless enlargement of testi(e)s. Bone marrow aspiration and cerebrospinal fluid examination were performed concomitantly to confirm or exclude disease at these sites. Results : Testicular relapse was documented in 30 boys. It was isolated in 17 patients and associated with bone marrow and/or central nervous system relapse in 13. At relapse, nine boys were over the age of 10 years. The majority were very early and early relapsers. Hyperleucocytosis was documented in five of 30 and seven of 137 relapsers and nonrelapsers, respectively (P = 0.04). Twelve of the 30 boys with testicular relapse were treated with testicular irradiation, reinduction and maintenance therapy. The estimated median overall survival was 33 months. Conclusion : Testicular relapse, which depends on the therapy administered, may manifest several months/years after completion of treatment. The high incidence of testicular relapse in our series implicates the need of revaluation of our protocol and incorporation of high/intermediate dose methotrexate therapy upfront.

Scrub typhus: a case report.

Fever with rash is a common cause for dermatological referral. The causes can range from viral to protozoal, bacterial or spirochaetal. A case of rickettsial fever is reported.

Needle necropsy in AIDS.

The value of autopsy in understanding the natural course of any disease is beyond any argument. The reluctance of pathologists to perform autopsy in HIV infected cadavers is justified due to the risks involved to the prosector and the morgue attendants. A relative low risk needle necropsy protocol is proposed using fine needle aspiration cytology, tru-cut biopsies and microbiological examination. Diagnosis could be offered in all the forty-four needle necropsies performed. Disseminated tuberculosis in 18/44 (40.9%) cases, disseminated cryptococcosis in 12/44 (27.2%) cases, poly-microbial infections in 27.2% cases and non-Hodgkin's lymphoma in 9% cases were detected in the study. Infectious agents like Histoplasma capsulatum, Isospora belli, tachyzoites of Toxoplasma gondii, Candida sp and Cryptococcus sp could be demonstrated in the samples obtained in the study. Lack of material for study of gross pathology, inaccessibility of deep-seated lesions and risk of needle stick injury to the prosector though low are the limitations of this procedure.

Paradoxical embolism through patent foramen ovale causing cerebellar infarction in a young boy.

A previously healthy young boy who suffered an acute stroke involving superior cerebellar artery circulation is presented here. Echocardiography revealed a patent foramen ovale through which paradoxical embolism had probably occurred. Low dose aspirin was started and surgical closure was planned to prevent further recurrences.

Portal hypertension secondary to Langerhans cell histiocytosis.

We report two children, aged 2 and 2 1/2 years, with multisystem Langerhans cell histiocytosis (LCH). Both were administered chemotherapy, with apparently good response. However, hepatic fibrosis and portal hypertension were detected 5 and 1 1/2 years after therapy, respectively. The first child died after a bout of hematemesis. Hepatic fibrosis can proceed despite apparently successful chemotherapy in LCH.

Ptosis in late infantile Tay-Sachs disease.

The brief communication describes a 2-year-old child who presented with delayed achievement and regression of milestones, seizures of multiple types, exaggerated response to sound, inability to see and bilateral cherry red spots. In addition to these typical manifestations of the late infantile variety of Tay-sachs disease, unilateral ptosis was present. The magnetic resonance imaging of brain revealed abnormalities consistent with an advanced stage of the disease.

Leucocytoclastic vasculitis in infant.

Acute hemorrhagic edema of infancy is a laucocytoclastic vasculitis characterized by a triad of fever, large purpuric skin lesions and edema. The presentation is often dramatic. The manifestations are often misinterpreted as a septicemic illness. We report the occurrence of this syndrome in a 1 1/2-year-old-child, highlighting some of the diagnostic and therapeutic problems encountered.