Infections in childhood acute lymphoblastic leukemia: an analysis of 222 febrile neutropenic episodes.

A retrospective analysis was performed on febrile neutropenic episodes in patients with acute lymphoblastic leukemia (ALL) from 1992 to 2002. There were 222 febrile neutropenic episodes in 266 ALL patients with documented ANC < 500/mm(3). Of the 222 episodes, 98 (44%) had documented focus of infection; the rest were fever without focus. There were 274 different sites of infection in the 98 episodes of documented focus of infection; pulmonary infections were the commonest site of infection (27.3%) followed by HEENT (22.9%). Of 69 bacterial isolates, gram-negative bacteria (n = 46, 67%) were twice as common as gram-positive bacteria (n = 23, 33%). Most common site of isolation for gram-negative bacteria was blood (50%) followed by urine (32.6%). Blood (78.3%) was predominant site of isolation of gram-positive bacteria followed by HEENT (8.7%). Escherichia coli (45.7%) was the commonest gram-negative isolate, while Staphylococcus aureus (39%) was the commonest gram-positive bacterial isolate. There were a total of 22 fungal isolates, the majority from urine (n = 12) and HEENT (n = 9). Of the 22 fungal isolates, 19 were detected in induction phase of chemotherapy. A total of 95/222 (42.8%) febrile neutropenic episodes improved with first-line antibiotic therapy, while modification was required in 127 episodes (57.2%). Antifungal therapy was used in 86 episodes (38.7%). There were a total of 13 deaths, 6 each during induction and intensification/consolidation phases, while 1 died during maintenance phase. Of the 13 deaths, 10 had pneumonia, 8 had bacteremia, and 7 had fungal infection. The current study stresses the importance of frequent reviewing of type, frequency, severity, and outcome of infection complications over the years to detect changing epidemiological patterns. The majority of fungal infections were detected during induction chemotherapy, which highlights the need to consider this type of infection in the evaluation of patients.

Etiology and outcome of oral mucosal lesions in children on chemotherapy for acute lymphoblastic leukemia.

Microbiological cultures were taken from oral cavity and blood in 100 mucositis episodes in 70 children with acute lymphoblastic leukemia (ALL). Oral mucositis was commonest in neutropenic children during induction chemotherapy. Fungal organisms (n=39) were commonest isolate from mucosa followed by bacteria (n=28). Isolation of organism from oral cavity had no association with those isolated from blood. Herpes serology was positive in 16% episodes compared to 2% of controls. Obtaining cultures from oral lesions is useful in appropriate management of lesions and thereby possibly preventing systemic spread.

Treatment of acute lymphoblastic leukaemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year period [corrected].

In the 1970s, survival rates after treatment for acute lymphoblastic leukaemia (ALL) in children and young adults (less than 25 years) in India were poor, even in specialised cancer centres. The introduction of a standard treatment protocol (MCP841) and improvements in supportive care in three major cancer centres in India led to an increase in the event-free survival rate (EFS) from less than 20% to 45-60% at 4 years. Results of treatment with protocol MCP841 between 1984 and 1990 have been published and are briefly reviewed here. In addition, previously unpublished data from 1048 patients treated between 1990 and 1997 are reported. Significant differences in both patient populations and treatment outcome were noted among the centres. In one centre, a sufficiently large number of patients were treated each year to perform an analysis of patient characteristics and outcome over time. Although steady improvement in outcome was observed, differences in the patient populations in the time periods examined were also noted. Remarkably, prognostic factors common to all three centres could not be defined. Total white blood cell count (WBC) was the only statistically significant risk factor identified in multivariate analyses in two of the centres. Age is strongly associated with outcome in Western series, but was not a risk factor for EFS in any of the centres. Comparison of patient characteristics with published series from Western nations indicated that patients from all three Indian centres had more extensive disease at presentation, as measured by WBC, lymphadenopathy and organomegaly. The proportions of ALLs with precursor T-cell immunophenotypes, particularly in Chennai, were also increased, even when differences in the age distribution were taken into consideration (in <18-year olds, the range was 21.1-42.7%), and in molecular analyses performed on leukaemic cells from over 250 patients less than 21-years-old with precursor B-cell ALL, a lower frequency of TEL-AML1-positive ALL cases than reported in Western series was observed. The worse outcome of treatment in Indian patients compared with recent Western series was probably due to the higher rate of toxic deaths in the Indian patients, and possibly also due to their more extensive disease - which is, at least partly, a consequence of delay in diagnosis. Differences in the spectrum of molecular subtypes may also have played a role. The higher toxic death rates observed are likely to have arisen from a combination of more extensive disease at diagnosis, co-morbidities (e.g., intercurrent infections), differences in the level of hygiene achievable in the average home, poor access to acute care, and more limited supportive care facilities in Indian hospitals. Toxic death was not associated with WBC at presentation, and hence would tend to obscure the importance of this, and, potentially, other risk factors, as prognostic indicators. Since the prevalence of individual risk factors varies in different populations and over time, their relative importance would also be expected to vary in different centres and in different time periods. This was, in fact, observed. These findings have important implications for the treatment of ALL in countries of low socioeconomic status; it cannot be assumed that risk factors defined in Western populations are equally appropriate for patient assignment to risk-adapted therapy groups in less affluent countries. They also demonstrate that heterogeneity in patient populations and resources can result in significant differences in outcome, even when the same treatment protocol is used. This is often overlooked when comparing published patient series.

Immunological subtypes of acute lymphoblastic leukemia in north India.

Pretreatment immunologic marker analysis in 152 adult and childhood patients of ALL and ALL/lymphoma employing multiple monoclonal antibodies and hetero-antisera revealed three major subgroups, i.e. T-ALL (37.7%), N-ALL (33.1%) and C-ALL (21.5%). The early age peak was absent, males predominated in all the subgroups and T-ALL had increased incidence of thymic mass. Leucocyte counts of 50,000 X 10(6)/l were equally frequent in the three groups. T-ALL showed marked heterogeneity by showing a variety of markers such as T-helper/inducer, T-suppressor/cytotoxic, p-24, Ia and CALLA. These results show a high prevalence of unfavourable prognostic factors in ALL in our geographic region which might be related to socioeconomic and/or environmental factors.

Detection of BCR-ABL transcripts in acute lymphoblastic leukemia in Indian patients.

Thirty-three patients with acute lymphoblastic leukemia (ALL) from India were studied for the presence of BCR-ABL chimeric transcripts, by a seminested cDNA-PCR. We report the presence of BCR-ABL chimeric transcripts in 4/17 (24%) children (under 15 years) and 3/16 (19%) adults (15-50 years). This is in sharp contrast to the published literature from the West where the presence of BCR-ABL has been reported in only 2-5% children and 35% adults. Whether the presence of BCR-ABL fusion mRNA, which is generally an attribute of ALL in adults and of poorer prognosis, may contribute to chemo-incurability in young Indian patients, remains to be seen, as a larger number of patients are studied for treatment outcome and survival on uniform therapy protocols.

Incidence, clinical characteristics and early treatment outcome in Indian patients of childhood acute lymphoblastic leukemia with ALL-1 gene rearrangement.

In a series of 185 patients (median age 7 years) of acute lymphoblastic leukaemia (ALL) from India, the overall incidence of ALL-1 gene rearrangement using the Southern blot technique was 11.4% (21/185). The incidence amongst the infants (age < or = 1 year, 70%) was significantly higher when compared to patients > 1 - < or = 10 years (7.4%, P = 0.00001) as well as > 10 years old (9.3%, P = 0.0001). ALL-1 gene rearrangement was associated with significantly higher WBC count (P = 0.01) and CD10 negativity (P = 0.00000001). Complete remission (CR) and relapse rates in 98 patients evaluable for response to therapy on a uniform therapy protocol was independent of ALL-1 gene status.

Role of serum ferritin in assessment of disease activity in acute & chronic leukemia.

Serum ferritin (SF) was estimated using double antibody sandwich ELISA in 83 patients of acute and chronic leukemia at various stages of the disease. In 35 patients of acute lymphoblastic leukemia (ALL) in remission, the SF levels fell significantly from 550.63 ng/ml at presentation to 319.56 ng/ml but remained significantly higher than the control values of 46.14 ng/ml. In 28 patients of acute myeloid leukemia (AML), the SF values at 775.0 ng/ml were much higher than those in ALL patients and showed no decline with remission. This pattern was also seen in patients of chronic myeloid leukemia in blast crisis (CML-BC) with SF levels of 804.03 ng/ml at presentation and 717.43 ng/ml at partial remission. The values of SF were lowest in patients of CML in chronic phase ranging from 271.5 ng/ml to 332.12 ng/ml and showed no relationship with variation in total leucocyte count. No correlation was found between SF values and various clinical and laboratory parameters such as age, sex, fever, organomegaly, haemoglobin and total leucocyte count. Thus, while there appeared to be a correlation between remission and SF values in ALL, no such correlation existed between the activity of the disease and SF in other types of leukemia.

Etiology of febrile episodes in children with acute lymphocytic leukaemia.

In 53 children (aged 5 months to 11 yr) with acute lymphoblastic leukemia, 68 febrile episodes were investigated for determining the etiology. Microbial organisms were isolated in 33 episodes. Bacteraemia was seen in 24 patients and in three of them Clostridium species were isolated. Escherichia coli was the commonest isolate and was seen in 11 (18.6%) febrile episodes. Other common organisms isolated were Staphylococcus aureus in nine (15.2%), and Klebsiella pneumoniae and coagulase negative Staph. in 6 (10.2%) episodes each. Pseudomonas aeruginosa and Acinetobactor were isolated in 5 (8.5%) episodes each.

Pyogenic liver abscesses in children.

Five children with pyogenic liver abscess were admitted to Institute of Child Health, Kabul during the period 1978 to 1980. All patients were males, and their ages ranged from 4 to 10 years. The clinical picture was characterized by fever, upper abdominal pain, enlarged tender liver with raised right dome of the diaphragm. The abscesses were located in the right lobe of liver in all cases, and they were solitary in three cases. Staphylococcus aureus was the etiologic agent in four cases and Escherichia coli in one. Open surgical drainage coupled with prompt parenteral antibiotic therapy in all cases seem to have favorably influenced the outcome. With a high index of suspicion pyogenic liver abscess in children can be diagnosed clinically without the aid of hepatic radionuclide scanning.

Efficacy of induction chemotherapy in retinoblastoma, alone or combined with other adjuvant modalities.

BACKGROUND: There are not much data available on the use of newer antimetabolites as an initial treatment modality in retinoblastoma, or their effect on vitreous seedings and de novo foci, especially in the Indian subcontinent. METHODS: To evaluate the efficacy of newer agents as induction chemotherapy, 34 tumors in 22 eyes of 19 children with bilateral retinoblastoma were treated with 2 cycles of carboplatin, etoposide, vincristine, and cyclophosphamide; each cycle was of 1 month duration. The tumor response was evaluated at 2 months and adjuvant salvage modalities (ie, cryotherapy, laser, and/or external beam radiotherapy) were added as needed. The cycles were continued and ophthalmoscopic and ultrasonographic monitorings were performed to determine further tumor response, tumor height regression, effect on vitreous seeds, and other ocular changes. RESULTS: Mean tumor height at presentation was 4.2 mm, which regressed to 2.61 mm at 6 months (P=0.000). The biggest tumor to respond was 12.5 mm, although smaller multiple tumors regressed better. Adjuvant modalities were used in 28 tumor foci in 16 eyes. A follow up of 6 to 24 months (mean, 12.8+/-6.21 months), showed complete regression in 12/34 tumors, partial regression in 15/34, stable disease in 6/34, and 1 tumor progressed despite all therapy. Results in all 6 eyes with vitreous seeds were most gratifying; at 1 year vitreous seeds disappeared in 4 eyes and showed complete calcification in 2. Fresh new lesions were not seen in any eye with complete response after the first 2 cycles of chemotherapy. Recurrences were nil and complications minor. CONCLUSIONS: The overall tumor response (complete and partial) of more than 80% indicates that chemoreduction is an effective modality alone and combined with adjuvant salvage modalities. The results with our treatment regime, even in cases with advanced intraocular retinoblastoma, are encouraging.

Etiopathophysiology of disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) involves activation of clotting as well as fibrinolytic pathways. Thrombosis from thrombin release results in end-organ damage, whereas consumption of coagulation factors results in bleeding. Sepsis is the commonest cause of DIC. The consumption of antithrombin in sepsis abrogates its anti-inflammatory role and so its low level is a poor prognostic marker in sepsis. The increased release of plasminogen activator inhibitor-1 (PAI-1) as seen in sepsis decreases fibrinolysis and promotes increased microvascular thrombosis. Here, we discuss the role of inhibitors of coagulation, cytokines, kinins, complement and vasoactive peptides in DIC.

Congenital factor XIII deficiency: two case reports.

Two patients with factor XIII deficiency, presenting with bleeding disorder since birth, are reported. The condition is rare and is likely to be missed unless clot solubility in 5 M urea is performed as a screening test in all patients with bleeding disorders. A correct diagnosis is essential as prophylactic management is practicable in this disorder.

Neuropsychological abnormalities following CNS prophylaxis in children with acute lymphatic leukemia.

The pattern and prevalence of neuropsychological abnormalities in children receiving combination CNS prophylaxis (2000 rads cranial irradiation and intrathecal methotrexate) during therapy for acute lymphoblastic leukemia (ALL) were studied. Thirty five children (25 boys) in the age group 5-15 years (mean 9.3) with no evidence of CNS leukemia were included and 20 age matched normal siblings served as controls. Neuropsychological parameters of general intelligence (Malin's modification of WISC test); attention and concentration (colour cancellation test); memory (modified PGI memory test) and visuomotor perception (Bender Gestalt test) were evaluated at least 6 months after CNS prophylaxis. Six (17.1%) patients had mean intelligence quotients (IQ) less than 85, while all controls had IQ > 85 (p < 0.05). The mean IQ of the patient population (93.4 +/- 11.9) was significantly lower than the control group (107 +/- 8.4) (p < 0.001). Scores on the colour cancellation test were lower in the patients as compared to controls (148.7 +/- 27.7 versus 184.9 +/- 23.9; p < 0.01). The mean memory quotient in the patient population was also lower than in controls (74.5 +/- 12 versus 93.6 +/- 9.2; p < 0.001). Scores on the Bender-Gestalt test did not show a significant difference. The presence of significant neuropsychological abnormalities in patients of ALL indicates the need for modification of the schedule of CNS prophylaxis. A comprehensive psychometric evaluation at regular intervals is essential for longterm rehabilitation.

Adenoid cystic carcinoma of the lacrimal gland.

Adenoid cystic carcinoma (ACC) of the lacrimal gland is a rare tumor from the epithelial structure. It is rare in children. The authors report a case of ACC in a girl child. Extensive excision of the tumor is advised to prevent later recurrences. Local control can be better achieved by a combination of radiochemotherapy as ACC has been shown to recur event after 10 years.

Breast feeding and childhood hematological malignancy.

Breast milk is known to have anti-infective and immunomodulating effects on infants, but its association with childhood cancer has not been well studied. Artificial feeding may affect the immune response in carcinogenesis. In this communication the authors have reviewed different articles describing the association between breast feeding (BF) and subsequent development of childhood hematological malignancy. It appears that BF may have a protective effect on childhood cancer, both the duration of BF as well as the quantity of milk ingested is probably critical to the beneficial immunological effects of BF against childhood cancer if any.

Cytogenetics investigation in childhood chronic myeloid leukemia.

Cytogenetics investigations, mostly from peripheral blood, were carried out in 30 children with CML. Amongst a sample of 30 patients, 18 had chronic myeloid leukemia of adult variety (ACML), while the remaining 12 children had the juvenile type of chronic myeloid leukemia (JCML). Sixteen (88.9%) out of the 18 patients suffering from ACML tested positive for the classical Philadelphia chromosome translocation t(9; 22). Of the remaining two ACML patients, one tested positive for t(9; 13; 22) while no visible chromosomal changes were observed in the other patient. The activity of Nucleolar Organizer Region (NOR) was significantly reduced in 11 (61.1%) of the 18 patients suffering from ACML, when compared to that of 21 normal healthy controls. Ten out of the 12 patients suffering from JCML had normal karyotypes, while monosomy 8 and 21 q deletion were seen in the remaining two patients respectively. Amongst the 30 CML patients, chromosomal abnormalities were observed in 19 patients. Variant Philadelphia chromosome translocation (9; 13; 22) and monosomy B were observed in ACML and JCML, respectively. In two ACML patients, cytogenetic studies were helpful in diagnosis of the disease.

Autoimmune hemolytic anemia complicating disseminated childhood tuberculosis.

An 8-year-old girl presented with severe autoimmune hemolytic anemia (AIHA) in association with mediastinal widening. Biopsy of mediastinal lymph node confirmed the diagnosis of tuberculosis. A diagnosis of disseminated tuberculosis in association with AIHA was made, and the patient was treated with steroids and antitubercular therapy. This is the first report case of AIHA in association with childhood tuberculosis; we also discuss other reported cases of AIHA in association with adult tuberculosis in English literature.

Symptomatic congenital syphilis presenting at birth.

We report here a case of congenital syphilis presenting in a newborn infant at birth. A negative infant VDRL test, pseudoparesis and more notably, joint swellings (arthritis) were features seen uncommonly. Florid skeletal involvement, which is rarely seen in the early neonatal period, prompted us to draw attention to the varied presentation of this disease, rightly referred to as the "master masquerader".

Hematological responses to hydroxyurea therapy in multitransfused thalassemic children.

Fifteen multi-transfused thalassemic children between 3-6 years of age (seven boys and eight girls) were administered hydroxyurea for 5 days and three such cycles were repeated at 15 days interval. Rise in hemoglobin levels was observed in 13, 8 and 7 cases, while rise in mean hemoglobin F was seen in 8, 11 and 10 cases following 1st, 2nd and 3rd course of hydroxyurea therapy respectively. Rise in hemoglobin level was associated with transient rise in fetal hemoglobin level. Though the changes in mean hemoglobin levels and hemoglobin F levels were statistically insignificant, a definite trend of rise in hemoglobin and hemoglobin F was observed.

Thrombocytopenic purpura as a presenting manifestation of tubercular lymphadenitis.

A 11-year-old girl presented with thrombocytopenic purpura along with cervical lymphadenopathy. There was no hepatosplenomegaly; no evidence of microangiopathy; bone marrow examination was normal. Acid fast bacilli were seen in fine needle aspiration cytology of the lymph node. A diagnosis of tubercular lymphadenitis in association with immune thrombocytopenia was made, and the platelet count recovered with antitubercular therapy. This report illustrates immune thrombocytopenia as a rare manifestation of childhood tuberculosis; the authors also discuss other causes of thrombocytopenia in childhood tuberculosis.