MTHFR Gene Polymorphisms and the Risk of Acute Lymphoblastic Leukemia in Adults and Children: A Case Control Study in India.

Genetic polymorphisms in the methylene tetrahydrofolate reductase (MTHFR) gene have been associated with the development of acute leukemias and various malignancies. The role of MTHFR polymorphism in the development of pediatric acute lymphoblastic leukemia (ALL) has been extensively studied among north Indians in various settings, yet its association with acute leukemias remains unresolved. To evaluate the relationship between functional MTHFR polymorphisms, C677T and A1298C and possible effect on risk of ALL in adults and children in North Indian population by comparing them with healthy controls. DNA was isolated from peripheral blood of 184 ALL patients (33 adults, 151 children) and 155 controls and analyzed by a PCR-restriction fragment length polymorphism assay. The frequency of MTHFR 677CT and 1298 AC genotypes were significantly lower among adult ALL cases when compared to the controls. We found a 1.74-fold reduced risk of ALL in individuals with 1298AC polymorphic variant and a 9.17-fold decreased risk of adult ALL. However, no statistically significant difference was evident between the above polymorphisms and susceptibility to ALL in children. Polymorphisms in the MTHFR gene possibly modulate risk of ALL in north Indian adults but not in children, although larger studies are needed.

Childhood T-lineage acute lymphoblastic leukemia: management and outcome at a tertiary care center in North India.

OBJECTIVE: To assess the clinical features, prognostic factors and outcome of childhood T-ALL in comparison with B-lineage ALL, treated with a uniform treatment regimen (MCP 841). SETTING: Pediatric oncology division of a tertiary care institution in Northern India. DESIGN: Retrospective analysis of clinical data and survival outcome. PARTICIPANTS: 60 children with T-ALL and 139 with B- lineage ALL, and less than 15 years of age treated over 15 years. RESULTS: T-ALL was observed in 30%. High risk features at presentation (age >10 years, WBC >50,000/mm3, mediastinal mass, and CNS leukemia) were significantly more frequent in T-ALL as compared to B-lineage ALL (P=0.049, P<0.001, P<0.001 and P=0.02, respectively). Fifty five of 60 T-ALL patients (91.7%) achieved complete remission after induction therapy. There were 3 induction and 10 remission deaths while 11 (18.3%) relapsed. The overall survival and event-free survival of T-lineage ALL (61.5±7.6 and 49.9±7.4, respectively) were similar to that of B-lineage patients (68.7±4.7 and 47.1±5.1, respectively). National Cancer Institute risk groups emerged as significant prognostic factor for event free survival only in B-lineage patients. CONCLUSIONS: Even though high risk features were significantly more frequent in T-ALL, survival outcome was similar to that of B-lineage patients. None of the routinely described prognostic parameters significantly impacted survival.

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.

Invasive colonic mucormycosis in early induction therapy of childhood acute lymphoblastic leukemia.

Fungal infections occur in patients who are severely immunocompromised with profound and prolonged neutropenia. We report a patient of acute lymphoblastic leukemia who developed nonspecific abdominal symptoms within two days after the onset of neutropenia in the early induction phase of chemotherapy, which was later found to be due to intestinal mucormycosis and resulted in a fatal outcome.

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.

Bone relapse in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) can occasionally relapse in unusual extramedullary sites like bone. Here we present a 6.5-year old boy with 'T' cell ALL who developed a swelling in left tibia which was infiltrated with lymphoblasts 7 months after completion of chemotherapy. Bone marrow and cerebrospinal fluid were negative for blasts. This is the first reported case of bone relapse in ALL from India. We discuss the previous cases of isolated bone relapse in ALL reported in English literature.

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.

Non hodgkin's lymphoma seven years following remission of acute lymphoblastic leukemia.

The authors describe a case of extramedullary relapse in lymph node presenting as lymphoblastic lymphoma seven years following remission of acute lymphoblastic leukemia. To the best of our knowledge, this is the first reported case of an isolated lymph node relapse with hematopoietic remission of leukemia. We have discussed cases of large cell lymphoma and other unusual areas of extramedullary relapse complicating acute lymphoblastic leukemia in hematopoietic remission.

Paucity of TEL-AML 1 translocation, by multiplex RT-PCR, in B-lineage acute lymphoblastic leukemia (ALL) in Indian patients.

A total of 69 patients of B lineage ALL, 35 children (32 males, 3 females) and 34 young adults (27 males, 7 females) were studied by multiplex RT-PCR to determine the relative frequency of t(9;22), t(12;21), t(1;19), and t(4;11,). Translocation (9;22) was seen in 1/35 (2.8%) and t(1;19) in 2/35 (5.7%) children. None of the children showed t(12;21) and t(4;11) translocations. In young adults, t(9;22) and t(1;19) were seen in 5/34 (14.7%) and 2/34 (5.8%) patients, respectively. None of the latter showed t(12;21) or t(4;11) translocations. Thus, there appears to be a significant under representation of the fusion transcripts for TEL-AML, a good prognostic marker, in this study, unlike in the West, where it is seen in 35% of children with ALL. This, together with the generally increased leukemic burden seen in Indian patients, may explain in part, the poor treatment outcome reported.

Transthoracic lung aspiration in etiology of pneumonia.

Transthoracic lung aspiration was performed in 30 episodes of pneumonia in 27 children with malignancy on chemotherapy to assess etiology of pulmonary infections. Total of 22 organisms were isolated in 16/30 (53.3%) episodes. No acid fast bacilli or Pneumocystis carinii were seen. Organisms grown by blood culture correlated with that of lung puncture in 5 episodes, while throat culture and nasopharyngeal organisms correlated with that of lung puncture on one occasion each. Organisms isolated in 8/18 episodes (44.4%) of antemorten transthoracic aspiration included: Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Streptococcus faecalis and Diphtheroids. In 3/18 episodes, lung puncture results altered treatment and thus resulted in survival of the patients. Only one minor complication occurred in this study--pneumothorax that resolved spontaneously. Thus, transthoracic lung puncture is an useful and safe procedure in immunocompromised patients with pneumonia who do not respond to initial broad spectrum antibiotics.

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.

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.

Venous thrombosis associated with Salmonella: report of a case and review of literature.

We describe here the first case of Salmonella paratyphi A bacteremia associated with deep vein thrombosis in a 10-year-old patient. In spite of aggressive antibiotic therapy and supportive care, the patient died of progressive respiratory distress and septic shock. Awareness of unusual clinical presentation of Salmonella infection in important. A review of the previously reported cases of Salmonella associated venous thrombosis worldwide is also presented.

Diagnosis and treatment of disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is a complex clinical syndrome with activation of the procoagulant and fibrinolytic systems along with inhibitor consumption. We discuss regarding the controversies in diagnosis and management of DIC. Bleeding is a more common manifestation of DIC but most of the morbidity and mortality of DIC is due to microvascular thrombosis. Routinely performed tests for DIC such as platelet count and prothrombin time may be normal in chronic DIC. There is no single test that would diagnose DIC, however, estimation of D-dimer appears to be the most sensitive and specific test. Therapy of DIC aims at treating the primary cause. Fresh frozen plasma and platelet concentrates are recommended only in bleeding patients and have the potential risk of adding procoagulant material to the already activated procoagulant system. Role of heparin and antithrombin in patients with sepsis and DIC is discussed.