Comparative treatment costs of risk-stratified therapy for childhood acute lymphoblastic leukemia in India.

BACKGROUND: To evaluate the treatment cost and cost effectiveness of a risk-stratified therapy to treat pediatric acute lymphoblastic leukemia (ALL) in India. METHODS: The cost of total treatment duration was calculated for a retrospective cohort of ALL children treated at a tertiary care facility. Children were risk stratified into standard (SR), intermediate (IR) and high (HR) for B-cell precursor ALL, and T-ALL. Cost of therapy was obtained from the hospital electronic billing systems and details of outpatient (OP) and inpatient (IP) from electronic medical records. Cost effectiveness was calculated in disability-adjusted life years. RESULTS: One hundred and forty five patients, SR (50), IR (36), HR (39), and T-ALL (20) were analyzed. Median cost of the entire treatment for SR, IR, HR, and T-ALL was found to be $3900, $5500, $7400, and $8700, respectively, with chemotherapy contributing to 25%-35% of total cost. Out-patient costs were significantly lower for SR (p < 0.0001). OP costs were higher than in-patient costs for SR and IR, while in-patient costs were higher in T-ALL. Costs for non-therapy admissions were significantly higher in HR and T-ALL (p < 0.0001), representing over 50% of costs of in-patient therapy. HR and T-ALL also had longer durations of non-therapy admissions. Based on WHO-CHOICE guidelines, the risk-stratified approach was very cost effective for all categories of patients. CONCLUSIONS: Risk-stratified approach to treat childhood ALL is very cost-effective for all categories in our setting. The cost for SR and IR patients is significantly reduced through decreased IP admissions for both, chemotherapy and non-chemotherapy reasons.

Protocol for ICiCLe-ALL-14 (InPOG-ALL-15-01): a prospective, risk stratified, randomised, multicentre, open label, controlled therapeutic trial for newly diagnosed childhood acute lymphoblastic leukaemia in India.

BACKGROUND: In the west, survival following treatment of childhood acute lymphoblastic leukaemia (ALL) approaches 90%. Outcomes in India do not exceed 70%. To address this disparity, the Indian Collaborative Childhood Leukaemia group (ICiCLe) developed in 2013 a contemporary treatment protocol for uniform risk-stratified management of first presentation ALL based on cytogenetics and minimal residual disease levels (MRD). A multicentre randomised clinical trial opened in 2016 (ICiCLe-ALL-14) and examines the benefit of randomised interventions to decrease toxicity and improve outcomes. METHODS: Patients 1-18 years with newly diagnosed ALL are categorised into four risk groups based on presentation features, tumour genetics and treatment response. Standard risk includes young (< 10 years) B cell precursor ALL (BCP-ALL) patients with low presentation leucocyte count (< 50 × 109/L) and no high-risk features. Intermediate risk includes BCP-ALL patients with no high-risk features but are older and have high presentation leucocyte counts and/or bulky disease. High risk includes BCP-ALL patients with any high-risk feature, including high-risk genetics, central nervous system leukaemia, poor prednisolone response at treatment day 8 and high MRD (≥ 0·01%) at the end of induction. Patients with T-lineage ALL constitute the fourth risk group. All patients receive four intensive treatment blocks (induction, consolidation, interim maintenance, delayed intensification) followed by 96 weeks of maintenance. Treatment intensity varies by risk group. Clinical data management is based on a web-based remote data capture system. The first randomisation examines the toxicity impact of a shorter induction schedule of prednisolone (3 vs 5 weeks) in young non-high-risk BCP-ALL. The second randomisation examines the survival benefit of substituting doxorubicin with mitoxantrone in delayed intensification for all patients. Primary outcome measures include event-free survival (overall, by risk groups), sepsis rates in induction (first randomisation) and event-free survival rates following second randomisation. DISCUSSION: ICiCLe-ALL-14 is the first multicentre randomised childhood cancer clinical trial in India. The pre-trial phase allowed standardisation of risk-stratification diagnostics and established the feasibility of collaborative practice, uniform treatment, patient enrolment and data capture. Pre-trial observations confirm the impact of risk-stratified therapy in reducing treatment-related deaths and costs. Uniform practice across centres allows patients to access care locally, potentially decreasing financial hardship and dislocation. TRIAL REGISTRATION: Clinical Trials Registry-India (CTRI) CTRI/2015/12/006434 . Registered on 11 December 2015.

Substantial Evidences Indicate That Inorganic Arsenic Is a Genotoxic Carcinogen: a Review.

Arsenic is one of the most toxic environmental toxicants. More than 150 million people worldwide are exposed to arsenic through ground water contamination. It is an exclusive human carcinogen. Although the hallmarks of arsenic toxicity are skin lesions and skin cancers, arsenic can also induce cancers in the lung, liver, kidney, urinary bladder, and other internal organs. Arsenic is a non-mutagenic compound but can induce significant cytogenetic damage as measured by chromosomal aberrations, sister chromatid exchanges, and micronuclei formation in human systems. These genotoxic end points are extensively used to predict genotoxic potentials of different environmental chemicals, drugs, pesticides, and insecticides. These cytogenetic end points are also used for evaluating cancer risk. Here, by critically reviewing and analyzing the existing literature, we conclude that inorganic arsenic is a genotoxic carcinogen.

Molecular regulation of follicle-stimulating hormone synthesis, secretion and action.

Follicle-stimulating hormone (FSH) plays fundamental roles in male and female fertility. FSH is a heterodimeric glycoprotein expressed by gonadotrophs in the anterior pituitary. The hormone-specific FSHß-subunit is non-covalently associated with the common α-subunit that is also present in the luteinizing hormone (LH), another gonadotrophic hormone secreted by gonadotrophs and thyroid-stimulating hormone (TSH) secreted by thyrotrophs. Several decades of research led to the purification, structural characterization and physiological regulation of FSH in a variety of species including humans. With the advent of molecular tools, availability of immortalized gonadotroph cell lines and genetically modified mouse models, our knowledge on molecular mechanisms of FSH regulation has tremendously expanded. Several key players that regulate FSH synthesis, sorting, secretion and action in gonads and extragonadal tissues have been identified in a physiological setting. Novel post-transcriptional and post-translational regulatory mechanisms have also been identified that provide additional layers of regulation mediating FSH homeostasis. Recombinant human FSH analogs hold promise for a variety of clinical applications, whereas blocking antibodies against FSH may prove efficacious for preventing age-dependent bone loss and adiposity. It is anticipated that several exciting new discoveries uncovering all aspects of FSH biology will soon be forthcoming.

Association of single nucleotide polymorphism with arsenic-induced skin lesions and genetic damage in exposed population of West Bengal, India.

Long term consumption of arsenic contaminated water causes a number of dermatological and non-dermatological health problems and cancer. In a Genome Wide Association Study (GWAS) on Bangladesh population, a significant association of asingle nucleotide polymorphism (SNP) in the C10orf32 region (rs 9527; G>A) with urinary metabolites and arsenic induced skin lesions was reported. This study aims to evaluate the association of the C10orf32 G to A polymorphism (rs9527), concerned with As3MT read-through transcription, with the development of arsenic induced skin lesions in the arsenic exposed individuals of West Bengal, India. A total of 157 individuals with characteristic skin lesions (cases) and 158 individuals without any skin lesion (controls) were recruited for this study. The G>A polymorphism (rs9527) having at least one minor allele 'A' was found to be significantly higher in cases compared to controls, implying increased risk toward the development of skin lesions. The risk genotype was also found to be significantly associated with cytogenetic damage as measured by chromosomal aberrations and micronuclei formation in lymphocytes. Hence, it can be concluded that G>A change in the C10orf32 region plays an important role in arsenic induced toxicity and susceptibility.

Association of NALP2 polymorphism with arsenic induced skin lesions and other health effects.

Prolonged consumption of arsenic-laden water above the threshold limit of 10µg/L causes a plethora of dermatological and non-dermatological multi-organ health problems, including cancer and death. Among several mechanisms of arsenic-induced toxicity and carcinogenicity studied so far, role of arsenic in impairment of immune system is less understood. Epidemiological data, animal model as well as cell line based studies have indicated that arsenic targets immune system and is associated with characteristic immunosupression, which may further adversely affect respiratory function. However, to the best of our knowledge, there is no study with respect to arsenic susceptibility investigating the role of genetic variation having immunological function. Hence, we have recruited a total of 432 arsenic-exposed individuals, of which 219 individuals with characteristic arsenic-induced skin lesions (cases) and 213 individuals without arsenic-induced skin lesion(controls), from arsenic-exposed districts of West Bengal, India. To find any probable association between arsenicism and the exonic single nucleotide polymorphisms (SNPs) in NALP2 gene, an important component of inflammasome complex, we screened the entire coding region (exon) in all the study participants. Among 9 SNPs found in NALP2 gene, the A1052E polymorphism (at least with one minor allele), was significantly overrepresented in controls and hence implies decreased risk toward the development of skin lesions [OR=0.67, 95% CI: 0.46-0.97]. Since, development of non-dermatological health effects are also important factor to properly look into, we have attempted to correlate the genetic variation of NALP2 with the extent of cytogenetic damage as measured by chromosomal aberration assay and adverse health effects including peripheral neuropathy, eye problem and respiratory diseases in the study population. We observed individuals with the protective genotype had less chromosomal aberration (p<0.05), and were also less susceptible toward arsenic-related respiratory diseases [OR=0.47; 95%CI: 0.23-0.89]. These findings suggest that NALP2 A1052E SNP plays an important role toward development of arsenic-induced skin lesions, chromosomal damage and respiratory diseases.

Arsenic-induced toxicity and carcinogenicity: a two-wave cross-sectional study in arsenicosis individuals in West Bengal, India.

In the state of West Bengal in India, over 26 million individuals are exposed to arsenic via drinking water. Dermatological, non-dermatological disorders and cancers are associated with arsenic toxicity. Of late, there has been a decrease in the arsenic concentration in drinking water owing to governmental efforts, raising the possibility of remediation. A cross-sectional study was conducted, where 189 arsenicosis and 171 unexposed individuals were recruited at two time points, (2005-06 and 2010-11) with concomitant decrease in the level of arsenic exposure via drinking water in the arsenicosis group in 2010-11. Parameters studied included dermatological, non-dermatological health status and cytogenetic damage. Decrease of arsenic exposure (190.1 µg/l to 37.94 µg/l) resulted in significant decline in the number of individuals having dermatological disorders (P<0.01) and in the severity of each dermatological outcome (P<0.0001). Micronucleus formation in urothelial cells and lymphocytes decreased significantly (P<0.001). However, there was a significant (P<0.001) rise in the incidence of each of the non-dermatological diseases, that is, peripheral neuropathy, conjunctivitis and respiratory distress over the period. Thirteen (6.87%) of the initially recruited arsenicosis individuals died of cancer, in this period. Remediation by arsenic-safe drinking water can reduce dermatological manifestations and cytogenetic insult; but is unable to counter the non-dermatological symptoms.

Arsenic exposure through drinking water increases the risk of liver and cardiovascular diseases in the population of West Bengal, India.

BACKGROUND: Arsenic is a natural drinking water contaminant affecting 26 million people in West Bengal, India. Chronic arsenic exposure causes cancer, cardiovascular disease, liver disease, neuropathies and ocular diseases. The aims of the present study were to assess bioindicators of hepatocellular injury as indicated by the levels of liver enzymes, to determine the auto immune status, as indicated by the amounts of anti-nuclear antibodies (ANA) and anti-dsDNA antibodies in their serum, and to predict cardiovascular risk in the arsenic exposed population. METHODS: Effect of chronic arsenic exposure on liver was determined by liver function tests. Autoimmune status was measured by measuring ANA and anti-dsDNA in serum. Inflammatory cytokines associated with increased cardiovascular disease risk, IL6, IL8 and MCP-1 were determined. RESULTS: Our results indicated that serum levels of bilirubin, alanine transaminase, aspartate transaminase, alkaline phosphatase and ANA were increased in the arsenic exposed population. Serum levels of IL6 and IL8 also increased in the arsenic exposed group. CONCLUSIONS: Chronic arsenic exposure causes liver injury, increases the serum levels of autoimmune markers and imparts increased cardiovascular risk.