Childhood acute lymphoblastic leukemia: Four years evaluation of protocols 2013 and 2016 in a single center in Indonesia, a lower-middle-income country.

BACKGROUND: The prognosis of childhood acute lymphoblastic leukemia (ALL) in Indonesia, a lower-middle-income country (LMIC), is lower than in high income countries (HICs). The Indonesian ALL2013 protocol resulted in too many toxic deaths (21%) and abandonments (11%). Therefore, we drafted an adapted protocol, ALL2016. Main changes: no anthracyclines in standard risk (SR), prednisone replaced dexamethasone at induction in high risk (HR), and anthracyclines and cyclophosphamide were rescheduled in HR. PROCEDURE: Patients (aged: 1-18 years) were stratified into SR and HR. HR was defined as age over 10 years, leucocyte count over 50 × 109 /L, central nervous system (CNS) involvement, mediastinal mass, T-cell phenotype, testicular involvement, or poor prednisone response. RESULTS: ALL2013 included 174 patients (106 SR and 68 HR) and ALL2016 188 (91 SR and 97 HR). Although the number of HR patients was significantly higher in ALL2016 (51.6% vs. 39.1%; p = .017), the outcome of ALL2016 improved over ALL2013 (4-year-probable overall survival (pOS) 60.1% vs. 50.0%; p = .042 and 4-year-probable event-free survival (pEFS) 49.5% vs. 36.8%; p = .018). ALL2016 showed a nonsignificant advantage for SR patients (4-year-pEFS 56.0% vs. 47.2%; p = .220 and 4-year-pOS 70.3% vs. 61.3%; p = .166), but less toxic deaths (7% vs. 20%; p = .011). In HR group, the outcomes were significantly better in ALL2016 (4-year-pEFS 43.3% vs. 20.6%; p = .004; 4-year-pOS 50.5% vs. 32.4%; p = .014) especially due to less relapses (31% vs. 62%; p = .001). Isolated CNS relapses went down from 18 to 8% in HR (p = .010) and 11 to 5% in SR (p = .474). Both SR and HR showed lower numbers of abandonment in ALL2016 (6% vs. 14%; p = .039). CONCLUSIONS: Overall ALL2016 results improved over ALL2013. Modest changes in protocol resulted in less initial toxicity and abandonments.

Impact of universal health coverage on childhood cancer outcomes in Indonesia.

BACKGROUND: Starting from 2014, the Indonesian government has implemented Universal Health Coverage (UHC) with the aim to make healthcare services accessible and affordable to all Indonesian citizens. A major reason for childhood cancer treatment failure in low- and middle-income countries, particularly among families with low socioeconomic status (SES), is abandonment of expensive cancer treatment. Our study compared childhood cancer treatment outcomes of the overall, low, and high SES population before and after introduction of UHC at a large Indonesian academic hospital. METHODS: Medical records of 1040 patients diagnosed with childhood cancer before (2011-2013, n = 506) and after (2014-2016, n = 534) introduction of UHC were abstracted retrospectively. Data on treatment outcome, SES, and health-insurance status at diagnosis were obtained. FINDINGS: After introduction of UHC, the number of insured patients increased from 38% to 82% (P < 0.001). Among low SES population, insurance coverage increased from 40% to 85% (P < 0.001), and among high SES population from 33% to 77% (P < 0.001). In the overall population, treatment abandonment decreased from 36% to 22% (P < 0.001). Event-free survival estimates at four years after diagnosis of overall population improved from 16% to 22% (P < 0.001). Hazard ratio for treatment failure was 1.26 (CI: 1.07-1.48, P = 0.006) for uninsured versus insured patients. In the low SES population, treatment abandonment decreased from 36% to 19% (P < 0.001). Event-free survival estimates at four years after diagnosis of low SES population improved from 14% to 22% (P < 0.001). INTERPRETATION: Introduction of UHC in Indonesia contributed significantly to better treatment outcome and event-free survival of children with cancer from low SES families.

Effect of different feeding management on the respiratory methane emission and feces-derived methane yield of goat.

OBJECTIVE: This study aimed to evaluate the respiratory methane emission and ultimate methane yield (B 0) of goat feces that fed roughage consisted of Pennisetum purpureum and Gliricidia) and fed roughage and concentrate with different protein source in the ration (fish meal and soybean meal). MATERIALS AND METHODS: Fifteen Kacang bucks were allocated to the control group (T0): goats were fed roughage only, T1: goats were fed roughage and concentrate with fish meal as protein sources, and T2: goats were fed roughage and concentrate and the protein source in the ration was soybean meal. RESULTS: The protein content of feces from T0 was significantly lower (p < 0.05) than that from the other treatments. The same phenomenon was also found in the respiratory methane emission in terms of l/head/d, l/kg digestible dry matter, and l/kg body weight. However, there was no significant effect (p > 0.05) of different ration composition on the ultimate methane yield (B0 ) of goat feces. This study found that B0 of goat feces from treatment T0, T1, and T2 was 17.40%, 25.78%, and 61.29%, respectively, higher than that from the international default value for developing countries. CONCLUSION: Feeding grass and legume can reduce methane respiration emission in goat. B0 of feces in the present study was higher than that in the international default value; therefore, the potential emission of goat manure in tropical developing countries could be higher than that in the present estimation.

Modifying effect of XmnI, BCL11A, and HBS1L-MYB on clinical appearances: A study on ß-thalassemia and hemoglobin E/ß-thalassemia patients in Indonesia.

OBJECTIVE/BACKGROUND: Thalassemia is a monogenic hematologic disease that has the highest prevalence globally. In addition, there is complexity of the genetic background associated with a variety of phenotypes presented among patients. Genetic heterogeneity related to fetal hemoglobin (HbF) production has been reported as an influencing phenotypic factor of ß-thalassemia (ß-thal). Therefore, this study aimed to find the effect of these genetic modifiers, especially in the XmnI locus, rs11886868, rs766432 (BCL11A), and rs9399137 (HBS1L-MYB), among ß-thal and HbE/ß-thal patients in Indonesia, according to laboratory and clinical outcomes, including HbF levels and clinical scores. This study was also designed to compare these modifying effects among ß-thal and HbE/ß-thal patients in Indonesia. METHODS: A total of 189 patients with genotyping of ß-thal and HbE/ß-thal were included in this study. The erythrocytes index and Hb electrophoresis measurements were calculated using appropriate methods. The severity of ß-thal and HbE/ß-thal was classified based on the Mahidol score. Polymorphism of the XmnI locus, rs11886868, rs766432 (BCL11A), and rs9399137 (HBS1L-MYB) was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system (ARMS) methods. RESULTS: The distributions of minor allele in the XmnI locus, rs11886868, rs766432, and rs9399137 were 14%, 22%, 19% and 18% respectively. The variation allele in the XmnI locus, rs11886868, and rs766432 showed a significant value for modifying HbF and clinical score in HbE/ß-thal patients, but rs9399137 did not demonstrate such features. In ß-thal patients, however, no correlation was found for any single-nucleotide polymorphisms and clinical appearance. CONCLUSION: The XmnI locus, rs11886868, and rs766432 have a modifying effect on HbF and clinical score in HbE/ß-thal patients in Indonesia, but not in ß-thal patients.

The effect of mixed-enzyme addition in anaerobic digestion on methane yield of dairy cattle manure.

This study investigates the effect of applying a mixture of enzymes (ME) to dairy cattle manure (DCM) as substrate in anaerobic digestion (AD). The aims of this study were to evaluate different methods of ME application to DCM at different temperatures and to investigate the effect of adding ME during the pre-treatment of the solid fractions of dairy cattle manure (SFDCM). The results showed that there was no positive effect of direct ME addition to substrate at either mesophilic (35 degrees C) or thermophilic (50 degrees C) process temperatures, but there was a significant 4.44% increase in methane yield when DCM, which had been incubated with ME addition at 50 degrees C for three days, was fed to a digester when compared to a control digester operating at the same retention time. Methane production was detected during the pre-treatment incubation, and the total sum methane yield during pre-treatment and digestion was found to be 8.33% higher than in the control. The addition of ME to the SFDCM in a pre-incubation stage of 20 h at 35 degrees C gave a significant increase in methane yield by 4.15% in a digester treating a mixed substrate (30% liquid fractions DCM and 70% enzyme-treated SFDCM) when compared with the control digester treating a similar mixed substrate with inactivated enzyme addition. The results indicate that direct physical contact of enzyme molecules and organic material in DCM prior to AD, without the intervention of extracellular enzymes from the indigenous microorganism population, was needed in order to increase methane yields.

Effects of high-temperature isochoric pre-treatment on the methane yields of cattle, pig and chicken manure.

Cattle manure, dewatered pig manure and chicken manure were pre-treated in a high-temperature reactor under isochoric conditions for 15 min at temperatures between 100 and 225 degrees C with 25 degrees C intervals to study the effect on their methane yield. After 27 days of batch incubation, cattle manure showed a significant improvement in its biochemical methane potential (BMP) of 13% at 175 degrees C and 21% at 200 degrees C. Pig manure showed improvements at temperatures of 125 degrees C and above, with a maximum 29% increase in yield at 200 degrees C. The BMP of chicken manure was reduced by 18% at 225 degrees C, but at lower temperatures there were no significant changes. It was found that this method of pre-treatment could be feasible if sufficient surplus energy was available or if the energy used in the pre-treatment could be recovered.

Randomized double blind trial of ciprofloxacin prophylaxis during induction treatment in childhood acute lymphoblastic leukemia in the WK-ALL protocol in Indonesia.

OBJECTIVES: Toxic death is a big problem in the treatment of childhood acute lymphoblastic leukemia (ALL), especially in low-income countries. Studies of ciprofloxacin as single agent prophylaxis vary widely in success rate. We conducted a double-blind, randomized study to test the effects of ciprofloxacin monotherapy as prophylaxis for sepsis and death in induction treatment of the Indonesian childhood ALL protocol. METHODS: Patients were randomized to the ciprofloxacin arm (n = 58) and to the placebo arm (n = 52). Oral ciprofloxacin monotherapy or oral placebo was administered twice a day. All events during induction were recorded: toxic death, abandonment, resistant disease, and complete remission rate. RESULTS: Of 110 patients enrolled in this study, 79 (71.8%) achieved CR. In comparison to the placebo arm, the ciprofloxacin arm had lower nadir of absolute neutrophil count during induction with median of 62 (range: 5-884) versus 270 (range: 14-25,480) × 10(9) cells/L (P < 0.01), greater risks for experiencing fever (50.0% versus 32.7%, P = 0.07), clinical sepsis (50.0% versus 38.5%, P = 0.22), and death (18.9% versus 5.8%, P = 0.05). CONCLUSION: In our setting, a reduced intensity protocol in a low-income situation, the data warn against using ciprofloxacin prophylaxis during induction treatment. A lower nadir of neutrophil count and higher mortality were found in the ciprofloxacin group.

L-asparaginase: long-term results of a randomized trial of the effect of additional 3 doses during consolidation treatment in the Indonesian WK-ALL-2000 protocol.

We conducted a randomized trial to compare the influence of 3 additional doses of L-asparaginase on clinical outcome of newly diagnosed childhood acute lymphoblastic leukemia (ALL). Patients were treated using Indonesian WK-ALL-2000 protocol between 1999 and 2005 and randomized to receive (3A arm, n=61) or not to receive (0A arm, n=56) an additional 3 weekly doses of 6000 IU/m(2)/dose of Escherichia coli L-asparaginase during consolidation treatment on top of 2 doses (standard-risk patients) or 5 doses (high-risk patients). Events after remission included relapse (37.6%), death (16.2%), and abandonment of therapy (15.4%). There was no significant difference in relapses between the 2 arms. Patients in arm 3A versus 0A tended to have a lower 5 years disease-free survival (47.4±7.9% vs. 51.7±7.9%, P=0.72) and lower 5 years event-free survival (29.5±5.8% vs. 35.7±6.4%, P=0.61). We conclude that in our setting the use of 3 additional doses of L-asparaginase during consolidation therapy did not result in survival advantage. Contrariwise, adverse effects from this drug included higher treatment cost and systemic toxicity.

Chemical composition and methane yield of reed canary grass as influenced by harvesting time and harvest frequency.

This study examined the influence of harvest time on biomass yield, dry matter partitioning, biochemical composition and biological methane potential of reed canary grass harvested twice a month in one-cut (OC) management. The regrowth of biomass harvested in summer was also harvested in autumn as a two-cut management with (TC-F) or without (TC-U) fertilization after summer harvest. The specific methane yields decreased significantly with crop maturity that ranged from 384 to 315 and from 412 to 283 NL (normal litre) (kgVS)(-1) for leaf and stem, respectively. Approximately 45% more methane was produced by the TC-F management (5430Nm(3)ha(-1)) as by the OC management (3735Nm(3)ha(-1)). Specific methane yield was moderately correlated with the concentrations of fibre components in the biomass. Larger quantity of biogas produced at the beginning of the biogas assay from early harvested biomass was to some extent off-set by lower concentration of methane.

Anaerobic digestion of acidified slurry fractions derived from different solid-liquid separation methods.

Batch assays investigating the ultimate methane yields (B(0)) of acidified slurry fractions produced with different solid-liquid slurry separation techniques were done. The result showed that the anaerobic digestion (AD) process was inhibited when raw and liquid fractions of sow, pig and dairy cow acidified slurry are digested, but AD treating solid fractions (SF) acidified slurry showed no sulphide inhibition. The B(0) of SF acidified sow slurry increased significantly with increasing screen size in the screw press. No significant effect of acidification processes on B(0) of SF dairy cow slurry (DCS) was observed. The ultimate methane yields of SF acidified DCS and SF non acidified DCS were 278±13 and 289±1LkgVS(-1), while in term of fresh weigh substrate were 59±2.8 and 59±0.3Lkgsubstrate(-1), respectively.

Early Response to Dexamethasone as Prognostic Factor: Result from Indonesian Childhood WK-ALL Protocol in Yogyakarta.

Early response to treatment has been shown to be an important prognostic factor of childhood acute lymphoblastic leukemia (ALL) patients in Western studies. We studied this factor in the setting of a low-income province in 165 patients treated on Indonesian WK-ALL-2000 protocol between 1999 and 2006. Poor early response, defined as a peripheral lymphoblasts count of ≥1000/µL after 7 days of oral dexamethasone plus one intrathecal methotrexate (MTX), occurred in 19.4% of the patients. Poor responders showed a higher probability of induction failures compared to good responders (53.1% versus 23.3%, P < 0.01), higher probability of resistant disease (15.6% versus 4.5%, P = 0.02), shorter disease-free survival (P = 0.034; 5-year DFS: 24.9% ± 12.1% versus 48.6% ± 5.7%), and shorter event-free survival (P = 0.002; 5-year EFS: 9.7% ± 5.3% versus 26.3% ± 3.8%). We observed that the percentage of poor responders in our setting was higher than reported for Western countries with prednisone or prednisolone as the steroids. The study did not demonstrate a significant additive prognostic value of early response over other known risk factors (age and white blood cell count) for DFS and only a moderately added value for EFS.

Thermophilic anaerobic co-digestion of separated solids from acidified dairy cow manure.

This study examined the potential for partly substituting dairy cow manure (DCM) with solids from solid to liquid separation of acidified dairy cow manure (SFDCM) during thermophilic anaerobic digestion. Three different substituting levels with a maximum of 30% substitution were tested. All digesters substituting DCM with SFDCM showed a stable biogas production with low volatile fatty acid concentrations after a short transition period. An increased methane yield in terms of digester volume compared to DCM alone was obtained with increasing amount of SFDCM and about 50% more methane was achieved when 30% of DCM was substituted with SFDCM. The digestates were subsequently digested in a post digestion, during which the methane yield increased proportionally with increasing amounts of SFDCM. It can be concluded that SFDCM is a suitable biomass for co-digestion and can be used to increase methane yield in terms of digester volume at ratios up to at least 30%.

NIR monitoring of ammonia in anaerobic digesters using a diffuse reflectance probe.

The feasibility of using a diffuse reflectance probe attached to a near infrared spectrometer to monitor the total ammonia nitrogen (TAN) content in an anaerobic digester run on cattle manure was investigated; as a previous study has indicated that this probe can be easily attached to an anaerobic digester. Multivariate modelling techniques such as partial least squares regression and interval partial least squares methods were used to build models. Various data pre-treatments were applied to improve the models. The TAN concentrations measured were in the range of 1.5 to 5.5 g/L. An R(2) of 0.91 with an RMSEP of 0.32 was obtained implying that the probe could be used for monitoring and screening purposes.

Incidence of childhood leukemia in Yogyakarta, Indonesia, 1998-2009.

BACKGROUND: In most developing countries, incidence data for childhood cancers are less reliable, because very few population-based registries exist. The aim of this study was to present the epidemiology of childhood leukemia in the Dr. Sardjito Hospital (DSH) region, which catchment area extends beyond the boundaries of the Yogyakarta Special Province (YSP). PROCEDURE: Health records of children, 0-14 years of age, who were diagnosed with leukemia between January 1998 and December 2009, were reviewed. Diagnosis of leukemia was confirmed by morphological and histochemical examination of marrow samples. RESULTS: The estimated average annual incidence rate (AAIR) of childhood acute leukemia in DSH was 46.2 per million per year. Interestingly, the annual incidence rate (AIR) of childhood acute leukemia from the catchment area of DSH significantly increased from 35 in 1999 to 70 in 2009 (ANOVA, P = 0.003). The YSP population data, analyzed separately, showed an increase in AIR from 15.7 to 32.9 (ANOVA, P = 0.325) and an AAIR of 28.8. Remarkably, a relatively high frequency (25.5% in DSH and 27.7% in YSP) of children with AML was found in the group of acute leukemias. CONCLUSION: The DSH incidence calculations may be overestimated due to an underestimation of the population number. Since the population count for YSP is more precise, the data of YSP were used for comparison with developed countries. AAIR of ALL (20.8) is relatively low compared to Western countries (22.4-37.9). The AAIR of AML (8.0) is similar to Western countries (5.0-8.0) resulting a relatively high percentage of AML versus ALL (27.7%) in YSP.