Cetuximab as first-line treatment for metastatic colorectal cancer (mCRC): a model-based economic evaluation in Indonesia setting.

OBJECTIVES: To assess the cost-effectiveness of cetuximab in combination with chemotherapy fluorouracil, oxaliplatin, and leucovorin (FOLFOX) or fluorouracil, irinotecan and leucovorin (FOLFIRI) compared to standard chemotherapy alone as a first-line treatment for metastatic colorectal cancer (mCRC) with positive KRAS wild type patients in Indonesia. METHODS: A cost-utility analysis applying Markov model was constructed, with a societal perspective. Clinical evidence was derived from published clinical trials. Direct medical costs were gathered from hospital billings. Meanwhile, direct non-medical costs, indirect costs, and utility data were collected by directly interviewing patients. We applied 3% discount rate for both costs and outcomes. Probabilistic sensitivity analysis was performed to explore the model's uncertainty. Additionally, using payer perspective, budget impact analysis was estimated to project the financial impact of treatment coverage. RESULTS: There was no significant difference in life years gained (LYG) between cetuximab plus FOLFOX/FOLFIRI and chemotherapy alone. The incremental QALY was only one month, and the incremental cost-effectiveness ratio (ICER) was approximately IDR 3 billion/QALY for cetuximab plus chemotherapy. Using 1-3 GDP per capita (IDR 215 million or USD 14,350) as the current threshold, the cetuximab plus chemotherapy was not cost-effective. The budget impact analysis resulted that if cetuximab plus chemotherapy remain included in the benefits package under the Indonesian national health insurance (NHI) system, the payer would need more than IDR 1 trillion for five years. CONCLUSIONS: The combination of cetuximab and chemotherapy for mCRC is unlikely cost-effective and has a substantial financial impact on the system.

Aortic Valve Replacement with Single-Strip Autologous Pericardium.

BACKGROUND: Aortic valve replacement with mechanical valves is the standard treatment for aortic valve disease in Indonesia. Its usage is associated with high cost, risk of endocarditis and thromboembolic event, and lifetime consumption of anticoagulants. We performed a novel replacement technique of the aortic valve using an autologous pericardium and evaluated the short-term outcomes. METHODS: From April 2017 to April 2020, 16 patients underwent aortic valve replacement with a single-strip autologous pericardium. Outcomes of the left ventricular reverse remodeling (LVRR), 6-minute walk test (6MWT), and soluble suppression of tumorigenicity-2 (sST-2) were measured at 6 months postoperation. RESULTS: A total of 16 surgeries were performed using aortic valve replacement with single-strip pericardium without conversion to mechanical valve replacement. The patients included eight males and eight females, and the mean age was 49.63 ± 12.54 years. The most common diagnosis was mixed aortic valve stenosis and regurgitation (9 cases). Five patients underwent a concomitant coronary artery bypass graft (CABG) procedure and 12 patients underwent either mitral or tricuspid valve repair. The mean aortic cross-clamp time was 139.88 ± 23.21 minutes and cardiopulmonary bypass time was 174.37 ± 33.53 minutes. At 6 months postoperation, there was an increase in the distance walked at the 6MWT (p = 0.006) and a decrease of the sST-2 level (p = 0.098). Echocardiogram showed two patients had LVRR. Survival and freedom from reoperation are 100% at 1 year of follow-up. CONCLUSION: Aortic valve replacement with a single strip of pericardium is a good alternative to aortic valve replacement with a mechanical valve. Short-term evaluation at 6 months postoperation showed improvement in clinical status and echocardiographic parameters compared to baseline.

Adding rituximab to chemotherapy for diffuse large B-cell lymphoma patients in Indonesia: a cost utility and budget impact analysis.

BACKGROUND: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has been used to treat patients with diffuse large B-cell lymphoma (DLBCL) under National Health Insurance (NHI) scheme in Indonesia. This study aims to estimate its cost-effectiveness and budget impact. METHODS: We conducted a cost utility analysis using Markov model over a lifetime horizon, from a societal perspective. Clinical evidence was derived from published clinical trials. Direct medical costs were gathered from hospital data. Direct non-medical costs, indirect costs, and utility data were primarily gathered by interviewing the patients. We applied 3% discount rate for both costs and effect. All monetary data are converted into USD (1 USD = IDR 14,000, 2019). Probabilistic sensitivity analysis was performed. In addition, from a payer perspective, budget impact analysis was estimated using price reduction scenarios. RESULTS: The incremental cost-effectiveness ratio (ICER) of R-CHOP was USD 4674/LYG and 9280/QALY. If we refer to the threshold three times the GDP per capita (USD 11,538), R-CHOP could thus be determined as a cost-effective therapy. Its significant health benefit has contributed to the considerable ICER result. Although the R-CHOP has been considered a cost-effective intervention, the financial consequence of R-CHOP if remain in benefit package under National Health Insurance (NHI) system in Indonesia is considerably substantial, approximately USD 35.00 million with 75% price reduction scenario. CONCLUSIONS: As a favorable treatment for DLBCL, R-CHOP ensures value for money in Indonesia. Budget impact analysis provides results which can be used as further consideration for decision-makers in matters related to benefit packages.

Economic Evaluation of Adding Bevacizumab to Chemotherapy for Metastatic Colorectal Cancer (mCRC) Patients in Indonesia.

OBJECTIVE: Since 2016, bevacizumab has been widely used to treat metastatic colorectal cancer (mCRC) in Indonesia. Nevertheless, the high cost of bevacizumab has raised the question of whether the therapy is considered cost-effective and should be included in the national health insurance system. This study aimed to assess the cost-effectiveness of bevacizumab plus chemotherapy versus chemotherapy alone for the treatment of mCRC patients. METHODS: A Markov model was applied using the perspective of the Indonesian healthcare system to assess cost-effectiveness. The health outcomes were expressed in terms of quality-adjusted life years (QALY) using the validated EuroQoL-5D-5L instrument. Data for medical costs were collected from hospital billings in four hospitals located in three different cities in Indonesia. Meanwhile, data for utility were obtained from interviewing 90 patients who came to the hospital. We compared those mCRC patients who received chemotherapy alone either with FOLFOX or FOLFIRI, versus patients who received the addition of bevacizumab. RESULTS: With the perspective of societal, the incremental cost-effectiveness ratio (ICER) of adding bevacizumab was USD 49,312 per QALY gained using secondary data and USD 28,446 per QALY using real world data. CONCLUSION: Using either a healthcare or societal perspective, the addition of bevacizumab for mCRC treatment was considered not cost-effective.

Role of terminal warm blood cardioplegia in complex congenital heart surgery.

Introduction Myocardial protection is vital to ensure successful open heart surgery. Cardioplegic solution is one method to achieve good myocardial protection. Inevitably, ischemia-reperfusion injury occurs with aortic crossclamping. Histidine-tryptophan-ketoglutarate solution is a frequently used cardioplegia for complex congenital heart surgery. We postulated that addition of terminal warm blood cardioplegia before removal of the aortic crossclamp might improve myocardial protection. Method A randomized controlled trial was conducted on 109 cyanotic patients aged, 1 to 5 years who underwent complex biventricular repair. They were divided into a control group of 55 patients who had histidine-tryptophan-ketoglutarate only and a treatment group of 54 who had histidine-tryptophan-ketoglutarate with terminal warm blood cardioplegia. Endpoints were clinical parameters, troponin I levels, and caspase-3 as an apoptosis marker. Results The incidence of low cardiac output syndrome was 34%, with no significant difference between groups (35.2% vs. 33.3%, p = 0.84). The incidence of arrhythmias in our treatment group was lower compared to the control group (36% vs. 12%, p = 0.005). Troponin I and caspase-3 results did not show any significant differences between groups. For cases with Aristotle score ≥ 10, weak expression of caspase-3 in the treatment group post-cardiopulmonary bypass was lower compared to the control group. Conclusion For complex congenital cardiac surgery, the addition of terminal warm blood cardioplegia does not significantly improve postoperative clinical or metabolic markers.

Oral Triiodothyronine for Infants and Children Undergoing Cardiopulmonary Bypass.

BACKGROUND: This study evaluated the efficacy and safety of oral triiodothyronine (T3; Tetronine, Dalim BioTech, Korea) for infants and children undergoing cardiopulmonary bypass in an Indonesian population. METHODS: We performed a single-center, randomized, double-blind, and placebo-controlled trial in children aged 3 years and younger undergoing congenital heart disease operations with cardiopulmonary bypass. We administered oral T3 (1 µg/kg per body weight/dose) or placebo (saccharum lactis) by nasogastric tube every 6 hours for 60 hours after induction of anesthesia. The primary end point, time to extubation, was compared with Cox regression. RESULTS: The modified intention-to-treat group included 101 placebo and 104 treated patients. The stratified log-rank test did not show a significant treatment difference (p = 0.061) for time to extubation, but after adjustment for age, the nutritional Z score, and Aristotle surgical complexity, the hazard ratio was 1.33 (95% confidence interval, 1.00 to 1.76; p = 0.049). The effect of T3 was stronger in the strata aged 5 months and younger (hazard ratio, 1.86; 95% confidence interval 1.02 to 3.39; p = 0.043). Median intubation time was 47.3 hours for the placebo and 32.1 hours for the T3 group in aged 5 months and younger. Adverse events rates, including arrhythmia, were similar between groups, although sepsis was more frequent with placebo. CONCLUSIONS: Oral T3 supplementation may shorten time to extubation in children undergoing congenital heart disease operations, particularly infants aged 5 months or younger. Administration is relatively safe, simple and inexpensive.

The role of curcumin as an inhibitor of oxidative stress caused by ischaemia re-perfusion injury in tetralogy of Fallot patients undergoing corrective surgery.

BACKGROUND: Cardiopulmonary bypass during tetralogy of Fallot corrective surgery is associated with oxidative stress, and contributes to peri-operative problems. Curcumin has been known as a potent scavenger of reactive oxygen species, which enhances the activity of antioxidants and suppresses phosphorylation of transcription factors involved in inflamation and apoptosis. OBJECTIVES: To evaluate the effects of curcumin as an antioxidant by evaluating the concentrations of malondialdehyde and glutathione, activity of nuclear factor-kappa B, c-Jun N-terminal kinase, caspase-3, and post-operative clinical outcomes. METHODS: Tetralogy of Fallot patients for corrective surgery were randomised to receive curcumin (45 mg/day) or placebo orally for 14 days before surgery. Malondialdehyde and glutathione concentrations were evaluated during the pre-ischaemia, ischaemia, re-perfusion phases, and 6 hours after aortic clamping-off. Nuclear factor-kappa B, c-Jun N-terminal kinase, and caspase-3, taken from the infundibulum, were assessed during the pre-ischaemia, ischaemia, and re-perfusion phases. Haemodynamic parameters were monitored until day 5 after surgery. RESULTS: In all the observation phases, malondialdehyde and glutathione concentrations were similar between groups. There was no significant difference in nuclear factor-kappa B activity between the groups for three observations; however, in the curcumin group, c-Jun N-terminal kinase significantly decreased from the pre-ischaemia to the re-perfusion phases, and caspase-3 expression was lower in the ischaemia phase. Patients in the curcumin group had lower temperature and better ventricular functions, but no significant differences were found in mechanical ventilation day or length of hospital stay in the two groups. CONCLUSION: Cardioprotective effects of curcumin may include inhibition of the c-Jun N-terminal kinase pathway and caspase-3 in cardiomyocytes, particularly in the ischaemia phase.

Transcatheter Closure of Patent Ductus Arteriosus in Adolescents and Adults: A Case Series.

During 11 years period from January 2005 to December 2015 there were 18 adolescent and adult patients  who underwent transcatheter closure of PDA using PDA Amplatzer Duct Occluder (ADO). There were 9 cases with age of 14 to 18 years and 9 cases with age of more than 18 years where the oldest case was 46 years old. Two cases were male and 16 cases were female. Prior to procedures, clinical assessment, ECG, chest x-ray and transthoracic echocardiography (TTE) were performed to confirm the diagnosis of PDA. The procedures of device implantation was performed under conscious sedation in adults and using general anesthesia in adolescents.The size of PDA ranged from 1.6 mm to 11.1 mm. Based on Kritchenko classification, the type of PDA were 15 type A1 and 3type A2. Flow ratio between pulmonary to systemic circulation was between 1.1 and 5.9. The procedure time ranged from 60-189 minutes and the fluoroscopic time 7.1-77.3 minutes. The PA pressure ranged from 22 to 63 mmHg. Immediate results after procedures as seen in angiography showed complete closure in 14 cases and smoky residual shunt or minimal residual shunts in 4 cases, which probably due to the temporary leaking through the devices. In 24 hours, complete closure was achieved in all cases (100%) and continued until 1months. At 6 month follow up, there was no residual shunts detected and also there was no significant complications, such as device embolization or recanalization. This case series suggest that transcatheter closure of PDA in adolescents and adults using Amplatzer duct occluder (ADO) is effective and has excellent resultswithout significant complication. However, long-term follow up is required to assess long term efficacy and safety.

Transcatheter Closure of Atrial Septal Defects in a Center With Limited Resources: Outcomes and Short Term Follow-Up.

BACKGROUND: Transcatheter closure of atrial septal defects (ASD) has been accepted world-wide as an alternative to surgical closure with excellent results. This interventional, non-surgical technique plays an important role in the treatment of ASD mostly in the developing world where resources are limited. OBJECTIVES: To report the outcomes and short term follow-up of transcatheter closure of ASD over a 12-year period at our institution with limited resources. PATIENTS AND METHODS: This retrospective study included all patients with the diagnosis of secundum ASD and significant shunting (Qp/Qs > 1.5:1) as well as dilated right atrium and right ventricle who had transcatheter closure at Integrated Cardiovascular Center (PJT), Dr. Cipto Mangunkusumo Hospital between October 2002 and October 2014. One hundred fifty-two patients enrolled in this study were candidates for device closure. Right and left heart cardiac catheterization was performed before the procedure. All patients underwent physical examination, ECG, chest X-ray and transthoracal echocardiography (TTE) prior to device implantation. RESULTS: A total of 152 patients with significant ASD underwent device implantation. Subjects' age ranged from 0.63 to 69.6 years, with median 9.36 years and mean 16.30 years. They consisted of 33 (21.7%) males and 119 (78.3%) females, with mean body weight of 29.9 kg (range 8 to 75; SD 18.2). The device was successfully implanted in 150 patients where the majority of cases received the Amplatzer septal occluder (147/150; 98%) and the others received the Heart Lifetech ASD occluder (3/150, 2%), whereas two other cases were not suitable for device closure and we decided for surgical closure. The mean ASD size was 19.75 (range 14 - 25) mm. During the procedure, 5 (4.9%) patients had bradycardia and 3 (2.9%) patients had supraventricular tachycardia (SVT), all of which resolved. CONCLUSIONS: In our center with limited facilities and manpower, transcatheter closure of atrial septal defect was effective and safe as an alternative treatment to surgery. The outcome and short-term follow-up revealed excellent results, but long-term follow-up is needed.

Effects of duration of breastfeeding during infancy on vascular dysfunction in adolescents.

AIM: to investigate the effect of breastfeeding duration on vascular characteristics in adolescence. METHODS: we conducted a retrospective cohort study on adolescents aged 15-18 years old. Breastfeeding duration was inquired using a questionnaire filled by parents and categorized into 0-<2, 2-<4, 4-<6, 6-<12, and >12 months. Outcomes assessed were flow mediated dilation (FMD), carotid intima media thickness (CIMT), anthropometrics. Analysis was done using linear regression and MANOVA general linear model with cardiovascular risk factors as the dependent variables and breastfeeding duration as the independent variable with further adjustment for confounders. RESULTS: 285 subjects aged 15-18 years were enrolled. Breastfeeding duration of 4-<6 months was associated with thinner CIMT and the effect was more prominent after adjustment for gender and postnatal tobacco exposure (mean difference=24.28 micrometer, p=0.045). No statistically significant association was found with FMD. CONCLUSION: breastfeeding duration of 4-<6 months is associated with thinner IMT and thus has a protective effect on the development of cardiovascular disease. However the association with FMD in adolescence is less clear.

Ischemic preconditioning reduces apoptosis in open heart surgery.

BACKGROUND: This study was performed to assess the role of ischemic preconditioning on cardiomyocyte apoptosis after open heart surgery, based on morphology by transmission electron microscopy, caspase-3 activity, biochemical markers, and cardiac performance. METHODS: 12 piglets were divided into 2 equal groups: an ischemic preconditioning group and a control group. Ventricular muscles were collected to examine apoptotic ultrastructure morphology and caspase-3 activity. Blood samples from the coronary sinus were obtained for measurement of tumor necrosis factor-α, malondialdehyde, and cardiac troponin I. Aortic blood samples were taken for lactate measurements before and after cardiopulmonary bypass. Cardiac performance was measured by echocardiography before and after surgery. RESULTS: Cardiomyocyte apoptosis occurred postoperatively, as shown by ultrastructure observation. Caspase-3 activity was less in the ischemic preconditioning group than the control group (p < 0.05). Measurements of specific markers of cardiomyocyte injury also showed lower increases in the ischemic preconditioning group, although not significantly different. Clinical outcomes showed that ischemic preconditioning was able to preserve cardiac performance in terms of ejection fraction, cardiac index, and stroke volume index; these were statistically significant, except for lactate concentration. CONCLUSIONS: Cardiomyocyte apoptosis occurs after open heart surgery. Ischemic preconditioning can reduce cardiomyocyte apoptosis and improve cardiac performance. Laboratory findings showed that ischemic preconditioning prevents injury of cardiomyocytes and reduces lactate concentration, although not statistically significant.

Effect of allopurinol on oxidative stress and hypoxic adaptation response during surgical correction of tetralogy of fallot.

AIM: to analyze the role of allopurinol in reducing the ischemia-reperfusion injury, and to confirm the HIF-1 binding activity changes during the surgical correction of tetralogy of fallot (TF). METHODS: randomized, double-blind experimental study on patients undergoing surgical correction of TF in the Integrated Cardiovascular Services, Cipto Mangunkusumo Hospital from September 2009-May 2010. Patients were randomly divided into two groups. The first group was given 10 mg/kg body weight of allopurinol 3 times before undergoing operation (n=13) and the other group was given placebo (n=13). Tissue specimen from right ventricular muscle were taken for measurement of reactive oxygen species (ROS) expression and blood specimens from intra-coronary sinus for measurement of TNF-, superoxide dismutase (SOD), and malondialdehyde (MDA). RESULTS: cardiomyocytes expressing ROS in placebo group increased (41.37±29.29%; 42.61±22.82% and 53.81±25.76%), while in allopurinol group decreased (44.68±19.79%, 56.87±15.50%, and 47.98±22.52%). Concentration of TNF- tend to decrease in allopurinol group, while it tended to increase in the placebo goup. Concentration of SOD increased in the allopurinol group, while in the placebo group there were no significant changes. Concentration of MDA was highly increased in the placebo group (1.75 pmol/mg; 2.37 pmol/mg; 2.72 pmol/mg; 4.82 pmol/mg), but statistically it was not significant. On the other hand, there was no significant change of MDA concentration in the allopurinol group. Expression of HIF-1 in TF patients decreased significantly (p=0.026) from pre ischemic phase to ischemic phase, but it increased in the reperfusion phase (0.95 OD/mg protein, 0.52 OD/mg protein, 0.9 OD/mg protein). CONCLUSION: pre-surgical oral allopurinol treatment reduced ischemia-reperfusion injury during TF surgical correction, as indicated by the decrease in the number of cardiomyocytes expressing ROS, reducing TNF-, SOD, and MDA concentration in blood. There was a decrease in HIF-1 concentration in cardiomyocytes of the right ventricle during ischemic phase.

Surgical perspective of T1799A BRAF mutation diagnostic value in papillary thyroid carcinoma.

BACKGROUND: Throughout Indonesia, thyroid cancer is one of the ten commonest malignancies, with papillary thyroid carcinoma (PTC) in our hospital accounting for about 60% of all thyroid nodules. Although fine needle aspiration biopsy (FNAB) is the most reliable diagnostic tool, some nodules are diagnosed as indeterminate and second surgery is common for PTC. The aim of this study was to establish the diagnostic value and feasibility of testing the BRAF T1799A mutation on FNA specimens for improving PTC diagnosis. MATERIALS AND METHODS: This prospective study enrolled 95 patients with thyroid nodules and future surgery planned. Results of mutational status were compared with surgical pathology diagnosis. RESULTS: Of the 70 cases included in the final analysis, 62.8% were PTC and the prevalence of BRAF mutation was 38.6%. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for BRAF mutation analysis were 36%, 100%, 100% and 48%, respectively. With other data findings, nodules with "onset less than 5 year" and "hard consistency" were proven as diagnostic determinants for BRAF mutation with a probability of 62.5%. This mutation was also a significant risk factor for extra-capsular extension. CONCLUSIONS: Molecular analysis of the BRAF T1799A mutation in FNAB specimens has high specificity and positive predictive value for PTC. It could be used in the selective patients with clinical characteristics to facilitate PTC diagnosis and for guidance regarding extent of thyroidectomy.

Correlation between T2* cardiovascular magnetic resonance with left ventricular function and mass in adolescent and adult major thalassemia patients with iron overload.

AIM: to assess for a correlation between T2*CMR with LV function and mass in thalassemic patients with iron overload. METHODS: a cross-sectional study on thalassemic patients was conducted between July and September 2010 at Cipto Mangunkusumo and Premier Hospitals, Jakarta, Indonesia. Clinical examinations, review of medical charts, electrocardiography, echocardiography, and T2*CMR were performed. Cardiac siderosis was measured by T2*CMR conduction time. Left ventricle diastolic and systolic functions, as well as LV mass index were measured using echocardiography. Correlations between T2*CMR and echocardiography findings, as well as serum ferritin were determined using Pearson's and Spearman's tests. RESULTS: thirty patients aged 13-41 years were enrolled, of whom two-thirds had -thalassemia major and one-third had HbE/-thalassemia. Diastolic dysfunction was identified in 8 patients, whereas systolic function was normal in all patients. Increased LV mass index was found in 3 patients. T2*CMR conduction times ranged from 8.98 to 55.04 ms and a value below 20 ms was demonstrated in 14 patients. There was a statistically significant moderate positive correlation of T2*CMR conduction time with E/A ratio (r = 0.471, P = 0.009), but no correlation was found with LV mass index (r=0.097, P=0.608). A moderate negative correlation was found between T2*CMR and serum ferritin (r = -0.514, P = 0.004), while a moderate negative correlation was found between serum ferritin and E/A ratio (r = -0.425, P = 0.019). CONCLUSION: T2*CMR myocardial conduction time has a moderate positive correlation with diastolic function, moderate negative correlation with serum ferritin, but not with LV mass index and systolic function.

Risk factors of obstructive sleep apnea syndrome in obese early adolescents: a prediction model using scoring system.

AIM: to obtain the OSAS prevalence and risk factors of OSAS in obese early adolescents and to create a scoring system based on risk factors for diagnosing OSAS. METHODS: an observational study in Jakarta, November 2007 until December 2008 on obese adolescents aged 10-12 years with snoring. Subjects underwent clinical examination, lung function test, paranasal sinus X-ray, and polisomnography. Measured outcomes were diagnosis of OSAS; sensitivity, specificity, predictive values, and likelihood ratios of a scoring system based on risk factors. RESULTS: the prevalence of OSAS in obese early adolescents is 38.2% using AHI cut-off point of ≥3 on PSG. Tonsillar hypertrophy, adenoid hypertrophy, and neck circumference were the main risk factors. Scoring system was designed based on these results: OS= T + A + NC; OS= OSAS score; T= tonsil hypertrophy (≥T3 scored 1,