Waiting list mortality for pediatric deceased donor liver transplantation in a Japanese living‐donor–dominant program

Living donor liver transplantation (LDLT) has become a major life‐saving procedure for children with end‐stage liver disease in Japan, whereas deceased donor liver transplantation (DDLT) has achieved only limited success. The annual number of pediatric liver transplantations is approximately 100‐120, with a patient 20‐year survival rate of 81.0%. In 2005, the liver transplantation program at the National Center for Child Health and Development in Tokyo, Japan, was initiated, with an overall number of 560 pediatric patients with end‐stage liver disease to date. In July 2010, our center was qualified as a pediatric DDLT center; a total of 132 patients were listed for DDLT up until February 2019. The indications for DDLT included acute liver failure (n = 46, 34.8%), metabolic liver disease (n = 26, 19.7%), graft failure after LDLT (n = 17, 12.9%), biliary atresia (n = 16, 12.1%), and primary sclerosing cholangitis (n = 10, 7.6%). Overall, 25.8% of the patients on the waiting list received a DDLT and 52.3% were transplanted from a living donor. The 5‐year patient and graft survivals were 90.5% and 88.8%, respectively, with an overall waiting list mortality of 3.0%. LDLT provides a better survival compared with DDLT among the recipients on the DDLT waiting list. LDLT is nevertheless of great importance in Japan; however, it cannot save all pediatric recipients. As the mortality of children on the waiting list has not yet been reduced to zero, both LDLT and DDLT should be implemented in pediatric liver transplantation programs.     

Non‐total body irradiation myeloablative conditioning with intravenous busulfan and cyclophosphamide in hematopoietic stem cell transplantation for malignant infantile osteopetrosis

HSCT is the only curative treatment for MIOP. We prospectively investigated the outcome of HSCT using intravenous busulfan‐based conditioning regimen from 2008 to 2013. Nineteen patients (median age = 17 months) underwent transplantation from HLA‐matched related donors (n = 14), HLA‐haploidentical related donors (n = 2), partially matched cord blood donors (n = 2), and HLA‐matched unrelated donor (n = 1). Bone marrow (n = 9), peripheral blood (n = 8), and cord blood (n = 2) were used as stem cell sources. All but one patient demonstrated primary engraftment. Two patients experienced secondary graft failure. During the follow‐up period, three patients showed mixed chimerism (45%, 45%, and 70% of donor cells were engrafted in each one of these patients) but are disease free. Two‐yr OS and DFS were 84.2% and 73.7%, respectively. Improvement of visual acuity and partial reversal of mild conductive hearing loss occurred in two and four patients, respectively. The causes of death among three patients were infection, GvHD, and disease progression. In conclusion, due to major side effects of MIOP such as visual and hearing loss, early treatment using myeloablative conditioning without irradiation HSCT is suggested. The use of an HLA‐matched related donor seems to be highly successful in this regard. Also, according to results of our study, mixed chimerism may be sufficient to resolve symptoms of disease.     

Hematopoietic stem cell transplantation for children with primary immunodeficiency diseases: Single center experience in Jordan

HSCT can be curative for many PID. Little is known about the outcome of HSCT for patients with PID in the developing countries. We retrospectively reviewed all children with PID who received HSCT at KHCC in Jordan between August 2003 and October 2011. Twenty‐eight patients were identified. The median age was 16 months (3 months–17 yr). Patients' diagnoses were SCID (n = 16), CHS (n = 3), HLH (n = 3), WAS (n = 2), Griscelli syndrome (n = 1), ALPS (n = 1), Omenn's syndrome (n = 1), and DiGeorge syndrome (n = 1). Seventeen patients received HLA‐matched related HSCT, eight received maternal un‐manipulated haploidentical HSCT, and three received unrelated cord blood transplantation. Nine patients (32%) developed BCGosis secondary to reactivation of pretransplant vaccination. Three died while still receiving anti‐tuberculosis drugs, one still on treatment, and all others have recovered. Six patients had graft failure; four of them received no conditioning regimens. At a median follow up of 32 months (range 1‐67), 21 patients are alive, with overall survival of 72%. We conclude that HSCT for PID patients can be performed with a good outcome in developing countries; however, delayed diagnosis or referral and BCG reactivation are unique challenges.     

Living donor liver transplantation for pediatric patients with metabolic disorders: The Japanese multicenter registry

LDLT is indicated for a variety of metabolic disorders, primarily in Asian countries due to the absolute scarcity of deceased donor LT. We analyzed data for all pediatric LDLTs performed between November 1989 and December 2010, during which 2224 pediatric patients underwent LDLT in Japan. Of these patients, 194 (8.7%) underwent LDLT for metabolic disorders. Wilson's disease (n = 59; 30.4%) was the most common indication in the patients with metabolic disorders, followed by OTCD (n = 40; 20.6%), MMA (n = 20; 10.3%), and GSD (n = 15; 7.7%). The one‐, five‐, 10‐, and 15‐yr patient and graft survival rates were 91.2%, 87.9%, 87.0%, and 79.3%, and 91.2%, 87.9%, 86.1%, and 74.4%, respectively. Wilson's disease and urea cycle deficiency were associated with better patient survival. The use of heterozygous donors demonstrated no negative impact on either the donors or recipients. With regard to X‐linked OTCD, symptomatic heterozygote maternal donors should not be considered potential donor candidates. Improving the understanding of the long‐term suitability of this treatment modality will require the registration and ongoing evaluation of all patients with inherited metabolic disease considered for LT.     

Prope tolerance after pediatric liver transplantation

pT, under mono‐ and infratherapeutic calcineurin inhibition, may constitute an optimal condition combining graft acceptance with low IS load and minimal IS‐related toxicity. We reviewed 171 pediatric (<15.0 yr) survivors beyond one yr after LT, transplanted between April 1999 and June 2007 under tacrolimus‐based regimens (median follow‐up post‐LT: 6.0 yr, range: 0.8–9.5 yr). Their current status regarding IS therapy was analyzed and correlated with initial immunoprophylaxis. pT was defined as tacrolimus monotherapy, with mean trough blood levels <4 ng/mL during the preceding year of follow‐up, combined with normal liver function tests. The 66 children transplanted before April 2001 received a standard tacrolimus–steroid regimen. Beyond April 2001, 105 patients received steroid‐free tacrolimus–basiliximab or tacrolimus–daclizumab immunoprophylaxis. In the latter group, 43 (41%) never experienced any acute rejection episode and never received steroids. In the long term, a total of 79 recipients (47%) developed pT (n = 73) or IS‐free operational tolerance (n = 6), 27 of them belonging to the 43 steroid‐free patients (63%). In contrast, only 52/128 (41%) children treated with steroids subsequently developed prope/operational tolerance (p = 0.012). Steroid‐free tacrolimus‐based IS seems to promote long‐term graft acceptance under minimal/no IS. These results constitute the first evidence that minimization of IS, including steroid avoidance, might be tolerogenic in the long term after pediatric LT.     

Allogeneic hematopoietic stem cell transplantation for infants with idiopathic myelofibrosis

IMF is a rare disease in children that can present during infancy and has a protracted course. The only known curative approach for this disease in adult patients is allogeneic HSCT. There are very few reports describing the long‐term outcome of young children following stem cell transplantation for IMF. We report on eight patients less than two yr of age with IMF that did not resolve with supportive care measures. All patients underwent myeloablative conditioning regimen with busulfan and cyclophosphamide ± ATG followed by HSCT from matched related (n = 6) or unrelated donor (n = 2). All patients achieved neutrophil and platelet engraftment. Four patients had grade II‐III acute GVHD, and chronic GVHD developed in five patients (three mild and two severe). At a median follow‐up of eight and a half yr (0.7–9), all patients are alive with complete resolution of their hematologic manifestations. At the last follow‐up, all patients had normal endocrine function except for one patient who developed hypothyroidism. To date, this is the largest cohort of young children with IMF treated successfully with HSCT, with the longest duration of follow‐up. In conclusion, our study showed that HSCT is a curative option for infants with IMF.     

Depletion of alloreactive T cells for tolerance induction in a recipient of kidney and hematopoietic stem cell transplantations

Tangnararatchakit K, Tirapanich W, Anurathapan U, Tapaneya‐Olarn W, Pakakasama S, Jootar S, Slavin S, Hongeng S. Depletion of alloreactive T cells for tolerance induction in a recipient of kidney and hematopoietic stem cell transplantations. Abstract: The present case report represents a successful attempt to induce transplantation tolerance to organ allograft by combined administration of donor hematopoietic cells and kidney based on in vivo deletion of alloreactive host‐vs‐graft and graft‐vs‐host alloreactive T cells following non‐myeloablative conditioning. We were able to induce mixed and eventually full donor chimerism and tolerance of kidney allograft in a 15‐yr‐old male with ESRD after cisplatin treatment and autologous HSCT for mediastinal germ cell tumor. Our approach to induce tolerance was based on preferential depletion of alloreactive T cells induced by exposure to donor’s alloantigens and administration of cyclophosphamide at day 2 and day 3 after stem cell infusion. Additional non‐specific immunosuppression as part of the conditioning included exposure to two fractions of TLI, treatment with alemtuzumab (monoclonal anti‐CD52) and short‐term conventional IS treatment to avoid early graft loss, because of request of IRB. Using this approach, with rapid tapering of all conventional IS treatment, the patient maintains good renal functions without evidence of both acute and chronic rejection for 32 months off all medications.     

Risk factors for oral mucositis in children receiving hematopoietic cell transplantation for primary immunodeficiencies: A retrospective study

OM is a frequent complication for patients undergoing HSCT. The aim of this study was to evaluate the possible risk factors for OM in children undergoing HSCT for PI. A retrospective study was carried out on 55 consecutive medical records of patients with PI (including osteopetrosis) who underwent HSCT. Age at the time of HSCT, gender, diagnosis, type of donor, conditioning regimen, engraftment, graft‐versus‐host disease, and severity and duration of OM were collected at the beginning of the conditioning until day 100 post‐HSCT or death. OM was measured using the WHO scale. Patients' age range at the time of HSCT was quite wide; 59.2% of the patients who were under nine months (n = 13) developed OM vs. 87.8% of the patients older than nine months (n = 29) (p = 0.01). T‐cell positive patients had a statistically significant higher risk of developing OM (p = 0.04), as did those receiving a more intensive conditioning regimen (p < 0.01). PI patients undergoing HSCT are at higher risk of developing OM if the PI is a T‐lymphocyte‐positive disease and/or if the HSCT recipient is over nine months of age.     

Late allograft fibrosis in pediatric liver transplant recipients: Assessed by histology and transient elastography

Late allograft fibrosis in LT recipients can cause graft dysfunction and may result in re‐transplantation. TE is a non‐invasive tool for the assessment of liver fibrosis. We aimed to evaluate the prevalence of allograft fibrosis in pediatric LT recipients, identify factors associated with allograft fibrosis, and determine the diagnostic value of TE, compared to histology. All children who underwent LT for ≥3 years were included. TE was performed for LSM in all patients. LSM of ≥7.5 kPa was considered as abnormal and suggestive of allograft fibrosis. Percutaneous liver biopsy was performed when patients had abnormal LSM and/or abnormal LFTs. Histological fibrosis was diagnosed when METAVIR score ≥F1 or LAF scores ≥1. TE was performed in 43 patients and 14 (32.5%) had abnormal LSM suggestive of allograft fibrosis. Histological fibrosis was identified in 10 of the 15 patients (66.7%) who underwent percutaneous liver biopsy and associated findings included chronic active HBV infection (n = 3), and late acute rejection (n = 3). Multivariate analysis showed that graft age was significantly associated with allograft fibrosis (OR = 1.22, 95% CI: 1.05‐1.41, P = 0.01). In conclusion, late allograft fibrosis is common in children undergoing LT for ≥3 years and associated with graft age. HBV infection and late acute rejection are common associated findings. Abnormal TE and/or LFTs may guide physicians to consider liver biopsy for the detection of late allograft fibrosis in LT children.     

Low‐dose total‐body irradiation and alemtuzumab‐based reduced‐intensity conditioning regimen results in durable engraftment and correction of clinical disease among children with chronic granulomatous disease

HSCT with MAC is associated with durable donor engraftment for patients with CGD; however, MAC is limited by high rates of RRT. We used a novel RIC regimen with LD‐TBI (200 cGy × two doses), fludarabine (30 mg/m² × three doses), and proximal alemtuzumab (0.5 mg/kg/dose × one dose) and unrelated donor grafts for consecutive patients with high‐risk CGD who were not candidates for MAC at our institution. Among four children with CGD transplanted at our institution, three PBSC recipients are alive with sustained donor engraftment (median follow‐up: two yr) and resolution of pre‐HSCT active infections while one patient with bone marrow graft is alive after graft failure and autologous recovery. RIC may be a curative option for children with high‐risk CGD.     

The impact of alternative donor types on viral infections in pediatric hematopoietic stem cell transplantation

Viral infections remain one of the most important complications following allogeneic HSCT. Few reports compare virus infection between different donor types in pediatric patients. We retrospectively analyzed viral infections and the outcome of one hundred and seventy‐one pediatric patients (median 7.38 years) who underwent allogeneic HSCT from matched related donor (MRD, n = 71), 10 of 10 HLA allele‐matched unrelated donors (MUD1; n = 29), 9 of 10 HLA allele‐matched unrelated donors (MUD2; n = 40), and haploidentical donors (n = 31). PCR screening for BK virus, adenovirus, Epstein‐Barr virus, parvovirus B19, human herpesvirus 6, and CMV were performed routinely weekly. Infections between 0‐30, 31‐100, and 101 days‐2 years were identified separately. BK virus and CMV reactivations were significantly low in MRD transplant patients (P = .046 and P < .0001, respectively), but incidences of all virus infections between MUD1, MUD2, and haplo‐HSCT were found statistically not different. The OS was found to be affected by having one or multiple virus infection (P = .04 and P = .0008). Despite antiviral prophylaxis and treatments, post‐transplant viral infections are associated with reduced overall survival. Haplo‐HSCT is comparable with MUD transplantation in the setting of viral infections. A larger study group and prospective studies are needed to confirm this observation.     

Renal transplantation in children under 3 years of age: Experience from a single‐center study

RTx remains challenging in children under 3 years of age. This single‐center study reviewed the medical records of children <3 years transplanted since 1987 (N = 32, Group 1). They were matched for donor type and RTx period with children aged 3‐13 years (N = 32, Group 2) and 13‐18 years (N = 32, Group 3). There were no between‐group significant differences regarding distributions of gender, primary renal disease, proportion of dialysis before RTx, and growth (SDS). Compared to Groups 2 and 3, Group 1 had more peritoneal dialyses (P < .001), more EBV mismatches (P = .04), and longer warm ischemia times (P < .001). The risk of graft loss was not significantly different among age groups (hazard ratio, 2.4 in Group 2 and 2.0 in Group 3 vs Group 1; P = .2). Death occurred in four patients (3 in Group 1 and 1 in Group 2) and graft loss occurred in 28 patients, mainly due to chronic allograft nephropathy. In recipients <3 years of age, the outcomes of RTx are close to those obtained in older pediatric age groups. Thus, young patients may be transplanted in experienced multidisciplinary teams without additional risks provided that particular attention is paid to donor selection and prevention/early diagnosis of comorbidities and complications.     

Surgical consultation and intervention during pediatric hematopoietic stem cell transplantation

Children undergoing HSCT are at risk for complications due to immune system impairment, toxicity from prior therapies and conditioning regimens, and long‐term use of indwelling catheters. These problems may require assessment by the surgical team. We sought to characterize the role of surgical consultation during primary hospital stay for HSCT. We retrospectively reviewed the records of consecutive patients undergoing HSCT between September 2010 and September 2012. One hundred and seventy‐three patients underwent 189 HSCTs. General surgery consultations occurred during 33% (n = 62) of primary hospitalizations for HSCT, with a total of 85 consults. Sixty‐three (73%) consults resulted in an intervention in the operating room or at the bedside. The majority of consults were for CVL issues (59%, n = 50), followed by abdominal complaints (16%, n = 14). Patients requiring surgical consultation had significantly higher in‐hospital mortality (16% vs. 2%, p < 0.01) and 100‐day TRM (10% vs. 2%, p < 0.01), compared with those not requiring consultation. Patients undergoing HSCT often require surgical consultation, most commonly for line‐related issues. Surgical consultation heralded an increased risk of in‐hospital and 100‐day TRM. Issues among this high‐risk cohort of children who have undergone HSCT must be familiar to the general surgeon and oncologist alike.     

Unrelated donor hematopoietic stem cell transplantation for pediatric de novo acute myeloid leukemia with intermediate‐ or high‐risk cytogenetics

The role of unrelated donor HSCT for children with de novo AML in CR1 is controversial. We performed this study to investigate the feasibility of unrelated donor HSCT who initially had intermediate‐ or high‐risk cytogenetics. We retrospectively reviewed medical records of patients with AML who received unrelated HSCT in CR1 at Samsung Medical Center between November 2001 and January 2012. Patients were allocated based on karyotype at diagnosis as follows: (a) low‐risk: inv(16), t(16;16), t(8;21), and t(15;17); (b) high‐risk: ‐5, 5q‐, ‐7, 3q abnormalities, t(8;16), t(6;9), t(6;11), t(6;21), t(10;11), complex karyotype (≥3 abnormalities), and acute megakaryocytic leukemia without t(1;22); and (c) IR: all the other karyotypes including normal. Patients in intermediate‐ or high‐risk group who were transplanted with either unrelated CB or matched unrelated BM/mobilized PB in their CR1 were included in this study. The projected OS and EFS rates were 74.9% and 71.1%, respectively, with a median follow‐up of 87.3 months after transplantation. The EFS was 70.1%, 80.7%, and 73.9% for CB, BM, and mobilized PB groups, respectively (P = 0.89), and 73.9% and 70.6% for IR and high‐risk groups (P = 0.76). The leading cause of death was relapse (n = 8), and only one patient died from non‐relapse cause. Unrelated donor HSCT seems a feasible approach for children with intermediate‐ or high‐risk AML in CR1. Relapse remains the leading cause of treatment failure among these patients.     

Matched related donor hematopoietic stem cell transplantation results in a long‐term follow‐up of a pediatric acquired severe aplastic anemia subset: A stem cell source perspective

HSCT has substantially improved pediatric acquired SAA patients' outcomes. Retrospectively, we attempted to assess the outcome of MRD HSCT in 65 pediatric patients referred to a single center from 1992 to 2012. We were particularly interested to find out whether source of SC (PB, n = 40 and BM, n = 25) significantly impacts EFS and GVHD incidence. With a median follow‐up of 45 months, total EFS was 87.7%; EFS for PB and BM groups was 87.5% and 88%, respectively. Acute GVHD (grades 3–4) occurred in 13 patients (PB, n = 10 [25%] and BM, n = 3 [12%]), acute GVHD (grades 2–4) occurred in 24 (PB, n = 16 [40%] and BM, n = 8 [32%]). Extensive chronic GVHD occurred in five patients (PB, n = 3 [7.5%] and BM, n = 2 [8%]). Cox regression revealed that elapsed time of <10 months between diagnosis and HSCT is associated with improved survival (hazard ratio, 95% CI = 1.204, 1.010–1.434, p = 0.038). SC source did not significantly affect EFS, incidence of acute GVHD (grades 3–4), or extensive chronic GVHD (p = 0.938, 0.121, and 0.487, respectively). Based on our findings, pediatric acquired SAA patients are benefitted most if MRD‐HSCT is carried out early in disease process and SC source does not affect outcome of MRD‐HSCT in these patients.     

Comparison of outcomes after HLA‐matched unrelated and αβ T‐cell‐depleted haploidentical hematopoietic stem cell transplantation for children with high‐risk acute leukemia

T‐cell‐depleted HAPLO HSCT is an option to treat children with high‐risk acute leukemia lacking an HLA‐identical donor. We reviewed the outcome of children with acute leukemia after HAPLO (n = 21) and HLA‐MUD (n = 32) transplantation. The proportion of patients with ≥CR2 was significantly higher in HAPLO transplantation than MUD transplantation. Patients with MUD transplantation were significantly higher ABO incompatible than patients with HAPLO transplantation. There was no difference between the 2 groups in terms of engraftment, aGvHD and cGvHD, VOD, hemorrhagic cystitis, infections, and relapse. The 5‐year OS of MUD transplantation and HAPLO transplantation groups was found 65.8% and 71.1%, respectively (log‐rank 0.51). The 5‐year RFS was 80.7% for MUD transplantation group and 86.9% for HAPLO transplantation group (log‐rank 0.48). There was no statistically significant difference between 2 groups according to TRM (25% MUD transplantation vs 16.3% HAPLO transplantation, log‐rank 0.48). These data suggest that survival for patients with high‐risk acute leukemia after HAPLO transplantation with ex vivo ɑβ⁺ T‐cell depletion is comparable with MUD transplantation.     

T cell replete–haploidentical second hematopoietic stem cell transplantation for primary graft failure in pediatric patients with hematologic malignancies

GF is one of the fatal complications of allogeneic HSCT. To rescue patients with primary GF, a second HSCT should be conducted as soon as possible, but the optimal donor source and technique have yet to be established. In this study, we retrospectively analyzed six children with hematologic malignancies who received TCR‐haploidentical second HSCT for primary GF. The median interval between the prior HSCT and the second HSCT was 37.5 days. All patients received fludarabine and ATG containing reduced‐intensity re‐conditioning before the second HSCT. All patients, except one who died early, achieved both neutrophil and Plt engraftment at a median time of 15 and 33 days, respectively. Chimerism analysis showed that all engrafted patients achieved complete donor chimerism within 3 weeks. Four patients developed acute GVHD, and three patients developed chronic GVHD. TRM occurred in two patients. Median follow‐up of the four survivors was 6.8 years, and all remained in sustained remission until the last follow‐up. These results suggested that a TCR‐haploidentical second HSCT for pediatric patients is feasible, and this approach may provide a potent option for children with primary GF.     

Optimizing hepatic venous outflow reconstruction for hepatic vein stenosis with indwelling stent in living donor liver retransplantation

The patient was a boy of 7 years and 5 months of age, who underwent LDLT for acute liver failure at 10 months of age. HV stent placement was performed 8 months after LDLT because of intractable HV stenosis. At 7 years of age, his liver function deteriorated due to chronic rejection. The patient therefore underwent living donor liver retransplantation from his father. The HV was transected with the stent in situ. The IVC was resected due to stenosis. The pericardial cavity was opened and detached around the IVC to elongate the IVC. The divided ends of the IVC were joined by suturing to the posterior wall of the IVC. A new triangular orifice was made by adding an incision on the anterior wall of the IVC. The graft HV was then anastomosed to the new orifice with continuous sutures in the posterior wall and interrupted sutures in the anterior wall using 5‐0 non‐absorbable sutures. Doppler ultrasound showed a triphasic waveform. We successfully performed HV reconstruction without a vascular graft. This is a feasible procedure for overcoming HV stenosis in LDLT patients with an indwelling stent.     

Epstein‐Barr virus DNA monitoring in serum and whole blood in pediatric liver transplant recipients who do or do not discontinue immunosuppressive therapy

The rate of PTLD can be reduced by weaned IS guided by monitoring of EBV DNA. In this single‐center retrospective case series study, we analyzed how reduction in IS influenced EBV DNA levels in whole blood and serum in 30 children during the first year after liver transplantation, and how these levels were related to symptoms putatively due to EBV. Primary and reactivated EBV infection was seen in 18 (60%) and eight patients (27%), respectively. Thirteen patients (42%) developed chronic high load the first year post‐transplant. IS was successfully discontinued in six patients the first year post‐transplant and in another two patients within 3 years. EBV DNA levels were reduced, but persisted long term in all the eight patients who had IS completely withdrawn. There was no case of PTLD. In summary, EBV DNAemia and chronic high load were very common after pediatric liver transplantation. Liver graft tolerance facilitates radical reduction in IS treatment, which may prevent PTLD, but EBV DNAemia may persist long term after discontinued IS.     

Treosulfan‐based reduced toxicity hematopoietic stem cell transplantation in X‐linked agammaglobulinemia: A cost‐effective alternative to long‐term immunoglobulin replacement in developing countries

X‐linked agammaglobulinemia (XLA) is a primary antibody disorder due to a mutation in the Bruton tyrosine kinase gene that requires lifelong immunoglobulin replacement resulting in a significant economic burden and treatment abandonment. Hematopoietic stem cell transplantation (HSCT) offers an alternative option for complete cure. In our series, two children with XLA underwent successful HSCT using a myeloablative conditioning with thiotepa, treosulfan, and fludarabine from a matched sibling donor. The second child had rejected his first graft following a busulfan‐based regimen with resultant autologous reconstitution. At 6 months post‐HSCT, serum IgG were normal, off IVIG, and had no infections. Both children after a median follow‐up of 20 months have 100% chimerism. Treosulfan‐based reduced toxicity myeloablative HSCT has encouraging results with a positive impact on the socioeconomics in developing countries.