Livedo-like acute cutaneous graft-versus-host disease in two children.

We present two pediatric patients who exhibited an unusual clinical presentation of cutaneous acute graft-versus-host disease (GVHD), characterized by livedo-like appearance. Such manifestations of cutaneous acute GVHD have not been previously documented.

Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro.

The evidence supporting the biological plausibility of the association of permethrin and malathion with hematological cancer is limited and contradictory; thus, further studies are needed. This study aimed to investigate whether in vitro exposure to 0.1 µM permethrin and malathion at 0, 24, 48 and 72 h after cell culture initiation induced changes in the gene expression and DNA methylation in mononuclear cells from bone marrow and peripheral blood (BMMCs, PBMCs). Both pesticides induced several gene expression modifications in both tissues. Through gene ontology analysis, we found that permethrin deregulates ion channels in PBMCs and BMMCs and that malathion alters genes coding proteins with nucleic acid binding capacity, which was also observed in PBMCs exposed to permethrin. Additionally, we found that both insecticides deregulate genes coding proteins with chemotaxis functions, ion channels, and cytokines. Several genes deregulated in this study are potentially associated with cancer onset and development, and some of them have been reported to be deregulated in hematological cancer. We found that permethrin does not induce DNA hypermethylation but can induce hypomethylation, and that malathion generated both types of events. Our results suggest that these pesticides have the potential to modify gene expression through changes in promoter DNA methylation and potentially through other mechanisms that should be investigated.

Genetic, Immunological, and Clinical Features of the First Mexican Cohort of Patients with Chronic Granulomatous Disease.

PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019. METHODS: Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds. RESULTS: Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations. CONCLUSIONS: The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.

Are apoptosis-determining techniques useful to establish an early diagnosis of acute graft-vs-host disease in pediatric patients under treatment with multiple drugs?

BACKGROUND: There are no pathognomonic histopathological features to distinguish acute graft-vs-host disease (aGVHD) from skin drug reactions (SDRs) in pediatric patients with multiple drug regimens that have received blood transfusions and/or transplants. We aimed to determine if the addition of apoptosis markers is helpful to distinguish aGVHD from SDRs in these patients. METHODS: Skin biopsy specimens from patients with a clinical diagnosis of aGVHD or SDRs were evaluated for the presence of apoptotic bodies, satellitosis, interface damage, vasculitis, and inflammatory infiltrate on H&E stain. Information was completed with apoptotic markers (transferase-mediated dUTP nick end-labeling [TUNEL], bcl-2, and caspase-3). RESULTS: The skin biopsy specimens of 32 patients with aGVHD and 11 with SDRs were included for study. Only the number of apoptotic keratinocytes per 10 high-power fields (hpf) showed a significant difference between both groups (P = 0.02); the presence of ≥4 apoptotic keratinocytes per 10 hpf was identified as the optimal cut-off point to discriminate aGVHD from SDRs. No SDRs cases had follicular apoptotic cells. TUNEL, bcl-2, and caspase-3 determination showed no difference between both groups. CONCLUSIONS: The presence of ≥4 apoptotic keratinocytes per 10 hpf (in aGVHD) and the absence of follicular apoptotic cells (in SDRs) might be a useful marker to distinguish between them.

Early clinical, histological, and immunohistochemical findings in suspected acute graft-versus-host disease and their association with patient outcomes.

BACKGROUND/OBJECTIVES: Acute graft-versus-host disease (aGVHD) is a serious condition after allogeneic hematopoietic stem cell transplantation (HSCT), frequently involving skin, gut, and liver. It can be difficult to diagnose early, yet this is vital for adequate management. We sought to identify initial clinical and histopathological features in children with suspected GVHD and the association with clinical course and outcomes. METHODS: Retrospective study of patients with skin biopsies for suspected aGVHD from 2006 to 2016. We collected demographic and clinical information, histologic, and immunohistochemical (IHC) findings, and outcomes during follow-up. Bivariate and multivariate analyses were done to identify risk factors associated with remission, development of severe/life-threatening aGVHD, and mortality. RESULTS: We included 42 patients, 15 females. Skin manifestations occurred 51 days (median) after HSCT. On biopsy, 76.2% had mild (stage 1-2) skin aGVHD; during the course of the disease, severity and systemic involvement increased to global grade III/IV in 66.6%. All patients received treatment; 15 are in remission from aGVHD and 23 have died. Histologic features were diagnostic in 83.3%. On bivariate and multivariate analysis, we identified initial clinical and histologic findings that were associated with the measured outcomes: odds of remission from aGVHD were increased when focal vacuolar changes were found on skin biopsy (OR 6.028; 95%CI:1.253-28.992) but decreased by initial hepatic aGVHD (OR 0.112; 95%CI: 0.017-0.748); severe/life-threatening aGVHD was associated with initial gastrointestinal aGVHD (OR 6.054; 95%CI:1.257-29.159); and odds of mortality were decreased with male donor (OR 0.056; 95%CI:0.004-0.804), nulliparous female donor (OR 0.076; 95%CI:0.009-0.669), and focal vacuolar changes on skin biopsy (OR 0.113; 95%CI:0.017-0.770). CONCLUSIONS: We found novel indicators predictive of remission, severity, and mortality in children with aGVHD. Further studies of this condition in children are needed.

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations.

X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.

IFNG +874 A/T is associated with acute lymphoblastic leukemia in Mexican Mestizos.

Acute lymphoblastic leukemia (ALL), the most common type of cancer in children worldwide, has one of the highest incidence rates in Mexico. It is a multifactorial disease and different cytokine single nucleotide polymorphisms (SNP), have been associated with ALL expression. Few studies have been published analyzing IFNG +874 T/A and IL2 -330 G/T in this type of leukemia. These SNPs are involved in high or low expression, and are central to cellular immunity, influencing greatly tumor growth. The purpose of this work was to explore the association of IFNG +874 A/T (rs2430561) and IL2 -330 G/T (rs2069762) SNPs with ALL susceptibility and/or protection in 488 Mexican Mestizos patients, as compared to 950 Mexican Mestizo healthy controls. The results demonstrated that IFNG +874 T allele (pc = 0.00004, OR = 0.673) and the TT genotype (pc = 0.00015, OR = 0.349), protect against ALL expression with no specific gender association; however, the TT homozygote genotype (vs. TA+AA) seems more protective in males (pc = 0.00683). IL2 -330 G/T does not contribute to the development of ALL. In healthy Mexicans, the most common genotypes for IL2 and IFNG, are the low cytokine producers, suggesting that the genetic background in this ethnic group, may be partly responsible for the high incidence of ALL. These results show for the first time in Mexicans, the relevant role that IFNG SNP has in the genetic etiology of ALL. Thus, a large group of patients belonging to different ethnicities will be very helpful to study in order to demonstrate if these SNPs contribute to the genetic etiology of ALL, as shown here in Mexican Mestizos.

The burden of childhood cancer in Mexico: Implications for low- and middle-income countries.

In Mexico, childhood cancer incidence and mortality have increased in the last decade. Through government actions since 2005, the Popular Medical Insurance (PMI) program for childhood cancer was created. The objective of PMI was to offer early cancer diagnosis, standardized treatment regimens, and numerous pediatric oncology residency programs. It has also accredited 55 national hospitals for the care of these children. Current problems still present under the PMI include shortage of pediatric oncologists and nurses and high rate of abandonment of treatment. Our aim is to describe the current scenario of childhood cancer care in Mexico, especially from the perspective of the PMI and how it has impacted human resources, infrastructure, and medical education.

Descriptive Epidemiology in Mexican children with cancer under an open national public health insurance program.

BACKGROUND: All the children registered at the National Council for the Prevention and Treatment of Childhood Cancer were analyzed. The rationale for this Federal Government Council is to financially support the treatment of all children registered into this system. All patients are within a network of 55 public certified hospitals nationwide. METHODS: In the current study, data from 2007 to 2012 are presented for all patients (0-18 years) with a pathological diagnosis of leukemia, lymphoma and solid tumors. The parameters analyzed were prevalence, incidence, mortality, and abandonment rate. RESULTS: A diagnosis of cancer was documented in 14,178 children. The incidence was of 156.9/million/year (2012). The median age was 4.9. The most common childhood cancer is leukemia, which occurs in 49.8% of patients (2007-2012); and has an incidence rate of 78.1/million/year (2012). The national mortality rate was 5.3/100,000 in 2012, however in the group between 15 to 18 years it reaches a level of 8.6. CONCLUSIONS: The study demonstrates that there is a high incidence of childhood cancer in Mexico. In particular, the results reveal an elevated incidence and prevalence of leukemia especially from 0 to 4 years. Only 4.7% of these patients abandoned treatment. The clinical outcome for all of the children studied improved since the establishment of this national program.

IKZF1plus is a frequent biomarker of adverse prognosis in Mexican pediatric patients with B-acute lymphoblastic leukemia.

Background: Recurrent genetic alterations contributing to leukemogenesis have been identified in pediatric B-cell Acute Lymphoblastic Leukemia (B-ALL), and some are useful for refining classification, prognosis, and treatment selection. IKZF1plus is a complex biomarker associated with a poor prognosis. It is characterized by IKZF1 deletion coexisting with PAX5, CDKN2A/2B, or PAR1 region deletions. The mutational spectrum and clinical impact of these alterations have scarcely been explored in Mexican pediatric patients with B-ALL. Here, we report the frequency of the IKZF1plus profile and the mutational spectrum of IKZF1, PAX5, CDKN2A/2B, and ERG genes and evaluate their impact on overall survival (OS) in a group of patients with B-ALL. Methods: A total of 206 pediatric patients with de novo B-ALL were included. DNA was obtained from bone marrow samples at diagnosis before treatment initiation. A custom-designed next-generation sequencing panel was used for mutational analysis. Kaplan-Meier analysis was used for OS estimation. Results: We identified the IKZF1plus profile in 21.8% of patients, which was higher than that previously reported in other studies. A significantly older age (p=0.04), a trend toward high-risk stratification (p=0.06), and a decrease in 5-year Overall Survival (OS) (p=0.009) were observed, although heterogeneous treatment protocols in our cohort would have impacted OS. A mutation frequency higher than that reported was found for IKZF1 (35.9%) and CDKN2A/2B (35.9%) but lower for PAX5 (26.6%). IKZF1MUT group was older at diagnosis (p=0.0002), and most of them were classified as high-risk (73.8%, p=0.02), while patients with CDKN2A/2BMUT had a higher leukocyte count (p=0.01) and a tendency toward a higher percentage of blasts (98.6%, >50% blasts, p=0.05) than the non-mutated patients. A decrease in OS was found in IKZF1MUT and CDKN2A/2BMUT patients, but the significance was lost after IKZF1plus was removed. Discussion: Our findings demonstrated that Mexican patients with B-ALL have a higher prevalence of genetic markers associated with poor outcomes. Incorporating genomic methodologies into the diagnostic process, a significant unmet need in low- and mid-income countries, will allow a comprehensive identification of relevant alterations, improving disease classification, treatment selection, and the general outcome.

Incidence of childhood cancer among Mexican children registered under a public medical insurance program.

Prior to 2005, 51% of children in Mexico diagnosed with cancer received no standardized optimal multidisciplinary medical care. A government-subsidized national cancer treatment program was therefore created for these patients and a National Cooperative Childhood Cancer Treatment Group was consequently formed for these patients. Pediatric patients with a proven diagnosis of leukemia, lymphoma or solid tumor and who were registered in the Popular Medical Insurance (PMI) program from January 2007 to December 2010, are described in this report. These patients had been enrolled and registered in one of the 49 nationwide certified medical institutions in Mexico. The national incidence and frequency data for childhood cancers were analyzed for the whole program. At the end of a 4-year study, the analysis revealed that 8,936 children from across Mexico had been diagnosed with cancer. The incidence rate for the PMI patients was 150.3/million/year (2010) for children of 0-18 years. The highest age incidence rate was 51.9 between 0 and 4 years and boys were the predominant group for all types of cancer. The leukemia incidence was 75.3/million/year (2010), and an average frequency of 50.75% throughout the 4 years. The overall mortality rate was measured at 5.4/100,000/year (2010). This study demonstrates a high frequency and incidence of childhood cancer and a beneficial impact of the PMI program over the quality of life in these children.

Childhood leukemias in Mexico: towards implementing CAR-T cell therapy programs.

Leukemias are the most common type of pediatric cancer around the world. Prognosis has improved during the last decades, and many patients are cured with conventional treatment as chemotherapy; however, many patients still present with a refractory disease requiring additional treatments, including hematopoietic stem cell transplantation. Immunotherapy with monoclonal antibodies or cellular therapy is a promising strategy for treating refractory or relapsed hematological malignancies. Particularly, CAR-T cells have shown clinical efficacy in clinical trials, and different products are now commercially approved by regulatory agencies in the USA and Europe. Many challenges still need to be solved to improve and optimize the potential of these therapies worldwide. Global access to cell therapy is a significant concern, and different strategies are being explored in the middle- and low-income countries. In Mexico, leukemias represent around 50% of total cancer diagnosed in pediatric patients, and the rate of relapsed or refractory disease is higher than reported in other countries, a multi-factorial problem. Although significant progress has been made during the last decades in leukemia diagnosis and treatment, making new therapies available to Mexican patients is a priority, and cell and gene therapies are on the horizon. Efforts are ongoing to make CAR-T cell therapy accessible for patients in Mexico. This article summarizes a general landscape of childhood leukemias in Mexico, and we give a perspective about the current strategies, advances, and challenges ahead to make gene and cell therapies for leukemia clinically available.

Triple-hit explanation for the worse prognosis of pediatric acute lymphoblastic leukemia among Mexican and Hispanic children.

Acute lymphoblastic leukemia (ALL) is the most common malignancy among Mexican and Hispanic children and the first cause of death by disease in Mexico. We propose a "triple-hit" explanation for the survival gap affecting this population. The first hit can be attributed to epidemiology and social, cultural, and economic burdens. The second hit refers to cancer biology, with a high incidence of unfavorable genetic characteristics associated with an unfavorable response to treatment and, subsequently, poor survival. Finally, the third hit relates to sub-optimal treatment and support. Society and culture, leukemia biology, and treatment approach limitations are key factors that should not be seen apart and must be considered comprehensively in any strategy to improve the prognosis of Mexican and Hispanic children with ALL.

Naturally occurring deamidated triosephosphate isomerase is a promising target for cell-selective therapy in cancer.

Human triosephosphate isomerase (HsTIM) is a central glycolytic enzyme and is overexpressed in cancer cells with accelerated glycolysis. Triple-negative breast cancer is highly dependent on glycolysis and is typically treated with a combination of surgery, radiation therapy, and chemotherapy. Deamidated HsTIM was recently proposed as a druggable target. Although thiol-reactive drugs affect cell growth in deamidated HsTIM-complemented cells, the role of this protein as a selective target has not been demonstrated. To delve into the usefulness of deamidated HsTIM as a selective target, we assessed its natural accumulation in breast cancer cells. We found that deamidated HsTIM accumulates in breast cancer cells but not in noncancerous cells. The cancer cells are selectively programmed to undergo cell death with thiol-reactive drugs that induced the production of methylglyoxal (MGO) and advanced glycation-end products (AGEs). In vivo, a thiol-reactive drug effectively inhibits the growth of xenograft tumors with an underlying mechanism involving deamidated HsTIM. Our findings demonstrate the usefulness of deamidated HsTIM as target to develop new therapeutic strategies for the treatment of cancers and other pathologies in which this post translationally modified protein accumulates.

Hematopoietic stem cell transplantation activity in Mexico during the COVID19 pandemic: on the way to recovery.

OBJECTIVE: To analyze the number of HSCTs performed in 2019 vs. 2020 and report the status of transplant centers (TCs) during and a year after the COVID-19 pandemic. METHODS: We performed a comprehensive cross-sectional nationwide study including active TCs interrogating HSCT activity from 2019 through September 2021. An electronic survey was sent to TCs and consisted of items regarding the number and characteristics of procedures performed and were compared yearly. Changes to their institutions' transplant policies and practices during the COVID19 pandemic were also documented. Fifty centers were invited to participate, 33 responded. RESULTS: Most TCs were part of the public health system (63.7%). Almost half are in the country's capital, Mexico City (45.5%). Most centers performed <10 procedures per year. The number of HSCTs decreased from 835 in 2019-505 in 2020 (p < .001), representing a 40% reduction in transplant activity. The monthly transplant rate in 2021 increased to 58.3, compared to 42 in 2020 and close to 69.5 in 2019 (p < .001). All types of HSCTs decreased excluding haploidentical transplants. All institutions treated patients with COVID19, and over two-thirds experienced some form of hospital reconversion. Transplant activity stopped completely in 23 TCs (70%) during the pandemic with a median closure duration of 9.9 months (range, 1-21). In 2021, 9.1% of TCs remained closed, all of them in the public setting. CONCLUSION(S): The limited transplant activity in Mexico decreased significantly during the pandemic but is recovering and nearly in pre-pandemic levels.

Academic paediatric surgery and work-life balance: Insights from Mexico.

Academic pediatric surgery in Mexico has many challenges and opportunities. Work life balance, health service delivery and committements to our many students and residents must be tailored to goals and aspirations respecting talent at every opportunity when we encounter it. This article offers a perspective on the landscape and how we can shape the future in our nation to embrace new leadership in academic pediatric surgery.

Long-term evolution of mucopolysaccharidosis type I in twins treated with enzyme replacement therapy plus hematopoietic stem cells transplantation.

Mucopolysaccharidoses (MPSs) are a heterogeneous group of diseases that have in common the accumulation of glycosaminoglycans (mucopolysaccharides) within the lysosome. The diseases are caused by a deficiency of the enzyme α-L-iduronidase which is responsible for the degradation of glycosaminoglycans (GAGs or mucopolysaccharides). More than 100 mutations in the gene have been reported, resulting in marked clinical/response variability. MPSs usually present as multisystem and progressive clinical disorders which affect psychomotor and cardiovascular development, the cornea and the musculoskeletal system. Seven phenotypically distinct diseases have been described, and MPS type I (MPS-I) is divided into three clinical forms: severe (Hurler syndrome), intermediate (Hurler-Scheie syndrome) or mild (Scheie syndrome). For the treatment of MPS-I, Enzyme Replacement Therapy (ERT) with α-L-iduronidase and Hematopoietic Stem Cells Transplantation (HSCT), separately or in combination, have produced clinical improvement, especially with regards cardiovascular symptoms and psychomotor development. This article presents the long-term (more than seven years) follow-up of monochorionic, diamniotic twins who were diagnosed with MPS-I at an early stage, and treated with ERT (from age 10 months) plus HSCT (from age 18 months). Overall, the treatment has facilitated stable development with an overall good response and better control of symptoms associated with MPS-I.

Outcomes of pediatric patients with therapy-related myeloid neoplasms.

Long-term outcomes after allogeneic hematopoietic cell transplantation (HCT) for therapy-related myeloid neoplasms (tMNs) are dismal. There are few multicenter studies defining prognostic factors in pediatric patients with tMNs. We have accumulated the largest cohort of pediatric patients who have undergone HCT for a tMN to perform a multivariate analysis defining factors predictive of long-term survival. Sixty-eight percent of the 401 patients underwent HCT using a myeloablative conditioning (MAC) regimen, but there were no statistically significant differences in the overall survival (OS), event-free survival (EFS), or cumulative incidence of relapse and non-relapse mortality based on the conditioning intensity. Among the recipients of MAC regimens, 38.4% of deaths were from treatment-related causes, especially acute graft versus host disease (GVHD) and end-organ failure, as compared to only 20.9% of deaths in the reduced-intensity conditioning (RIC) cohort. Exposure to total body irradiation (TBI) during conditioning and experiencing grade III/IV acute GVHD was associated with worse OS. In addition, a diagnosis of therapy-related myelodysplastic syndrome and having a structurally complex karyotype at tMN diagnosis were associated with worse EFS. Reduced-toxicity (but not reduced-intensity) regimens might help to decrease relapse while limiting mortality associated with TBI-based HCT conditioning in pediatric patients with tMNs.

FANCC Dutch founder mutation in a Mennonite family from Tamaulipas, México.

BACKGROUND: Fanconi anemia (FA) (OMIM #227650) is a rare hereditary disease characterized by genomic instability. The clinical phenotype involves malformations, bone marrow failure, and cancer predisposition. Genetic heterogeneity is a remarkable feature of FA; at least 22 FANC genes are known to cooperate in a unique FA/BRCA repair pathway. A common rule on the mutations found in these genes is allelic heterogeneity, except for mutations known to have arisen from a founder effect like the FANCC c.67delG in the Dutch Mennonite Community. Here, we present an 11-year-old male patient, member of the Mennonite Community of Tamaulipas México, with a clinical and cytogenetic diagnosis of FA. METHOD: Chromosome fragility test was performed in all siblings. Genomic DNA was obtained from peripheral blood samples. Sanger sequencing was used to identify the FANCC c.67delG mutation (NC_000009.11(NM_000136.2):c.67delG p.(Asp23IlefsTer23)) and its accompanying haplotype. RESULTS: The FANCC c.67delG mutation in 13 members of his family confirmed a FA diagnosis in two of his siblings and identified heterozygous carriers. Haplotype analysis supports that in this family, FA is caused by the founder mutation that initially appeared in Mennonite Dutch and followed this population's migrations through Canada and further to Mexico. CONCLUSION: The identification of the FANCC c.67delG mutation in this family not only allows proper genetic counseling, but it also grants the possibility to raise awareness of FA risk among the Mennonite community living in Mexico.