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1.
Nat Commun ; 10(1): 4343, 2019 09 25.
Article in English | MEDLINE | ID: mdl-31554817

ABSTRACT

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.


Subject(s)
Brain Neoplasms/genetics , DNA Methylation , Epigenomics/methods , Gene Expression Regulation, Neoplastic , Glioma/genetics , Receptor Protein-Tyrosine Kinases/genetics , Anaplastic Lymphoma Kinase/genetics , Anaplastic Lymphoma Kinase/metabolism , Brain Neoplasms/classification , Brain Neoplasms/metabolism , Female , Glioma/classification , Glioma/metabolism , Humans , Infant , Infant, Newborn , Male , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Receptor, trkA/genetics , Receptor, trkA/metabolism , Survival Analysis , Exome Sequencing/methods
3.
Pediatr Emerg Care ; 34(12): e229-e232, 2018 Dec.
Article in English | MEDLINE | ID: mdl-28486262

ABSTRACT

Gliomatosis cerebri is a diffuse infiltrating glioma of neuroepithelial origin that affects more than 2 cerebral lobes. This is rarely seen in pediatric patients. The clinical presentation and imaging are very unspecific, and a biopsy is typically needed for the diagnosis. Given the widespread nature of the disease, surgical treatment is not possible and has a poor overall prognosis. A pediatric patient presented with elevated intracranial pressure. All initial studies were negative, and the imaging showed a symmetrical affection involving the supratentorial and infratentorial regions. A biopsy ultimately confirmed gliomatosis cerebri. This case describes a unique clinical presentation of gliomatosis cerebri in a pediatric patient.


Subject(s)
Brain Neoplasms/diagnosis , Neoplasms, Neuroepithelial/diagnosis , Seizures/etiology , Adolescent , Brain/pathology , Brain Neoplasms/complications , Diagnosis, Differential , Humans , Intracranial Hypertension/etiology , Magnetic Resonance Imaging , Male , Neoplasms, Neuroepithelial/complications
4.
J Neurooncol ; 137(1): 205-213, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29248974

ABSTRACT

Non-medulloblastoma CNS embryonal tumors (former PNET/Pineoblastomas) are aggressive malignancies with poor outcome that have been historically treated with medulloblastoma protocols. The purpose of this study is to present a tumor-specific, real-world data cohort of patients with CNS-PNET/PB to analyze quality indicators that can be implemented to improve the outcome of these patients. Patients 0-21 years with CNS-PNET treated in eight large institutions were included. Baseline characteristics, treatment and outcome [progression-free and overall survival (PFS and OS respectively)] were analyzed. From 2005 to 2014, 43 patients fulfilled entry criteria. Median age at diagnosis was 3.6 years (range 0.0-14.7). Histology was pineoblastoma (9%), ependymoblastoma (5%), ETANTR (7%) and PNET (77%). Median duration of the main symptom was 2 weeks (range 0-12). At diagnosis, 28% presented with metastatic disease. Seventeen different protocols were used on frontline treatment; 44% had gross total resection, 42% craniospinal radiotherapy, 86% chemotherapy, and 33% autologous hematopoietic stem cell transplantation (aHSCT). Median follow-up for survivors was 3.5 years (range 1.7-9.3). 3-year PFS was 31.9% (95% CI 17-47%) and OS 35.1% (95% CI 20-50%). Age, extent of resection and radiotherapy were prognostic of PFS and OS in univariate analysis (p < 0.05). Our series shows a dismal outcome for CNS-PNET, especially when compared to patients included in clinical trials. Establishing a common national strategy, implementing referral circuits and collaboration networks, and incorporating new molecular knowledge into routine clinical practice are accessible measures that can improve the outcome of these patients.


Subject(s)
Brain Neoplasms/therapy , Pinealoma/therapy , Standard of Care , Adolescent , Brain Neoplasms/diagnosis , Child , Child, Preschool , Cohort Studies , Female , Humans , Male , Outcome and Process Assessment, Health Care , Pinealoma/diagnosis , Spain , Survival Analysis , Treatment Outcome
5.
Front Pharmacol ; 9: 1508, 2018.
Article in English | MEDLINE | ID: mdl-30687088

ABSTRACT

Alterations of the PI3K/Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway are causally involved in a subset of malformations of cortical development (MCDs) ranging from focal cortical dysplasia (FCD) to hemimegalencephaly and megalencephaly. These MCDs represent a frequent cause of refractory pediatric epilepsy. The endocannabinoid system -especially cannabinoid CB1 receptor- exerts a neurodevelopmental regulatory role at least in part via activation of mTORC1 signaling. Therefore, we sought to characterize the possible contribution of endocannabinoid system signaling to FCD. Confocal microscopy characterization of the CB1 receptor expression and mTORC1 activation was conducted in FCD Type II resection samples. FCD samples were subjected to single nucleotide polymorphism screening for endocannabinoid system elements, as well as CB1 receptor gene sequencing. Cannabinoid CB1 receptor levels were increased in FCD with overactive mTORC1 signaling. CB1 receptors were enriched in phospho-S6-positive cells including balloon cells (BCs) that co-express aberrant markers of undifferentiated cells and dysplastic neurons. Pharmacological regulation of CB1 receptors and the mTORC1 pathway was performed in fresh FCD-derived organotypic cultures. HU-210-evoked activation of CB1 receptors was unable to further activate mTORC1 signaling, whereas CB1 receptor blockade with rimonabant attenuated mTORC1 overactivation. Alterations of the endocannabinoid system may thus contribute to FCD pathological features, and blockade of cannabinoid signaling might be a new therapeutic intervention in FCD.

7.
J Pediatr Endocrinol Metab ; 29(2): 217-20, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26352088

ABSTRACT

Rhabdomiomas are rare mesenchymal benign tumors of striated muscle origin. Setting aside the cardiac (most atrial) rhabdomiomas typically associated to neurocutaneous syndromes (tuberous sclerosis), extracardiac rhabdomyomas appear clinically as a subcutaneous nodule or as a submucosal polypoid lesion. Among them, three main histologic subtypes can be differentiated on the basis of the degree of tumor differentiation: 1) fetal rhabdomioma, usually diagnosed during childhood and almost exclusively located in the in the head and neck region with rare reports in other locations; 2) adult rhabdomioma; and 3) genital rhabdomioma, reported to occur in the lower genital tract of young and middle-aged women and, exceptionally, in children (5).


Subject(s)
Disorders of Sex Development , Fetal Diseases/diagnosis , Rhabdomyoma/diagnosis , Vulvar Neoplasms/diagnosis , Diagnosis, Differential , Female , Fetal Diseases/genetics , Humans , Rhabdomyoma/genetics , Vulvar Neoplasms/genetics
8.
Cytotherapy ; 17(11): 1594-603, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26341478

ABSTRACT

BACKGROUND AIMS: Preliminary data suggest that T-cell-depleted haplo-identical stem cell transplantation (haplo-SCT) has a clinically beneficial allograft-versus-tumor effect associated with natural killer (NK) cell immune reconstitution. METHODS: This phase I/II trial descriptively evaluates the feasibility of interleukin (IL)-15-stimulated NK cell infusion after haplo-SCT in pediatric patients with refractory solid tumors. RESULTS: Six patients received an IL-15-stimulated NK cell infusion at 30 days after haplo-SCT. The mean number of infused NK cells per product was 11.3 × 10(6)/kg (range, 3-27 × 10(6)/kg). The T-cell count was <1 × 10(3)/kg in all patients (range, 0-0.75 × 10(3)/kg). No toxic effects related to IL-15--stimulated NK cell infusion were observed. Four of the six patients showed a clinical response (one achieved very good partial remission, two achieved partial remission and one had stable disease). One patient had progressive disease, and the response was not evaluated in the remaining patient. After a median follow-up period of 310 days, all patients had died: four of cancer relapse, one of cancer-associated thrombotic micro-angiopathy and one of acute graft-versus-host disease. CONCLUSIONS: The adoptive transfer of allogeneic IL-15--stimulated NK cells might be feasible and safe in heavily pretreated pediatric patients with refractory solid tumors, though the advanced stage of disease and toxic effects of haplo-SCT may limit the efficacy of NK cell infusion in this population.


Subject(s)
Interleukin-15/pharmacology , Killer Cells, Natural/transplantation , Neoplasms/therapy , Stem Cell Transplantation/methods , Adolescent , Child , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/immunology , Humans , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Lymphocyte Count , Male , Neoplasms/immunology , Neoplasms/pathology , Stem Cell Transplantation/adverse effects , T-Lymphocytes/immunology , Transplantation, Homologous , Treatment Outcome
11.
Eur J Paediatr Neurol ; 18(3): 273-81, 2014 May.
Article in English | MEDLINE | ID: mdl-24423631

ABSTRACT

Acute inflammation of a single cerebellar hemisphere (hemicerebellitis) is a rare disorder of unknown origin. The clinical presentation is mainly characterized by headache, ataxia, dysmetria, and vomiting. In addition, some children may develop severe intracranial hypertension. The neuroimaging of hemicerebellitis raises a challenging differential diagnosis, particularly with posterior fossa tumours. Although there is no standard treatment for hemicerebellitis, its outcome is usually favourable. However, ipsilateral hemicerebellar atrophy develops in up to half of cases, and a minority of children may show persisting fine motor and/or neurocognitive sequelae. In this article, we contribute with three new reports and review a total of 35 cases of hemicerebellitis.


Subject(s)
Cerebellar Diseases/diagnosis , Cerebellum/pathology , Encephalitis/diagnosis , Magnetic Resonance Imaging , Neuroimaging , Cerebellar Diseases/pathology , Child, Preschool , Diagnosis, Differential , Encephalitis/pathology , Female , Humans , Male
12.
J Pediatr Hematol Oncol ; 36(7): 583-5, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24390451

ABSTRACT

Aneurysm of the inferior vena cava is a rare finding in the pediatric population. We report the case of a 5-month-old infant presenting with anemia, hypertension, and dehydration in the emergency room. A renal mass was found with ultrasound and MRI and a renal tumor was first considered. Histopathologic review of the surgical specimen led to the diagnosis of aneurysmal dilatation of the vena cava.


Subject(s)
Aneurysm/diagnosis , Kidney Neoplasms/diagnosis , Vena Cava, Inferior/pathology , Aneurysm/surgery , Diagnosis, Differential , Humans , Infant , Laparotomy , Magnetic Resonance Imaging , Male , Ultrasonography , Vena Cava, Inferior/diagnostic imaging , Vena Cava, Inferior/surgery
13.
J Pediatr Hematol Oncol ; 36(2): e69-74, 2014 Mar.
Article in English | MEDLINE | ID: mdl-23337550

ABSTRACT

BACKGROUND: Lymphomatoid granulomatosis (LG) is an Epstein-Barr virus-associated, multisystemic disease that combines a granulomatous inflammatory process with lymphoproliferative potential. It is a rare disorder with a variable clinical presentation ranging from an indolent process to an aggressive B-cell lymphoma. Outcome is unpredictable, and a standard treatment has not yet been established. Cases treated with rituximab, an anti-CD20 monoclonal antibody, have been reported with variable results. OBSERVATION: We report on 2 children with LG treated with rituximab and review the literature. The first patient had good response but the second did not. CONCLUSIONS: Rituximab is a treatment option for LG.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Agents/therapeutic use , Lymphomatoid Granulomatosis/drug therapy , Child, Preschool , Humans , Male , Rituximab
14.
Pediatr Neurol ; 49(6): 451-457.e1, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24080276

ABSTRACT

BACKGROUND: Rasmussen encephalitis is a devastating pediatric syndrome of unknown etiology that is characterized by progressive loss of neurological function and intractable focal epilepsy. Cytotoxic T lymphocytes have an active role in the pathogenic process of Rasmussen encephalitis. We studied the implication of CXCL10-CXCR3, a chemotactic axis involved in the pathogenesis of several cases of immune encephalitis. METHODS: We analyzed surgical specimens of children with Rasmussen encephalitis, and performed functional in vitro assays to test the implications of the pathological findings. RESULTS: We found that cytotoxic T lymphocytes infiltrating the damaged areas of primary biopsies expressed CXCR3, whereas neurons and astrocytes in the same areas expressed CXCL10. The in vitro assays demonstrated we found that astrocytes upregulated the expression of CXCL10 messenger RNA and the release of CXCL10 to the supernatants on stimulation with polyinosinic-polycyticylic acid, a synthetic double-stranded RNA that mimics infections with either RNA or DNA viruses. Activated T lymphocytes responded to the production of CXCL10 by astrocytes by increasing their migration in a transwell assay. Finally, the chemotaxis induced by the stimulated astrocytes was completely abrogated in the presence of a small molecule antagonist of CXCR3. CONCLUSIONS: Our results suggest that the CXCR3-CXCL10 axis has a role in recruiting pathogenic T lymphocytes into the brains of patients with Rasmussen encephalitis. This chemotactic mechanism may be targeted pharmacologically.


Subject(s)
Brain/pathology , Chemokine CXCL10/metabolism , Encephalitis/metabolism , Receptors, CXCR3/metabolism , Adolescent , Amides/pharmacology , Animals , Astrocytes/drug effects , Astrocytes/metabolism , Astrocytes/pathology , Cells, Cultured , Child , Child, Preschool , Coculture Techniques , Dose-Response Relationship, Drug , Encephalitis/pathology , Female , Humans , Interferon Inducers/pharmacology , Male , Mice , Nerve Tissue Proteins/metabolism , Poly I-C/pharmacology , Quaternary Ammonium Compounds/pharmacology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , T-Lymphocytes/pathology
15.
J Pediatr Hematol Oncol ; 35(4): 308-10, 2013 May.
Article in English | MEDLINE | ID: mdl-23612382

ABSTRACT

Ataxia-telangiectasia (A-T) is an autosomal recessive disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, a high incidence of lymphoreticular tumors, and an increased sensitivity to chemoradiotherapy-induced DNA damage. The appropriate cancer therapy remains unknown because of high toxicity rates with full-dose conventional protocols. We present a patient with A-T and nephroblastoma, who received an adapted treatment regimen. To our knowledge this is the second report on nephroblastoma in a patient with A-T but the first with confirmed premortem studies. Although the patient tolerated the chemotherapy regimen well, the patient relapsed and died a year after initial diagnosis.


Subject(s)
Ataxia Telangiectasia/complications , Ataxia Telangiectasia/therapy , Kidney Neoplasms/complications , Kidney Neoplasms/therapy , Wilms Tumor/complications , Wilms Tumor/therapy , Ataxia Telangiectasia/drug therapy , Ataxia Telangiectasia/radiotherapy , Child, Preschool , Fatal Outcome , Female , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/radiotherapy , Wilms Tumor/drug therapy , Wilms Tumor/radiotherapy
16.
Front Oncol ; 3: 94, 2013.
Article in English | MEDLINE | ID: mdl-23626949

ABSTRACT

How the immune system attacks medulloblastoma (MB) tumors effectively is unclear, although natural killer (NK) cells play an important role in immune defense against tumor cells. Interactions between receptors on NK cells and ligands expressed by tumor cells are critical for tumor control by immunotherapy. In this study, we analyzed tumor samples from 54 MB patients for expression of major histocompatibility complex class I-related chains A (MICA) and UL16 binding protein (ULPB-2), which are ligands for the NK group 2 member D activatory receptor (NKG2D). The percentage of MICA and ULBP-2 positive cells was higher than 25% in 68% and 6% of MB patients, respectively. A moderate-high intensity of MICA cytoplasmic staining was observed in 46% MB patients and weak ULBP-2 staining was observed in 8% MB patients. No correlation between MICA/ULBP-2 expression and patient outcome was found. We observed that HTB-186, a MB cell line, was moderately resistant to NK cell cytotoxicity in vitro. Blocking MICA/ULBP-2 on HTB-186, and NKG2D receptor on NK cells increased resistance to NK cell lysis in vitro. However, HLA class I blocking on HTB-186 and overnight incubation with IL-15 stimulated NK cells efficiently killed tumor cells in vitro. We conclude that although NKG2D/MICA-ULBP-2 interactions have a role in NK cell cytotoxicity against MB, high expression of HLA class I can protect MB from NK cell cytotoxicity. Even so, our in vitro data indicate that if NK cells are appropriately stimulated, they may have the potential to target MB in vivo.

17.
J Pediatr Hematol Oncol ; 34(1): e42-4, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22134609

ABSTRACT

BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common lung neoplasms in childhood. Usually presents as recurrent respiratory infections and in some cases as pneumothorax. CASE REPORT: We report the case of a 2-year-old patient that was diagnosed with PPB, that first manifested as recurrent pneumothorax. Three chest computed tomography were necessary for the diagnosis. The first 2 tomographies showed no abnormalities suggestive of malignancy. The patient had a family history of both PPB and leukemia. Three years and a half after completion of treatment, the patient is in complete remission. CONCLUSIONS: PPB is an uncommon disease but is the most common pulmonary neoplasms in childhood. We must suspect it in patients with a suggestive family history and recurrent pneumothorax in the same location.


Subject(s)
Lung Neoplasms/complications , Pneumothorax/etiology , Pulmonary Blastoma/complications , Child, Preschool , Female , Humans , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Pulmonary Blastoma/pathology , Pulmonary Blastoma/therapy
18.
Rev. neurol. (Ed. impr.) ; 52(11): 641-642, 1 jun., 2011. ilus, tab
Article in Spanish | IBECS | ID: ibc-89249

ABSTRACT

Introducción. Los tumores de la región pineal se localizan en una encrucijada de estructuras neurovasculares de difícil acceso quirúrgico y limitadas posibilidades de resección; por ello, el manejo de estas lesiones habitualmente requiere la asociación de tratamiento adyuvante radioterápico y/o quimioterápico. Pacientes y métodos. Análisis retrospectivo de las características epidemiológicas, clínicas, neurorradiológicas y anatomopatológicas de 23 pacientes con tumores de la región pineal tratados entre los años 1997 y 2010 en el Hospital Infantil Niño Jesús. Se discuten los factores implicados en el pronóstico de esta cohorte tras el tratamiento quirúrgico o adyuvante. Resultados. El estudio incluyó 6 niñas y 17 niños con edades comprendidas entre los 4 meses y 18 años. El 95% de los pacientes comenzó con signos de hidrocefalia aguda o subaguda, que precisaron la implantación de una derivación ventriculoperitoneal (82%). Se obtuvo una muestra histológica tumoral en todos los casos. Cinco pacientes fueron biopsiadosy 18 fueron intervenidos mediante craneotomía. El germinoma (ocho casos) y el teratoma maduro (un caso) fueron los tumores con mayor supervivencia; los tumores no germinomatosos (tres casos), del parénquima pineal (cuatro casos) y gliomas (cinco casos) presentaron mayor tasa de recidiva y un peor pronóstico. Conclusión. El estudio de marcadores tumorales permite orientar el diagnóstico de determinados tumores de la región pineal. Actualmente, se recomienda realizar una toma histológica tumoral para establecer un diagnóstico preciso y un tratamiento oncológico específico (AU)


Introduction. Tumours in the pineal region are located at a meeting point of several neurovascular structures that are difficult to reach surgically and for which the possibility of resection is limited; as a result the management of these lesions usually requires associated adjunctive treatment with radiotherapy and/or chemotherapy. Patients and methods. This study is a retrospective analysis of the epidemiological, clinical, neuroimaging and pathological characteristics of 23 patients with tumours in the pineal region who were treated between the years 1997 and 2010 in the Hospital Infantil Niño Jesús. The factors involved in the prognosis of this cohort following surgical or adjunctive treatment are also discussed. Results. Subjects included in the study were 6 girls and 17 boys with ages ranging from 4 months to 18 years. It was found that the initial symptoms in 95% of the patients were signs of acute or subacute hydrocephalus, which required the placement of a ventriculoperitoneal shunt (82%). A histological sample of the tumour tissue was collected in all cases. Biopsy samples were taken in the case of five patients and 18 underwent surgery involving a craniotomy. Germinoma (eight cases) and mature teratoma (one case) were the tumours with the longest survival times; non-germinomatous tumours (three cases), those of the pineal parenchyma (four cases) and gliomas (five cases) presented the highest rates of recurrence and a poorer prognosis. Conclusions. The study of tumour markers can be used to guide the diagnosis of certain tumours of the pineal region. At present, the recommended procedure involves taking a histological sample of the tumour in order to establish an accurate diagnosis and a specific oncological treatment (AU)


Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Child , Adolescent , Pinealoma/pathology , Brain Neoplasms/pathology , Pineal Gland/pathology , Retrospective Studies , Germinoma/pathology , Astrocytoma/pathology
20.
Parasitol Res ; 105(1): 65-70, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19241092

ABSTRACT

The effect of Trichinella spiralis infection on the pharmacokinetic profile of orally administered albendazol has been investigated in mice during the intestinal phase of the disease. Swiss CD-1 mice were orally infected with 300 +/- 50 muscle larvae of T. spiralis and then treated with albendazole (ABZ) formulated in hydroxy-propyl-beta-cyclodextrins at the dose of 10 mg/kg given orally on days 0, 5, 10 and 22 post-infection (p.i.). Blood samples were taken at 0.25, 0.5, 0.75, 1, 5, 6 and 24 h post-treatment (p.t.). Adult worm establishment as well as the histopathological alterations induced in the small intestine was assessed on days 0, 5, 10 and 22 p.i. The area under the blood concentrations to time curve (AUC) for ABZ sulphoxide was not significantly higher in infected mice than in control during the first step of intestinal infection (day 5 p.i.), whereas in the late step (day 10 p.i.), it was significantly lower. On day 22 p.i., the AUC showed similar values in both groups. The histopathological analysis showed a transient acute inflammatory reaction that varied from moderate to severe as the infection progressed from the early to the late intestinal stage. After intestinal infection, the inflammation was mild or absent with no signs of chronic effects. The histopathological studies correlated with the pharmacokinetics of ABZ and show that after transient inflammation induced by intestinal T. spiralis infection, the mucosa is restored to allow absorption of ABZ up to levels comparable to those observed in non-infected controls.


Subject(s)
Albendazole/administration & dosage , Albendazole/pharmacokinetics , Anthelmintics/administration & dosage , Anthelmintics/pharmacokinetics , Intestinal Diseases/drug therapy , Intestinal Diseases/parasitology , Trichinellosis/drug therapy , Administration, Oral , Animals , Biological Availability , Intestinal Diseases/pathology , Intestinal Mucosa/pathology , Mice , Plasma/chemistry , Trichinella spiralis/isolation & purification , Trichinellosis/pathology
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