ABSTRACT
Precision cancer medicine brought the promise of improving outcomes for patients with cancer. High-throughput molecular profiling of tumors at treatment failure aims to direct a patient to a treatment matched to the tumor profile. In this way, improved outcome has been achieved in a small number of patients whose tumors exhibit unique targetable oncogenic drivers. Most cancers, however, contain multiple genetic alterations belonging to and of various hallmarks of cancer; for most of these alterations, there is limited knowledge on the level of evidence, their hierarchical roles in oncogenicity, and utility as biomarkers for response to targeted treatment(s). We developed a proof-of-concept trial that explores new treatment strategies in a molecularly-enriched tumor-agnostic, pediatric population. The evaluation of novel agents, including first-in-child molecules, alone or in combination, is guided by the available understanding of or hypotheses for the mechanisms of action of the diverse cancer events. Main objectives are: to determine 1) recommended phase 2 doses, 2) activity signals to provide the basis for disease specific development, and 3) to define new predictive biomarkers. Here we outline concepts, rationales and designs applied in the European AcSé-ESMART trial and highlight the feasibility but also complexity and challenges of such innovative platform trials.
Subject(s)
Neoplasms , Precision Medicine , Humans , Precision Medicine/methods , Neoplasms/drug therapy , Neoplasms/genetics , Biomarkers, Tumor/genetics , Molecular Targeted Therapy/methods , Research Design/standards , Clinical Trials, Phase II as Topic , Proof of Concept StudyABSTRACT
BACKGROUND AND OBJECTIVE: Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL. METHODS: From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data. RESULTS: Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 103 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants. CONCLUSIONS: The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.
Subject(s)
Antineoplastic Agents, Immunological , Inotuzumab Ozogamicin , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Humans , Inotuzumab Ozogamicin/pharmacokinetics , Inotuzumab Ozogamicin/administration & dosage , Child , Male , Female , Adolescent , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/blood , Child, Preschool , Antineoplastic Agents, Immunological/pharmacokinetics , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/therapeutic use , Adult , Young Adult , Middle Aged , Models, Biological , Recurrence , Infant , AgedABSTRACT
PURPOSE: The aim of the Innovative Therapies for Children with Cancer (ITCC) consortium is to improve access to novel therapies for children and adolescents with cancer. The evolution of the ITCC clinical trial portfolio since 2003 was reviewed. METHODS: All ITCC-labeled phase I/II trials opened between January 1, 2003 and February 3, 2018 were analyzed in two periods (2003-2010 and 2011-2018), and data were extracted from the ITCC database, regulatory agencies' registries, and publications. RESULTS: Sixty-one trials (62% industry-sponsored) enrolled 3,198 patients. The number of trials in the second period increased by almost 300% (16 v 45). All biomarker-driven trials (n = 14) were conducted in the second period. The use of rolling six and model-based designs increased (1 of 9, 11% v 21 of 31, 68%), and that of 3 + 3 designs decreased (5 of 9, 55% v 5 of 31, 16%; P = .014). The proportion of studies evaluating chemotherapeutics only decreased (5 of 16, 31% v 4 of 45, 9%), the proportion of single-agent targeted therapies did not change (9 of 16, 56.2% v 24 of 45, 53.3%), the proportion of combination targeted therapies trials increased (2 of 16, 12%, v 17 of 45, 38%), the proportion of randomized phase II trials increased (1 of 7, 14% v 8 of 14, 57%). More trials were part of a pediatric investigation plan in the second period (4 of 16, 25% v 21 of 45, 46%). The median time for Ethics Committees' approvals was 1.7 times longer for academic compared with industry-sponsored trials. CONCLUSION: This study reports a shift in the paradigm of early drug development for childhood cancers, with more biologically relevant targets evaluated in biomarker-driven trials or in combination with other therapies and with more model-based or randomized designs and a greater focus on fulfilling regulatory requirements. Improvement of trial setup and recruitment could increase the number of patients benefiting from novel agents.
Subject(s)
Drug Development , Neoplasms , Humans , Child , Neoplasms/drug therapy , Adolescent , Clinical Trials, Phase II as Topic , Antineoplastic Agents/therapeutic use , Clinical Trials, Phase I as Topic , Therapies, Investigational , Research DesignABSTRACT
INTRODUCTION: ECLIM-SEHOP platform was created in 2017. Its main objective is to establish the infrastructure to allow Spanish participation into international academic collaborative clinical trials, observational studies, and registries in pediatric oncology. The aim of this manuscript is to describe the activity conducted by ECLIM-SEHOP since its creation. METHODS: The platform's database was queried to provide an overview of the studies integrally and partially supported by the organization. Data on trial recruitment and set-up/conduct metrics since its creation until November 2023 were extracted. RESULTS: ECLIM-SEHOP has supported 47 studies: 29 clinical trials and 18 observational studies/registries that have recruited a total of 5250 patients. Integral support has been given to 25 studies: 16 trials recruiting 584 patients and nine observational studies/registries recruiting 278 patients. The trials include front-line studies for leukemia, lymphoma, brain and solid extracranial tumors, and other key transversal topics such as off-label use of targeted therapies and survivorship. The mean time from regulatory authority submission to first patient recruited was 12.2 months and from first international site open to first Spanish site open was 31.3 months. DISCUSSION: ECLIM-SEHOP platform has remarkably improved the availability and accessibility of international academic clinical trials and has facilitated the centralization of resources in childhood cancer treatment. Despite the progressive improvement on clinical trial set-up metrics, timings should still be improved. The program has contributed to leveling survival rates in Spain with those of other European countries that presented major differences in the past.
ABSTRACT
Inotuzumab Ozogamicin (InO) is a CD22-directed antibody conjugated with calicheamicin. The Phase 1B of the ITCC-059 trial tested InO combined with chemotherapy in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Relapsed /refractory CD22+ BCP-ALL pediatric patients were enrolled. The primary objective was to establish the Recommended Phase 2 Dose (RP2D). Secondary objectives included preliminary efficacy and tolerability. InO was combined with 1.5 mg/m2 of vincristine (days 3, 10, 17, 24), 20 mg/m2 of dexamethasone (two 5-day blocks, then amended), and intrathecal therapy. A rolling-6 design was used testing InO from 0.8 to 1.8 mg/m2/cycle. Between May-2020 and Apr-2022, 30 patients were treated, and 29 were evaluable for dose limiting toxicities (DLTs). At 1.1 mg/m2/cycle, two out of four patients had DLTs (liver toxicity). InO was de-escalated to 0.8 mg/m2/cycle (n=6) without DLTs while awaiting a protocol amendment to reduce dexamethasone dose to 10 mg/m2. Post amendment, InO was re-escalated to 1.1 mg/m2/cycle (n=6, 1 DLT), then to 1.4 mg/m2/cycle (n=3, no DLTs), and finally to 1.8 mg/m2/cycle (n=7, 1 DLT). Three additional patients were treated in an expansion cohort. The pooled response rate was 80% (24/30; 95%CI: 61.4% to 92.3%) and, among responders, 66.7% achieved minimal residual disease negativity. The RP2D of InO combined with vincristine, dexamethasone and IT therapy was declared at 1.8 mg/m2/cycle (1.5 mg/m2/cycle after remission) in a fractionated schedule. This combination showed an response rate similar to the single agent cohorts of this trial, with liver toxicity issues at the initial higher dexamethasone dose. #NTR5736.
ABSTRACT
Methotrexate is an essential drug in the treatment of childhood cancer that is not exempt from toxicities. Glucarpidase is a drug used to reduce the toxic concentration of plasma methotrexate in patients with delayed elimination or at risk of toxicity. We describe the characteristics of a cohort of pediatric patients that received glucarpidase and analyze its role in the treatment of toxicity induced by high doses of methotrexate (HDMTX). Retrospective observational study of all pediatric cancer patients who received glucarpidase between 2012 and 2022 at a single center. Fifteen patients were treated with a single dose of glucarpidase, eleven of them presented with acute lymphoblastic leukemia and received HDMTX at 5 g/m2 in 24-hour infusion. In eight patients, glucarpidase was administered during the first cycle of HDMTX. The indication in thirteen cases was acute renal failure with delayed elimination of plasma methotrexate. The median maximum creatinine was 1.22 mg/dl (0.68 2.01 mg/dl), with a median increase over its baseline level of 313%. All patients normalized renal function after glucarpidase administration, with a median methotrexate excretion time of 193 hours (42-312 hours). No grade ≥2 adverse events derived from carboxypeptidase administration. Eleven patients received new doses of HDMTX in subsequent cycles, without new episodes of serious toxicity. The use of glucarpidase is effective and safe in the treatment of acute renal failure and methotrexate elimination delay in pediatric cancer patients. Further HDMTX doses may be prescribed without additional toxicities.
ABSTRACT
BACKGROUND: Advanced myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematological malignancies in children. A second allograft is recommended if a relapse occurs after hematopoietic stem cell transplantation, but the outcome is poor. OBJECTIVE: We conducted a phase I/II multicenter study to evaluate the safety, pharmacokinetics, and activity of azacitidine in children with relapsed MDS/JMML prior to the second hematopoietic stem cell transplantation. METHODS: Patients enrolled from June 2013 to March 2019 received azacitidine intravenously/subcutaneously once daily on days 1-7 of a 28-day cycle. The MDS and JMML cohorts followed a two-stage design separately, with a safety run-in for JMML. Response and safety data were used to evaluate efficacy and establish the recommended dose. Pharmacokinetics was also analyzed. The study closed prematurely because of low recruitment. RESULTS: Six patients with MDS and four patients with JMML received a median of three and five cycles, respectively. Azacitidine 75 mg/m2 was well tolerated and plasma concentration-time profiles were similar to observed in adults. The most prevalent grade 3-4 adverse event was myelotoxicity. No responses were seen in patients with MDS, but 83% achieved stable disease; four patients underwent an allotransplant. Overall response rate in the JMML cohort was 75% (two complete responses; one partial response) and all responders underwent hematopoietic stem cell transplantation. One-year overall survival was 67% (95% confidence interval 38-100) in MDS and 50% (95% confidence interval 19-100) in JMML. CONCLUSIONS: Azacitidine 75 mg/m2 prior to a second hematopoietic stem cell transplantation is safe in children with relapsed MDS/JMML. Although the long-term advantage remains to be assessed, this study suggests that azacitidine is an efficacious option for relapsed JMML. CLINICAL TRIAL REGISTRATION: EudraCT 2010-022235-10.
Subject(s)
Hematologic Neoplasms , Leukemia, Myeloid, Acute , Leukemia, Myelomonocytic, Juvenile , Myelodysplastic Syndromes , Adult , Humans , Child , Azacitidine/adverse effects , Leukemia, Myelomonocytic, Juvenile/drug therapy , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/chemically induced , Remission Induction , Leukemia, Myeloid, Acute/chemically induced , Leukemia, Myeloid, Acute/drug therapyABSTRACT
BACKGROUND: There are no guidelines to screen haemato-oncologic children when a tuberculosis (TB) outbreak is suspected. METHODS: After exposition to an adult with active TB, children exposed from a haemato-oncology unit were screened according to immunosuppression status and time of exposure. Until an evaluation after 8-12 weeks from last exposure, isoniazid was indicated to those with negative initial work-up. RESULTS: After 210 interventions, we detected a case of pulmonary TB, and another with latent TB infection. Pulmonary findings and treatment approach were challenging in some patients. CONCLUSIONS: The TB screening of oncologic children required a multidisciplinary approach, and clinicians managed challenging situations.
Subject(s)
Latent Tuberculosis , Tuberculosis , Adult , Antitubercular Agents/therapeutic use , Child , Humans , Isoniazid , Latent Tuberculosis/diagnosis , Prevalence , Tuberculosis/diagnosis , Tuberculosis/epidemiology , Tuberculosis/prevention & controlABSTRACT
Background: There are no guidelines to screen haemato-oncologic children when a tuberculosis (TB) outbreak is suspected. Methods: After exposition to an adult with active TB, children exposed from a haemato-oncology unit were screened according to immunosuppression status and time of exposure. Until an evaluation after 812 weeks from last exposure, isoniazid was indicated to those with negative initial work-up. Results: After 210 interventions, we detected a case of pulmonary TB, and another with latent TB infection. Pulmonary findings and treatment approach were challenging in some patients. Conclusions: The TB screening of oncologic children required a multidisciplinary approach, and clinicians managed challenging situations.(AU)
Antecedentes: No existen pautas para el cribado de niños hematooncológicos cuando se sospecha de un brote de tuberculosis (TB). Métodos: Después de la exposición a un adulto con TB activa, se evaluó a los niños expuestos de una unidad de hematooncología según el estado de inmunosupresión y el tiempo de exposición. Hasta una evaluación después de ocho a12 semanas desde la última exposición, se indicó isoniazida para aquellos con un proceso inicial negativo. Resultados: Tras 210 intervenciones se detectó un caso de tuberculosis pulmonar y otro con infección por TB latente. Los hallazgos pulmonares y el método de tratamiento fueron un desafío en algunos pacientes. Conclusiones: El cribado de TB en niños oncológicos requirió un método multidisciplinario y los médicos manejaron situaciones complejas.(AU)
Subject(s)
Humans , Child , Tuberculosis , Hematology , Medical Oncology , Pediatrics , Mass Screening , Immunosuppression Therapy , Isoniazid , Tuberculosis, Pulmonary , Microbiology , Communicable DiseasesABSTRACT
INTRODUCTION: We aimed to analyse health care services for adolescents and young adults (AYA) with sarcomas in Spain. METHODS: A survey was sent to all Spanish cancer centres, including questions about demographic, facilities, and treatment strategies for AYAs with sarcomas in the last 2 years. RESULTS: Thirty-five units participated in the survey, 17 paediatric and 15 adult units. There were three specialized AYA units. First line regimen varied depending on whether the treating unit was paediatric or not, for osteosarcomas, rhabdomyosarcomas, and non-rhabdomyosarcomas. By contrast, 91.4% of Ewing sarcomas were treated according to EE2012. In the relapse setting, differences between units were higher in all tumours. Additionally, 48% of the units reported not having trials for this population. CONCLUSION: There are major differences in the treatment of AYAs with sarcomas between adult and paediatric units. Enormous efforts are needed to homogenize treatments and increase the access to innovation.
Subject(s)
Bone Neoplasms , Neoplasms , Osteosarcoma , Sarcoma , Soft Tissue Neoplasms , Adolescent , Bone Neoplasms/epidemiology , Bone Neoplasms/therapy , Child , Humans , Neoplasm Recurrence, Local , Neoplasms/epidemiology , Osteosarcoma/therapy , Sarcoma/therapy , Spain , Young AdultABSTRACT
OBJECTIVES: Neuroblastoma is the most common extracranial tumour in children, and prognosis for refractory and relapsed disease is still poor. Early-phase clinical trials play a pivotal role in the development of novel drugs. Ensuring adequate recruitment is crucial. The primary aim was to determine the rate of participation trials for children with refractory/relapsed neuroblastoma in two of the largest drug development European institutions. METHODS: Data from patients diagnosed with refractory/relapsed neuroblastoma between January 2012 and December 2018 at the two institutions were collected and analysed. RESULTS: Overall, 48 patients were included. A total of 31 (65%) refractory/relapsed cases were enrolled in early-phase trials. The main reasons for not participating in clinical trials included not fulfilling eligibility criteria prior to consent (12/17, 70%) and screening failure (2/17, 12%). Median time on trial was 4.3 months (range 0.6-13.4). Most common cause for trial discontinuation was disease progression (67.7%). Median overall survival was longer in refractory (28 months, 95% CI: 20.9-40.2) than in relapsed patients (14 months, 95% CI: 8.1-20.1) (p = .034). CONCLUSIONS: Although two thirds of children with refractory/relapsed neuroblastoma were enrolled in early-phase trials, recruitment rates can still be improved. The main cause for not participating on trials was not fulfilling eligibility criteria prior to consent, mainly due to performance status and short life expectancy. This study highlights the hurdles to access to innovative therapies for children with relapsed/refractory neuroblastomas, and identifies key areas of development to improve recruitment to early-phase trials.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Neuroblastoma , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Drug Administration Schedule , Humans , Neoplasm Recurrence, Local/pathology , Neuroblastoma/drug therapy , Neuroblastoma/pathology , PrognosisABSTRACT
BACKGROUND: There are no guidelines to screen haemato-oncologic children when a tuberculosis (TB) outbreak is suspected. METHODS: After exposition to an adult with active TB, children exposed from a haemato-oncology unit were screened according to immunosuppression status and time of exposure. Until an evaluation after 8-12 weeks from last exposure, isoniazid was indicated to those with negative initial work-up. RESULTS: After 210 interventions, we detected a case of pulmonary TB, and another with latent TB infection. Pulmonary findings and treatment approach were challenging in some patients. CONCLUSIONS: The TB screening of oncologic children required a multidisciplinary approach, and clinicians managed challenging situations.
ABSTRACT
INTRODUCTION: Data regarding real-world impact on cancer clinical research during COVID-19 are scarce. We analysed the impact of the COVID-19 pandemic on the conduct of paediatric cancer phase I-II trials in Europe through the experience of the Innovative Therapies for Children with Cancer (ITCC). METHODS: A survey was sent to all ITCC-accredited early-phase clinical trial hospitals including questions about impact on staff activities, recruitment, patient care, supply of investigational products and legal aspects, between 1st March and 30th April 2020. RESULTS: Thirty-one of 53 hospitals from 12 countries participated. Challenges reported included staff constraints (30% drop), reduction in planned monitoring activity (67% drop of site initiation visits and 64% of monitoring visits) and patient recruitment (61% drop compared with that in 2019). The percentage of phase I, phase II trials and molecular platforms closing to recruitment in at least one site was 48.5%, 61.3% and 64.3%, respectively. In addition, 26% of sites had restrictions on performing trial assessments because of local contingency plans. Almost half of the units suffered impact upon pending contracts. Most hospitals (65%) are planning on improving organisational and structural changes. CONCLUSION: The study reveals a profound disruption of paediatric cancer early-phase clinical research due to the COVID-19 pandemic across Europe. Reported difficulties affected both patient care and monitoring activity. Efforts should be made to reallocate resources to avoid lost opportunities for patients and to allow the continued advancement of oncology research. Identified adaptations to clinical trial procedures may be integrated to increase preparedness of clinical research to futures crises.
Subject(s)
COVID-19/epidemiology , Clinical Trials, Phase I as Topic/statistics & numerical data , Clinical Trials, Phase II as Topic/statistics & numerical data , Drug Development/statistics & numerical data , Neoplasms/therapy , COVID-19/diagnosis , Child , Europe/epidemiology , Female , Health Policy , Humans , Male , Neoplasms/epidemiology , Pandemics , SARS-CoV-2/isolation & purification , Surveys and QuestionnairesABSTRACT
Composite sarcoma of bone is a very rare entity that primarily affects adolescent and young adult patients. It usually combines areas of liposarcoma and osteosarcoma, and up to 60% of cases have metastatic disease at diagnosis. It is a highly aggressive pathology with intrinsic resistance to bone sarcoma conventional treatments. The prognosis is poor, with long-term survival rates not exceeding 30%. We present the case of an adolescent female diagnosed with an aggressive composite sarcoma of bone with rhabdomyosarcoma foci and loco-regional lymph node involvement.
Subject(s)
Bone Neoplasms/secondary , Osteosarcoma/secondary , Rhabdomyosarcoma/pathology , Soft Tissue Neoplasms/secondary , Adolescent , Bone Neoplasms/surgery , Female , Humans , Lymphatic Metastasis , Osteosarcoma/surgery , Prognosis , Rhabdomyosarcoma/surgery , Soft Tissue Neoplasms/surgerySubject(s)
Betacoronavirus , Neoplasms , COVID-19 , Child , Coronavirus Infections , Humans , Pandemics , Pneumonia, Viral , SARS-CoV-2ABSTRACT
No disponible
Subject(s)
Humans , Animals , Male , Female , Infant , Child, Preschool , Child , Adolescent , Young Adult , Polycystic Kidney, Autosomal Recessive/physiopathology , Prognosis , Cohort Studies , Follow-Up Studies , Retrospective StudiesABSTRACT
BACKGROUND: Chagas disease (CD) is an emergent disease in Europe, due to immigration. The aims of this study are to describe the epidemiological characteristics of a cohort of Chagas infected pregnant women in Spain, to assess the vertical transmission (VT) rate and evaluate the usefulness of the PCR in the diagnosis of congenital infection in the first months of life. METHODS: A descriptive, retrospective study including Chagas seropositive pregnant women who were attended at three tertiary hospitals in Madrid, from January 2012 to September 2016. Infants were examined by PCR at birth and 1 month later and serologically studied at 9 months or later. Children were considered infected when the parasite was detected by PCR at any age or when serology remained positive without decline over the age of 9 months. RESULTS: We included 122 seropositive-infected pregnant women, 81% were from Bolivia and only 8.2% had been treated before. 125 newborns were studied and finally 109 were included (12.8% lost the follow-up before performing the last serology). The VT rate was 2.75% (95% CI: 0,57-8,8%). Infected infants had positive PCR at birth and 1 month later. All of them were treated successfully with benznidazole (PCR and serology became negative later on). All non-infected children presented negative PCR. The mean age at which uninfected patients had negative serology was 10.5 months. CONCLUSIONS: The VT rate is in keeping with literature and confirms the need to carry out a screening in pregnant women coming from endemic areas. PCR seems to be a useful tool to provide early diagnosis of congenital CD.
Subject(s)
Chagas Disease/diagnosis , Chagas Disease/transmission , Adult , Bolivia/epidemiology , Chagas Disease/epidemiology , Early Diagnosis , Emigration and Immigration , Female , Humans , Infant, Newborn , Infectious Disease Transmission, Vertical , Pregnancy , Pregnancy Complications, Parasitic/diagnosis , Pregnancy Complications, Parasitic/epidemiology , Retrospective Studies , Spain/epidemiology , Trypanosoma cruzi/isolation & purification , Young AdultSubject(s)
Hypoglycemia/etiology , Liver Neoplasms/diagnosis , Child , Humans , Liver Neoplasms/complications , MaleABSTRACT
No disponible
Subject(s)
Humans , Male , Child , Hypoglycemia/etiology , Liver Neoplasms/diagnosis , Liver Neoplasms/complicationsABSTRACT
No disponible