Fiorela Hernández - Academia.edu (original) (raw)

Papers by Fiorela Hernández

Journal of Evaluation in Clinical Practice, 2011

Experimental & molecular medicine, Jan 19, 2016

Cancer cells typically display increased rates of aerobic glycolysis that are correlated with tum... more Cancer cells typically display increased rates of aerobic glycolysis that are correlated with tumor aggressiveness and a poor prognosis. Targeting the glycolytic pathway has emerged as an attractive therapeutic route mainly because it should spare normal cells. Here, we evaluate the effects of combining the inhibition of glycolysis with application of the polyphenolic compound resveratrol (RSV) in neuroblastoma (NB) cancer cell lines. Inhibiting glycolysis with 2-deoxy-D-glucose (2-DG) significantly reduced NB cell viability and was associated with increased endoplasmic reticulum (ER) stress and Akt activity. Administration of 2-DG increased the expression of the ER molecular chaperones GRP78 and GRP94, the prodeath protein C/EBP homology protein (CHOP) and the phosphorylation of Akt at S473, T450 and T308. Combined treatment with both RSV and 2-DG reduced GRP78, GRP94 and Akt phosphorylation but increased CHOP and NB cell death when compared with the administration of 2-DG alone. T...

Biology of Blood and Marrow Transplantation, Aug 1, 2017

Previous studies in adults have shown that peripheral blood absolute lymphocyte and monocyte coun... more Previous studies in adults have shown that peripheral blood absolute lymphocyte and monocyte count ratio (ALC/AMC) after autologous stem cell transplantation (ASCT) can predict outcome in patients with relapsed/ refractory (R/R) Hodgkin lymphoma (HL). We retrospectively reviewed all of our children, adolescent, and young adult (CAYA) patients (age ≤26) who underwent transplantation for R/R HL between 2004 and 2015. Seventysix patients (median age, 21; range, 10 to 26 years) who reached day 100 disease free were analyzed; 33% of them had positron emission tomography (PET)-positive tumors before ASCT. Patients received high-dose carmustine, etoposide, cytarabine, and melphalan (n = 40) or gemcitabine/busulfan/melphalan (n = 36). Median follow-up after day 100 was 3.9 years (95% confidence interval [CI], 2.8 to 4.9). A day 100 ALC/AMC ratio >2.1 correlated with lower risk of relapse (hazard ratio, .097; 95% CI, .03 to .29; P < .0001). Patients with day 100 ALC/AMC ratios >2.1 and ≤2.1 had 4-year relapse-free survival rates of 93% and 33%, respectively (P = .0001) and 4-year overall survival rates of 96% and 76%, respectively (P = .0001). In addition, an ALC/AMC ratio increase >1.8 from day 15 to day 100 correlated with lower risk of relapse (hazard ratio, .24; 95% CI, .08 to 0.73; P = .01). Likewise, an ALC/AMC ratio change >.26 from day 30 to day 100 also correlated with a lower likelihood of relapse (hazard ratio, .20; 95% CI, .081 to .51; P = .0007). Multivariate analysis showed that a positive PET scan at ASCT, day 100 ALC/AMC ratio ≤ 2.1, and an ALC/AMC ratio change either ≤1.8 from day 15 to day 100 or ≤.26 from day 30 to day 100 were independent adverse predictors. In conclusion, our analysis confirms in CAYA patients prior observations in adults indicating a major prognostic effect of peripheral lymphocyte and monocyte counts at day 100 and earlier post-ASCT time points in R/R HL.

Biology of Blood and Marrow Transplantation, Mar 1, 2016

, were other pre-HCT factors associated with decreased PFS on univariate analysis, though these w... more , were other pre-HCT factors associated with decreased PFS on univariate analysis, though these were no longer significant in a multivariate model. Among HCTrelated variables, use of alemtuzumab was associated with poorer PFS (3 yr ePFS 47.5%, 95% CI 35.2-64.2; vs. 23.5%, 95% CI 9.99-55.4), p ¼ .019. HL stage, prior ASCT, HCT CI, and HLA match status did not significantly influence PFS. Conclusion: Allo HCT offered long-term remission for a considerable population of patients with rel/ref HL, with a strong trend toward enhanced PFS with normalized functional imaging pre-HCT. On univariate analysis, PFS was optimized with HCT in CR, and patients with extranodal disease, impaired PS, or alemtuzumab-based conditioning had poorer outcomes.

Nature Reviews Clinical Oncology, 2021

In the original version of this Consensus Statement, the name of the author Christine N. Duncan w... more In the original version of this Consensus Statement, the name of the author Christine N. Duncan was incorrectly written as Christine N. Duncun. In addition, Fig. 1 contained errors regarding the criteria to grade cytokine-release syndrome (CRS). "Hypotension not requiring vasopressors" has now been corrected to "hypotension requiring one vasopressor ± vasopressin" for grade 3 CRS and "hypotension requiring multiple vasopressors, not including vasopressin" for grade 4 CRS. The affiliations and Fig. 1 have been corrected in the HTML and PDF versions of the manuscript.

Pediatric Drugs, 2021

Asparaginase therapy is a vital agent in the treatment of acute lymphoblastic leukemia (ALL), wit... more Asparaginase therapy is a vital agent in the treatment of acute lymphoblastic leukemia (ALL), with increasing evidence of its high importance in high-risk ALL populations. However, despite the clear clinical and biological benefits of asparaginase therapy, many patients experience toxicities. A well-known treatment-limiting toxicity is asparaginase-associated pancreatitis (AAP). If severe, it necessitates discontinuation of asparaginase therapy, which can lead to a higher risk of relapse in patients with ALL. New protocols for ALL therapy have increased overall total doses of asparaginase therapy in select high-risk populations and have incorporated longer half-life formulations of pegylated asparaginase. Treatment drug monitoring has also allowed assurance of adequate levels of asparagine depletion throughout treatment. It is currently unknown if these changes will increase rates of AAP. Interestingly, important pharmacogenomics data, such as single nucleotide polymorphisms, can identify patients at the highest risk for severe AAP. The incidence of AAP in recent trials, current pharmacogenomic data that could further our understanding of the disease, and the importance of cautiously re-exposing patients to further asparaginase treatment after an initial episode of AAP are discussed.

Nature Reviews Clinical Oncology, 2021

Cancer immunotherapies harness components of the immune system to induce long-term cancer remissi... more Cancer immunotherapies harness components of the immune system to induce long-term cancer remission. Immunotherapeutic agents include immune-checkpoint inhibitors (ICIs), bispecific T cell engagers (BiTEs) and immune-effector cells (IECs), which have all revolutionized oncology in the past decade. Nevertheless, these therapies have been associated with unique and potentially life-threatening toxicities, which include cytokine-release syndrome (CRS), IEC-associated neurotoxicity syndrome (ICANS) and other severe immune-related adverse events (irAEs). Vigilance, prompt recognition and management of these toxicities, with attention to age-appropriate considerations, can lead to optimized outcomes in children and in adolescents and young adults (AYAs) receiving these therapies. Paediatric populations are defined as those

Current Oncology Reports, 2020

Purpose of Review The prognosis of pediatric patients who present with metastatic or recurrent sa... more Purpose of Review The prognosis of pediatric patients who present with metastatic or recurrent sarcomas remains poor. In this review, we summarize the advances in the management of metastatic and relapsed pediatric sarcoma by highlighting recent and future clinical trials. Recent Findings Research into the identification of novel therapies for refractory pediatric sarcomas continues to advance. Outcomes have not improved in several decades underlying a need for improved understanding of the biology behind these tumors and the identification of novel therapeutic molecular targets that can be exploited pharmacologically. Multiple challenges remain for novel therapy in sarcomas such as the selection of effective targets, management of toxicities, and the tumor microenvironment. Summary Many unique challenges remain in the treatment of patients with refractory pediatric sarcomas. Multiple strategies and targets are under investigation that hold promise.

Journal of Clinical Oncology, 2018

10523Background: Adoptive transfer of chimeric antigen receptor (CAR)-modified T cells is predict... more 10523Background: Adoptive transfer of chimeric antigen receptor (CAR)-modified T cells is predicted to provide a treatment option for advanced/refractory neuroblastoma. One potential target, recept...

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 20, 2017

Previous studies in adults have shown that peripheral blood absolute lymphocyte and monocyte coun... more Previous studies in adults have shown that peripheral blood absolute lymphocyte and monocyte count ratio (ALC/AMC) after autologous stem cell transplant (ASCT) can predict outcome in patients with relapsed/refractory Hodgkin's lymphoma (R/R HL). We retrospectively reviewed all of our children, adolescent, and young adult (CAYA) patients (age ≤26) transplanted for R/R HL between 2004 and 2015. Seventy-six patients (median age 21, range 10-26 years) who reached d100 (d100) disease free were analyzed; 33% of them had PET-positive tumors prior to ASCT. Patients received high-dose BEAM (n=40) or gemcitabine/busulfan/melphalan (n=36). Median follow-up after d100 was 3.9 years (95% confidence interval (CI) = 2.8-4.9). A d100 ALC/AMC ratio >2.1 correlated with lower risk of relapse (hazard ratio [HR] = 0.097; 95% CI = 0.03-0.29; P<0.0001). Patients with d100 ALC/AMC ratios >2.1 and ≤2.1 had 4-year RFS rates of 93% and 33%, respectively (P=0.0001) and 4-year OS rates of 96% and ...

Pediatric Blood & Cancer, 2016

A 10-year-old boy, previously healthy, was referred to our institution for surgical resection of ... more A 10-year-old boy, previously healthy, was referred to our institution for surgical resection of a posterior mediastinal ganglioneuroma. The patient was asymptomatic; the mass had been an incidental finding on CONFLICT OF INTEREST The authors declare that there is no conflict of interest.

Frontiers in Pediatrics, 2014

Notch signaling can play oncogenic and tumor suppressor roles depending on cell type. Hematologic... more Notch signaling can play oncogenic and tumor suppressor roles depending on cell type. Hematologic malignancies encompass a wide range of transformed cells, and consequently the roles of Notch are diverse in these diseases. For example Notch is a potentT-cell oncogene, with >50% of T-cell acute lymphoblastic leukemia (T-ALL) cases carry activating mutations in the Notch1 receptor.Targeting Notch signaling inT-ALL with gamma-secretase inhibitors, which prevent Notch receptor activation, has shown pre-clinical activity, and is under evaluation clinically. In contrast, Notch signaling inhibits acute myeloblastic leukemia growth and survival, and although targeting Notch signaling in AML with Notch activators appears to have pre-clinical activity, no Notch agonists are clinically available at this time. As such, despite accumulating evidence about the biology of Notch signaling in different hematologic cancers, which provide compelling clinical promise, we are only beginning to target this pathway clinically, either on or off. In this review, we will summarize the evidence for oncogenic and tumor suppressor roles of Notch in a wide range of leukemias and lymphomas, and describe therapeutic opportunities for now and the future.

Journal of Evaluation in Clinical Practice, 2011

Efforts to implement evidence-based medicine (EBM) training in developing countries are limited. ... more Efforts to implement evidence-based medicine (EBM) training in developing countries are limited. We describe the results of an international effort to improve research capacity in a developing country; we conducted a course aimed at improving basic EBM attitudes and identified challenges. Method Between 2005 and 2009, we conducted an annual 3-day course in Perú consisting of interactive lectures and case-based workshops. We assessed self-reported competence and importance in EBM using a Likert scale (1 = low, 5 = high). Results Totally 220 clinicians participated. For phase I (2005-2007), self-reported EBM competence increased from a median of 2 to 3 (P < 0.001) and the perceived importance of EBM did not change (median = 5). For phase II (2008II ( -2009, before the course, 8-72% graded their competence very low (score of 1-2). After the course, 67-92% of subjects graded their increase in knowledge very high (score of 4-5). The challenges included limited availability of studies relevant to the local reality written in Spanish, participants' limited time and lack of long-term follow-up on practice change. Informal discussion and written evaluation from participants were universally in agreement that more training in EBM is needed. Conclusions In an EBM course in a resource-poor country, the baseline self-reported competence and experience on EBM were low, and the course had measurable improvements of self-reported competence, perceived utility and readiness to incorporate EBM into their practices. Similar to developed countries, translational research and building the research capacity in developing countries is critical for translating best available evidence into practice.

Journal of Evaluation in Clinical Practice, 2011

Experimental & molecular medicine, Jan 19, 2016

Cancer cells typically display increased rates of aerobic glycolysis that are correlated with tum... more Cancer cells typically display increased rates of aerobic glycolysis that are correlated with tumor aggressiveness and a poor prognosis. Targeting the glycolytic pathway has emerged as an attractive therapeutic route mainly because it should spare normal cells. Here, we evaluate the effects of combining the inhibition of glycolysis with application of the polyphenolic compound resveratrol (RSV) in neuroblastoma (NB) cancer cell lines. Inhibiting glycolysis with 2-deoxy-D-glucose (2-DG) significantly reduced NB cell viability and was associated with increased endoplasmic reticulum (ER) stress and Akt activity. Administration of 2-DG increased the expression of the ER molecular chaperones GRP78 and GRP94, the prodeath protein C/EBP homology protein (CHOP) and the phosphorylation of Akt at S473, T450 and T308. Combined treatment with both RSV and 2-DG reduced GRP78, GRP94 and Akt phosphorylation but increased CHOP and NB cell death when compared with the administration of 2-DG alone. T...

Biology of Blood and Marrow Transplantation, Aug 1, 2017

Previous studies in adults have shown that peripheral blood absolute lymphocyte and monocyte coun... more Previous studies in adults have shown that peripheral blood absolute lymphocyte and monocyte count ratio (ALC/AMC) after autologous stem cell transplantation (ASCT) can predict outcome in patients with relapsed/ refractory (R/R) Hodgkin lymphoma (HL). We retrospectively reviewed all of our children, adolescent, and young adult (CAYA) patients (age ≤26) who underwent transplantation for R/R HL between 2004 and 2015. Seventysix patients (median age, 21; range, 10 to 26 years) who reached day 100 disease free were analyzed; 33% of them had positron emission tomography (PET)-positive tumors before ASCT. Patients received high-dose carmustine, etoposide, cytarabine, and melphalan (n = 40) or gemcitabine/busulfan/melphalan (n = 36). Median follow-up after day 100 was 3.9 years (95% confidence interval [CI], 2.8 to 4.9). A day 100 ALC/AMC ratio >2.1 correlated with lower risk of relapse (hazard ratio, .097; 95% CI, .03 to .29; P < .0001). Patients with day 100 ALC/AMC ratios >2.1 and ≤2.1 had 4-year relapse-free survival rates of 93% and 33%, respectively (P = .0001) and 4-year overall survival rates of 96% and 76%, respectively (P = .0001). In addition, an ALC/AMC ratio increase >1.8 from day 15 to day 100 correlated with lower risk of relapse (hazard ratio, .24; 95% CI, .08 to 0.73; P = .01). Likewise, an ALC/AMC ratio change >.26 from day 30 to day 100 also correlated with a lower likelihood of relapse (hazard ratio, .20; 95% CI, .081 to .51; P = .0007). Multivariate analysis showed that a positive PET scan at ASCT, day 100 ALC/AMC ratio ≤ 2.1, and an ALC/AMC ratio change either ≤1.8 from day 15 to day 100 or ≤.26 from day 30 to day 100 were independent adverse predictors. In conclusion, our analysis confirms in CAYA patients prior observations in adults indicating a major prognostic effect of peripheral lymphocyte and monocyte counts at day 100 and earlier post-ASCT time points in R/R HL.

Biology of Blood and Marrow Transplantation, Mar 1, 2016

, were other pre-HCT factors associated with decreased PFS on univariate analysis, though these w... more , were other pre-HCT factors associated with decreased PFS on univariate analysis, though these were no longer significant in a multivariate model. Among HCTrelated variables, use of alemtuzumab was associated with poorer PFS (3 yr ePFS 47.5%, 95% CI 35.2-64.2; vs. 23.5%, 95% CI 9.99-55.4), p ¼ .019. HL stage, prior ASCT, HCT CI, and HLA match status did not significantly influence PFS. Conclusion: Allo HCT offered long-term remission for a considerable population of patients with rel/ref HL, with a strong trend toward enhanced PFS with normalized functional imaging pre-HCT. On univariate analysis, PFS was optimized with HCT in CR, and patients with extranodal disease, impaired PS, or alemtuzumab-based conditioning had poorer outcomes.

Nature Reviews Clinical Oncology, 2021

In the original version of this Consensus Statement, the name of the author Christine N. Duncan w... more In the original version of this Consensus Statement, the name of the author Christine N. Duncan was incorrectly written as Christine N. Duncun. In addition, Fig. 1 contained errors regarding the criteria to grade cytokine-release syndrome (CRS). "Hypotension not requiring vasopressors" has now been corrected to "hypotension requiring one vasopressor ± vasopressin" for grade 3 CRS and "hypotension requiring multiple vasopressors, not including vasopressin" for grade 4 CRS. The affiliations and Fig. 1 have been corrected in the HTML and PDF versions of the manuscript.

Pediatric Drugs, 2021

Asparaginase therapy is a vital agent in the treatment of acute lymphoblastic leukemia (ALL), wit... more Asparaginase therapy is a vital agent in the treatment of acute lymphoblastic leukemia (ALL), with increasing evidence of its high importance in high-risk ALL populations. However, despite the clear clinical and biological benefits of asparaginase therapy, many patients experience toxicities. A well-known treatment-limiting toxicity is asparaginase-associated pancreatitis (AAP). If severe, it necessitates discontinuation of asparaginase therapy, which can lead to a higher risk of relapse in patients with ALL. New protocols for ALL therapy have increased overall total doses of asparaginase therapy in select high-risk populations and have incorporated longer half-life formulations of pegylated asparaginase. Treatment drug monitoring has also allowed assurance of adequate levels of asparagine depletion throughout treatment. It is currently unknown if these changes will increase rates of AAP. Interestingly, important pharmacogenomics data, such as single nucleotide polymorphisms, can identify patients at the highest risk for severe AAP. The incidence of AAP in recent trials, current pharmacogenomic data that could further our understanding of the disease, and the importance of cautiously re-exposing patients to further asparaginase treatment after an initial episode of AAP are discussed.

Nature Reviews Clinical Oncology, 2021

Cancer immunotherapies harness components of the immune system to induce long-term cancer remissi... more Cancer immunotherapies harness components of the immune system to induce long-term cancer remission. Immunotherapeutic agents include immune-checkpoint inhibitors (ICIs), bispecific T cell engagers (BiTEs) and immune-effector cells (IECs), which have all revolutionized oncology in the past decade. Nevertheless, these therapies have been associated with unique and potentially life-threatening toxicities, which include cytokine-release syndrome (CRS), IEC-associated neurotoxicity syndrome (ICANS) and other severe immune-related adverse events (irAEs). Vigilance, prompt recognition and management of these toxicities, with attention to age-appropriate considerations, can lead to optimized outcomes in children and in adolescents and young adults (AYAs) receiving these therapies. Paediatric populations are defined as those

Current Oncology Reports, 2020

Purpose of Review The prognosis of pediatric patients who present with metastatic or recurrent sa... more Purpose of Review The prognosis of pediatric patients who present with metastatic or recurrent sarcomas remains poor. In this review, we summarize the advances in the management of metastatic and relapsed pediatric sarcoma by highlighting recent and future clinical trials. Recent Findings Research into the identification of novel therapies for refractory pediatric sarcomas continues to advance. Outcomes have not improved in several decades underlying a need for improved understanding of the biology behind these tumors and the identification of novel therapeutic molecular targets that can be exploited pharmacologically. Multiple challenges remain for novel therapy in sarcomas such as the selection of effective targets, management of toxicities, and the tumor microenvironment. Summary Many unique challenges remain in the treatment of patients with refractory pediatric sarcomas. Multiple strategies and targets are under investigation that hold promise.

Journal of Clinical Oncology, 2018

10523Background: Adoptive transfer of chimeric antigen receptor (CAR)-modified T cells is predict... more 10523Background: Adoptive transfer of chimeric antigen receptor (CAR)-modified T cells is predicted to provide a treatment option for advanced/refractory neuroblastoma. One potential target, recept...

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 20, 2017

Previous studies in adults have shown that peripheral blood absolute lymphocyte and monocyte coun... more Previous studies in adults have shown that peripheral blood absolute lymphocyte and monocyte count ratio (ALC/AMC) after autologous stem cell transplant (ASCT) can predict outcome in patients with relapsed/refractory Hodgkin's lymphoma (R/R HL). We retrospectively reviewed all of our children, adolescent, and young adult (CAYA) patients (age ≤26) transplanted for R/R HL between 2004 and 2015. Seventy-six patients (median age 21, range 10-26 years) who reached d100 (d100) disease free were analyzed; 33% of them had PET-positive tumors prior to ASCT. Patients received high-dose BEAM (n=40) or gemcitabine/busulfan/melphalan (n=36). Median follow-up after d100 was 3.9 years (95% confidence interval (CI) = 2.8-4.9). A d100 ALC/AMC ratio >2.1 correlated with lower risk of relapse (hazard ratio [HR] = 0.097; 95% CI = 0.03-0.29; P<0.0001). Patients with d100 ALC/AMC ratios >2.1 and ≤2.1 had 4-year RFS rates of 93% and 33%, respectively (P=0.0001) and 4-year OS rates of 96% and ...

Pediatric Blood & Cancer, 2016

A 10-year-old boy, previously healthy, was referred to our institution for surgical resection of ... more A 10-year-old boy, previously healthy, was referred to our institution for surgical resection of a posterior mediastinal ganglioneuroma. The patient was asymptomatic; the mass had been an incidental finding on CONFLICT OF INTEREST The authors declare that there is no conflict of interest.

Frontiers in Pediatrics, 2014

Notch signaling can play oncogenic and tumor suppressor roles depending on cell type. Hematologic... more Notch signaling can play oncogenic and tumor suppressor roles depending on cell type. Hematologic malignancies encompass a wide range of transformed cells, and consequently the roles of Notch are diverse in these diseases. For example Notch is a potentT-cell oncogene, with >50% of T-cell acute lymphoblastic leukemia (T-ALL) cases carry activating mutations in the Notch1 receptor.Targeting Notch signaling inT-ALL with gamma-secretase inhibitors, which prevent Notch receptor activation, has shown pre-clinical activity, and is under evaluation clinically. In contrast, Notch signaling inhibits acute myeloblastic leukemia growth and survival, and although targeting Notch signaling in AML with Notch activators appears to have pre-clinical activity, no Notch agonists are clinically available at this time. As such, despite accumulating evidence about the biology of Notch signaling in different hematologic cancers, which provide compelling clinical promise, we are only beginning to target this pathway clinically, either on or off. In this review, we will summarize the evidence for oncogenic and tumor suppressor roles of Notch in a wide range of leukemias and lymphomas, and describe therapeutic opportunities for now and the future.

Journal of Evaluation in Clinical Practice, 2011

Efforts to implement evidence-based medicine (EBM) training in developing countries are limited. ... more Efforts to implement evidence-based medicine (EBM) training in developing countries are limited. We describe the results of an international effort to improve research capacity in a developing country; we conducted a course aimed at improving basic EBM attitudes and identified challenges. Method Between 2005 and 2009, we conducted an annual 3-day course in Perú consisting of interactive lectures and case-based workshops. We assessed self-reported competence and importance in EBM using a Likert scale (1 = low, 5 = high). Results Totally 220 clinicians participated. For phase I (2005-2007), self-reported EBM competence increased from a median of 2 to 3 (P < 0.001) and the perceived importance of EBM did not change (median = 5). For phase II (2008II ( -2009, before the course, 8-72% graded their competence very low (score of 1-2). After the course, 67-92% of subjects graded their increase in knowledge very high (score of 4-5). The challenges included limited availability of studies relevant to the local reality written in Spanish, participants' limited time and lack of long-term follow-up on practice change. Informal discussion and written evaluation from participants were universally in agreement that more training in EBM is needed. Conclusions In an EBM course in a resource-poor country, the baseline self-reported competence and experience on EBM were low, and the course had measurable improvements of self-reported competence, perceived utility and readiness to incorporate EBM into their practices. Similar to developed countries, translational research and building the research capacity in developing countries is critical for translating best available evidence into practice.