Pub Date : 2021-05-11DOI: 10.1080/23808993.2021.1923400
G. D’Abbronzo, Renato Franco
For a long time, the pathologist has mainly been dedicated to the morphological diagnosis, including macroscopic and microscopic examination of organs and tissues. Moreover, interaction between clinicians and pathologists was limited to the morphological diagnostic reports provided by pathologists. Recently, medical science has dramatically changed due to technological progress, recent discoveries in cellular and molecular pathways, the growing sub-specialization in the medical fields, the need to individualize oncological therapies. Indeed, due to the development of an increasingly individualbased therapy, the ‘companion diagnostic,’ specifically analyzing tumor markers able to predict the response of the patients to targeted therapies [1]. Thus, while the previous approach in diagnostic pathology were addressed to define prognostic biomarkers, currently the pathologists are required to identify biomarkers useful to predict patient’s potential response to target drugs [2]. For this reasons, classifications of the diseases, particularly neoplasms, enriched of immunohistochemical and molecular features. In this scenario, the pathologist has gone beyond the morphological diagnosis, definitively entering the patients’ clinical management, and leading the therapeutic addresses. Indeed, pathologists in a synergic collaboration with molecular biologists can provide necessary molecular information useful for a complete diagnosis. Therefore, pathologists become the final certifier of a complex diagnostic process, being medical professionals with the required skills to integrate morphological and molecular information in a report, including diagnosis and predictive biomarkers. This integrated information allows clinicians to choose the best therapeutic procedure for the individual patient (e.g. chemotherapy or immunotherapy or gene therapy) [3].
{"title":"The changing role of the pathologist in the era of targeted therapy in personalized medicine","authors":"G. D’Abbronzo, Renato Franco","doi":"10.1080/23808993.2021.1923400","DOIUrl":"https://doi.org/10.1080/23808993.2021.1923400","url":null,"abstract":"For a long time, the pathologist has mainly been dedicated to the morphological diagnosis, including macroscopic and microscopic examination of organs and tissues. Moreover, interaction between clinicians and pathologists was limited to the morphological diagnostic reports provided by pathologists. Recently, medical science has dramatically changed due to technological progress, recent discoveries in cellular and molecular pathways, the growing sub-specialization in the medical fields, the need to individualize oncological therapies. Indeed, due to the development of an increasingly individualbased therapy, the ‘companion diagnostic,’ specifically analyzing tumor markers able to predict the response of the patients to targeted therapies [1]. Thus, while the previous approach in diagnostic pathology were addressed to define prognostic biomarkers, currently the pathologists are required to identify biomarkers useful to predict patient’s potential response to target drugs [2]. For this reasons, classifications of the diseases, particularly neoplasms, enriched of immunohistochemical and molecular features. In this scenario, the pathologist has gone beyond the morphological diagnosis, definitively entering the patients’ clinical management, and leading the therapeutic addresses. Indeed, pathologists in a synergic collaboration with molecular biologists can provide necessary molecular information useful for a complete diagnosis. Therefore, pathologists become the final certifier of a complex diagnostic process, being medical professionals with the required skills to integrate morphological and molecular information in a report, including diagnosis and predictive biomarkers. This integrated information allows clinicians to choose the best therapeutic procedure for the individual patient (e.g. chemotherapy or immunotherapy or gene therapy) [3].","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"295 - 297"},"PeriodicalIF":1.2,"publicationDate":"2021-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1923400","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48823521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-05-03DOI: 10.1080/23808993.2021.1920834
M. Sadiq, Juliette Servante, S. Madhusudan
ABSTRACT Introduction: Triple negative breast cancer (TNBC) is a challenging disease generally following an aggressive clinical phenotype with poor survival outcomes. Scarcity of druggable targets coupled with molecular and genetic diversity has raised barriers in effective management of this disease; however, novel therapeutic strategies are on the horizon. Areas covered: We aim to present an overview of promising drugs that have emerged from preclinical studies undergoing investigation in early and late clinical trials alongside current challenges in the implementation of these in clinic. Expert opinion: The advent of immunotherapy and PARP inhibitors has finally started to diversify the cytotoxic chemotherapy-dependent treatment portfolio for TNBC. During this process, numerous challenges around novel biomarker discovery, optimum patient selection and combinatorial toxicity have been exposed. There is a clear need to further our understanding of the molecular pathways involved in the evolution of TNBC to optimize targets and explain inadequacies of current investigational treatments. We expect progressive expansion in diagnostic and prognostic biomarker panels allowing for further personalization of TNBC treatment.
{"title":"Precision medicine for the treatment of triple negative breast cancer: opportunities and challenges","authors":"M. Sadiq, Juliette Servante, S. Madhusudan","doi":"10.1080/23808993.2021.1920834","DOIUrl":"https://doi.org/10.1080/23808993.2021.1920834","url":null,"abstract":"ABSTRACT Introduction: Triple negative breast cancer (TNBC) is a challenging disease generally following an aggressive clinical phenotype with poor survival outcomes. Scarcity of druggable targets coupled with molecular and genetic diversity has raised barriers in effective management of this disease; however, novel therapeutic strategies are on the horizon. Areas covered: We aim to present an overview of promising drugs that have emerged from preclinical studies undergoing investigation in early and late clinical trials alongside current challenges in the implementation of these in clinic. Expert opinion: The advent of immunotherapy and PARP inhibitors has finally started to diversify the cytotoxic chemotherapy-dependent treatment portfolio for TNBC. During this process, numerous challenges around novel biomarker discovery, optimum patient selection and combinatorial toxicity have been exposed. There is a clear need to further our understanding of the molecular pathways involved in the evolution of TNBC to optimize targets and explain inadequacies of current investigational treatments. We expect progressive expansion in diagnostic and prognostic biomarker panels allowing for further personalization of TNBC treatment.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"259 - 270"},"PeriodicalIF":1.2,"publicationDate":"2021-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1920834","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42836353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-05-03DOI: 10.1080/23808993.2021.1911638
A. Cimadamore, A. Rizzo, V. Mollica, F. Massari, A. López-Beltran, M. Scarpelli, Liang Cheng, M. Santoni, R. Montironi
Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy; Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy; Department of Surgery, Cordoba University Medical School, Cordoba, Spain; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, USA; Oncology department, Macerata Hospital, Macerata, Italy
{"title":"An update on immunotherapy in uro-oncology","authors":"A. Cimadamore, A. Rizzo, V. Mollica, F. Massari, A. López-Beltran, M. Scarpelli, Liang Cheng, M. Santoni, R. Montironi","doi":"10.1080/23808993.2021.1911638","DOIUrl":"https://doi.org/10.1080/23808993.2021.1911638","url":null,"abstract":"Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy; Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy; Department of Surgery, Cordoba University Medical School, Cordoba, Spain; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, USA; Oncology department, Macerata Hospital, Macerata, Italy","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"229 - 233"},"PeriodicalIF":1.2,"publicationDate":"2021-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1911638","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45847278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-04-19DOI: 10.1080/23808993.2021.1915693
E. Coart, E. Saad
ABSTRACT Introduction: Precision medicine is impacting clinical practice and drug development in oncology, promoting notable changes in the design of early-phase cancer trials. There is increasing pressure on sponsors and clinical trialists to strike the right balance between speed and reliability in the design and implementation of such trials, which now commonly assess activity in expansion cohorts. Areas covered: We discuss methodological issues related to trial design and sample sizes for phase 1 trials with expansion cohorts and phase 1/2 trials. We review the pertinent literature, present fictitious cases to illustrate the different designs, and discuss their advantages and disadvantages, with a focus on randomized designs in which an experimental and a control treatment are assessed. Expert Opinion: Designing a phase 1 trial with expansion cohorts requires statistical input and explicit consideration about interpretation of future results. There is currently insufficient emphasis on the role of randomization in expansion cohorts and phase 2 components of early-phase trials. The results from single-arm cohorts may be misleading due to selection bias, but comparative randomized trials may not be feasible in many cases due to budget constraints or ethical arguments. Randomized, non-comparative trials with a control arm used for calibration of historical results are an interesting intermediate solution between single-arm expansion cohorts and randomized comparative studies.
{"title":"Considerations on the mechanics and sample sizes for early trials of targeted agents and immunotherapy in oncology","authors":"E. Coart, E. Saad","doi":"10.1080/23808993.2021.1915693","DOIUrl":"https://doi.org/10.1080/23808993.2021.1915693","url":null,"abstract":"ABSTRACT Introduction: Precision medicine is impacting clinical practice and drug development in oncology, promoting notable changes in the design of early-phase cancer trials. There is increasing pressure on sponsors and clinical trialists to strike the right balance between speed and reliability in the design and implementation of such trials, which now commonly assess activity in expansion cohorts. Areas covered: We discuss methodological issues related to trial design and sample sizes for phase 1 trials with expansion cohorts and phase 1/2 trials. We review the pertinent literature, present fictitious cases to illustrate the different designs, and discuss their advantages and disadvantages, with a focus on randomized designs in which an experimental and a control treatment are assessed. Expert Opinion: Designing a phase 1 trial with expansion cohorts requires statistical input and explicit consideration about interpretation of future results. There is currently insufficient emphasis on the role of randomization in expansion cohorts and phase 2 components of early-phase trials. The results from single-arm cohorts may be misleading due to selection bias, but comparative randomized trials may not be feasible in many cases due to budget constraints or ethical arguments. Randomized, non-comparative trials with a control arm used for calibration of historical results are an interesting intermediate solution between single-arm expansion cohorts and randomized comparative studies.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"271 - 280"},"PeriodicalIF":1.2,"publicationDate":"2021-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1915693","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48850348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-04-13DOI: 10.1080/23808993.2021.1911639
M. Mussap, A. Noto, C. Piras, L. Atzori, V. Fanos
ABSTRACT Introduction Despite an impressive amount of metabolomics studies in animal models and humans, most findings have not yet translated into the clinical setting, and the road ahead remains still long. Areas covered This review provides the most challenging applications of clinical metabolomics testing in human health and disease. Personalized clinical metabolomics testing is incorporated within the test panel to diagnose inborn errors of metabolism, optimize dietary regimens, and discover and develop new drugs. The potential routine utilization of metabolomics in precision medicine has been revised in cancer and nutrition. The association between metabolomics with artificial intelligence and machine learning may open emerging perspectives for more effective utilization and timely introduction of clinical metabolomics testing in the care of patients with acute and chronic diseases. Expert opinion In conclusion, slotting metabolomics into routine precision medicine implies the direct relationship between metabolomic results and clinical decision-making, similarly to any other clinical test result, as well as it requires the application of clinical laboratory standards, protocols, training, the oversight to a global biochemical profiling technology, and the availability of metabolic profiles from reference populations, defining cutoff values and decision levels.
{"title":"Slotting metabolomics into routine precision medicine","authors":"M. Mussap, A. Noto, C. Piras, L. Atzori, V. Fanos","doi":"10.1080/23808993.2021.1911639","DOIUrl":"https://doi.org/10.1080/23808993.2021.1911639","url":null,"abstract":"ABSTRACT Introduction Despite an impressive amount of metabolomics studies in animal models and humans, most findings have not yet translated into the clinical setting, and the road ahead remains still long. Areas covered This review provides the most challenging applications of clinical metabolomics testing in human health and disease. Personalized clinical metabolomics testing is incorporated within the test panel to diagnose inborn errors of metabolism, optimize dietary regimens, and discover and develop new drugs. The potential routine utilization of metabolomics in precision medicine has been revised in cancer and nutrition. The association between metabolomics with artificial intelligence and machine learning may open emerging perspectives for more effective utilization and timely introduction of clinical metabolomics testing in the care of patients with acute and chronic diseases. Expert opinion In conclusion, slotting metabolomics into routine precision medicine implies the direct relationship between metabolomic results and clinical decision-making, similarly to any other clinical test result, as well as it requires the application of clinical laboratory standards, protocols, training, the oversight to a global biochemical profiling technology, and the availability of metabolic profiles from reference populations, defining cutoff values and decision levels.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"173 - 187"},"PeriodicalIF":1.2,"publicationDate":"2021-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1911639","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42840621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-04-13DOI: 10.1080/23808993.2021.1915126
A. Rizzo, A. Ricci, G. Brandi
ABSTRACT Introduction: Cholangiocarcinomas (CCAs) are rare and heterogeneous malignancies associated with poor prognosis, with most of the patients presenting with advanced disease at diagnosis. The recent advent of molecular profiling has led to the identification of several druggable genetic aberrations, and among these, there is an increasing interest in isocitrate dehydrogenase-1 (IDH-1) mutations, with the IDH-1 inhibitor ivosidenib that has reported interesting results in advanced CCA patients. Areas covered: Herein, we will critically discuss the current state of the art of ivosidenib in IDH-mutant CCA, especially focusing on efficacy and safety results of recent trials assessing this IDH-1 inhibitor. Expert opinion: According to the results of phase I studies and the recently published ClarIDHy phase III trial, the IDH-1 inhibitor ivosidenib seems to be associated with a manageable safety profile and interesting antitumor efficacy. In particular, the ClarIDHy showed that ivosidenib treatment reported improved progression-free survival (PFS) compared to placebo in previously treated patients, with median PFS of 2.7 and 1.4 months, respectively. However, several questions remain unanswered and the effective impact of ivosidenib in IDH-mutant CCA remains open.
{"title":"Ivosidenib in IDH-mutant cholangiocarcinoma: where do we stand?","authors":"A. Rizzo, A. Ricci, G. Brandi","doi":"10.1080/23808993.2021.1915126","DOIUrl":"https://doi.org/10.1080/23808993.2021.1915126","url":null,"abstract":"ABSTRACT Introduction: Cholangiocarcinomas (CCAs) are rare and heterogeneous malignancies associated with poor prognosis, with most of the patients presenting with advanced disease at diagnosis. The recent advent of molecular profiling has led to the identification of several druggable genetic aberrations, and among these, there is an increasing interest in isocitrate dehydrogenase-1 (IDH-1) mutations, with the IDH-1 inhibitor ivosidenib that has reported interesting results in advanced CCA patients. Areas covered: Herein, we will critically discuss the current state of the art of ivosidenib in IDH-mutant CCA, especially focusing on efficacy and safety results of recent trials assessing this IDH-1 inhibitor. Expert opinion: According to the results of phase I studies and the recently published ClarIDHy phase III trial, the IDH-1 inhibitor ivosidenib seems to be associated with a manageable safety profile and interesting antitumor efficacy. In particular, the ClarIDHy showed that ivosidenib treatment reported improved progression-free survival (PFS) compared to placebo in previously treated patients, with median PFS of 2.7 and 1.4 months, respectively. However, several questions remain unanswered and the effective impact of ivosidenib in IDH-mutant CCA remains open.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"217 - 224"},"PeriodicalIF":1.2,"publicationDate":"2021-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1915126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44246783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-04-13DOI: 10.1080/23808993.2021.1909420
T. Reungwetwattana, N. Rohatgi, T. Mok, K. Prabhash
ABSTRACT Introduction: Dacomitinib is a second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). Recent results from ARCHER 1050, the first randomized, open-label, Phase 3 trial of a second-generation vs. a first-generation EGFR TKI, showed that dacomitinib improves progression-free survival and overall survival compared with gefitinib as a first-line treatment in patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). Areas covered: We review the efficacy and safety of dacomitinib as a first-line treatment of EGFR mutation-positive NSCLC, including the management of toxicity, and evaluate the activity of dacomitinib against brain metastases. Additionally, the optimal treatment sequence given EGFR TKI choice, resistance mechanisms, activity against rare mutations, and real-world dosing is discussed. Expert opinion: The introduction of EGFR TKIs has changed the treatment strategy for patients with EGFR mutation-positive NSCLC. The second- and third-generation EGFR TKIs are the result of research elucidating mechanisms of resistance to first-generation EGFR TKIs. There is now more than one treatment option for patients with EGFR mutation-positive advanced NSCLC that improves survival, highlighting the need to more clearly understand the use of the right drug for the right person at the right time and how the appropriate treatment sequence may provide optimal outcomes for these patients.
{"title":"Dacomitinib as first-line treatment for EGFR mutation-positive non-small cell lung cancer","authors":"T. Reungwetwattana, N. Rohatgi, T. Mok, K. Prabhash","doi":"10.1080/23808993.2021.1909420","DOIUrl":"https://doi.org/10.1080/23808993.2021.1909420","url":null,"abstract":"ABSTRACT Introduction: Dacomitinib is a second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). Recent results from ARCHER 1050, the first randomized, open-label, Phase 3 trial of a second-generation vs. a first-generation EGFR TKI, showed that dacomitinib improves progression-free survival and overall survival compared with gefitinib as a first-line treatment in patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). Areas covered: We review the efficacy and safety of dacomitinib as a first-line treatment of EGFR mutation-positive NSCLC, including the management of toxicity, and evaluate the activity of dacomitinib against brain metastases. Additionally, the optimal treatment sequence given EGFR TKI choice, resistance mechanisms, activity against rare mutations, and real-world dosing is discussed. Expert opinion: The introduction of EGFR TKIs has changed the treatment strategy for patients with EGFR mutation-positive NSCLC. The second- and third-generation EGFR TKIs are the result of research elucidating mechanisms of resistance to first-generation EGFR TKIs. There is now more than one treatment option for patients with EGFR mutation-positive advanced NSCLC that improves survival, highlighting the need to more clearly understand the use of the right drug for the right person at the right time and how the appropriate treatment sequence may provide optimal outcomes for these patients.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"161 - 171"},"PeriodicalIF":1.2,"publicationDate":"2021-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1909420","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45533208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-04-08DOI: 10.1080/23808993.2021.1903314
K. Miura, N. Iriyama, Y. Hatta, M. Takei
ABSTRACT Introduction Whereas most patients with aggressive hematological malignancies can achieve disease remission after receiving current standard first-line chemotherapies, the prognosis of those with primary refractory disease remains poor. Conventional salvage chemotherapies are usually unsuccessful, but significant advances have been achieved in precision medicine for these patients in recent years. Areas covered This article presents a comprehensive review of current personalized care for patients with primary refractory aggressive hematological malignancies, focusing on acute leukemias and aggressive non-Hodgkin lymphomas. Expert opinions Salvage treatment for refractory acute myeloid leukemia (AML) should be personalized by the FMS-like tyrosine kinase 3 (FLT3) mutation status. Additionally, treatment for isocitrate dehydrogenase 1 or 2 (IDH1/2)-mutated refractory AML can be specified. Inotuzumab ozogamicin and blinatumomab are essential drugs for refractory B-cell acute lymphoblastic leukemia. These antibodies can be selected based on the disease status, such as measurable residual disease. For refractory diffuse large B-cell lymphoma, treatment options are different according to the cell-of-origin. Finally, accurate pathological phenotyping is an essential first step to optimize refractory peripheral T-cell lymphoma treatment. Although novel personalized approaches have improved the clinical outcomes of these patients, consolidation with hematopoietic stem cell transplantation has a vital role in most cases.
{"title":"Personalized patient care with aggressive hematological malignancies in non-responders to first-line treatment","authors":"K. Miura, N. Iriyama, Y. Hatta, M. Takei","doi":"10.1080/23808993.2021.1903314","DOIUrl":"https://doi.org/10.1080/23808993.2021.1903314","url":null,"abstract":"ABSTRACT Introduction Whereas most patients with aggressive hematological malignancies can achieve disease remission after receiving current standard first-line chemotherapies, the prognosis of those with primary refractory disease remains poor. Conventional salvage chemotherapies are usually unsuccessful, but significant advances have been achieved in precision medicine for these patients in recent years. Areas covered This article presents a comprehensive review of current personalized care for patients with primary refractory aggressive hematological malignancies, focusing on acute leukemias and aggressive non-Hodgkin lymphomas. Expert opinions Salvage treatment for refractory acute myeloid leukemia (AML) should be personalized by the FMS-like tyrosine kinase 3 (FLT3) mutation status. Additionally, treatment for isocitrate dehydrogenase 1 or 2 (IDH1/2)-mutated refractory AML can be specified. Inotuzumab ozogamicin and blinatumomab are essential drugs for refractory B-cell acute lymphoblastic leukemia. These antibodies can be selected based on the disease status, such as measurable residual disease. For refractory diffuse large B-cell lymphoma, treatment options are different according to the cell-of-origin. Finally, accurate pathological phenotyping is an essential first step to optimize refractory peripheral T-cell lymphoma treatment. Although novel personalized approaches have improved the clinical outcomes of these patients, consolidation with hematopoietic stem cell transplantation has a vital role in most cases.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"203 - 215"},"PeriodicalIF":1.2,"publicationDate":"2021-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1903314","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42194701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-03-31DOI: 10.1080/23808993.2021.1910023
A. Rizzo, A. Ricci, G. Brandi
Cholangiocarcinomas (CCAs) are rare and aggressive tumors accounting for less than 1% of all malignancies worldwide and approximately the 10–15% of all primary liver cancers [1]. Unfortunately, advanced CCA carries a poor prognosis and the benefit provided from systemic treatments is modest [2]. In the last decade, CCA has emerged as a disease entity presenting several potentially druggable mutations, and the advent of next-generation sequencing (NGS) has led to a new era in CCA management [3]. In fact, a number of potential therapeutic targets have been described, including fibroblast growth factor receptor (FGFR) fusions, isocitrate dehydrogenase (IDH)-1 and IDH-2 mutations, and BRAF mutations [4]. In particular, some molecularly targeted treatments have been shown to improve progression-free survival (PFS) and overall survival (OS), with these therapies that add to the armamentarium of therapeutic options currently available for CCA patients [5]. Few data are available on the putative role of other molecular aberrations which have already provided interesting results in other solid tumors, including neurotrophic tropomyosin receptor kinase (NTRK) fusions. Several genes have been suggested to represent fusions partner of NTRK, including the transcription factor ETV6 and BCAN. Notably enough, NTRK1, NTRK2, and NTRK3 gene fusions have been suggested to act as oncogenic drivers in a range of solid tumors, including gastrointestinal cancers such as CCA [6]; these fusions have been highlighted in around 1% of all pediatric and adult malignancies, with recent studies suggesting their role as promising therapeutic targets for anticancer treatment [7]. In particular, the frequency of these fusions seems to vary from less than 1% in cancer types such as colorectal, lung, pancreatic, breast cancers, melanoma and other hematological and solid tumors, up to 25% in tumors including thyroid, spitzoid, and gastrointestinal stromal tumors, to more than 90% in rare cancer types such as secretory breast carcinoma, mammary analogue secretory carcinoma, congenital infantile fibrosarcoma, and congenital mesoblastic nephroma [6–8]. Typically, these molecular aberrations occur following the fusion of the C-terminal tyrosine kinase with a N-terminal fusion partner, leading to ligand-independent phosphorylation. Consequently, several pathways are activated, resulting in cellular growth and increase proliferation [8]. In recent years, several methods have been used to diagnose NTRK fusions. Among these, fluorescent in situ hybridization reverse-transcriptase PCR, and NGS; in addition, beyond tumor-based approaches, NTRK fusions can be potentially detected also through plasma-based cell-free DNA testing. As regards biliopancreatic malignancies, in a report presented at ESMO World Congress on Gastrointestinal Cancer 2020, Demols and colleagues explored the prevalence of NTRK gene fusions in 149 CCAs and pancreatic adenocarcinomas through the use of different techniques [9
{"title":"Detecting and targeting NTRK gene fusions in cholangiocarcinoma: news and perspectives","authors":"A. Rizzo, A. Ricci, G. Brandi","doi":"10.1080/23808993.2021.1910023","DOIUrl":"https://doi.org/10.1080/23808993.2021.1910023","url":null,"abstract":"Cholangiocarcinomas (CCAs) are rare and aggressive tumors accounting for less than 1% of all malignancies worldwide and approximately the 10–15% of all primary liver cancers [1]. Unfortunately, advanced CCA carries a poor prognosis and the benefit provided from systemic treatments is modest [2]. In the last decade, CCA has emerged as a disease entity presenting several potentially druggable mutations, and the advent of next-generation sequencing (NGS) has led to a new era in CCA management [3]. In fact, a number of potential therapeutic targets have been described, including fibroblast growth factor receptor (FGFR) fusions, isocitrate dehydrogenase (IDH)-1 and IDH-2 mutations, and BRAF mutations [4]. In particular, some molecularly targeted treatments have been shown to improve progression-free survival (PFS) and overall survival (OS), with these therapies that add to the armamentarium of therapeutic options currently available for CCA patients [5]. Few data are available on the putative role of other molecular aberrations which have already provided interesting results in other solid tumors, including neurotrophic tropomyosin receptor kinase (NTRK) fusions. Several genes have been suggested to represent fusions partner of NTRK, including the transcription factor ETV6 and BCAN. Notably enough, NTRK1, NTRK2, and NTRK3 gene fusions have been suggested to act as oncogenic drivers in a range of solid tumors, including gastrointestinal cancers such as CCA [6]; these fusions have been highlighted in around 1% of all pediatric and adult malignancies, with recent studies suggesting their role as promising therapeutic targets for anticancer treatment [7]. In particular, the frequency of these fusions seems to vary from less than 1% in cancer types such as colorectal, lung, pancreatic, breast cancers, melanoma and other hematological and solid tumors, up to 25% in tumors including thyroid, spitzoid, and gastrointestinal stromal tumors, to more than 90% in rare cancer types such as secretory breast carcinoma, mammary analogue secretory carcinoma, congenital infantile fibrosarcoma, and congenital mesoblastic nephroma [6–8]. Typically, these molecular aberrations occur following the fusion of the C-terminal tyrosine kinase with a N-terminal fusion partner, leading to ligand-independent phosphorylation. Consequently, several pathways are activated, resulting in cellular growth and increase proliferation [8]. In recent years, several methods have been used to diagnose NTRK fusions. Among these, fluorescent in situ hybridization reverse-transcriptase PCR, and NGS; in addition, beyond tumor-based approaches, NTRK fusions can be potentially detected also through plasma-based cell-free DNA testing. As regards biliopancreatic malignancies, in a report presented at ESMO World Congress on Gastrointestinal Cancer 2020, Demols and colleagues explored the prevalence of NTRK gene fusions in 149 CCAs and pancreatic adenocarcinomas through the use of different techniques [9","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"225 - 227"},"PeriodicalIF":1.2,"publicationDate":"2021-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1910023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49594347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-03-11DOI: 10.1080/23808993.2021.1897464
H. Reikvam, Silje Johansen, C. Koenecke
Acute myelogenous leukemia (AML) is a malignant disease of the blood and bone marrow, characterized by proliferation, lack of apoptosis, and block in differentiation of leukemic blasts [1]. These immature cells compromise normal bone marrow function, resulting in severe bone marrow failure, with anemia, thrombocytopenia, and granulocytopenia [1]. The disease has a highly malignant and aggressive course, and without treatment the patients will usually die within weeks to months. Except for promyelocytic AML, the only possibility for a longtime cure is intensive chemotherapy, and in high-risk patients combined with allogenic hematopoietic stem cell transplantation (allo-HSCT) [1,2]. Allo-HSCT is the most potent antileukemic treatment, by utilization of the immune mediated graft versus leukemia (GVL) effect derived from immune competent donor cells. However, alloHSCT is associated with a high degree of morbidity and mortality, especially due to severe graft versus host disease (GVHD). Furthermore, the occurrence of relapse of the disease even after transplantation is still prevalent, especially for patients present with genetic markers associated with inferior prognosis at the time of diagnosis [2,3]. In the following, we will discuss the current and future aspects of allo-HSCT in the setting of AML, untangling the possibilities to optimize the treatment approaches based on precision medicine.
{"title":"Future perspective: precision medicine to improve treatment results in the settings of allogenic stem cell transplantation for acute myelogenous leukemia","authors":"H. Reikvam, Silje Johansen, C. Koenecke","doi":"10.1080/23808993.2021.1897464","DOIUrl":"https://doi.org/10.1080/23808993.2021.1897464","url":null,"abstract":"Acute myelogenous leukemia (AML) is a malignant disease of the blood and bone marrow, characterized by proliferation, lack of apoptosis, and block in differentiation of leukemic blasts [1]. These immature cells compromise normal bone marrow function, resulting in severe bone marrow failure, with anemia, thrombocytopenia, and granulocytopenia [1]. The disease has a highly malignant and aggressive course, and without treatment the patients will usually die within weeks to months. Except for promyelocytic AML, the only possibility for a longtime cure is intensive chemotherapy, and in high-risk patients combined with allogenic hematopoietic stem cell transplantation (allo-HSCT) [1,2]. Allo-HSCT is the most potent antileukemic treatment, by utilization of the immune mediated graft versus leukemia (GVL) effect derived from immune competent donor cells. However, alloHSCT is associated with a high degree of morbidity and mortality, especially due to severe graft versus host disease (GVHD). Furthermore, the occurrence of relapse of the disease even after transplantation is still prevalent, especially for patients present with genetic markers associated with inferior prognosis at the time of diagnosis [2,3]. In the following, we will discuss the current and future aspects of allo-HSCT in the setting of AML, untangling the possibilities to optimize the treatment approaches based on precision medicine.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"151 - 155"},"PeriodicalIF":1.2,"publicationDate":"2021-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1897464","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46736678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：