Pub Date : 2022-01-02DOI: 10.1080/23808993.2022.2053285
Aurino M. Kemas, Sonia Youhanna, V. Lauschke
ABSTRACT Introduction Non-alcoholic fatty liver disease (NAFLD) constitutes a highly prevalent liver disorder whose rise in prevalence is closely connected to the growing rates of obesity, dyslipidemia, and type 2 diabetes. Importantly, kinetics and likelihood of NAFLD onset and its progression to non-alcoholic steatohepatitis (NASH) and fibrosis differs considerably between individuals. In recent years, the understanding of NAFLD pathogenesis has increased substantially and a multitude of factors, genetic predispositions, molecular signatures or NAFLD-related liver injury and comorbidities have been identified. Areas Covered This article summarizes inter-individual differences in NAFLD, including genetic variations, epigenetic and metabolic alterations and differences in the microbiome. We also discuss how these features might be leveraged for treatment personalization. Expert opinion The complexity and heterogeneity of NAFLD provides considerable challenges for drug developers and has resulted in numerous costly project failures. We expect that increased knowledge and appreciation of patient-specific factors will facilitate better patient stratification and identification of those individuals that benefit most from a given therapeutic strategy. Furthermore, we anticipate that pathophysiologically relevant in vivo and ex vivo disease models as well as large-scale chemogenomic projects hold promise to drastically improve NAFLD drug development to complement lifestyle and surgical interventions with pharmacological approaches.
{"title":"Non-alcoholic fatty liver disease - opportunities for personalized treatment and drug development","authors":"Aurino M. Kemas, Sonia Youhanna, V. Lauschke","doi":"10.1080/23808993.2022.2053285","DOIUrl":"https://doi.org/10.1080/23808993.2022.2053285","url":null,"abstract":"ABSTRACT Introduction Non-alcoholic fatty liver disease (NAFLD) constitutes a highly prevalent liver disorder whose rise in prevalence is closely connected to the growing rates of obesity, dyslipidemia, and type 2 diabetes. Importantly, kinetics and likelihood of NAFLD onset and its progression to non-alcoholic steatohepatitis (NASH) and fibrosis differs considerably between individuals. In recent years, the understanding of NAFLD pathogenesis has increased substantially and a multitude of factors, genetic predispositions, molecular signatures or NAFLD-related liver injury and comorbidities have been identified. Areas Covered This article summarizes inter-individual differences in NAFLD, including genetic variations, epigenetic and metabolic alterations and differences in the microbiome. We also discuss how these features might be leveraged for treatment personalization. Expert opinion The complexity and heterogeneity of NAFLD provides considerable challenges for drug developers and has resulted in numerous costly project failures. We expect that increased knowledge and appreciation of patient-specific factors will facilitate better patient stratification and identification of those individuals that benefit most from a given therapeutic strategy. Furthermore, we anticipate that pathophysiologically relevant in vivo and ex vivo disease models as well as large-scale chemogenomic projects hold promise to drastically improve NAFLD drug development to complement lifestyle and surgical interventions with pharmacological approaches.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"7 1","pages":"39 - 49"},"PeriodicalIF":1.2,"publicationDate":"2022-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43318378","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 : 2022-01-02DOI: 10.1080/23808993.2022.2095903
Alessandro Rizzo, Alessandro Di Federico, G. Palmiotti, G. Brandi
Biliary tract cancers (BTCs) encompass a heterogeneous group of rare malignancies accounting for approximately the 10–15% of primary liver cancers [1]. Most of these hepatobiliary tumors are diagnosed at a metastatic stage, and more than a decade after the publication of the ABC-02 trial establishing gemcitabine plus cisplatin as front-line standard for metastatic BTC, the prognosis of this patient population remains grim [2]. BTC include intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), and gallbladder carcinoma (GBC); recent years have registered that the incidence of BTC has progressively increased worldwide, and a proportion of cases ranging from 60% to 70% is diagnosed with advanced stage – locally advanced or metastatic disease. Surgical resection represents the only potentially curative treatment option for BTC patients, but even following radical surgery with curative intent, 5-year overall survival (OS) is only 20–35%. Systemic treatment options for BTC are limited, and more than a decade after the practice-changing ABC-02 phase III trial, cisplatin-gemcitabine remains the standard first-line therapy for patients with metastatic disease. Recent years have witnessed the advent of molecular profiling in this setting, and new techniques and technologies have led to the identification of several molecular alterations in BTC [3]. Thus, precision oncology approaches have been widely evaluated and are currently under assessment in BTC patients, as shown by the recent development of a wide range of agents targeting Fibroblast Growth Factor Receptor (FGFR) 2, Isocitrate Dehydrogenase 1 (IDH-1), and BRAF [4–6]. However, a number of molecularly targeted therapies, including antiangiogenic agents, have shown limited efficacy in BTC, and several questions regarding the effective role of these anticancer treatments remain unanswered. A recently published phase 2 trial has evaluated the addition of ramucirumab or merestinib to first-line cisplatin-gemcitabine, reporting no improvement of progression-free survival (PFS) in patients with locally advanced or metastatic BTC [7]. Ramucirumab is a fully humanized monoclonal antibody with a high binding affinity for the extracellular domain of VEGFR-2, with preclinical studies showing that targeting of this VEGF family receptor was associated with inhibition of VEGF-mediated signaling, proliferation and migration of human endothelial cells, and antitumor activity in animal models. Conversely, merestinib is a small molecule inhibitor of MET and several other receptor tyrosine kinases such as MST1R, FLT3, AXL, MERTK, TEK, ROS1, NTRK1/2/3, and DDR1/2. Aiming to interpret the results of the study conducted by Valle and colleagues, some comments come to mind. First, the rationale for this international, double-blind, phase 2 study regarding antiangiogenic agents was probably based on the limited availability of treatments in advanced BTC at the time this trial was designed. Several st
{"title":"Ramucirumab or merestinib in biliary tract cancer: new combinations, old mistakes?","authors":"Alessandro Rizzo, Alessandro Di Federico, G. Palmiotti, G. Brandi","doi":"10.1080/23808993.2022.2095903","DOIUrl":"https://doi.org/10.1080/23808993.2022.2095903","url":null,"abstract":"Biliary tract cancers (BTCs) encompass a heterogeneous group of rare malignancies accounting for approximately the 10–15% of primary liver cancers [1]. Most of these hepatobiliary tumors are diagnosed at a metastatic stage, and more than a decade after the publication of the ABC-02 trial establishing gemcitabine plus cisplatin as front-line standard for metastatic BTC, the prognosis of this patient population remains grim [2]. BTC include intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), and gallbladder carcinoma (GBC); recent years have registered that the incidence of BTC has progressively increased worldwide, and a proportion of cases ranging from 60% to 70% is diagnosed with advanced stage – locally advanced or metastatic disease. Surgical resection represents the only potentially curative treatment option for BTC patients, but even following radical surgery with curative intent, 5-year overall survival (OS) is only 20–35%. Systemic treatment options for BTC are limited, and more than a decade after the practice-changing ABC-02 phase III trial, cisplatin-gemcitabine remains the standard first-line therapy for patients with metastatic disease. Recent years have witnessed the advent of molecular profiling in this setting, and new techniques and technologies have led to the identification of several molecular alterations in BTC [3]. Thus, precision oncology approaches have been widely evaluated and are currently under assessment in BTC patients, as shown by the recent development of a wide range of agents targeting Fibroblast Growth Factor Receptor (FGFR) 2, Isocitrate Dehydrogenase 1 (IDH-1), and BRAF [4–6]. However, a number of molecularly targeted therapies, including antiangiogenic agents, have shown limited efficacy in BTC, and several questions regarding the effective role of these anticancer treatments remain unanswered. A recently published phase 2 trial has evaluated the addition of ramucirumab or merestinib to first-line cisplatin-gemcitabine, reporting no improvement of progression-free survival (PFS) in patients with locally advanced or metastatic BTC [7]. Ramucirumab is a fully humanized monoclonal antibody with a high binding affinity for the extracellular domain of VEGFR-2, with preclinical studies showing that targeting of this VEGF family receptor was associated with inhibition of VEGF-mediated signaling, proliferation and migration of human endothelial cells, and antitumor activity in animal models. Conversely, merestinib is a small molecule inhibitor of MET and several other receptor tyrosine kinases such as MST1R, FLT3, AXL, MERTK, TEK, ROS1, NTRK1/2/3, and DDR1/2. Aiming to interpret the results of the study conducted by Valle and colleagues, some comments come to mind. First, the rationale for this international, double-blind, phase 2 study regarding antiangiogenic agents was probably based on the limited availability of treatments in advanced BTC at the time this trial was designed. Several st","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"7 1","pages":"60 - 61"},"PeriodicalIF":1.2,"publicationDate":"2022-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44903206","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 : 2022-01-02DOI: 10.1080/23808993.2022.2038562
S. Arifi
ABSTRACT Introduction Soft tissue sarcomas (STS) are a rare and heterogeneous group of tumors. The role of molecular testing to inform diagnosis, disease prognosis, and therapy has become critical to optimal treatment. Areas covered This review reports updated data on precision therapy in patients with STS, particularly those of immediate utility in clinical practice. Expert opinion There is a high unmet need for effective systemic therapy for patients with STS. In the era of precision medicine, doxorubicin-based chemotherapy is still the standard of care in first-line treatment for the majority of histologic subtypes with a median overall survival of only 20 months. Precision therapy for STS has only been partially effective. A new wave of targeted therapeutic agents has been approved with preferential benefit in subgroups of patients. Immunotherapy is now undergoing clinical trials. There is a heterogeneity in the benefit of immune checkpoint inhibitors across subtypes. Strategies targeted to antigen bearing sarcomas including vaccine and adoptive T-cell have yielded promising results in selected histotypes.
{"title":"Personalised pharmacotherapy options for soft tissue sarcomas","authors":"S. Arifi","doi":"10.1080/23808993.2022.2038562","DOIUrl":"https://doi.org/10.1080/23808993.2022.2038562","url":null,"abstract":"ABSTRACT Introduction Soft tissue sarcomas (STS) are a rare and heterogeneous group of tumors. The role of molecular testing to inform diagnosis, disease prognosis, and therapy has become critical to optimal treatment. Areas covered This review reports updated data on precision therapy in patients with STS, particularly those of immediate utility in clinical practice. Expert opinion There is a high unmet need for effective systemic therapy for patients with STS. In the era of precision medicine, doxorubicin-based chemotherapy is still the standard of care in first-line treatment for the majority of histologic subtypes with a median overall survival of only 20 months. Precision therapy for STS has only been partially effective. A new wave of targeted therapeutic agents has been approved with preferential benefit in subgroups of patients. Immunotherapy is now undergoing clinical trials. There is a heterogeneity in the benefit of immune checkpoint inhibitors across subtypes. Strategies targeted to antigen bearing sarcomas including vaccine and adoptive T-cell have yielded promising results in selected histotypes.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"7 1","pages":"17 - 28"},"PeriodicalIF":1.2,"publicationDate":"2022-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49556230","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 : 2022-01-02DOI: 10.1080/23808993.2022.2106852
J. Kratz, Wei Zhang, M. Patel, N. Uboha
ABSTRACT Introduction The goal of precision oncology is to match each patient with the most appropriate therapeutic agent based on patient- and tumor-specific characteristics. Many therapeutics in development target tumors with specific biomarkers, in addition to considering tumor histologic classification and clinical presentation. Areas Covered Appropriate patient selection for research studies is critical to elucidate the potential effectiveness of therapies in development, as well as to spare the toxicities from ineffective therapies in patients who are unlikely to benefit. Biomarker-based clinical studies provide a platform to bring forward the expanse of therapeutics beyond the use of chemotherapy, including novel immunotherapeutic and targeted strategies. There are a number of issues to be considered when developing these types of studies. They range from biomarker validity to patient enrollment and trial availability. In this review, we discuss challenges that are frequently confronted in the design, enrollment, and analysis of biomarker-based clinical trials for patients with gastrointestinal (GI) cancers. Expert opinion The challenges encountered in biomarker-based trials for patients with GI cancers must be considered and addressed early during drug development to ensure proper therapy and patient selection in a timeframe acceptable for both patient diseases and rapidly changing oncology standards.
{"title":"Challenges in biomarker-based clinical trials for patients with gastrointestinal malignancies","authors":"J. Kratz, Wei Zhang, M. Patel, N. Uboha","doi":"10.1080/23808993.2022.2106852","DOIUrl":"https://doi.org/10.1080/23808993.2022.2106852","url":null,"abstract":"ABSTRACT Introduction The goal of precision oncology is to match each patient with the most appropriate therapeutic agent based on patient- and tumor-specific characteristics. Many therapeutics in development target tumors with specific biomarkers, in addition to considering tumor histologic classification and clinical presentation. Areas Covered Appropriate patient selection for research studies is critical to elucidate the potential effectiveness of therapies in development, as well as to spare the toxicities from ineffective therapies in patients who are unlikely to benefit. Biomarker-based clinical studies provide a platform to bring forward the expanse of therapeutics beyond the use of chemotherapy, including novel immunotherapeutic and targeted strategies. There are a number of issues to be considered when developing these types of studies. They range from biomarker validity to patient enrollment and trial availability. In this review, we discuss challenges that are frequently confronted in the design, enrollment, and analysis of biomarker-based clinical trials for patients with gastrointestinal (GI) cancers. Expert opinion The challenges encountered in biomarker-based trials for patients with GI cancers must be considered and addressed early during drug development to ensure proper therapy and patient selection in a timeframe acceptable for both patient diseases and rapidly changing oncology standards.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"7 1","pages":"121 - 130"},"PeriodicalIF":1.2,"publicationDate":"2022-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48204554","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 : 2022-01-01DOI: 10.1080/23808993.2022.2028548
Jane A Leopold
Introduction: Cardiovascular disease persists as the leading cause of death worldwide despite continued advances in diagnostics and therapeutics. Our current approach to patients with cardiovascular disease is rooted in reductionism, which presupposes that all patients share a similar phenotype and will respond the same to therapy; however, this is unlikely as cardiovascular diseases exhibit complex heterogeneous phenotypes.
Areas covered: With the advent of high-throughput platforms for omics testing, phenotyping cardiovascular diseases has advanced to incorporate large-scale molecular data with classical history, physical examination, and laboratory results. Findings from genomics, proteomics, and metabolomics profiling have been used to define more precise cardiovascular phenotypes and predict adverse outcomes in population-based and disease-specific patient cohorts. These molecular data have also been utilized to inform drug efficacy based on a patient's unique phenotype.
Expert opinion: Multiscale phenotyping of cardiovascular disease has revealed diversity among patients that can be used to personalize pharmacotherapies and predict outcomes. Nonetheless, precision phenotyping for cardiovascular disease remains a nascent field that has not yet translated into widespread clinical practice despite its many potential advantages for patient care. Future endeavors that demonstrate improved pharmacotherapeutic responses and associated reduction in adverse events will facilitate mainstream adoption of precision cardiovascular phenotyping.
{"title":"Personalizing treatments for patients based on cardiovascular phenotyping.","authors":"Jane A Leopold","doi":"10.1080/23808993.2022.2028548","DOIUrl":"https://doi.org/10.1080/23808993.2022.2028548","url":null,"abstract":"<p><strong>Introduction: </strong>Cardiovascular disease persists as the leading cause of death worldwide despite continued advances in diagnostics and therapeutics. Our current approach to patients with cardiovascular disease is rooted in reductionism, which presupposes that all patients share a similar phenotype and will respond the same to therapy; however, this is unlikely as cardiovascular diseases exhibit complex heterogeneous phenotypes.</p><p><strong>Areas covered: </strong>With the advent of high-throughput platforms for omics testing, phenotyping cardiovascular diseases has advanced to incorporate large-scale molecular data with classical history, physical examination, and laboratory results. Findings from genomics, proteomics, and metabolomics profiling have been used to define more precise cardiovascular phenotypes and predict adverse outcomes in population-based and disease-specific patient cohorts. These molecular data have also been utilized to inform drug efficacy based on a patient's unique phenotype.</p><p><strong>Expert opinion: </strong>Multiscale phenotyping of cardiovascular disease has revealed diversity among patients that can be used to personalize pharmacotherapies and predict outcomes. Nonetheless, precision phenotyping for cardiovascular disease remains a nascent field that has not yet translated into widespread clinical practice despite its many potential advantages for patient care. Future endeavors that demonstrate improved pharmacotherapeutic responses and associated reduction in adverse events will facilitate mainstream adoption of precision cardiovascular phenotyping.</p>","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"7 1","pages":"4-16"},"PeriodicalIF":1.2,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913616/pdf/nihms-1772637.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10698029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-12-27DOI: 10.1080/23808993.2022.2020091
A. Rizzo, A. Ricci, G. Brandi
The phase III IMbrave150 trial evaluating the combination of the PD-L1 inhibitor atezolizumab plus bevacizumab has recently represented an important step forward in the medical management of HCC [1]. According to the results of this study, advanced HCC patients receiving atezolizumab – bevacizumab reported statistically significant and clinically meaningful improvements in terms of overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and complete response rate, compared with sorafenib monotherapy [2,3]. Of note, immunotherapy seems to have find its role in the management of HCC as part of combinatorial strategies, as also witnessed by the recently published results of the phase I/II HIMALAYA trial [4]. In addition, an interesting line of research currently concerns the addition of locoregional therapies to immune checkpoint inhibitors, in order to produce a synergistic effect and improve clinical outcomes [5]. Locoregional treatments, including transarterial chemoembolization (TACE), radiofrequency ablation (RFA), selective internal radiation therapy (SIRT), and stereotactic body radiotherapy (SBRT), are considered of pivotal importance in the management of HCC patients [6]. These approaches are currently under evaluation in combination with immunotherapy, since locoregional therapies not only attack primary tumors but have been also suggested to boost antitumor immunity though the release of neoplasm antigens [7]. Recent years have seen the presentation or publication of several clinical trials combining immune checkpoint inhibitors with locoregional treatments (Table 1). A phase I/II trial published by Duffy and colleagues investigated the role of the combination of the CTLA-4 inhibitor tremelimumab plus TACE or RFA in Barcelona Clinic Liver Cancer (BCLC) Stage B and C HCC patients [8]. According to the results of this study, partial response (PR) was observed in 26.3% of cases, with 6-month PFS of 57.1% and median OS of 12.3 months (95% CI, 9.3–15.4). An interesting finding of this study concerns the HCVpositive population, with 12 of 14 HCC patients experiencing a notable reduction in viral load and a dramatical increase in CD8 + T cells reported in tumor biopsies after 6 weeks [8]. In another phase II trial conducted by Zhao and colleagues, the authors evaluated the role of thermal ablation plus a PD-1 inhibitor (pembrolizumab or nivolumab or JS001) in 50 HCC patients [9]. Median PFS, median Time to Progression (TTP), and median OS were 5 months (95% CI, 2.9–7.1), 6.1 months (95% CI, 2.6–11.2), and 16.9 months (95% CI, 7.7–26.1), respectively [9]. Another strategy under assessment is based on the combination of TACE plus immunotherapy. With efficacy data still pending, the preliminary results of the PETAL phase I/II study on conventional TACE followed by the PD-1 inhibitor pembrolizumab reported an acceptable safety profile for this combination [10]. Similarly, the IMMUTACE phase II trial is investigating the
{"title":"Combining immune checkpoint inhibitors with locoregional therapies in hepatocellular carcinoma","authors":"A. Rizzo, A. Ricci, G. Brandi","doi":"10.1080/23808993.2022.2020091","DOIUrl":"https://doi.org/10.1080/23808993.2022.2020091","url":null,"abstract":"The phase III IMbrave150 trial evaluating the combination of the PD-L1 inhibitor atezolizumab plus bevacizumab has recently represented an important step forward in the medical management of HCC [1]. According to the results of this study, advanced HCC patients receiving atezolizumab – bevacizumab reported statistically significant and clinically meaningful improvements in terms of overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and complete response rate, compared with sorafenib monotherapy [2,3]. Of note, immunotherapy seems to have find its role in the management of HCC as part of combinatorial strategies, as also witnessed by the recently published results of the phase I/II HIMALAYA trial [4]. In addition, an interesting line of research currently concerns the addition of locoregional therapies to immune checkpoint inhibitors, in order to produce a synergistic effect and improve clinical outcomes [5]. Locoregional treatments, including transarterial chemoembolization (TACE), radiofrequency ablation (RFA), selective internal radiation therapy (SIRT), and stereotactic body radiotherapy (SBRT), are considered of pivotal importance in the management of HCC patients [6]. These approaches are currently under evaluation in combination with immunotherapy, since locoregional therapies not only attack primary tumors but have been also suggested to boost antitumor immunity though the release of neoplasm antigens [7]. Recent years have seen the presentation or publication of several clinical trials combining immune checkpoint inhibitors with locoregional treatments (Table 1). A phase I/II trial published by Duffy and colleagues investigated the role of the combination of the CTLA-4 inhibitor tremelimumab plus TACE or RFA in Barcelona Clinic Liver Cancer (BCLC) Stage B and C HCC patients [8]. According to the results of this study, partial response (PR) was observed in 26.3% of cases, with 6-month PFS of 57.1% and median OS of 12.3 months (95% CI, 9.3–15.4). An interesting finding of this study concerns the HCVpositive population, with 12 of 14 HCC patients experiencing a notable reduction in viral load and a dramatical increase in CD8 + T cells reported in tumor biopsies after 6 weeks [8]. In another phase II trial conducted by Zhao and colleagues, the authors evaluated the role of thermal ablation plus a PD-1 inhibitor (pembrolizumab or nivolumab or JS001) in 50 HCC patients [9]. Median PFS, median Time to Progression (TTP), and median OS were 5 months (95% CI, 2.9–7.1), 6.1 months (95% CI, 2.6–11.2), and 16.9 months (95% CI, 7.7–26.1), respectively [9]. Another strategy under assessment is based on the combination of TACE plus immunotherapy. With efficacy data still pending, the preliminary results of the PETAL phase I/II study on conventional TACE followed by the PD-1 inhibitor pembrolizumab reported an acceptable safety profile for this combination [10]. Similarly, the IMMUTACE phase II trial is investigating the","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"7 1","pages":"1 - 3"},"PeriodicalIF":1.2,"publicationDate":"2021-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42826751","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 : 2021-11-29DOI: 10.1080/23808993.2021.2008144
A. Rizzo, A. Ricci, G. Gadaleta-Caldarola, G. Brandi
Cholangiocarcinomas (CCAs) include a heterogeneous group of hepatobiliary tumors accounting for approximately the 10–15% of primary liver cancers [1]. Unfortunately, most of these tumors are diagnosed at an advanced stage, and more than ten years after the publication of the landmark phase III ABC-02 trial establishing gemcitabine-cisplatin as first-line standard for metastatic CCA, the prognosis of this patient population remains grim [2]. In fact, most of patients treated with front-line treatment fail to achieve a response or responses are short lived [3]. Recent years have witnessed the advent of molecular profiling in this setting, and new techniques and technologies have led to the identification of a variety of molecular alterations in CCA [4]. Over the last decade, several potentially actionable genetic aberrations have been highlighted, and precision oncology approaches have been evaluated and are under investigation in these hepatobiliary malignancies (Figure 1). A large number of anticancer agents are currently in development, including Fibroblast Growth Factor Receptor (FGFR) 2, Isocitrate Dehydrogenase 1 (IDH-1), and BRAF inhibitors [5]. FGFR2 aberrations have been reported in approximately the 20% of intrahepatic cholangiocarcinomas (iCCAs), with these alterations highlighted as most common in female patients and young adults [6]. Of note, FGFR2 aberrations are mainly represented by fusions, while mutations are detected only in a minority of patients. As regards IDH-1, missense mutations are the most frequent aberrations, involving a single residue in the active site of the enzyme [7]; typically, IDH-1 missense mutations have been reported to be more common in small duct type iCCAs and in poorly differentiated or undifferentiated forms [8]. Several other molecular aberrations have been observed in CCA patients, including BRCA mutations, NTRK fusions, and BRAF V600E mutations [9,10]. Nonetheless, several questions remain unanswered, and the adoption of precision oncology in CCA patients remains still far from everyday clinical practice, with some important exceptions. Among current obstacles, a crucial point to highlight is the limited access to anticancer treatments. For example, although the final overall survival (OS) analysis of the ClarIDHy phase III trial has been presented and on 25 August 2021 the FDA approved ivosidenib use in IDH-1 mutant iCCA, the IDH-1 inhibitor is not available in several countries, according to different choices by the regulatory agencies [11]. Second, biopsy samples are often inadequate for molecular profiling since tissue sampling has reported low sensitivity in the diagnosis of malignant biliary strictures; in fact, the highly desmoplastic nature of CCA severely limits the accuracy of pathological and cytological methodologies. On the basis of these premises, it is urgent to develop in this scenario novel strategies aimed at anticipating the diagnosis by detecting CCA at an early, resectable stage, a
{"title":"Precision oncology in cholangiocarcinoma: current issues in clinical trial design and access to targeted therapies","authors":"A. Rizzo, A. Ricci, G. Gadaleta-Caldarola, G. Brandi","doi":"10.1080/23808993.2021.2008144","DOIUrl":"https://doi.org/10.1080/23808993.2021.2008144","url":null,"abstract":"Cholangiocarcinomas (CCAs) include a heterogeneous group of hepatobiliary tumors accounting for approximately the 10–15% of primary liver cancers [1]. Unfortunately, most of these tumors are diagnosed at an advanced stage, and more than ten years after the publication of the landmark phase III ABC-02 trial establishing gemcitabine-cisplatin as first-line standard for metastatic CCA, the prognosis of this patient population remains grim [2]. In fact, most of patients treated with front-line treatment fail to achieve a response or responses are short lived [3]. Recent years have witnessed the advent of molecular profiling in this setting, and new techniques and technologies have led to the identification of a variety of molecular alterations in CCA [4]. Over the last decade, several potentially actionable genetic aberrations have been highlighted, and precision oncology approaches have been evaluated and are under investigation in these hepatobiliary malignancies (Figure 1). A large number of anticancer agents are currently in development, including Fibroblast Growth Factor Receptor (FGFR) 2, Isocitrate Dehydrogenase 1 (IDH-1), and BRAF inhibitors [5]. FGFR2 aberrations have been reported in approximately the 20% of intrahepatic cholangiocarcinomas (iCCAs), with these alterations highlighted as most common in female patients and young adults [6]. Of note, FGFR2 aberrations are mainly represented by fusions, while mutations are detected only in a minority of patients. As regards IDH-1, missense mutations are the most frequent aberrations, involving a single residue in the active site of the enzyme [7]; typically, IDH-1 missense mutations have been reported to be more common in small duct type iCCAs and in poorly differentiated or undifferentiated forms [8]. Several other molecular aberrations have been observed in CCA patients, including BRCA mutations, NTRK fusions, and BRAF V600E mutations [9,10]. Nonetheless, several questions remain unanswered, and the adoption of precision oncology in CCA patients remains still far from everyday clinical practice, with some important exceptions. Among current obstacles, a crucial point to highlight is the limited access to anticancer treatments. For example, although the final overall survival (OS) analysis of the ClarIDHy phase III trial has been presented and on 25 August 2021 the FDA approved ivosidenib use in IDH-1 mutant iCCA, the IDH-1 inhibitor is not available in several countries, according to different choices by the regulatory agencies [11]. Second, biopsy samples are often inadequate for molecular profiling since tissue sampling has reported low sensitivity in the diagnosis of malignant biliary strictures; in fact, the highly desmoplastic nature of CCA severely limits the accuracy of pathological and cytological methodologies. On the basis of these premises, it is urgent to develop in this scenario novel strategies aimed at anticipating the diagnosis by detecting CCA at an early, resectable stage, a","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"7 1","pages":"102 - 104"},"PeriodicalIF":1.2,"publicationDate":"2021-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42393575","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 : 2021-11-15DOI: 10.1080/23808993.2021.1994186
K. Blum, P. Thanos, Gene-Jack Wang, A. Bowirrat, Luis Llanos Gomez, D. Baron, Rehan Jalali, M. Gondré-Lewis, M. Gold
ABSTRACT Introduction Eating Disorders and Obesity are a primary global public health concern. Areas Covered This article aims to trace the neurochemical mechanisms of unwanted eating disorders and target specific loci, within the Brain Reward Cascade (BRC) for therapeutic interventions. Changes due to BRC polymorphisms in functional connectivity and neurotransmission can manifest as overeating, Bulimia Nervosa, and Anorexia Nervosa, and other related eating disorders. Expert opinion Variations in dopamine function within the Ventral Tegmental Area (VTA), Nucleus Accumbens (NAc), and Ventral Striatum of individuals result in different outcomes related to maladaptive eating behaviors. The goal is to reduce maladaptive eating behaviors by implementing novel strategies that induce Dopamine Homeostasis within the BRC. Clinicians determine genetic risk severity and identify polymorphic targets for either pharmaceutical or nutraceutical interventions. Precision neuro-nutrient formulations of KB220 (Research ID Code) matched precisely to deficient neurotransmitter systems may promote the long-term development of ‘dopamine homeostasis’ to treat and prevent overeating, Bulimia, and Anorexia Nervosa.
{"title":"Dopaminergic and other genes related to reward induced overeating, Bulimia, Anorexia Nervosa, and Binge eating","authors":"K. Blum, P. Thanos, Gene-Jack Wang, A. Bowirrat, Luis Llanos Gomez, D. Baron, Rehan Jalali, M. Gondré-Lewis, M. Gold","doi":"10.1080/23808993.2021.1994186","DOIUrl":"https://doi.org/10.1080/23808993.2021.1994186","url":null,"abstract":"ABSTRACT Introduction Eating Disorders and Obesity are a primary global public health concern. Areas Covered This article aims to trace the neurochemical mechanisms of unwanted eating disorders and target specific loci, within the Brain Reward Cascade (BRC) for therapeutic interventions. Changes due to BRC polymorphisms in functional connectivity and neurotransmission can manifest as overeating, Bulimia Nervosa, and Anorexia Nervosa, and other related eating disorders. Expert opinion Variations in dopamine function within the Ventral Tegmental Area (VTA), Nucleus Accumbens (NAc), and Ventral Striatum of individuals result in different outcomes related to maladaptive eating behaviors. The goal is to reduce maladaptive eating behaviors by implementing novel strategies that induce Dopamine Homeostasis within the BRC. Clinicians determine genetic risk severity and identify polymorphic targets for either pharmaceutical or nutraceutical interventions. Precision neuro-nutrient formulations of KB220 (Research ID Code) matched precisely to deficient neurotransmitter systems may promote the long-term development of ‘dopamine homeostasis’ to treat and prevent overeating, Bulimia, and Anorexia Nervosa.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"7 1","pages":"79 - 95"},"PeriodicalIF":1.2,"publicationDate":"2021-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46550213","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 : 2021-11-10DOI: 10.1080/23808993.2021.1999585
T. Hida
ABSTRACT Introduction : Clinical studies of MET-targeted treatments have so far failed to provide adequate outcomes. Capmatinib, a newly designed MET receptor inhibitor, has demonstrated considerable anticancer efficacy in patients with advanced NSCLC who have a MET exon 14 skipping mutation. Areas covered : This review offers a summary of the findings from capmatinib clinical studies in NSCLC patients with a MET exon 14 skipping mutation, as well as preclinical data and post-market reporting of capmatinib. Expert opinion : Capmatinib has a tolerable safety profile and preliminary evidence of effectiveness in patients with a MET exon 14 skipping mutation, according to data from a phase 1 clinical study. The GEOMETRY mono-1 phase 2 study revealed objective response rates of 68% and 41%, and median OS of 20.8 and 13.6 months in treatment-naive and pretreated MET exon 14 skipping mutant patients, respectively. Furthermore, capmatinib penetrates the blood–brain barrier, and capmatinib activity in the brain was shown to be encouraging in the study. However, the effectiveness of immunotherapy for MET exon 14 skipping mutation remains debatable. To enhance therapy choices, researchers have begun to focus on the mechanisms of intrinsic and acquired resistance of the MET exon 14 skipping mutation.
{"title":"A profile on capmatinib in treating adult patients with metastatic NSCLC tumors with MET exon 14 skipping mutations","authors":"T. Hida","doi":"10.1080/23808993.2021.1999585","DOIUrl":"https://doi.org/10.1080/23808993.2021.1999585","url":null,"abstract":"ABSTRACT Introduction : Clinical studies of MET-targeted treatments have so far failed to provide adequate outcomes. Capmatinib, a newly designed MET receptor inhibitor, has demonstrated considerable anticancer efficacy in patients with advanced NSCLC who have a MET exon 14 skipping mutation. Areas covered : This review offers a summary of the findings from capmatinib clinical studies in NSCLC patients with a MET exon 14 skipping mutation, as well as preclinical data and post-market reporting of capmatinib. Expert opinion : Capmatinib has a tolerable safety profile and preliminary evidence of effectiveness in patients with a MET exon 14 skipping mutation, according to data from a phase 1 clinical study. The GEOMETRY mono-1 phase 2 study revealed objective response rates of 68% and 41%, and median OS of 20.8 and 13.6 months in treatment-naive and pretreated MET exon 14 skipping mutant patients, respectively. Furthermore, capmatinib penetrates the blood–brain barrier, and capmatinib activity in the brain was shown to be encouraging in the study. However, the effectiveness of immunotherapy for MET exon 14 skipping mutation remains debatable. To enhance therapy choices, researchers have begun to focus on the mechanisms of intrinsic and acquired resistance of the MET exon 14 skipping mutation.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"7 1","pages":"96 - 101"},"PeriodicalIF":1.2,"publicationDate":"2021-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45105946","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 : 2021-11-01DOI: 10.1080/23808993.2021.1993595
L. Yasnitsky, A. Dumler, F. Cherepanov, V. L. Yasnitsky, Natalia A. Uteva
ABSTRACT Objectives Currently, there is an active use of neural networks in various areas of human activity. Problems of recognition, diagnostics, optimization, forecasting, control, as well as obtaining new scientific knowledge are successfully solved. However, in medicine, due to the particular complexity of the human body, neural networks are mainly used only for solving the simplest problems of classification and diagnostics. The purpose of this article is to show that the possibilities of neural network modeling in medicine are much wider. Methods This goal is achieved by using special mathematical techniques developed by the authors that allow us to overcome these difficulties. Results The intellectual system created in this way made it possible to reveal a number of interesting scientific knowledge, which sometimes does not coincide with the generally accepted ideas of doctors. Virtual experiments conducted on computer models of patients using our intelligent system clearly demonstrate which lifestyle and medication variations can benefit a particular patient in the long term, and which can cause harm. Conclusion Our intellectual system allows us to identify new scientific knowledge, to carry out long-term forecasting of the development of the disease, to select the optimal courses of treatment and prevention of diseases.
{"title":"Capabilities of neural network technologies for extracting new medical knowledge and enhancing precise decision making for patients","authors":"L. Yasnitsky, A. Dumler, F. Cherepanov, V. L. Yasnitsky, Natalia A. Uteva","doi":"10.1080/23808993.2021.1993595","DOIUrl":"https://doi.org/10.1080/23808993.2021.1993595","url":null,"abstract":"ABSTRACT Objectives Currently, there is an active use of neural networks in various areas of human activity. Problems of recognition, diagnostics, optimization, forecasting, control, as well as obtaining new scientific knowledge are successfully solved. However, in medicine, due to the particular complexity of the human body, neural networks are mainly used only for solving the simplest problems of classification and diagnostics. The purpose of this article is to show that the possibilities of neural network modeling in medicine are much wider. Methods This goal is achieved by using special mathematical techniques developed by the authors that allow us to overcome these difficulties. Results The intellectual system created in this way made it possible to reveal a number of interesting scientific knowledge, which sometimes does not coincide with the generally accepted ideas of doctors. Virtual experiments conducted on computer models of patients using our intelligent system clearly demonstrate which lifestyle and medication variations can benefit a particular patient in the long term, and which can cause harm. Conclusion Our intellectual system allows us to identify new scientific knowledge, to carry out long-term forecasting of the development of the disease, to select the optimal courses of treatment and prevention of diseases.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"27 1","pages":"70 - 78"},"PeriodicalIF":1.2,"publicationDate":"2021-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41283522","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}
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