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Karim H, Winkelmann M, Grawe F, Völter F, Auernhammer C, Rübenthaler J, Ricke J, Ingenerf M, Schmid-Tannwald C. Quantitative SSTR-PET/CT: a potential tool for predicting everolimus response in neuroendoctine tumour patients. Radiol Oncol 2024; 58:348-356. [PMID: 38861687 PMCID: PMC11406901 DOI: 10.2478/raon-2024-0032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 05/10/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND This study aimed to assess 68Ga-DOTA-TATE (-TOC) PET/CT quantitative parameters in monitoring and predicting everolimus response in neuroendocrine tumor (NET) patients with hepatic metastases (NELM). PATIENTS AND METHODS This retrospective analysis included 29 patients with 62 target lesions undergoing everolimus treatment and pre-therapy, and follow-up 68Ga-DOTA-TATE (-TOC) PET/CT scans. Response evaluation utilized progression-free survival (PFS) categorized as responders (R; PFS > 6 months) and non-responders (NR; PFS ≤ 6 months). Lesion size and density, along with maximum and median standardize uptake value (SUV) in target lesions, liver, and spleen were assessed. Tumor-to-spleen (T/S) and tumor-to-liver (T/L) ratios were calculated, including the tumor-to-spleen (T/S) ratio and tumor-to-liver (T/L) ratio (using SUVmax/SUVmax, SUVmax/SUVmean, and SUVmean/SUVmean). RESULTS PET/CT scans were acquired 19 days (interquartile range [IQR] 69 days) pre-treatment and 127 days (IQR 74 days) post-starting everolimus. The overall median PFS was 264 days (95% CI: 134-394 days). R exhibited significant decreases in Tmax/Lmax and Tmean/Lmax ratios compared to NR (p = 0.01). In univariate Cox regression, Tmean/Lmax ratio was the sole prognostic parameter associated with PFS (HR 0.5, 95% CI 0.28-0.92, p = 0.03). Percentage changes in T/L and T/S ratios were significant predictors of PFS, with the highest area under curve (AUC) for the percentage change of Tmean/Lmax (AUC = 0.73). An optimal threshold of < 2.5% identified patients with longer PFS (p = 0.003). No other imaging or clinical parameters were predictive of PFS. CONCLUSIONS This study highlights the potential of quantitative SSTR-PET/CT in predicting and monitoring everolimus response in NET patients. Liver metastasis-to-liver parenchyma ratios outperformed size-based criteria, and Tmean/Lmax ratio may serve as a prognostic marker for PFS, warranting larger cohort investigation.
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Affiliation(s)
- Homeira Karim
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Michael Winkelmann
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Freba Grawe
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Friederike Völter
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Christoph Auernhammer
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
- Department of Internal Medicine 4, University Hospital, LMU Munich, Munich, Germany
| | - Johannes Rübenthaler
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
| | - Maria Ingenerf
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Christine Schmid-Tannwald
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
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Deng Y, Yang D, Tan X, Xu H, Xu L, Ren A, Liu P, Yang Z. Preoperative evaluation of microvascular invasion in hepatocellular carcinoma with a radiological feature-based nomogram: a bi-centre study. BMC Med Imaging 2024; 24:29. [PMID: 38281008 PMCID: PMC10821254 DOI: 10.1186/s12880-024-01206-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 01/18/2024] [Indexed: 01/29/2024] Open
Abstract
PURPOSE To develop a nomogram for preoperative assessment of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) based on the radiological features of enhanced CT and to verify two imaging techniques (CT and MRI) in an external centre. METHOD A total of 346 patients were retrospectively included (training, n = 185, CT images; external testing 1, n = 90, CT images; external testing 2, n = 71, MRI images), including 229 MVI-negative patients and 117 MVI-positive patients. The radiological features and clinical information of enhanced CT images were analysed, and the independent variables associated with MVI in HCC were determined by logistic regression analysis. Then, a nomogram prediction model was constructed. External validation was performed on CT (n = 90) and MRI (n = 71) images from another centre. RESULTS Among the 23 radiological and clinical features, size, arterial peritumoral enhancement (APE), tumour margin and alpha-fetoprotein (AFP) were independent influencing factors for MVI in HCC. The nomogram integrating these risk factors had a good predictive effect, with AUC, specificity and sensitivity values of 0.834 (95% CI: 0.774-0.895), 75.0% and 83.5%, respectively. The AUC values of external verification based on CT and MRI image data were 0.794 (95% CI: 0.700-0.888) and 0.883 (95% CI: 0.807-0.959), respectively. No statistical difference in AUC values among training set and testing sets was found. CONCLUSION The proposed nomogram prediction model for MVI in HCC has high accuracy, can be used with different imaging techniques, and has good clinical applicability.
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Affiliation(s)
- Yuhui Deng
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Yongan Road 95, West District, Beijing, 100050, China
- Medical Imaging Division, Heilongjiang Provincial Hospital, Harbin Institute of Technology, Zhongshan Road 82, Xiangfang District, Harbin, 150036, China
| | - Dawei Yang
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Yongan Road 95, West District, Beijing, 100050, China
| | - Xianzheng Tan
- Department of Radiology, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China
| | - Hui Xu
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Yongan Road 95, West District, Beijing, 100050, China
| | - Lixue Xu
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Yongan Road 95, West District, Beijing, 100050, China
| | - Ahong Ren
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Yongan Road 95, West District, Beijing, 100050, China
| | - Peng Liu
- Department of Radiology, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China.
| | - Zhenghan Yang
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Yongan Road 95, West District, Beijing, 100050, China.
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Ingenerf M, Karim H, Auernhammer C, Zacherl M, Wenter V, Winkelmann M, Ricke J, Berger F, Schmid-Tannwald C. Quantitative SSTR-PET/CT for predicting response and survival outcomes in patients with pancreatic neuroendocrine tumors receiving CAPTEM. Radiol Oncol 2023; 57:436-445. [PMID: 38038419 PMCID: PMC10690751 DOI: 10.2478/raon-2023-0055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 09/25/2023] [Indexed: 12/02/2023] Open
Abstract
BACKGROUND This study aimed to evaluate the predictive and monitoring role of somatostatin receptor (SSTR) positron emission tomography-computed tomography (PET/CT) and clinical parameters in patients with neuroendocrine liver metastases (NELM) from pancreatic neuroendocrine tumors (pNET) receiving capecitabine and temozolomide (CAPTEM). PATIENTS AND METHODS This retrospective study included twenty-two patients with pNET and NELM receiving CAPTEM who underwent pre- and post-therapeutic 68Ga-DOTATATE/-TOC PET/CT. Imaging (including standardized uptake value [SUV] of target lesions [NELM and pNET], normal spleen and liver) and clinical (Chromogranin A [CgA], Ki-67) parameters were assessed. Treatment outcome was evaluated as response according to RECIST 1.1, progression free survival (PFS) and overall survival (OS). RESULTS The median PFS (mPFS) was 7 months. Responders had a significantly longer mPFS compared to non-responders (10 vs. 4 months p = 0.022). Median OS (mOS) was 33 months (mOS: responders = 80 months, non-responders = 24 months p = 0.182). Baseline imaging showed higher SUV in responders, including absolute SUV, tumor-to-spleen (T/S), and tumor-to-liver (T/L) ratios (p < 0.02). All SUV parameters changed only in the responders during follow-up. Univariable Cox regression analysis identified baseline Tmax/Smean ratio and percentage change in size of pNETs as significant factors associated with PFS. A baseline Tmax/Smean ratio < 1.5 was associated with a shorter mPFS (10 vs. 4 months, (p < 0.05)). Prognostic factors for OS included age, percentage change in CgA and in T/S ratios in univariable Cox regression. CONCLUSIONS SSTR-PET/CT can be useful for predicting response and survival outcomes in pNET patients receiving CAPTEM: Higher baseline SUV values, particularly Tmax/Smean ratios of liver metastases were associated with better response and prolonged PFS.
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Affiliation(s)
- Maria Ingenerf
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Homeira Karim
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Christoph Auernhammer
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
- Department of Internal Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Matthias Zacherl
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Vera Wenter
- Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Michael Winkelmann
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
| | - Frank Berger
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Christine Schmid-Tannwald
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
- ENETS Centre of Excellence, Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System at the University Hospital of Munich (GEPNET-KUM), University Hospital of Munich, Munich, Germany
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Hoffmann E, Gerwing M, Krähling T, Hansen U, Kronenberg K, Masthoff M, Geyer C, Höltke C, Wachsmuth L, Schinner R, Hoerr V, Heindel W, Karst U, Eisenblätter M, Maus B, Helfen A, Faber C, Wildgruber M. Vascular response patterns to targeted therapies in murine breast cancer models with divergent degrees of malignancy. Breast Cancer Res 2023; 25:56. [PMID: 37221619 DOI: 10.1186/s13058-023-01658-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 05/14/2023] [Indexed: 05/25/2023] Open
Abstract
BACKGROUND Response assessment of targeted cancer therapies is becoming increasingly challenging, as it is not adequately assessable with conventional morphological and volumetric analyses of tumor lesions. The tumor microenvironment is particularly constituted by tumor vasculature which is altered by various targeted therapies. The aim of this study was to noninvasively assess changes in tumor perfusion and vessel permeability after targeted therapy in murine models of breast cancer with divergent degrees of malignancy. METHODS Low malignant 67NR or highly malignant 4T1 tumor-bearing mice were treated with either the multi-kinase inhibitor sorafenib or immune checkpoint inhibitors (ICI, combination of anti-PD1 and anti-CTLA4). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with i.v. injection of albumin-binding gadofosveset was conducted on a 9.4 T small animal MRI. Ex vivo validation of MRI results was achieved by transmission electron microscopy, immunohistochemistry and laser ablation-inductively coupled plasma-mass spectrometry. RESULTS Therapy-induced changes in tumor vasculature differed between low and highly malignant tumors. Sorafenib treatment led to decreased tumor perfusion and endothelial permeability in low malignant 67NR tumors. In contrast, highly malignant 4T1 tumors demonstrated characteristics of a transient window of vascular normalization with an increase in tumor perfusion and permeability early after therapy initiation, followed by decreased perfusion and permeability parameters. In the low malignant 67NR model, ICI treatment also mediated vessel-stabilizing effects with decreased tumor perfusion and permeability, while ICI-treated 4T1 tumors exhibited increasing tumor perfusion with excessive vascular leakage. CONCLUSION DCE-MRI enables noninvasive assessment of early changes in tumor vasculature after targeted therapies, revealing different response patterns between tumors with divergent degrees of malignancy. DCE-derived tumor perfusion and permeability parameters may serve as vascular biomarkers that allow for repetitive examination of response to antiangiogenic treatment or immunotherapy.
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Grants
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
- 446302350, 194468054, 431460824 Deutsche Forschungsgemeinschaft
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Affiliation(s)
- Emily Hoffmann
- Clinic of Radiology, University of Münster, Münster, Germany.
| | - Mirjam Gerwing
- Clinic of Radiology, University of Münster, Münster, Germany
| | - Tobias Krähling
- Clinic of Radiology, University of Münster, Münster, Germany
| | - Uwe Hansen
- Institute for Musculoskeletal Medicine, University of Münster, Münster, Germany
| | - Katharina Kronenberg
- Institute of Inorganic and Analytical Chemistry, University of Münster, Münster, Germany
| | - Max Masthoff
- Clinic of Radiology, University of Münster, Münster, Germany
| | | | - Carsten Höltke
- Clinic of Radiology, University of Münster, Münster, Germany
| | - Lydia Wachsmuth
- Clinic of Radiology, University of Münster, Münster, Germany
| | - Regina Schinner
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Verena Hoerr
- Clinic of Radiology, University of Münster, Münster, Germany
- Heart Center Bonn, Department of Internal Medicine II, University Hospital Bonn, Bonn, Germany
| | - Walter Heindel
- Clinic of Radiology, University of Münster, Münster, Germany
| | - Uwe Karst
- Institute of Inorganic and Analytical Chemistry, University of Münster, Münster, Germany
| | - Michel Eisenblätter
- Clinic of Radiology, University of Münster, Münster, Germany
- Department of Diagnostic and Interventional Radiology, Medical Faculty OWL, University of Bielefeld, Bielefeld, Germany
| | - Bastian Maus
- Clinic of Radiology, University of Münster, Münster, Germany
| | - Anne Helfen
- Clinic of Radiology, University of Münster, Münster, Germany
| | - Cornelius Faber
- Clinic of Radiology, University of Münster, Münster, Germany
| | - Moritz Wildgruber
- Clinic of Radiology, University of Münster, Münster, Germany
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
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Ippolito D, Maino C, Gatti M, Marra P, Faletti R, Cortese F, Inchingolo R, Sironi S. Radiological findings in non-surgical recurrent hepatocellular carcinoma: From locoregional treatments to immunotherapy. World J Gastroenterol 2023; 29:1669-1684. [PMID: 37077517 PMCID: PMC10107213 DOI: 10.3748/wjg.v29.i11.1669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/10/2023] [Accepted: 03/02/2023] [Indexed: 03/17/2023] Open
Abstract
Since hepatocellular carcinoma (HCC) represents an important cause of mortality and morbidity all over the world. Currently, it is fundamental not only to achieve a curative treatment but also to manage in the best way any possible recurrence. Even if the latest update of the Barcelona Clinic Liver Cancer guidelines for HCC treatment has introduced new locoregional techniques and confirmed others as well-established clinical practices, there is still no consensus about the treatment of recurrent HCC (RHCC). Locoregional treatments and medical therapy represent two of the most widely accepted approaches for disease control, especially in the advanced stage of liver disease. Different medical treatments are now approved, and others are under investigation. On this basis, radiology plays a central role in the diagnosis of RHCC and the assessment of response to locoregional treatments and medical therapy for RHCC. This review summarized the actual clinical practice by underlining the importance of the radiological approach both in the diagnosis and treatment of RHCC.
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Affiliation(s)
- Davide Ippolito
- Department of Radiology, IRCCS San Gerardo dei Tintori, Monza 20900, Italy
- School of Medicine and Surgery, University of Milano-Bicocca, Milano 20121, Italy
| | - Cesare Maino
- Department of Radiology, IRCCS San Gerardo dei Tintori, Monza 20900, Italy
| | - Marco Gatti
- Department of Surgical Sciences, University of Turin, Turin 10126, Italy
| | - Paolo Marra
- Department of Diagnostic and Interventional Radiology, Papa Giovanni XXIII Hospital, Bergamo 24127, Italy
| | - Riccardo Faletti
- Department of Surgical Sciences, University of Turin, Turin 10126, Italy
| | - Francesco Cortese
- Interventional Radiology Unit, “F. Miulli” Regional General Hospital, Bari 70121, Italy
| | - Riccardo Inchingolo
- Interventional Radiology Unit, “F. Miulli” Regional General Hospital, Bari 70121, Italy
| | - Sandro Sironi
- School of Medicine and Surgery, University of Milano-Bicocca, Milano 20121, Italy
- Department of Diagnostic and Interventional Radiology, Papa Giovanni XXIII Hospital, Bergamo 24127, Italy
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Treatment Assessment of pNET and NELM after Everolimus by Quantitative MRI Parameters. Biomedicines 2022; 10:biomedicines10102618. [PMID: 36289880 PMCID: PMC9599819 DOI: 10.3390/biomedicines10102618] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/01/2022] [Accepted: 10/11/2022] [Indexed: 11/17/2022] Open
Abstract
Assessment of treatment response to targeted therapies such as everolimus is difficult, especially in slow-growing tumors such as NETs. In this retrospective study, 17 patients with pancreatic neuroendocrine tumors (pNETs) and hepatic metastases (NELMs) (42 target lesions) who received everolimus were analyzed. Intralesional signal intensities (SI) of non-contrast T1w, T2w and DCE imaging, and apparent diffusion coefficients (ADCmean and ADCmin) of DWI, were measured on baseline and first follow-up MRI after everolimus initiation. Response assessment was categorized according to progression-free survival (PFS), with responders (R) showing a PFS of ≥11 months. ADCmin of NELMs decreased in Rs whereas it increased in non-responders (NR). Percentual changes of ADCmin and ADCmean differed significantly between response groups (p < 0.03). By contrast, ADC of the pNETs tended to increase in Rs, while there was no change in NRs. Tumor-to-liver (T/L) ratio of T1 SI of NELMs increased in Rs and decreased in NRs, and percentual changes differed significantly between response groups (p < 0.02). T1 SI of the pNETs tended to decrease in Rs and increase in Ns. The quotient of pretherapeutic and posttherapeutic ADCmin values (DADCmin) and length of everolimus treatment showed significant association with PFS in univariable Cox analysis. In conclusion, quantitative MRI, especially DWI, seems to allow treatment assessment of pNETs with NELMs under everolimus. Interestingly, the responding NELMs showed decreasing ADC values, and there might be an opposite effect on ADC and T1 SI between NELMs and pNETs.
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Chen Q, Chen AZ, Jia G, Li J, Zheng C, Chen K. Molecular Imaging of Tumor Microenvironment to Assess the Effects of Locoregional Treatment for Hepatocellular Carcinoma. Hepatol Commun 2021; 6:652-664. [PMID: 34738743 PMCID: PMC8948593 DOI: 10.1002/hep4.1850] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/12/2021] [Accepted: 10/17/2021] [Indexed: 12/22/2022] Open
Abstract
Liver cancer is one of the leading causes of cancer deaths worldwide. Among all primary liver cancers, hepatocellular carcinoma (HCC) is the most common type, representing 75%‐85% of all primary liver cancer cases. Median survival following diagnosis of HCC is approximately 6 to 20 months due to late diagnosis in its course and few effective treatment options. Interventional therapy with minimal invasiveness is recognized as a promising treatment for HCC. However, due to the heterogeneity of HCC and the complexity of the tumor microenvironment, the long‐term efficacy of treatment for HCC remains a challenge in the clinic. Tumor microenvironment, including factors such as hypoxia, angiogenesis, low extracellular pH, interstitial fluid pressure, aerobic glycolysis, and various immune responses, has emerged as a key contributor to tumor residual and progression after locoregional treatment for HCC. New approaches to noninvasively assess the treatment response and assist in the clinical decision‐making process are therefore urgently needed. Molecular imaging tools enabling such an assessment may significantly advance clinical practice by allowing real‐time optimization of treatment protocols for the individual patient. This review discusses recent advances in the application of molecular imaging technologies for noninvasively assessing changes occurring in the microenvironment of HCC after locoregional treatment.
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Affiliation(s)
- Quan Chen
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.,Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Austin Z Chen
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Guorong Jia
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jindian Li
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Chen
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Moawad AW, Szklaruk J, Lall C, Blair KJ, Kaseb AO, Kamath A, Rohren SA, Elsayes KM. Angiogenesis in Hepatocellular Carcinoma; Pathophysiology, Targeted Therapy, and Role of Imaging. J Hepatocell Carcinoma 2020; 7:77-89. [PMID: 32426302 PMCID: PMC7188073 DOI: 10.2147/jhc.s224471] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 12/24/2019] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, usually occurring on a background of liver cirrhosis. HCC is a highly vascular tumor in which angiogenesis plays a major role in tumor growth and spread. Tumor-induced angiogenesis is usually related to a complex interplay between multiple factors and pathways, with vascular endothelial growth factor being a major player in angiogenesis. In the past decade, understanding of tumor-induced angiogenesis has led to the emergence of novel anti-angiogenic therapies, which act by reducing neo-angiogenesis, and improving patient survival. Currently, Sorafenib and Lenvatinib are being used as the first-line treatment for advanced unresectable HCC. However, a disadvantage of these agents is the presence of numerous side effects. A major challenge in the management of HCC patients being treated with anti-angiogenic therapy is effective monitoring of treatment response, which decides whether to continue treatment or to seek second-line treatment. Several criteria can be used to assess response to treatment, such as quantitative perfusion on cross-sectional imaging and novel/emerging MRI techniques, including a host of known and emerging biomarkers and radiogenomics. This review addresses the pathophysiology of angiogenesis in HCC, accurate imaging assessment of angiogenesis, monitoring effects of anti-angiogenic therapy to guide future treatment and assessing prognosis.
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Affiliation(s)
- Ahmed W Moawad
- Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Janio Szklaruk
- Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Chandana Lall
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Katherine J Blair
- Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Ahmed O Kaseb
- Department of Gastrointestinal Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Amita Kamath
- Department of Radiology, Icahn School of Medicine at Mount Sinai West, New York, NY, USA
| | - Scott A Rohren
- School of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Khaled M Elsayes
- Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
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Campos M, Candelária I, Papanikolaou N, Simão A, Ferreira C, Manikis GC, Caseiro-Alves F. Perfusion Magnetic Resonance as a Biomarker for Sorafenib-Treated Advanced Hepatocellular Carcinoma: A Pilot Study. GE-PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2019; 26:260-267. [PMID: 31328140 DOI: 10.1159/000493351] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 08/27/2018] [Indexed: 12/12/2022]
Abstract
Background Sorafenib is the currently recommended therapy in patients with advanced hepatocellular carcinoma (HCC). Among the several biomarkers available for the evaluation of the therapeutic response and prognosis, there is perfusion magnetic resonance imaging (p-MRI) that, through measurement of the vascular permeability unit (ktrans), may retrieve useful information regarding the microvascular properties of focal liver lesions. The aim of this study was to evaluate the impact of sorafenib therapy in patients with advanced HCC using the p-MRI technique. Materials and Methods In this retrospective study, 27 patients with the diagnosis of advanced HCC were included for palliative therapy using sorafenib. MRI of the liver was performed before the beginning of the oral therapy (T0), after 3 (T3), and after 6 months (T6). Dynamic acquisitions of the tumor (n = 50, during the first 2 min after contrast injection) were obtained in the coronal plane and were used to compute the parametric perfusion maps, acquiring the ktrans value using the extended Tofts pharmacokinetic model. Results The value of ktrans obtained at T0 was significantly different from the value of ktrans obtained at T6 (p = 0.028). There were no significant differences between T0 and T3 (p = 0.115) or a correlation between ktrans at T0 and the size of the lesion (p = 0.376). The ktrans value at T0 in patients with progression-free survival (PFS) > 6 months was not significantly different from the ktrans value in patients with PFS ≤6 months (p = 0.113). The ktrans value at T0 was not significantly different between patients who were previously submitted to chemoembolization and those who were not submitted (p = 0.587). Conclusion In this pilot study, the ktrans value may serve as a biomarker of tumor response to antiangiogenic therapy, but only 6 months after its initiation. Clinical outcomes such as PFS were not predicted before the initiation of treatment.
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Affiliation(s)
- Marta Campos
- Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal
| | - Isabel Candelária
- Medical Imaging Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.,Local Healthcare Unit, Castelo Branco, Portugal
| | | | - Adélia Simão
- Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal.,Department of Internal Medicine, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Carlos Ferreira
- Coimbra Institute for Biomedical Imaging and Translational Research, Coimbra, Portugal.,Institute of Nuclear Sciences Applied to Health, Universidade de Coimbra, Coimbra, Portugal
| | - Georgios C Manikis
- Computational BioMedicine Laboratory, Institute of Computer Science, Foundation for Research and Technology - Hellas (FORTH), Heraklion, Greece
| | - Filipe Caseiro-Alves
- Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal.,Medical Imaging Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
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Advantage of sorafenib combined with radiofrequency ablation for treatment of hepatocellular carcinoma. TUMORI JOURNAL 2016; 103:286-291. [PMID: 28058713 DOI: 10.5301/tj.5000585] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Among the surgical and nonsurgical treatments available, radiofrequency ablation (RFA) and sorafenib have been shown to have efficacy. There is little evidence whether combination of these therapies would have additional benefits. METHODS In a mouse model of HCC, effects of sorafenib were determined by tumor size, RFA-induced necrosis area (triphenyltetrazolium chloride staining), microvascular density (MVD; 4',6-diamidino-2-phenylindole and anti-CD31 antibody staining), and tumor perfusion (magnetic resonance imaging). RESULTS The RFA-induced necrosis area was 80.98 ± 9.14 and 69.49 ± 7.46 mm2 in mice administered 80 and 40 mg/kg sorafenib, respectively, but only 57.29 ± 3.39 mm2 in controls. Sorafenib also reduced tumor volume and enhanced RFA-induced tumor destruction in a dose-dependent manner, and reduced both MVD and tumor perfusion. CONCLUSIONS The results of our study suggest a potential role for combining RFA with sorafenib for treatment of HCC. Sorafenib could enhance RFA efficiency, possibly through its angiogenesis suppressive effects.
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Chen X, Ma Z, Huang Y, He L, Liang C, Shi C, Zhang Z, Liang C, Liu Z. Multiparametric MR diffusion-weighted imaging for monitoring the ultra-early treatment effect of sorafenib in human hepatocellular carcinoma xenografts. J Magn Reson Imaging 2016; 46:248-256. [PMID: 27783444 DOI: 10.1002/jmri.25527] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Accepted: 10/10/2016] [Indexed: 12/20/2022] Open
Abstract
PURPOSE To investigate the value of multiparametric magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) for monitoring the ultra-early (within 24 hours) treatment effect of sorafenib in human hepatocellular carcinoma (HCC) xenografts. MATERIALS AND METHODS With institutional Animal Care and Use Committee approval, 16 BALB/c nude mice bearing subcutaneous HCC xenografts underwent serial Gaussian and non-Gaussian DWI at baseline and 1, 3, 6, 12, and 24 hours posttreatment using a 1.5T whole-body MRI system. Gaussian-DWI-derived apparent diffusion coefficient (ADC), D, D*, and f, and non-Gaussian-DWI-derived MD, MK, DDC, and α were calculated and compared between the control (n = 6) and sorafenib-treated groups (n = 10) with respect to each timepoint using Mann-Whitney or Wilcoxon signed-rank test. Results were validated by pathology. RESULTS Compared to baseline, ADC and D at 1 hour posttreatment (P = 0.005 and P = 0.013, respectively) and MD and DDC at 3 hours posttreatment (P = 0.009 and P = 0.005, respectively) significantly decreased and remained lower through 12 hours of follow-up (P = 0.005-0.022), followed by recovery to baseline levels at 24 hours posttreatment (P = 0.139-0.646). MK significantly increased at 1 hour posttreatment (P = 0.013) and remained higher through 24 hours of follow-up (P = 0.009-0.028). No significant differences were found in D*, f, and α at different timepoints (P = 0.188-0.714). Light microscopy did not reveal abnormal findings until 3 hours posttreatment, when central patchy necrosis was observed; more prominent diffuse necrosis was observed at 24 hours. Electron microscopy revealed swollen mitochondria at 1 hour posttreatment and accumulation of intracellular autophagosomes from 3 to 24 hours posttreatment. CONCLUSION Multiparametric DWI might evaluate therapeutic effects of sorafenib in HCC, where metrics of ADC, D, and MK could potentially serve as imaging biomarkers for monitoring therapeutic effects as early as 1 hour after treatment. Level of Evidence 1 Technical Efficacy: Stage 4 J. MAGN. RESON. IMAGING 2017;46:248-256.
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Affiliation(s)
- Xin Chen
- Department of Radiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Department of Radiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zelan Ma
- Department of Radiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yanqi Huang
- Department of Radiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Lan He
- Department of Radiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,School of Medicine, South China University of Technology, Guangzhou, China
| | - Cuishan Liang
- Department of Radiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Changzheng Shi
- Medical Imaging Center, First Affiliated Hospital, Jinan University, Guangzhou, China
| | | | - Changhong Liang
- Department of Radiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zaiyi Liu
- Department of Radiology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Sacco R, Mismas V, Romano A, Bertini M, Bertoni M, Federici G, Metrangolo S, Parisi G, Tumino E, Bresci G, Giacomelli L, Marceglia S, Bargellini I. Assessment of clinical and radiological response to sorafenib in hepatocellular carcinoma patients. World J Hepatol 2015; 7:33-39. [PMID: 25624994 PMCID: PMC4295191 DOI: 10.4254/wjh.v7.i1.33] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 10/10/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is an effective anti-angiogenic treatment for hepatocellular carcinoma (HCC). The assessment of tumor progression in patients treated with sorafenib is crucial to help identify potentially-resistant patients, avoiding unnecessary toxicities. Traditional methods to assess tumor progression are based on variations in tumor size and provide unreliable results in patients treated with sorafenib. New methods to assess tumor progression such as the modified Response Evaluation Criteria in Solid Tumors or European Association for the Study of Liver criteria are based on imaging to measure the vascularization and tumor volume (viable or necrotic). These however fail especially when the tumor response results in irregular development of necrotic tissue. Newer assessment techniques focus on the evaluation of tumor volume, density or perfusion. Perfusion computed tomography and Dynamic Contrast-Enhanced-UltraSound can measure the vascularization of HCC lesions and help predict tumor response to anti-angiogenic therapies. Mean Transit Time is a possible predictive biomarker to measure tumor response. Volumetric techniques are reliable, reproducible and time-efficient and can help measure minimal changes in viable tumor or necrotic tissue, allowing the prompt identification of non-responders. Volume ratio may be a reproducible biomarker for tumor response. Larger trials are needed to confirm the use of these techniques in the prediction of response to sorafenib.
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