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Fan Z, Wu M, Tang Z, He A, Liu F, Liang W, Wang Z, Yang D. Predictive Value of Platelet-Related Measures in Patients with Hepatocellular Carcinoma. Technol Cancer Res Treat 2022; 21:15330338211064414. [PMID: 35225081 PMCID: PMC8891878 DOI: 10.1177/15330338211064414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: Increasing numbers of studies reported platelet (PLT)- related measures could play a creative role in many malignancies, while the prognostic impact of these measures in hepatocellular carcinoma (HCC) remains limited and controversial. It is worth exploring the predictive value of PLT-related measures in HCC. Methods: A total of 279 HCC patients with hepatectomy were analyzed in the retrospective cohort study. The optimal cut-off points of these PLT-related indices were obtained by the receiver operating characteristic (ROC) curve. The associations of these indices with clinical characteristics and overall survival (OS) were evaluated by Kaplan–Meier curves and Cox proportional hazards models. Results: High PLT count and low prognostic nutritional index (low-PNI) were significantly associated with larger tumor size. The low gamma-glutamyl transpeptidase-to-platelet ratio (low-GPR) group was inclined to more hepatitis infections. Survival curves indicated that preoperative high-PLT, low-GPR, and low-PNI had a worse prognosis after surgery in the cohort. In addition, PLT≥220 × 109/L (HR, 2.274; 95% CI, 1.061-4.876; P = .035), PNI≥51.9 (HR, 0.503; 95% CI, 0.265-0.954; P = .035), and GPR≥0.2 (HR, 0.432; 95% CI, 0.204-0.912; P = .028) were identified as independent prognostic factors for survival outcomes in the multivariable analysis. Conclusion: High-PLT, low-GPR, and low-PNI as the preoperative predictors were associated with poor OS in HCC patients with hepatectomy. Our data reveal that they could be simple, easily obtained, and effective predictors for evaluation of survival outcomes in patients.
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Affiliation(s)
- Zhijia Fan
- Huashan Hospital, 159397Fudan University, Shanghai, China
| | - Mengmeng Wu
- Huashan Hospital, 159397Fudan University, Shanghai, China
| | - Zihui Tang
- Huashan Hospital, 159397Fudan University, Shanghai, China
| | - Anfang He
- Huashan Hospital, 159397Fudan University, Shanghai, China
| | - Fuchen Liu
- 535219Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wei Liang
- The Second People's Hospital of Lianyungang City, Jiangsu Province, China
| | - Zhicheng Wang
- Huashan Hospital, 159397Fudan University, Shanghai, China
| | - Dongqin Yang
- Huashan Hospital, 159397Fudan University, Shanghai, China
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Han S. Possible roles of platelets in liver transplantation: regeneration and cancer recurrence. Anesth Pain Med (Seoul) 2021; 16:225-231. [PMID: 34352964 PMCID: PMC8342825 DOI: 10.17085/apm.21063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 07/03/2021] [Indexed: 12/28/2022] Open
Abstract
When tissue injury results in breakage, platelets are not only involved in plug formation and wound sealing, but they also play an important role throughout the tissue recovery process. Specifically, platelets accumulate at the site of injury and release a large number of biologically active mediators at injury sites, which initiate or modulate damaged tissue regeneration. Moreover, extensive experimental evidence has elucidated the involvement of platelets in tumor growth and metastasis. As such, this mini-review aimed to highlight the relatively lesser known functions of platelets.
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Affiliation(s)
- Sangbin Han
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Scheiner B, Kirstein M, Popp S, Hucke F, Bota S, Rohr-Udilova N, Reiberger T, Müller C, Trauner M, Peck-Radosavljevic M, Vogel A, Sieghart W, Pinter M. Association of Platelet Count and Mean Platelet Volume with Overall Survival in Patients with Cirrhosis and Unresectable Hepatocellular Carcinoma. Liver Cancer 2019; 8:203-217. [PMID: 31192156 PMCID: PMC6547277 DOI: 10.1159/000489833] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 05/06/2018] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Platelets have been reported to influence tumor biology and may promote metastasis. Traditionally, thrombocytopenia, a hallmark of cirrhosis, was associated with hepatocellular carcinoma (HCC) development. However, the impact of platelet count on outcome in patients with established HCC is not well studied. METHODS Outcomes of patients with cirrhosis diagnosed with HCC between 1995 and 2013 (derivation cohort) and 2000-2016 (validation cohort) who were not eligible for surgical treatment and did not receive antiplatelet therapy were retrospectively studied. Thrombocytopenia was defined as platelet count < 150 g/L. High mean platelet volume (MPV) was defined as ≥median value of the respective cohort (derivation cohort: ≥11 fL; validation cohort: ≥10.6 fL). RESULTS Among 626 patients with unresectable HCC, thrombocytopenia was present in 378 (60.4%) and was associated with favorable baseline tumor characteristics: lower diameter of the largest nodule (5.6 ± 3.2 vs. 7.6 ± 4.2 cm), less extrahepatic spread (9.5 vs. 20.2%, both p < 0.001), less macrovascular invasion (21.2 vs. 31.0%, p = 0.005), and lower BCLC stages (63.0 vs. 73.4% BCLC C/D; p = 0.007) as compared to patients with normal platelet count. On univariate analysis, thrombocytopenia and larger MPV were associated with longer overall survival (OS) (thrombocytopenia: median OS [95% CI], 11.5 [9.3-13.8] vs. 5.5 [3.8-7.1] months; p = 0.001; MPV ≥11 fL: 11.7 [9.1-14.2] vs. 6.0 [4.4-7.6] months; p < 0.001). In multivariate analysis, the combined variable of thrombocytopenia and larger MPV was independently associated with longer OS (HR [95% CI], 0.80 [0.65-0.98]; p = 0.029). These results were confirmed in an independent external validation cohort of 525 patients with cirrhosis and HCC. Again, patients with thrombocytopenia and high MPV had significantly longer OS (15.3 [11.7-18.9] vs. 9.3 [7.4-11.2] months; p < 0.001). CONCLUSIONS Thrombocytopenia and higher MPV are associated with better outcome in patients with advanced HCC. These findings may prompt further clinical research on additive antiplatelet therapy in the prevention and management of HCC.
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Affiliation(s)
- Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria,Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - Martha Kirstein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Sabine Popp
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Florian Hucke
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria,Department of Gastroenterology and Hepatology, Endocrinology, Rheumatology and Nephrology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Simona Bota
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria,Department of Gastroenterology and Hepatology, Endocrinology, Rheumatology and Nephrology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Nataliya Rohr-Udilova
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - Christian Müller
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Markus Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria,Department of Gastroenterology and Hepatology, Endocrinology, Rheumatology and Nephrology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria,Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Wolfgang Sieghart
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria,*Matthias Pinter, MD, PhD, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18–20, AT–1090 Vienna (Austria), E-Mail
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Wei Y, Dai F, Zhao T, Tao C, Wang L, Ye W, Zhao W. Transcatheter arterial chemoembolization monotherapy vs combined transcatheter arterial chemoembolization-percutaneous microwave coagulation therapy for massive hepatocellular carcinoma (≥10 cm). Cancer Manag Res 2018; 10:5273-5282. [PMID: 30464624 PMCID: PMC6219403 DOI: 10.2147/cmar.s172395] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background The prognosis of massive hepatocellular carcinomas (MHCCs; ≥10 cm) remains worse. Purpose The aim of this study was to evaluate the clinical benefits of transcatheter arterial chemoembolization (TACE) or TACE combined with percutaneous microwave coagulation therapy (PMCT) and the long-term survival rate of MHCC patients treated with these techniques. Patients and methods A retrospective study was performed using data involving 102 MHCC patients admitted to the Second Hospital of Nanjing from September 2010 to August 2015. The median interval between treatments and overall survival (OS) was hierarchically analyzed using log-rank tests. Multivariate analysis was done using Cox regression model analysis. Results The median survival time of MHCC patients was 3 months (range, 1–10 months) in the palliative group, 3 months (range, 1–39 months) in the TACE group, and 7.5 months (range, 3–30 months) in the TACE–PMCT group (P=0.038). The 6-, 12-, and 18-month OS rates for MHCC patients were 15%, 0%, and 0% in the palliative group, 30%, 25.63%, and 17.97% in the TACE group, and 50%, 41.67%, and 16.67% in the TACE–PMCT group, respectively (P=0.0467). In addition, TACE sessions had positive correlation with the survival time of MHCC patients (rho = 0.462, P<0.001). TACE treatment more than three times (HR =0.145, P<0.001) was an independent predictor of the survival of MHCC patients, which was identified by the Cox regression model analysis. Conclusions These results indicated that TACE–PMCT treatment in MHCC patients had advantages in prolonging OS and improving liver function. Multiple TACE treatments might be a suitable treatment for the MHCC patients.
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Affiliation(s)
- Yanyan Wei
- Liver Disease Department, The Second Hospital of Nanjing, Medical School of Southeast University, Nanjing, China, ;
| | - Feng Dai
- Liver Disease Department, The Second Hospital of Nanjing, Medical School of Southeast University, Nanjing, China, ;
| | - Tianhui Zhao
- Liver Disease Department, The Second Hospital of Nanjing, Medical School of Southeast University, Nanjing, China, ;
| | - Chen Tao
- Liver Disease Department, The Second Hospital of Nanjing, Medical School of Southeast University, Nanjing, China, ;
| | - Lili Wang
- Liver Disease Department, The Second Hospital of Nanjing, Medical School of Southeast University, Nanjing, China, ;
| | - Wei Ye
- Liver Disease Department, The Second Hospital of Nanjing, Medical School of Southeast University, Nanjing, China, ;
| | - Wei Zhao
- Liver Disease Department, The Second Hospital of Nanjing, Medical School of Southeast University, Nanjing, China, ;
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Ventura Y, Carr BI, Kori I, Guerra V, Shibolet O. Analysis of aggressiveness factors in hepatocellular carcinoma patients undergoing transarterial chemoembolization. World J Gastroenterol 2018; 24:1641-1649. [PMID: 29686471 PMCID: PMC5910547 DOI: 10.3748/wjg.v24.i15.1641] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 03/10/2018] [Accepted: 03/25/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate novel predictors of survival in hepatocellular carcinoma (HCC) patients following transarterial chemoembolization (TACE).
METHODS One hundred sixty seven patients with un-resectable HCC were retrospectively analyzed to identify factors that might contribute to their HCC biology and aggressiveness. We correlated routine laboratory results (total bilirubin, AST, ALKP, GGTP, albumin etc.) to maximum tumor diameter, number of tumor nodules, portal vein thrombosis and blood alpha-fetoprotein levels. These 4 parameters were previously combined to form an aggressiveness index (AgI). We used The Wilcoxon rank-sum (Mann-Whitney), to test the correlation between the AgI categories and liver function parameters. The Cox proportional hazards model was applied to evaluate the categories of AgI associated with overall survival.
RESULTS The AgI was strongly correlated with survival in this novel patient population. Three year survival probability for AgI > or < 4 was 42.4% vs 61.8%; P < 0.0863 respectively. Several factors independently correlated with AgI using univariate multiple logistic regression of AgI with 8 laboratory parameters. Lower albumin levels had an OR of 2.56 (95%CI: 1.120-5.863 P < 0.026), elevated Alkaline phosphatase and gamma glutamyl transpeptidase (GGTP) had ORs of 1.01 (95%CI: 1.003-1.026, P < 0.017) and 0.99 (95%CI: 0.99-1.00, P < 0.053) respectively. In a Cox proportional hazard model combining mortality for AgI score and liver function parameters, only GGTP levels and the AgI were independently associated with survival. An AgI > 4 had HR for mortality of 2.18 (95%CI: 1.108-4.310, P < 0.024). GGTP’s single unit change had a HR for mortality of 1.003 (95%CI: 1.001-1.006, P < 0.016). These were considered in the final multivariate model with the total cohort. An AgI > 4 had a HR for mortality of 2.26 (95%CI: 1.184-4.327, P < 0.016). GGTP had a HR of 1.003 (95%CI: 1.001-1.004, P < 0.001).
CONCLUSION Our study validates the AgI in a new population with un-resectable HCC patients undergoing TACE. The analysis establishes a correlation between GGTP and the AgI.
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Affiliation(s)
- Yossi Ventura
- Liver Unit, Department of Gastroenterology and Hepatology, Tel-Aviv Medical Center, Tel-Aviv 62431, Israel
- Sackler faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel
| | - Brian I Carr
- Izmir Biomedicine and Genome Center, Dokuz Eylul University, Izmir 35340, Turkey
| | - Issac Kori
- Interventional Radiology, Division of Imaging Tel Aviv Medical Center, Tel-Aviv 62431, Israel
| | - Vito Guerra
- Department of Clinical Trials and Epidemiology, IRCCS de Bellis, Castellana Grotte 70013, Italy
| | - Oren Shibolet
- Liver Unit, Department of Gastroenterology and Hepatology, Tel-Aviv Medical Center, Tel-Aviv 62431, Israel
- Sackler faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel
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Gu L, Wen W, Wu Z, Bai K, Liu W, Lai G, Li D. Abnormal platelet count correlates with poor survival in hepatocellular carcinoma. INFECTION INTERNATIONAL 2018. [DOI: 10.1515/ii-2017-0160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
AbstractBackgroundNormal platelet (PLT) plays a vital role in thrombosis, the inflammatory response, and liver regeneration. The effect of abnormal PLT counts has been seldom explored in hepatocellular carcinoma (HCC); hence, this investigation was conducted to evaluate the prognostic importance of preoperative abnormal PLT count in HCC patients after liver resection retrospectively.MethodologyThe PLT counts were determined using Sysmex XT-1800i automated hematology analyzer and its matching reagents. Patients were divided into two groups: a normal PLT group and an abnormal PLT group. Chi-square test, Kaplan–Meier method, and Cox univariable and multivariable regressions were utilized to analyze the data.ResultsA total of 391 HCC patients who underwent liver resection were included in this study. The overall survival (OS) rates were 59% and 31%, and the median survival time was 69 months and 31 months in the normal and abnormal PLT groups, respectively. The PLT level was associated with OS in univariate and multivariate analyses (hazard ratio [HR], 1.991 [95% confidence interval {CI}, 1.412–2.808] and HR, 2.217 [95% CI, 1.556–3.159], respectively).ConclusionsPatients with normal PLT had a better outcome in terms of OS. The results suggested that abnormal PLT count is an independent prognostic factor for HCC patients after liver resection.
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Han S, Lee S, Yang JD, Leise MD, Ahn JH, Kim S, Jung K, Gwak MS, Kim GS, Ko JS. Risk of posttransplant hepatocellular carcinoma recurrence is greater in recipients with higher platelet counts in living donor liver transplantation. Liver Transpl 2018; 24:44-55. [PMID: 29024412 DOI: 10.1002/lt.24961] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 09/15/2017] [Accepted: 09/25/2017] [Indexed: 12/12/2022]
Abstract
Platelets interact with tumor cells and promote metastasis. The importance of platelets in posttransplant hepatocellular carcinoma (HCC) recurrence is unclear. Thus, we aimed to evaluate the association between preoperative platelet count (PLT) and HCC recurrence after living donor liver transplantation. Of 359 recipients of livers from living donors for HCC, 209 of 240 patients who had preoperative PLT ≤75 × 109 /L were matched with 97 of 119 patients who had preoperative PLT >75 × 109 /L using propensity score matching, with an unfixed matching ratio based on factors such as tumor biology. The cutoff value of 75 × 109 /L was set based on optimum stratification analysis. Survival analysis was performed with death as a competing risk event. The primary outcome was overall HCC recurrence. The median follow-up time was 59 months. Before matching, recurrence probability at 1, 2, and 5 years after transplantation was 4.7%, 9.2%, and 11.3% for the low platelet group and 14.5%, 23.0%, and 30.5% for the high platelet group. Recurrence risk was significantly greater in the high platelet group in both univariate (hazard ratio [HR] = 3.09; 95% confidence interval [CI], 1.86-5.14; P < 0.001) and multivariate analyses (HR = 2.10; 95% CI, 1.23-3.60; P = 0.007). In the matched analysis, recurrence risk was also greater in the high platelet group in both univariate (HR = 2.33; 95% CI, 1.36-4.01; P = 0.002) and multivariate analyses (HR = 1.90; 95% CI, 1.02-3.54; P = 0.04). Preoperative PLT had no interaction with the Milan criteria, alpha-fetoprotein level, Edmonson grade, microvascular invasion, or intrahepatic metastasis. Incorporation of preoperative PLT into the Milan criteria significantly improved predictive power. Inflammation-based scores including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and the inflammation-based index did not show superiority to preoperative PLT in predicting HCC recurrence. In conclusion, preoperative PLT appears to be an important host factor affecting HCC recurrence after living donor liver transplantation. Liver Transplantation 24 44-55 2018 AASLD.
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Affiliation(s)
- Sangbin Han
- Department of Anesthesiology and Pain Medicine
| | - Sanghoon Lee
- Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Ju Dong Yang
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
| | - Michael Douglas Leise
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
| | - Joong Hyun Ahn
- Statistics and Data Center, Samsung Medical Center, Seoul, South Korea
| | - Seonwoo Kim
- Statistics and Data Center, Samsung Medical Center, Seoul, South Korea
| | - Kangha Jung
- Department of Anesthesiology and Pain Medicine
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8
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Akkiz H, Carr BI, Yalçın K K, Guerra V, Kuran S, Altıntaş E, Üsküdar O, Karaoğullarından Ü, Özakyol A, Tokmak S, Yücesoy M, Bahçeci Hİ, Ülkü A, Akçam T, Yalçın Polat K, Ekinci N, Şimşek H, Örmeci N, Sonsuz A, Demir M, Kılıç M, Uygun A, Ballı T, Demir A, Arslan B, Doran F. Characteristics of Hepatocellular Carcinoma Aggressiveness Factors in Turkish Patients. Oncology 2017; 94:116-124. [PMID: 29207378 DOI: 10.1159/000484564] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 10/24/2017] [Indexed: 01/06/2023]
Abstract
A large cohort of hepatocellular carcinoma (HCC) patients from several collaborating Turkish institutions were examined for the tumor parameters of maximum diameter (MTD), portal vein thrombosis (PVT), and α-fetoprotein (AFP) levels. A relationship was found between MTD and blood platelet levels. Patients with large ≥5 cm tumors who had normal platelet levels had significantly larger tumors, higher percent of PVT, and significantly lower blood total bilirubin and liver cirrhosis than similar ≥5 cm tumor patients having thrombocytopenia. A comparison of patients with and without PVT showed significantly larger tumors, greater multifocality, blood AFP, and C-reactive protein levels, and, interestingly, lower HDL levels in the patients with PVT. Fifty-eight percent of the total cohort had AFP levels ≤100 IU/mL (and 42.1% had values ≤20 IU/mL). These patients had significantly smaller tumors, less tumor multifocality and percent PVT, lower total bilirubin, and less cirrhosis. There was considerable geographic heterogeneity within Turkey in the patterns of HCC presentation, with areas of higher and lower hepatitis B virus, hepatitis D virus, cirrhosis, and tumor aggressiveness parameters. Turkish patients thus have distinct patterns of presentation, but the biological relationships between MTD and both platelets and bilirubin levels are similar to the relationships that have been reported in other ethnic patient groups.
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Affiliation(s)
- Hikmet Akkiz
- Gastroenterology Department, Çukurova Üniversitesi, Adana, Turkey
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Shaker O, Alhelf M, Morcos G, Elsharkawy A. miRNA-101-1 and miRNA-221 expressions and their polymorphisms as biomarkers for early diagnosis of hepatocellular carcinoma. INFECTION GENETICS AND EVOLUTION 2017; 51:173-181. [PMID: 28366737 DOI: 10.1016/j.meegid.2017.03.030] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 03/27/2017] [Accepted: 03/28/2017] [Indexed: 02/07/2023]
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Carr BI, Guerra V, Giannini EG, Farinati F, Ciccarese F, Rapaccini GL, Di Marco M, Benvegnù L, Zoli M, Borzio F, Caturelli E, Masotto A, Trevisani F. A Liver Index and its Relationship to Indices of HCC Aggressiveness. JOURNAL OF INTEGRATIVE ONCOLOGY 2016; 5:178. [PMID: 28580457 PMCID: PMC5450974 DOI: 10.4172/2329-6771.1000178] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A Hepatocellular (HCC) Aggressiveness Index was recently constructed, consisting of the sum of the scores for the 4 clinical parameters of maximum tumor size, multifocality, presence of portal vein thrombus and blood alphafetoprotein levels. It was observed that there was an association with several liver function tests. We have now formed a Liver Index from the 4 liver parameters with the highest hazard ratios with respect to HCC aggressiveness, namely: blood total bilirubin, gamma glutamyl transpeptidase (GGTP), albumin and platelet levels (cirrhosis surrogate). We found that the scores for the Liver Index related significantly to survival, but also to the Aggressiveness Index and to its individual HCC components as well as showing significant trends with the components. These results support the hypothesis that liver function is not only an important prognostic factor in HCC patients, but may also be involved in HCC biology and aggressiveness. Blood albumin, GGTP, albumin and platelet levels were used to create a Liver Index that related significantly to parameters of HCC aggressiveness.
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Affiliation(s)
- Brian I Carr
- Izmir Biomedicine and Genome Center, Dokuz Eylul University, Turkey and Lusaka Apex Medical University, Zambia
| | - Vito Guerra
- Department of Clinical Trials and Epidemiology, IRCCS de Bellis, Castellana Grotte, Italy
| | - Edoardo G Giannini
- Department of Internal Medicine, Gastroenterology Unit, University of Genoa, Italy
| | - Fabio Farinati
- Department of Surgical Science and Gastroenterology, Gastroenterology Unit, University of Padua, Italy
| | | | | | - Maria Di Marco
- Division of Medicine, Azienda Ospedaliera Bolognini, Seriate, Italy
| | - Luisa Benvegnù
- Department of Clinical and Experimental Medicine, Medical Unit, University of Padua, Italy
| | - Marco Zoli
- Department of Medical and Surgical Science, Internal Medicine Unit, Alma Mater Studiorum, University of Bologna, Italy
| | - Franco Borzio
- Department of Medicine, Internal Medicine and Hepatology Unit, Ospedale Fatebenefratelli, Milan, Italy
| | | | - Alberto Masotto
- Gastroenterology Unit, Ospedale Sacro Cuore Don Calabria, Negrar, Italy
| | - Franco Trevisani
- Department of Medical Surgical Sciences, Medical Semiotics Unit, Alma Mater Studiorum, University of Bologna, Italy
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Adverse effects of platelets on post-hepatectomy outcomes in patients with hepatocellular carcinoma. J Hepatol 2016; 64:518-519. [PMID: 26551517 DOI: 10.1016/j.jhep.2015.10.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 09/27/2015] [Accepted: 10/01/2015] [Indexed: 12/04/2022]
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Li X, Han Z, Cheng Z, Yu J, Yu X, Liang P. Clinical significance of preoperative platelet-to-lymphocyte ratio in recurrent hepatocellular carcinoma after thermal ablation: A retrospective analysis. Int J Hyperthermia 2015; 31:758-63. [DOI: 10.3109/02656736.2015.1068958] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Lippolis C, Refolo MG, D'Alessandro R, Carella N, Messa C, Cavallini A, Carr BI. Resistance to multikinase inhibitor actions mediated by insulin like growth factor-1. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2015; 34:90. [PMID: 26329608 PMCID: PMC4557596 DOI: 10.1186/s13046-015-0210-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 08/20/2015] [Indexed: 12/22/2022]
Abstract
Background Blood platelet numbers are correlated with growth and aggressiveness of several tumor types, including hepatocellular carcinoma (HCC). We previously found that platelet lysates (hPLs) both stimulated HCC cell growth and migration, and antagonized the growth-inhibitory and apoptotic effects of Regorafenib, multikinase growth inhibitor, on HCC cell lines. We evaluated the effects of human insulin-like growth factor-1 (IGF1), a mitogen contained in platelets, on the Regorafenib-mediated growth inhibition. Methods An Elisa kit was used to evaluate hPL IGF1 concentrations. The effects of IGF1 on cell proliferation were assessed with MTT assay and analysis of cell cycle progression. Apoptosis assays, scratch assay and Transwell assay were performed to measure apoptosis, cell migration and invasion respectively. Western blots were performed by standard protocols. Results IGF1 antagonized growth inhibition exerted by Regorafenib on HCC cell lines. Moreover the mitogen blocked Regorafenib-induced apoptosis and decreased the rate of cell migration and invasion. The IGF1 effects were in turn antagonized by actions of a potent IGF1 receptor inhibitor, GSK1838705A, showing that the IGF1 receptor was involved in the mechanisms of IGF1-mediated blocking of Regorafenib action. GSK1838705A also partially blocked the effects of hPLs in antagonizing Regorafenib-mediated growth inhibition, showing that IGF1 was an important component of hPL actions. Conclusions These results show that IGF1 antagonized Regorafenib-mediated growth, migration and invasion inhibition, as well as the drug-mediated induction of apoptosis in HCC cells and reinforce the idea that microenvironmental factors can influence cancer drug actions.
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Affiliation(s)
- Catia Lippolis
- Department Clinical Pathology, Laboratory of Cellular and Molecular Biology, National Institute for Digestive Diseases, IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, BA, Italy.
| | - Maria Grazia Refolo
- Department Clinical Pathology, Laboratory of Cellular and Molecular Biology, National Institute for Digestive Diseases, IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, BA, Italy.
| | - Rosalba D'Alessandro
- Department Clinical Pathology, Laboratory of Cellular and Molecular Biology, National Institute for Digestive Diseases, IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, BA, Italy.
| | - Nicola Carella
- Department Clinical Pathology, Laboratory of Cellular and Molecular Biology, National Institute for Digestive Diseases, IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, BA, Italy.
| | - Caterina Messa
- Department Clinical Pathology, Laboratory of Cellular and Molecular Biology, National Institute for Digestive Diseases, IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, BA, Italy.
| | - Aldo Cavallini
- Department Clinical Pathology, Laboratory of Cellular and Molecular Biology, National Institute for Digestive Diseases, IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, BA, Italy.
| | - Brian Irving Carr
- Izmir Biomedicine and Genome Center, Dokuz Eylul University, Izmir, Turkey.
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Long Z, Wang B, Tao D, Liu Y, Zhang J, Tan J, Luo J, Shi F, Tao Z. Clinical research on alternating hyperfraction radiotherapy for massive hepatocellular carcinoma. Oncol Lett 2015; 10:523-527. [PMID: 26171062 DOI: 10.3892/ol.2015.3185] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Accepted: 04/13/2015] [Indexed: 02/06/2023] Open
Abstract
The delivery of high tumoricidal doses of radiation with low rates of toxicity is of particular significance for massive hepatocellular carcinoma (HCC) radiotherapy. In order to observe the efficacy and adverse reactions of alternating hyperfraction radiotherapy treatment of massive HCC, seventy-two cases of massive HCC were randomly divided into two groups, group A and group B. The liver lesions of group A were divided into sublesions and treated with alternating hyperfraction radiotherapy [intensity modulated radiotherapy (IMRT)]. The interval between radiotherapy to the sublesions was a minimum of six hours. The average radiotherapy dose to the sublesions was 2 Gy/fraction, once a day, five times per week, treating the gross tumor volume with a total dose of 40-50 Gy, and the clinical target volume with a total dose of 30-40 Gy. By contrast, the lesions of group B were not divided into sublesions for the IMRT treatment, but were treated with an otherwise identical protocol, by 2 Gy/fraction, once a day, five times per week, and with the same total dose. Patients were followed up with regular blood tests, liver function tests, measurements of serum α-fetoprotein levels and contrast-enhanced magnetic resonance imaging (MRI) of the liver. Treatment responses were assessed every 3 months by MRI. The results revealed that the overall response rates of the two groups were 82.9 and 81.3%, respectively (P=0.864). The alternating hyperfraction radiotherapy protocol resulted in enhanced survival (P=0.002). The median survival time of the two groups was 9.7 and 6.5 months, respectively. The overall 6-month, 1-year, 2-year and 3-year survival rates of the two groups were 62.9 and 59.4% (P=0.770), 48.6 and 21.9% (P=0.040), 17.1 and 0.0% (P=0.025) and 2.9 and 0.0% (P=1.000), respectively. The I-II degree of abnormal liver function and radiation-induced liver disease of group B was higher than that of group A (P=0.021 and 0.046, respectively). In addition, the incidence rate of radiation-induced liver injury of group A was lower than that of group B. Therefore, treatment of massive HCC with alternating hyperfraction radiotherapy improved the quality of life and prolonged the overall survival time, compared with conventional IMRT, suggesting that it was an effective radiation pattern.
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Affiliation(s)
- Zhixiong Long
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Bin Wang
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Dan Tao
- Department of Oncology, The Fifth Hospital of Wuhan, Wuhan, Hubei 430050, P.R. China
| | - Yanping Liu
- Department of Oncology, The Fifth Hospital of Wuhan, Wuhan, Hubei 430050, P.R. China
| | - Jiangzhou Zhang
- Department of Oncology, The Fifth Hospital of Wuhan, Wuhan, Hubei 430050, P.R. China
| | - Jiaan Tan
- Department of Oncology, Hubei Provincial Traditional Chinese Medical Hospital, Wuhan, Hubei 430061, P.R. China
| | - Jing Luo
- Department of Oncology, Hubei Provincial Traditional Chinese Medical Hospital, Wuhan, Hubei 430061, P.R. China
| | - Feifei Shi
- Department of Oncology, Hubei Provincial Traditional Chinese Medical Hospital, Wuhan, Hubei 430061, P.R. China
| | - Zezhang Tao
- Department of Otolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Modulation of Regorafenib effects on HCC cell lines by epidermal growth factor. Cancer Chemother Pharmacol 2015; 75:1237-1245. [PMID: 25907508 DOI: 10.1007/s00280-015-2751-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 04/14/2015] [Indexed: 12/14/2022]
Abstract
PURPOSE Blood platelet numbers are correlated to growth and aggressiveness of several tumor types, including hepatocellular carcinoma (HCC). We previously found that platelet lysates (hPLs) also stimulated growth and migration, and antagonized the growth-inhibitory and apoptotic effects of both Sorafenib and Regorafenib, two multikinase inhibitors, on three HCC cell lines. In this study, in vitro function of human epidermal growth factor (EGF) with and without Sorafenib or Regorafenib was investigated. METHODS An ELISA kit was used to evaluate the EGF concentrations in hPLs. In vitro function of EGF was assessed with proliferation MTT test. Apoptosis assay, scratch assays, and Transwell assays were performed for apoptosis, invasion, and migration, respectively. MAPK Activation Kit was used to explore MAPK phosphorylation. RESULTS EGF antagonized the growth inhibition of Regorafenib on three HCC cell lines. Regorafenib-mediated growth inhibition was blocked by 70 % when the cells were pre-treated with EGF. EGF also blocked Regorafenib-induced apoptosis, as well as Regorafenib-induced decreases in cell migration and invasion. The EGF effects were in turn antagonized by concomitant addition to the cultures of EGF receptor antagonist Erlotinib, showing that the EGF receptor was involved in the mechanisms of EGF-mediated blocking of Regorafenib effects. Erlotinib also partially blocked the effects of hPLs in antagonizing Regorafenib-mediated growth inhibition, showing that EGF was an important component of hPL actions. CONCLUSIONS All these results show that EGF antagonized Regorafenib-mediated growth and migration inhibition and apoptosis induction in HCC cells and reinforce the idea that microenvironment can influence cancer drug actions.
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16
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Pančoška P, Skála L, Nešetřil J, Carr BI. Evaluation of total hepatocellular cancer lifespan, including both clinically evident and preclinical development, using combined network phenotyping strategy and fisher information analysis. Semin Oncol 2015; 42:339-46. [PMID: 25843738 PMCID: PMC4388062 DOI: 10.1053/j.seminoncol.2014.12.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
We previously showed that for hepatocellular cancer (HCC) prognostication, disease parameters need to be considered within a total personal clinical context. This requires preserving the coherence of data values, observed simultaneously for each patient during baseline diagnostic evaluation. Application of the Network Phenotyping Strategy (NPS) provided quantitative descriptors of these patient coherences. Combination of these descriptors with Fisher information about the patient tumor mass and the histogram of the tumor masses in the whole cohort permitted estimation of the time from disease onset until clinical diagnosis (t(baseline)). We found faster growth of smaller tumors having total masses<70 (80% of cohort) which involved about three times more interacting cellular processes than were observed for slower growing larger tumors (20% of cohort) with total masses>70. Combining the clinical survival and t(baseline) normalized all HCC patients to a common 1,045 days of mean total disease duration (t(baseline) plus post diagnosis survival). We also found a simple relationship between the baseline clinical status, t(baseline), and survival. Every difference between individual patient baseline clinical profiles and special coherent clinical status (HL1) reduced the above common overall survival (OVS) by 65 days. In summary, we showed that HCC patients with any given tumor can best have their tumor biology understood, when account is taken of the total clinical and liver contexts, and with knowing the point in the tumor history when an HCC diagnosis is made. This ability to compute the t(baseline) from standard clinical data brings us closer to calculating survival from diagnosis of individual HCC patients.
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Affiliation(s)
- Petr Pančoška
- Department of Medicine and Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA; Computer Science Institute (IUUK) of Charles University Prague, Czech Republic
| | - Lubomír Skála
- Department of Chemical Physics and Optics, Faculty of Mathematics and Physics, Charles University Prague, Czech Republic
| | - Jaroslav Nešetřil
- Computer Science Institute (IUUK) of Charles University Prague, Czech Republic
| | - Brian I Carr
- Department of Gastroenterology and Liver Diseases Tel-Aviv Sourasky Medical Center Tel Aviv, Israel.
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Low alpha-fetoprotein HCC and the role of GGTP. Int J Biol Markers 2014; 29:e395-402. [PMID: 24832180 DOI: 10.5301/jbm.5000092] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/24/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND HCC patients are heterogeneous in terms of both tumor and liver factors. Alpha-fetoprotein (AFP) is an important prognostic tumor marker for those patients with elevated AFP levels. AIMS To examine the differences in HCC patients with high or low AFP levels in blood and evaluate the prognostic parameters in low AFP patients. METHODS A cohort of 2,440 HCC patients from 11 Italian medical centers was studied. AFP-positive patients were compared to AFP-negative ones, and the blood and tumor parameters of AFP-negative patients were examined. RESULTS Low blood AFP levels were found in 58% of the total cohort, in 64% of patients with small HCCs, and in 51% of patients with large HCCs. In patients with large tumors, platelet and gamma glutamyl transpeptidase (GGTP) levels, tumor multifocality and portal vein thrombosis (PVT) incidence were all greater than in patients with small tumors, regardless of AFP status. Patients with higher AFP levels had worse survival rates than those with low AFP in each tumor size group. In patients with small tumors, the elevated AFP was associated with significantly increased PVT and worse survival. In patients with large tumors, the elevated AFP was associated with significantly higher GGTP, ALKP, and bilirubin levels, as well as with increased PVT and multifocality, and worse survival. Low-AFP patients with high GGTP levels had worse survival than patients with low GGTP levels. CONCLUSION Patients with low AFP were the majority in this cohort, and patients with elevated GGTP had worse prognosis than those with low GGTP. GGTP may be a useful tumor and prognosis marker in low-AFP patients. AFP-negative patients are important to identify due to their enhanced survival.
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18
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Significance of platelet and AFP levels and liver function parameters for HCC size and survival. Int J Biol Markers 2014; 29:e215-23. [PMID: 24526315 DOI: 10.5301/jbm.5000064] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a heterogeneous disease with both tumor and liver factors being involved. AIMS To investigate HCC clinical phenotypes and factors related to HCC size. METHODS Prospectively-collected HCC patients' data from a large Italian database were arranged according to the maximum tumor diameter (MTD) and divided into tumor size terciles, which were then compared in terms of several common clinical parameters and patients' survival. RESULTS An higer MTD tercile was significantly associated with increased blood alpha-fetoprotein (AFP), gamma-glutamyl transpeptidase (GGTP), and platelet levels. Patients with higher platelet levels had larger tumors and higher GGTP levels, with lower bilirubin levels. However, patients with the highest AFP levels had larger tumors and higher bilirubin levels, reflecting an aggressive biology. AFP correlation analysis revealed the existence of 2 different groups of patients: those with higher and with lower AFP levels, each with different patient and tumor characteristics. The Cox proportional-hazard model showed that a higher risk of death was correlated with GGTP and bilirubin levels, tumor size and number, and portal vein thrombosis (PVT), but not with AFP or platelet levels. CONCLUSIONS An increased tumor size was associated with increased blood platelet counts, AFP and GGTP levels. Platelet and AFP levels were important indicators of tumor size, but not of survival.
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Carr BI, Pancoska P, Giannini EG, Farinati F, Ciccarese F, Rapaccini GL, Marco MD, Benvegnù L, Zoli M, Borzio F, Caturelli E, Chiaramonte M, Trevisani F. Identification of two clinical hepatocellular carcinoma patient phenotypes from results of standard screening parameters. Semin Oncol 2014; 41:406-414. [PMID: 25023357 DOI: 10.1053/j.seminoncol.2014.04.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Previous work has shown that two general processes contribute to hepatocellular cancer (HCC) prognosis: liver damage, monitored by indices such as blood bilirubin, prothrombin time (PT), and aspartate aminostransferase (AST); and tumor biology, monitored by indices such as tumor size, tumor number, presence of portal vein thrombosis (PVT) and blood alpha-fetoprotein (AFP) levels. These processes may affect one another, with prognostically significant interactions between multiple tumor and host parameters. These interactions form a context that provide personalization of the prognostic meaning of these factors for every patient. Thus, a given level of bilirubin or tumor diameter might have a different significance in different personal contexts. We previously applied network phenotyping strategy (NPS) to characterize interactions between liver function indices of Asian HCC patients and recognized two clinical phenotypes, S and L, differing in tumor size and tumor nodule numbers. Our aim was to validate the applicability of the NPS-based HCC S/L classification on an independent European HCC cohort, for which survival information was additionally available. Four sets of peripheral blood parameters, including AFP-platelets, derived from routine blood parameter levels and tumor indices from the ITA.LI.CA database, were analyzed using NPS, a graph-theory-based approach that compares personal patterns of complete relationships between clinical data values to reference patterns with significant association to disease outcomes. Without reference to the actual tumor sizes, patients were classified by NPS into two subgroups with S and L phenotypes. These two phenotypes were recognized using solely the HCC screening test results, consisting of eight common blood parameters, paired by their significant correlations, including an AFP-platelets relationship. These trends were combined with patient age, gender, and self-reported alcoholism into NPS personal patient profiles. We subsequently validated (using actual scan data) that patients in L phenotype group had 1.5× larger mean tumor masses relative to S, P = 6 × 10(-16). Importantly, with the new data, liver test pattern-identified S-phenotype patients had typically 1.7× longer survival compared to L-phenotype patients. NPS integrated the liver, tumor, and basic demographic factors. Cirrhosis-associated thrombocytopenia was typical for smaller S tumors. In L tumor phenotype, typical platelet levels increased with the tumor mass. Hepatic inflammation and tumor factors contributed to more aggressive L tumors, with parenchymal destruction and shorter survival. NPS provides integrative interpretation for HCC behavior, identifying two tumor and survival phenotypes by clinical parameter patterns. The NPS classifier is provided as an Excel tool. The NPS system shows the importance of considering each tumor marker and parameter in the total context of all the other parameters of an individual patient.
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Affiliation(s)
- Brian I Carr
- Department of Liver Tumor Biology IRCCS de Bellis, National Institute for Digestive Diseases, Castellana Grotte , BA, Italy
| | - Petr Pancoska
- Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Edoardo G Giannini
- Department of Internal Medicine, Gastroenterology Unit, University of Genoa
| | - Fabio Farinati
- Department of Surgical Science and Gastroenterology, Gastroenterology Unit, University of Padua
| | | | | | - Maria Di Marco
- Division of Medicine, Azienda Ospedaliera Bolognini, Seriate
| | - Luisa Benvegnù
- Departiment of Clinical and Experimental Medicine, Medical Unit, University of Padua
| | - Marco Zoli
- Department of Medical and Surgical Science, Internal Medicine Unit, Alma Mater Studiorum - University of Bologna
| | - Franco Borzio
- Department of Medicine, Internal Medicine and Hepatology Unit, Ospedale Fatebenefratelli, Milan
| | | | | | - Franco Trevisani
- Department of Medical Surgical Sciences, Medical Semiotics Unit, Alma Mater Studiorum - University of Bologna, Italy
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Abstract
Small hepatocellular carcinomas (HCCs) usually arise in cirrhosis, often with associated thrombocytopenia. Many patients with large HCCs have normal blood platelet counts. In this review, we compare parameter and phenotype patterns of patients with small (≤ 3 cm) and larger HCCs. A retrospective analysis was undertaken of a 4,139-patient HCC database to compare patient demographics, and liver and tumor characteristics associated with small and large HCCs, especially with respect to platelet counts. We found that patients with larger HCCs had more tumor nodules and portal vein thrombosis (PVT) positivity, and had higher blood alpha-fetoprotein (AFP), bilirubin, and platelet counts. In patients with larger tumors and normal platelets (43.7% of the cohort), tumors were larger and AFP levels were higher, with lower bilirubin and aspartate aminotransferase (AST) levels than in patients with larger tumors and thrombocytopenia (17.5%). A parsimonious multinomial regression model showed a high odds ratio for AFP and platelets for tumors>3 cm with PVT. We conclude that platelet levels are associated with distinct large HCC phenotypes.
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Affiliation(s)
- Brian I Carr
- Department of Liver Tumor Biology, IRCCS S. de Bellis, Castellana Grotte, Italy.
| | - Chih-Yun Lin
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center and Chang Gung University, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center and Chang Gung University, Kaohsiung, Taiwan
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Giuliante F, De Rose AM, Guerra V, Ardito F, Nuzzo G, Carr BI. Clinical characteristics and survival of European patients with resectable large hepatocellular carcinomas. J Gastrointest Cancer 2014; 44:329-35. [PMID: 23912605 DOI: 10.1007/s12029-013-9523-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE Large hepatocellular carcinoma (HCC) presents on cirrhosis or in the absence of cirrhosis. Prognostic factors include both tumor and liver factors. Evaluate clinical and tumor characteristics of a group of large resected HCC in European patients. METHODS Data for patients with HCC >7 cm who underwent liver resection between 1992 and 2011 were analyzed. Patients were dichotomized into those with tumor diameters of 7-10 cm or >10 cm and their characteristics and outcomes were compared. RESULTS A total of 65 hepatectomies for HCC ≥7 cm were performed. Severe fibrosis or cirrhosis was present in 41.5 % of patients. Thirty-seven (56.9 %) patients had HCC ≥10 cm. Mortality and morbidity rates were 1.5 % and 37.5 %, respectively. Preoperative blood platelet levels and serum alkaline phosphatase (ALKP) levels showed significant differences between the groups. The 3-year survival was 43.5 % and 17.4 % for patients with tumors 7-10 and ≥10 cm, respectively. CONCLUSIONS Patients with large size HCC and preserved liver function can be resected with low operative risk. ALKP levels and platelet counts were higher in the larger tumors. Given these patterns of clinical and biochemical characteristics, this group of tumors may be a selected subset of large HCCs and might potentially benefit from surgical resection.
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Affiliation(s)
- Felice Giuliante
- Hepatobiliary Surgery Unit, Department of Surgery, School of Medicine, Catholic University of the Sacred Heart, L. go A. Gemelli, 8 00168, Rome, Italy.
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Carr BI, Guerra V, Giannini EG, Farinati F, Ciccarese F, Ludovico Rapaccini G, Di Marco M, Benvegnù L, Zoli M, Borzio F, Caturelli E, Chiaramonte M, Trevisani F. Association of abnormal plasma bilirubin with aggressive hepatocellular carcinoma phenotype. Semin Oncol 2014; 41:252-8. [PMID: 24787296 DOI: 10.1053/j.seminoncol.2014.03.006] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cirrhosis-related abnormal liver function is associated with predisposition to hepatocellular carcinoma (HCC). It features in several HCC classification systems and is an HCC prognostic factor. The aim of the present study was to examine the phenotypic tumor differences in HCC patients with normal or abnormal plasma bilirubin levels. A 2,416-patient HCC cohort was studied and dichotomized into normal and abnormal plasma bilirubin groups. Their HCC characteristics were compared for tumor aggressiveness features, namely, blood alpha-fetoprotein (AFP) levels, tumor size, presence of portal vein thrombosis (PVT) and tumor multifocality. In the total cohort, elevated bilirubin levels were associated with higher AFP levels, increased PVT and multifocality, and lower survival, despite similar tumor sizes. When different tumor size terciles were compared, similar results were found, even among patients with small tumors. A multiple logistic regression model for PVT or tumor multifocality showed increased odds ratios for elevated levels of gamma glutamyl transpeptidase (GGTP), bilirubin, and AFP and for larger tumor sizes. We conclude that HCC patients with abnormal bilirubin levels had worse prognosis than patients with normal bilirubin. They also had an increased incidence of PVT and tumor multifocality, and higher AFP levels, in patients with both small and larger tumors. The results show an association between bilirubin levels and indices of HCC aggressiveness.
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Affiliation(s)
- Brian I Carr
- Liver Tumor Program, IRCCS de Bellis, Castellana Grotte, Italy.
| | - Vito Guerra
- Liver Tumor Program, IRCCS de Bellis, Castellana Grotte, Italy
| | - Edoardo G Giannini
- Departiment of Internal Medicine, Gastroenterology Unit, University of Genoa, Italy
| | - Fabio Farinati
- Departiment of Surgical Science and Gastroenterology, Gastroenterology Unit, University of Padua, Italy
| | | | | | - Maria Di Marco
- Division of Medicine, Azienda Ospedaliera Bolognini, Seriate, Italy
| | - Luisa Benvegnù
- Departiment of Clinical and Experimental Medicine, Medical Unit, University of Padua, Italy
| | - Marco Zoli
- Department of Medical and Surgical Science, Internal Medicine Unit, Alma Mater Studiorum-University of Bologna, Italy
| | - Franco Borzio
- Department of Medicine, Internal Medicine and Hepatology Unit, Ospedale Fatebenefratelli, Milan, Italy
| | | | - Maria Chiaramonte
- Gastroenterology Unit, Ospedale Sacro Cuore Don Calabria, Negrar, Italy
| | - Franco Trevisani
- Department of Medical Surgical Sciences, Medical Semiotics Unit, Alma Mater Studiorum-University of Bologna, Italy
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Carr BI, Cavallini A, D'Alessandro R, Refolo MG, Lippolis C, Mazzocca A, Messa C. Platelet extracts induce growth, migration and invasion in human hepatocellular carcinoma in vitro. BMC Cancer 2014; 14:43. [PMID: 24468103 PMCID: PMC3974148 DOI: 10.1186/1471-2407-14-43] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 01/21/2014] [Indexed: 12/21/2022] Open
Abstract
Background Thrombocytopenia has been reported to be associated with small size HCCs, and thrombocytosis to be associated with large size HCCs. The aim was to examine the effects of platelets in relation to HCC cell growth. Methods The effects of time-expired pooled normal human platelets were examined on human HCC cell line growth and invasion. Results Blood platelet numbers increased with increasing HCC tumor size and portal vein invasion. Platelet extracts enhanced cell growth in 4 human HCC cell lines, as well as cell migration, medium AFP levels and decreased apoptosis. Cell invasion was significantly enhanced, using a Matrigel-coated trans-well membrane and3D (Real-Time Imaging) invasion assay. Western blots showed that platelets caused enhanced phospho-ERK and phospho–JNK signaling and anti-apoptotic effect with increase of Bcl-xL (anti-apoptotic marker) and decrease of Bid (pro-apoptotic marker) levels. Their growth effects were blocked by a JNK inhibitor. Conclusions Platelets stimulated growth and invasion of several HCC cell lines in vitro, suggesting that platelets or platelet growth factors could be a potential pharmacological target.
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Affiliation(s)
- Brian I Carr
- Laboratory of biochemistry and tumor biology, National Institute for Digestive Diseases, IRCCS 'Saverio de Bellis', via Turi 27, 70013 Castellana Grotte, BA, Italy.
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Abstract
BACKGROUND Massive hepatocellular carcinomas (HCCs) are uncommon and poorly characterized. AIM To characterize a large cohort of HCC patients with massive tumors, with documented baseline characteristics and survival data. METHODS Records were examined of a cohort of 344 biopsy-proven and randomly presenting unresectable HCC patients with tumors of at least 10 cm diameter (massive), which were analyzed for their clinical characteristics and survival. RESULTS Massive HCC patients were significantly different from others, in having less severe cirrhosis and higher blood platelet counts, α-fetoprotein (AFP), alkaline phosphatase (ALKP), and γ-glutamyl transpeptidase (GGTP) levels. Platelets, ALKP, and GGTP correlated with tumor size. Within massive HCCs, ALKP levels related to tumor number, whereas platelet counts related to tumor size. AFP and GGTP related to neither. All four parameters related to survival. A multivariate Cox proportional hazard model showed that ALKP and AFP were significant for overall survival. Survival of massive tumors was not significantly worse than for other larger tumors. CONCLUSION Massive HCCs were characterized by high blood platelets, AFP, ALKP, and GGTP levels. AFP levels were important for survival, but did not directly relate to tumor size or number, suggesting that AFP represents some other property of massive HCC biology. Patients with massive HCC should thus be considered for active therapeutic intervention, just as for other sizes of HCC.
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Carr BI, Guerra V. Hepatocellular carcinoma size: platelets, γ-glutamyl transpeptidase, and alkaline phosphatase. Oncology 2013; 85:153-9. [PMID: 23988857 DOI: 10.1159/000354416] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Accepted: 07/10/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Thrombocytopenia is a cirrhosis surrogate which is associated with hepatocellular carcinoma (HCC) development. AIMS To compare the clinical characteristics of HCC in the presence and absence of thrombocytopenia. METHODS The baseline clinical data of a large cohort of randomly presenting, biopsy-proven HCC patients was examined for phenotypic patterns, after organizing the data by tumor size and subdivision into tumor size terciles. RESULTS Small tumor size tercile I patients had the lowest platelet counts. Patients with higher platelets within each size tercile had the lowest bilirubin and prothrombin time and higher γ-glutamyl transpeptidase (GGTP) and alkaline phosphatase (ALKP) levels. When patients with similar platelet and bilirubin levels were compared, α-fetoprotein, GGTP, and ALKP were significantly increased in patients with larger tumors and in the presence of portal vein thrombus. Large tumor size tercile III patients without thrombocytopenia had larger tumors, higher GGTP and ALKP, and lower bilirubin levels than did patients with thrombocytopenia. CONCLUSIONS Thrombocytopenia occurred in 40.7% of patients with smaller tumors but only in 11.3% of patients with larger tumors. Patients without thrombocytopenia had elevated GGTP and ALKP and lower bilirubin levels, regardless of tumor size, but they also had larger tumors within the large tumor tercile.
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Affiliation(s)
- Brian I Carr
- Department of Nutritional Carcinogenesis, IRCCS S. de Bellis National Institute for Digestive Diseases, Castellana Grotte, Italy
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Abstract
BACKGROUND Thrombocytopenia has been reported to be both a risk factor for hepatocellular carcinoma (HCC) development as well as a prognostic factor. Many HCCs also occur in presence of normal platelets. AIM To examine a cohort of HCC patients with associated thrombocytosis. METHODS Records were examined of a cohort of 634 biopsy-proven and randomly presenting HCC patients without thrombocytopenia. RESULTS In the total cohort, 52 patients were identified with thrombocytosis (platelet levels >400 × 10(9)/L) and compared with 582 patients with normal platelet values. The average tumor sizes were 13.1 versus 8.8 cm (p < 0.0001), and their total average bilirubin levels were 0.9 versus 1.5 (p = 0.02), comparing thrombocytosis patients versus normal platelet count HCC patients. These differences were even more pronounced in patients with HCC sizes >5 cm. Thrombocytosis patients were younger and had less cirrhosis, but similar percent with hepatitis B or C or alcohol consumption. CONCLUSION Thrombocytosis in association with HCC occurs in patients with larger tumor sizes and better liver function.
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Pancoska P, Lu SN, Carr BI. Phenotypic Categorization and Profiles of Small and Large Hepatocellular Carcinomas. ACTA ACUST UNITED AC 2013; Suppl 12. [PMID: 23956952 DOI: 10.4172/2161-069x.s12-001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We used a database of 4139 Taiwanese HCC patients to take a new approach (Network Phenotyping Strategy) to HCC subset identification. Individual parameters for liver function tests, complete blood count, portal vein thrombosis, AFP levels and clinical demographics of age, gender, hepatitis or alcohol consumption, were considered within the whole context of complete relationships, being networked with all other parameter levels in the entire cohort. We identified 4 multi-parameter patterns for one tumor phenotype of patients and a separate 5 multi-parameter patterns to characterize another tumor phenotype of patterns. The 2 subgroups were quite different in their clinical profiles. The means of the tumor mass distributions in these phenotype subgroups were significantly different, one being associated with larger (L) and the other with smaller (S) tumor masses. These significant differences were seen systematically throughout the tumor mass distributions. Essential and common clinical components of L-phenotype patterns included simultaneously high blood levels of AFP and platelets plus presence of portal vein thrombosis. S included higher levels of liver inflammatory parameters. The 2 different parameter patterns of L and S subgroups suggest different mechanisms; L, possibly involving tumor-driven processes and S more associated with liver inflammatory processes.
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Affiliation(s)
- Petr Pancoska
- Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA, USA
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Markman M. Retrospective analyses of cancer trials or existing clinical databases: potential for highly clinically relevant hypothesis generation. Oncology 2012; 83:329-30. [PMID: 23007076 DOI: 10.1159/000342174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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