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ABSTRACT: Preliminary results demonstrated that concurrent sunitinib and stereotactic body radiation therapy (SBRT) is an active regimen for metastases limited in number and extent. This analysis was conducted to determine the long-term survival and cancer control outcomes for this novel regimen. Forty-six patients with oligometastases, defined as five or fewer clinical detectable metastases from any primary site, were treated on a phase I/II trial from February 2007 to September 2010. The majority of patients were treated with 37.5 mg sunitinib (days 1-28) and SBRT 50 Gy (days 8-12 and 15-19) and maintenance sunitinib was used in 39 % of patients. Median follow up for surviving patients is 3.6 years. The 4-year estimates for local control, distant control, progression-free and overall survival were 75 %, 40 %, 34 % and 29 %, respectively. At last follow-up, 26 % of patients were alive without evidence of disease, 7 % were alive with distant metastases, 48 % died from distant metastases, 2 % died from local progression, 13 % died from comorbid illness, and 4 % died from treatment-related toxicities. Patients with kidney and prostate primary tumors were associated with a significantly improved overall survival (hazard ratio = 0.25, p = 0.04). Concurrent sunitinib and SBRT is a promising approach for the treatment of oligometastases and further study of this novel combination is warranted.
Targeted Oncology 05/2013; · 3.61 Impact Factor
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Hepatology 01/2013; · 11.66 Impact Factor
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ABSTRACT: Hepatocellular adenoma (HCA) is a benign neoplasm arising from hepatocytes. There is evidence that the inflammatory subtype may be associated with obesity and alcohol use and that men with metabolic syndrome may be at risk for malignant transformation of HCA. We sought to explore the combined experience of US centers as reported in the literature to document the epidemiologic shift in risk factors for HCA formation in the United States, namely, a shift from oral contraceptive pills (OCPs) to an emerging role of obesity as a contributing factor. Methods. Publications reporting HCA in the United States were identified through a PubMed search and a review of the literature. We excluded publications prior to 1970, single case reports, and publications for which there was no data available regarding patient characteristics including OCP use and the number of adenomas. Conclusion. Whereas earlier reports of HCA in the United States described cases exclusively in women exposed to OCPs, there is a trend towards an increase in HCAs reported in men, HCAs in the absence of OCP use, and increased reporting of multiple HCAs. This may be a result of newer OCP formulations and increasing prevalence of obesity.
International journal of hepatology. 01/2013; 2013:604860.
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ABSTRACT: OBJECTIVES: The relative roles of liver resection (LR) and liver transplantation (LT) in the treatment of a solitary hepatocellular carcinoma (HCC) remain unclear. This study was conducted to provide a retrospective intention-to-treat comparison of these two curative therapies. METHODS: Records maintained at the study centre for all patients treated with LR or listed for LT for hepatitis C-associated HCC between January 2002 and December 2007 were reviewed. Inclusion criteria required: (i) an initial diagnosis of a solitary HCC lesion measuring ≤ 5 cm, and (ii) Child-Pugh class A or B cirrhosis. The primary endpoint analysed was intention-to-treat survival. RESULTS: A total of 75 patients were listed for transplant (LT-listed group) and 56 were resected (LR group). Of the 75 LT-listed patients, 23 (30.7%) were never transplanted because they were either removed from the waiting list (n = 13) or died (n = 10). Intention-to-treat median survival was superior in the LR group compared with the LT-listed group (61.8 months vs. 30.6 months), but the difference did not reach significance. Five-year recurrence was higher in the LR group than in the 52 LT patients (71.5% vs. 30.5%; P < 0.001). CONCLUSIONS: In the context of limited donor organ availability, partial hepatectomy represents an efficacious primary approach in properly selected patients with hepatitis C-associated HCC.
HPB 08/2012; · 1.60 Impact Factor
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Anja Lachenmayer,
Clara Alsinet,
Radoslav Savic,
Laia Cabellos,
Sara Toffanin,
Yujin Hoshida,
Augusto Villanueva,
Beatriz Minguez,
Philippa Newell,
Hung-Wen Tsai,
Jordi Barretina,
Swan Thung,
Stephen C Ward,
Jordi Bruix,
Vincenzo Mazzaferro, Myron Schwartz,
Scott L Friedman,
Josep M Llovet
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ABSTRACT: PURPOSE: Hepatocellular carcinoma (HCC) is a heterogeneous cancer with active Wnt signaling. Underlying biologic mechanisms remain unclear and no drug targeting this pathway has been approved to date. We aimed to characterize Wnt-pathway aberrations in HCC patients, and to investigate sorafenib as a potential Wnt modulator in experimental models of liver cancer. EXPERIMENTAL DESIGN: The Wnt-pathway was assessed using mRNA (642 HCCs and 21 liver cancer cell lines) and miRNA expression data (89 HCCs), immunohistochemistry (108 HCCs), and CTNNB1-mutation data (91 HCCs). Effects of sorafenib on Wnt signaling were evaluated in four liver cancer cell lines with active Wnt signaling and a tumor xenograft model. RESULTS: Evidence for Wnt activation was observed for 315 (49.1%) cases, and was further classified as CTNNB1 class (138 cases [21.5%]) or Wnt-TGFβ class (177 cases [27.6%]). CTNNB1 class was characterized by upregulation of liver-specific Wnt-targets, nuclear β-catenin and glutamine-synthetase immunostaining, and enrichment of CTNNB1-mutation-signature, whereas Wnt-TGFβ class was characterized by dysregulation of classical Wnt-targets and the absence of nuclear β-catenin. Sorafenib decreased Wnt signaling and β-catenin protein in HepG2 (CTNNB1 class), SNU387 (Wnt-TGFβ class), SNU398 (CTNNB1-mutation), and Huh7 (lithium-chloride-pathway activation) cell lines. In addition, sorafenib attenuated expression of liver-related Wnt-targets GLUL, LGR5, and TBX3. The suppressive effect on CTNNB1 class-specific Wnt-pathway activation was validated in vivo using HepG2 xenografts in nude mice, accompanied by decreased tumor volume and increased survival of treated animals. CONCLUSIONS: Distinct dysregulation of Wnt-pathway constituents characterize two different Wnt-related molecular classes (CTNNB1 and Wnt-TGFβ), accounting for half of all HCC patients. Sorafenib modulates β-catenin/Wnt signaling in experimental models that harbor the CTNNB1 class signature. Clin Cancer Res; 18(18); 4997-5007. ©2012 AACR.
Clinical Cancer Research 07/2012; 18(18):4997-5007. · 7.74 Impact Factor
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ABSTRACT: Asian series have shown 5 year survival of ∼70% after resection of hepatocellular cancer (HCC) <2cm. Western outcomes with resection have not been as good. In addition ablation of HCC ≤ 2cm has been shown to achieve competitive results leaving the role of resection unclear in these patients. Records of patients undergoing resection at two Western centers between 1/1990 and 12/2009 were reviewed. Patients with a single HCC ≤ 2cm on pathology were included. Thirty clinical variables including demographics, liver function, tumor characteristics, nature of the surgery, and the surrounding liver were examined. An exploratory statistical analysis was conducted to determine variables associated with recurrence and survival. The study included 132 patients with a median follow-up of 37.5 months. There was 1 (<1%) 90-day mortality. There were 32 deaths with a median survival of 74.5 months and 5-year survival of 70% (63% in cirrhotics). Median time-to-recurrence was 31.6 months and 5-year recurrence rate was 68%. Presence of satellites (HR=2.46, p=0.031) and platelet count <150,000/μl (HR=2.37, p=0.026) were independently associated with survival. Presence of satellites (HR=2.79, p=0.003), cirrhosis (HR=2.3, p=0.010), and non-anatomic resection (HR=1.79, p=0.031) were independently associated with recurrence. Patients with a single HCC ≤ 2cm and platelet count ≥150,000/μl achieved median and 5-year survivals of 138 months and 81%, respectively. CONCLUSION: Resection of HCC ≤ 2cm is safe and achieves excellent results in Western centers. Recurrence continues to be a significant problem. Presence of satellites, platelet count, anatomic resection and cirrhosis are associated with outcomes after resection even among such early tumors. Resection should continue to be considered a primary treatment modality in patients with small HCC and well preserved liver function. (HEPATOLOGY 2012.).
Hepatology 05/2012; · 11.66 Impact Factor
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ABSTRACT: The aim of this study was to examine the features and outcomes of noncirrhotic patients undergoing resection for hepatocellular carcinoma.
Ten percent to 40% of hepatocellular carcinoma cases arise within a noncirrhotic liver parenchyma. Resection is the standard therapy, yet the published resection series from the West are small.
From January 1987 to December 2009, our center performed 206 partial liver resections for nonfibrotic or minimally fibrotic (Scheuer stage 0-2) hepatocellular carcinoma. We retrospectively reviewed these cases and performed univariate and multivariate analyses for predictors of long-term outcomes.
Eighty-one patients (39.3%) had chronic hepatitis B infection and 23 patients (11.2%) had chronic hepatitis C. The remaining 83 (39.8%) had no underlying liver disease. Average age was 60.2 years, and 68.4% of the patients were male. Average tumor size was 8.2 cm. Overall survival at 5 years was 46.3%. Recurrence at 5 years was 50.0%. Independent predictors for decreased survival were tumor size larger than 7.0 cm, creatinine more than 1.0 mg/dL, satellite nodules, albumin less than 3.5 gm/dL, alpha-fetoprotein more than 100 ng/mL, and any vascular invasion. Chronic hepatitis B virus infection predicted longer survival. Independent predictors for decreased time to recurrence were albumin less than 3.5 gm/dL, any vascular invasion, age more than 60 years, tumor size larger than 7.0 cm, and alpha-fetoprotein more than 100 ng/mL. Treatment of recurrence with either repeat resection or ablation was associated with a median survival of 50.4 months from time of recurrence.
Hepatocellular carcinoma can develop in a minimally fibrotic hepatitis C patient. Tumor-related factors such as vascular invasion primarily determine long-term outcomes. Hepatitis B virus-associated tumors seem to have a better prognosis in the nonfibrotic or minimally fibrotic population. Aggressive treatment of recurrence is warranted.
Annals of surgery 01/2012; 255(6):1135-43. · 7.90 Impact Factor
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Charles C L Tong,
Eric C Ko,
Max W Sung,
Jamie A Cesaretti,
Richard G Stock,
Stuart H Packer,
Kevin Forsythe,
Eric M Genden, Myron Schwartz,
K H Vincent Lau,
Matthew Galsky,
Junko Ozao-Choy,
Shu-Hsia Chen,
Johnny Kao
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ABSTRACT: Preclinical data suggest that sunitinib enhances the efficacy of radiotherapy. We tested the combination of sunitinib and hypofractionated image-guided radiotherapy (IGRT) in a cohort of patients with historically incurable distant metastases.
Twenty five patients with oligometastases, defined as 1-5 sites of active disease on whole body imaging, were enrolled in a phase II trial from 2/08 to 9/10. The most common tumor types treated were head and neck, liver, lung, kidney and prostate cancers. Patients were treated with the recommended phase II dose of 37.5 mg daily sunitinib (days 1-28) and IGRT 50 Gy (days 8-12 and 15-19). Maintenance sunitinib was used in 33% of patients. Median follow up was 17.5 months (range, 0.7 to 37.4 months).
The 18-month local control, distant control, progression-free survival (PFS) and overall survival (OS) were 75%, 52%, 56% and 71%, respectively. At last follow-up, 11 (44%) patients were alive without evidence of disease, 7 (28%) were alive with distant metastases, 3 (12%) were dead from distant metastases, 3 (12%) were dead from comorbid illness, and 1 (4%) was dead from treatment-related toxicities. The incidence of acute grade ≥ 3 toxicities was 28%, most commonly myelosuppression, bleeding and abnormal liver function tests.
Concurrent sunitinib and IGRT achieves major clinical responses in a subset of patients with oligometastases.
ClinicalTrials.gov NCT00463060.
PLoS ONE 01/2012; 7(6):e36979. · 4.09 Impact Factor
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ABSTRACT: Serous cystic neoplasms of the pancreas are generally considered benign lesions. Malignant counterparts have been occasionally described, and the diagnosis of malignancy is based solely on the presence of synchronous or metachronous metastases to the lymph nodes or liver, direct tumor invasion into adjacent organs, or vascular invasion. However, these malignant serous cystic tumors are lined by benign-appearing glycogen-rich cuboidal cells, which have been morphologically indistinguishable from benign microcystic serous cystadenoma in all the cases reported so far. We report a unique case of microcystic serous cystadenoma giving rise to carcinoma with distinctive histologic features including signet ring-like cells and solid nests. We believe that this case represents the first case of a cytologically malignant neoplasm arising from a benign serous cystadenoma (carcinoma ex microcystic serous cystadenoma).
The American journal of surgical pathology 12/2011; 36(2):305-10. · 4.06 Impact Factor
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Liver Transplantation 06/2011; 17 Suppl 2:S162-6. · 3.39 Impact Factor
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Beatriz Mínguez,
Yujin Hoshida,
Augusto Villanueva,
Sara Toffanin,
Laia Cabellos,
Swan Thung,
John Mandeli,
Daniela Sia,
Craig April,
Jian-Bing Fan,
Anja Lachenmayer,
Radoslav Savic,
Sasan Roayaie,
Vincenzo Mazzaferro,
Jordi Bruix, Myron Schwartz,
Scott L Friedman,
Josep M Llovet
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ABSTRACT: Vascular invasion is a major predictor of tumor recurrence after surgical treatments for hepatocellular carcinoma (HCC). While macroscopic vascular invasion can be detected by radiological techniques, pre-operative detection of microscopic vascular invasion, which complicates 30-40% of patients with early tumors, remains elusive.
A total of 214 patients with hepatocellular carcinoma who underwent resection were included in the study. By using genome-wide gene-expression profiling of 79 hepatitis C-related hepatocellular carcinoma samples (training set), a gene-expression signature associated with vascular invasion was defined. The signature was validated in formalin-fixed paraffin-embedded tissues obtained from an independent set of 135 patients with various etiologies.
A 35-gene signature of vascular invasion was defined in the training set, predicting vascular invasion with an accuracy of 69%. The signature was independently associated with the presence of vascular invasion (OR 3.38, 95% CI 1.48-7.71, p=0.003) along with tumor size (diameter greater than 3 cm, OR 2.66, 95% CI 1.17-6.05, p=0.02). In the validation set, the signature discarded the presence of vascular invasion with a negative predictive value of 0.77, and significantly improved the diagnostic power of tumor size alone (p=0.045).
The assessment of a gene-expression signature obtained from resected biopsied tumor specimens improved the diagnosis of vascular invasion beyond clinical variable-based prediction. The signature may aid in candidate selection for liver transplantation, and guide the design of clinical trials with experimental adjuvant therapies.
Journal of Hepatology 04/2011; 55(6):1325-31. · 9.26 Impact Factor
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Davide Ghinolfi,
Josep Martí,
Gonzalo Rodríguez-Laiz,
Mark Sturdevant,
Kishore Iyer,
Domenico Bassi,
Corey Scher, Myron Schwartz,
Thomas Schiano,
Hiroshi Sogawa,
Juan del Rio Martin
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ABSTRACT: The use of temporary porto-caval shunt (TPCS) has been shown to improve hemodynamic stability and renal function in patients undergoing orthotopic liver transplantation (OLT). We evaluated the impact of TPCS in OLT and analyzed the differences according to model for end-stage liver disease (MELD), donor risk index (DRI) and D-MELD. This is a retrospective single-center analysis of 148 consecutive OLT. Fifty-eight OLT were performed using TPCS and 90 without TPCS. Donor and recipient data with pre-OLT, intraoperative and postoperative variables were reviewed. Overall graft survival was 89.9% at 3 months and 81.7% at 1 year. Graft survival at 3 months and 1 year was 93.1% and 79.2%, respectively, in TPCS group versus 85.6% and 82.2%, respectively, in non-TPCS group (P = NS). Intraoperative packed red blood cells requirement was lower in TPCS group (7.5 ± 5.8 vs. 12.2 ± 14.2, P = 0.006) and non-TPCS group required higher intraoperative total dose of phenylephrine (16% vs. 28%, P = 0.04). TPCS group had lower 30-day postoperative mortality (1.7% vs. 10%, P = 0.04), no difference was observed at 90 days. Graft survival was lower in patients with high DRI; in this group graft loss was higher at 1 month (25% vs. 4.3%, P = 0.005) and 3 months (25% vs. 4.3%, P = 0.005) when TPCS was not used. TPCS improves perioperative outcome, this being more evident when high-risk grafts are placed into high-risk patients.
Transplant International 03/2011; 24(3):243-50. · 2.92 Impact Factor
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Sara Toffanin,
Yujin Hoshida,
Anja Lachenmayer,
Augusto Villanueva,
Laia Cabellos,
Beatriz Minguez,
Radoslav Savic,
Stephen C Ward,
Swan Thung,
Derek Y Chiang,
Clara Alsinet,
Victoria Tovar,
Sasan Roayaie, Myron Schwartz,
Jordi Bruix,
Samuel Waxman,
Scott L Friedman,
Todd Golub,
Vincenzo Mazzaferro,
Josep M Llovet
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ABSTRACT: Hepatocellular carcinoma (HCC) is a heterogeneous tumor that develops via activation of multiple pathways and molecular alterations. It has been a challenge to identify molecular classes of HCC and design treatment strategies for each specific subtype. MicroRNAs (miRNAs) are involved in HCC pathogenesis, and their expression profiles have been used to classify cancers. We analyzed miRNA expression in human HCC samples to identify molecular subclasses and oncogenic miRNAs.
We performed miRNA profiling of 89 HCC samples using a ligation-mediated amplification method. Subclasses were identified by unsupervised clustering analysis. We identified molecular features specific for each subclass using expression pattern (Affymetrix U133 2.0; Affymetrix, Santa Clara, CA), DNA change (Affymetrix STY Mapping Array), mutation (CTNNB1), and immunohistochemical (phosphor[p]-protein kinase B, p-insulin growth factor-IR, p-S6, p-epidermal growth factor receptor, β-catenin) analyses. The roles of selected miRNAs were investigated in cell lines and in an orthotopic model of HCC.
We identified 3 main clusters of HCCs: the wingless-type MMTV integration site (32 of 89; 36%), interferon-related (29 of 89; 33%), and proliferation (28 of 89; 31%) subclasses. A subset of patients with tumors in the proliferation subclass (8 of 89; 9%) overexpressed a family of poorly characterized miRNAs from chr19q13.42. Expression of miR-517a and miR-520c (from ch19q13.42) increased proliferation, migration, and invasion of HCC cells in vitro. MiR-517a promoted tumorigenesis and metastatic dissemination in vivo.
We propose miRNA-based classification of 3 subclasses of HCC. Among the proliferation class, miR-517a is an oncogenic miRNA that promotes tumor progression. There is rationale for developing therapies that target miR-517a for patients with HCC.
Gastroenterology 02/2011; 140(5):1618-28.e16. · 11.68 Impact Factor
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ABSTRACT: Cholangiocarcinomas are malignant tumors that derive from cholangiocytes of small intrahepatic bile ducts or bile ductules (intrahepatic cholangiocarcinoma; ICC), or of large hilar or extrahepatic bile ducts (extrahepatic cholangiocarcinoma; ECC). ICC and ECC differ in morphology, pathogenesis, risk factors, treatment, and prognosis. This review focuses on ICC, which is rising in incidence with the emergence of hepatitis C virus (HCV) infection as a risk factor. The authors examined 73 ICC, which were resected at The Mount Sinai Medical Center in New York City, and reviewed the literature. The tumors were categorized into classical and nonclassical ICCs based on histopathology. Classical ICCs (54.8%) were characterized by a tubular, glandular, or nested pattern of growth, were significantly associated with tumor size of more than 5 cm and the absence of underlying liver disease and/or advanced fibrosis. Nonclassical ICCs (45.2%) consisted of tumors with trabecular architecture, tumors that exhibited features of extrahepatic carcinomas, and carcinomas considered to be derived from hepatic progenitor cells, i.e., combined hepatocellular/cholangiocarcinomas and cholangiolocellular carcinomas (ductular type of ICC). They were smaller and often arose in chronic liver disease, mostly HCV infection, and/or with significant fibrosis. The role of immunohistochemistry in the diagnosis of ICC and the importance of the new American Joint Committee on Cancer Staging System for ICC are also discussed.
Seminars in Liver Disease 02/2011; 31(1):49-60. · 7.05 Impact Factor
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ABSTRACT: The authors present an interesting case of a 60-year-old man who underwent right hepatectomy for a diagnosis of hepatocellular carcinoma (HCC) on a background of noncirrhotic chronic hepatitis C. Pathologic examination confirmed the presence of HCC near the porta hepatis, which invaded the right portal vein branch. In addition, a well-demarcated 13.5 × 7.8 × 4.0 cm yellow and firm area upstream of the HCC was noted. This yellow area corresponded to a tumoral ductular proliferation, which cytologically was extremely bland, but invaded portal tracts and the adjacent liver parenchyma. This tumoral proliferation mimicked ductular reaction, except that it had more anastomosing structures and was associated with abundant hyalinized fibrotic stroma. Cytologically, the tumor cells had round to oval nuclei with fine chromatin, indistinct nucleoli, and scant cytoplasm. They exhibited immunohistochemical features of hepatic progenitor cells, i.e., expressing CK7, CK19, and N-CAM; and their malignancy was supported by the p53 and Ki67 immunoreactivity. The authors concluded that the patient had cholangiolocellular carcinoma with an aggressive hepatocellular carcinoma component. Cholangiolocellular carcinoma has been reported to be associated with chronic hepatitis C viral infection and to derive from hepatic progenitor cells, which explains why hepatocellular carcinoma and/or cholangiocarcinoma component may be present.
Seminars in Liver Disease 02/2011; 31(1):104-10. · 7.05 Impact Factor
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ABSTRACT: Recurrence of hepatocellular cancer after resection is a significant problem. The optimal treatment of patients with intrahepatic recurrence after resection and well-preserved liver function is not clear. We analyzed the outcomes of patients undergoing a second hepatic resection for recurrent hepatocellular cancer at a single Western center.
The records of all patients undergoing primary hepatic resection for hepatocellular cancer between January 1994 and January 2009 were reviewed. Patients with a single intrahepatic recurrence, Child's A liver function, and platelet count>100,000/μl underwent a second hepatic resection. Clinical data was recorded and analyzed.
Of the 487 patients undergoing primary resection, 221 developed recurrence, and 35 underwent a second hepatic resection. There were no perioperative mortalities. There were 10 deaths during the study period; 5-year overall survival was 67% from second resection. Time to recurrence from primary resection<1 year and gross vascular invasion at second resection were predictors of survival and recurrence. Patients with recurrence>1 year from primary resection and without gross vascular invasion had a 5-year survival of 81%. There were 17 recurrences with a 3-year recurrence rate of 55%.
Second hepatic resection for recurrent hepatocellular cancer is applicable in about 15% of patient with recurrence. The procedure is safe and can achieve excellent results in well-selected patients. Recurrence continues to be a significant problem.
Journal of Hepatology 12/2010; 55(2):346-50. · 9.26 Impact Factor
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ABSTRACT: Primary hepatic signet ring cell neuroendocrine tumor is extremely rare and is characterized by distinct intracytoplasmic hyaline vacuoles that are mucin negative and cytokeratin positive. The unique histological features may cause difficulty in diagnosis and delay patient care. Here the authors report a 49-year-old man with an incidental finding of a 2.7 cm liver mass in the absence of chronic liver disease. The resected tumor was grossly unencapsulated but well demarcated with friable tissue texture. Microscopically, the entire tumor consisted of sheets of monotonous cells separated by delicate microvasculature. The tumor cells had granular chromatin, inconspicuous nucleoli, and eosinophilic cytoplasm. Many of the tumor cells had eccentric, pale intracytoplasmic vacuoles resembling signet ring cells in adenocarcinoma. Immunohistochemical studies showed that the tumor cells were positive for neuroendocrine markers and that the intracytoplasmic vacuoles were negative for mucin but strongly positive for cytokeratins. Careful systemic search including OctreoScan scintigraphy (Mallinckrodt Medical, Inc., St. Louis, MO) and capsule endoscopy failed to reveal any other tumors. A diagnosis of primary hepatic signet ring cell neuroendocrine tumor was established. Ten months after surgery, the patient is well without any other detectable tumor on radiology. Serological neuroendocrine markers are also within normal limits.
Seminars in Liver Disease 11/2010; 30(4):422-8. · 7.05 Impact Factor
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ABSTRACT: More than 90% of cases of hepatocellular carcinoma develop as a consequence of underlying liver disease (most commonly viral hepatitis), often resulting in impaired liver function. In such cases, transplantation is an appealing alternative as it can potentially treat both the malignancy and the underlying disease. When a transplant is not readily available due to organ scarcity, borderline cases must be considered for resection. The function of the underlying liver can be assessed by the Child-Pugh score or by quantitative tests such as indocyanine green clearance, lidocaine metabolism, and arterial body ketone ratio; liver biopsy pathology scoring and the platelet count can serve as indicators of fibrosis and portal hypertension. Another important factor to be considered is the risk of tumor recurrence, either because of unrecognized metastasis or due to de novo tumor formation. Both factors must be considered in weighing resection against nonsurgical alternatives. Preoperative portal vein embolization is a strategy that can evoke 'regeneration' in anticipation of surgery, serving as a 'stress test' of the liver's regenerative capacity.
Oncology 07/2010; 78 Suppl 1:131-4. · 2.27 Impact Factor
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Victoria Tovar,
Clara Alsinet,
Augusto Villanueva,
Yujin Hoshida,
Derek Y Chiang,
Manel Solé,
Swan Thung,
Susana Moyano,
Sara Toffanin,
Beatriz Mínguez,
Laia Cabellos,
Judit Peix, Myron Schwartz,
Vincenzo Mazzaferro,
Jordi Bruix,
Josep M Llovet
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ABSTRACT: IGF signaling has a relevant role in a variety of human malignancies. We analyzed the underlying molecular mechanisms of IGF signaling activation in early hepatocellular carcinoma (HCC; BCLC class 0 or A) and assessed novel targeted therapies blocking this pathway.
An integrative molecular dissection of the axis was conducted in a cohort of 104 HCCs analyzing gene and miRNA expression, structural aberrations, and protein activation. The therapeutic potential of a selective IGF-1R inhibitor, the monoclonal antibody A12, was assessed in vitro and in a xenograft model of HCC.
Activation of the IGF axis was observed in 21% of early HCCs. Several molecular aberrations were identified, such as overexpression of IGF2 -resulting from reactivation of fetal promoters P3 and P4-, IGFBP3 downregulation and allelic losses of IGF2R (25% of cases). A gene signature defining IGF-1R activation was developed. Overall, activation of IGF signaling in HCC was significantly associated with mTOR signaling (p=0.035) and was clearly enriched in the Proliferation subclass of the molecular classification of HCC (p=0.001). We also found an inverse correlation between IGF activation and miR-100/miR-216 levels (FDR<0.05). In vitro studies showed that A12-induced abrogation of IGF-1R activation and downstream signaling significantly decreased cell viability and proliferation. In vivo, A12 delayed tumor growth and prolonged survival, reducing proliferation rates and inducing apoptosis.
Integrative genomic analysis showed enrichment of activation of IGF signaling in the Proliferation subclass of HCC. Effective blockage of IGF signaling with A12 provides the rationale for testing this therapy in clinical trials.
Journal of Hepatology 02/2010; 52(4):550-9. · 9.26 Impact Factor
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ABSTRACT: More than 90% of cases of hepatocellular carcinoma (HCC) develop as a consequence of underlying liver disease (most commonly viral hepatitis), often resulting in impaired liver function. In such cases, transplantation is an appealing alternative as it can potentially cure both the malignancy and the underlying disease. When transplant is not readily available due to organ scarcity, borderline cases must be considered for resection. The function of the underlying liver can be assessed by the Child Pugh score or by quantitative tests such as indocyanine green (ICG) clearance, metabolism of lidocaine to the metabolite MEG-X, and the arterial body ketone ratio (AKBR); liver biopsy pathology scoring and the platelet count can serve as indicators of fibrosis and portal hypertension. Another important factor to be considered is the risk of tumor recurrence, either because of unrecognized metastasis or due to de-novo tumor formation. Both factors must be considered in weighing resection against nonsurgical alternatives. Preoperative portal vein embolization is a strategy that can evoke regeneration in anticipation of surgery, serving as a "stress test" of the liver's regenerative capacity.
Journal of hepato-biliary-pancreatic sciences. 11/2009; 17(4):385-8.
