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ABSTRACT: The present study examines the presentation and outcomes of hepatocellular carcinoma (HCC) at a Western centre over the last decade.
Between January 2000 and September 2009, 1010 patients with HCC were evaluated at the University of Pittsburgh Medical Center (UPMC). Retrospectively, four treatment groups were classified: no treatment (NT), systemic therapy (ST), hepatic artery-based therapy (HAT) and surgical intervention (SI) including radiofrequency ablation, hepatic resection and transplantation. Kaplan-Meier analysis assessed survival between groups. Cox regression analysis identified factors predicting survival.
Patients evaluated were 75% male, 87% Caucasian, 84% cirrhotic, and predominantly diagnosed with hepatitis C. In all, 169 patients (16.5%) received NT, 25 (2.4%) received ST, 529 (51.6%) received HAT and 302 (29.5%) received SI. Median survival was 3.6, 5.6, 8.8, and 83.5 months with NT, ST, HAT and SI, respectively (P= 0.001). Transplantation increased from 9.5% to 14.2% after the model for end-stage liver disease (MELD) criteria granted HCC patients priority points. Survival was unaffected by bridging transplantation with HAT or SI (P= 0.111). On multivariate analysis, treatment modality was a robust predictor of survival after adjusting for age, gender, AFP, Child-Pugh classification and cirrhosis (P < 0.001, χ(2) = 460).
Most patients were not surgical candidates and received HAT alone. Surgical intervention, especially transplantation, yields the best survival.
HPB 10/2011; 13(10):712-22. · 1.60 Impact Factor
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ABSTRACT: Gallstones appear more frequently in patients with cirrhosis and open cholecystectomy in this patient population is associated with higher morbidity and mortality. The aim of the present study was to evaluate experience with laparoscopic cholecystectomy in patients with cirrhosis and to provide recommendations for management.
Retrospective review of laparoscopic cholecystectomy in patients with cirrhosis from March 1999 to May 2008 was performed. Peri-operative characteristics and subgroup analysis were performed in patients with Child-Pugh's classes A, B and C cirrhosis.
A total of 68 patients were reviewed in this study. In all, 69% of the patients were Child's class A. The most common indication for cholecystectomy was chronic/symptomatic cholelithiasis (68%). Compared with patients with Child's class B and C, laparoscopic cholecystectomy in patients with Child's class A was associated with significantly decreased operative time (P= 0.01), blood loss (P= 0.001), conversion to open cholecystectomy (P= 0.001) and length of hospital stay (P= 0.001).
Laparoscopic cholecystectomy in patients with cirrhosis is feasible with no mortality and low morbidity, especially in patients with Child's class A cirrhosis.
HPB 03/2011; 13(3):192-7. · 1.60 Impact Factor
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ABSTRACT: Adult hepatic progenitor cells are activated during regeneration when hepatocytes and bile duct epithelium are damaged or unable to proliferate. On the basis of its role as a tumor suppressor and in the potential malignant transformation of stem cells in hepatocellular carcinoma, we investigated the role of key transforming growth factor beta (TGF-beta) signaling components, including the Smad3 adaptor protein beta2-Spectrin (beta2SP), in liver regeneration. We demonstrate a streaming hepatocyte-specific dedifferentiation process in regenerating adult human liver less than 6 weeks following living donor transplantation. We then demonstrate a spatial and temporal expansion of TGF-beta signaling components, especially beta2SP, from the periportal to the pericentral zone as regeneration nears termination via immunohistochemical analysis. This expansion is associated with an expanded remaining pool of octamer 3/4 (Oct3/4)-positive progenitor cells localized to the portal tract in adult human liver from more than 6 weeks posttransplant. Furthermore, disruption of TGF-beta signaling as in the beta2SP (beta2SP+/-) knockout mouse demonstrated a striking 2 to 4-fold (P < 0.05) expanded population of Oct3/4-positive cells with activated Wnt signaling occupying an alpha-fetoprotein (AFP)+/cytokeratin-19 (CK-19)-positive progenitor cell niche following two-thirds partial hepatectomy. Conclusion: TGF-beta signaling, particularly beta2SP, plays a critical role in hepatocyte proliferation and transitional phenotype and its loss is associated with activation of hepatic progenitor cells secondary to delayed mitogenesis and activated Wnt signaling.
Hepatology 04/2010; 51(4):1373-82. · 11.66 Impact Factor
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ABSTRACT: Background. Liver metastases are common in advanced breast cancer. We sought to evaluate the role of transcatheter arterial chemoembolization (TACE) in breast cancer patients with hepatic metastases. Methods. A retrospective review of ten patients with breast cancer who were treated with TACE for unresectable liver metastases (1998-2008). Results. All patients, median age 46.5, had received prior systemic chemotherapies. Adriamycin was administered for 6, cisplatin/gemcitabine for 2, cisplatin for one and oxaliplatin for one patient. Median number of TACE cycles was 4. Kaplan Meier survival analysis showed an increase in median survival for patients who responded to treatment when compared to those who did not respond (24 vs 7 months, P = .02). Conclusions. This is one of the largest series of breast cancer patients with liver metastases treated with TACE. It suggests that TACE is a feasible palliative option and warrants further investigations.
International journal of surgical oncology. 01/2010; 2010:251621.
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Hye Jung Baek,
Sung Chul Lim, Krit Kitisin,
Wilma Jogunoori,
Yi Tang,
M Blair Marshall,
Bibhuti Mishra,
Tae Hyun Kim,
Kwan Ho Cho,
Sang Soo Kim,
Lopa Mishra
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ABSTRACT: We have previously demonstrated that 40%-70% of elf(+/-) mice spontaneously develop hepatocellular cancer (HCC) within 15 months, revealing the importance of the transforming growth factor-beta (TGF-beta) signaling pathway in suppressing tumorigenesis in the liver. The current study was carried out to investigate mechanisms by which embryonic liver fodrin (ELF), a crucial Smad3/4 adaptor, suppresses liver tumor formation. Histological analysis of hyperplastic liver tissues from elf(+/-) mice revealed abundant newly formed vascular structures, suggesting aberrant angiogenesis with loss of ELF function. In addition, elf(+/-) mice displayed an expansion of endothelial progenitor cells. Ectopic ELF expression in fetal bovine heart endothelial (FBHE) cells resulted in cell cycle arrest and apoptosis. Further analysis of developing yolk sacs of elf(-/-) mice revealed a failure of normal vasculature and significantly decreased endothelial cell differentiation with embryonic lethality. Immunohistochemical analysis of hepatocellular cancer (HCC) from the elf(+/-) mice revealed an abnormal angiogenic profile, suggesting the role of ELF as an angiogenic regulator in suppressing HCC. Lastly, acute small interfering RNA (siRNA) inhibition of ELF raised retinoblastoma protein (pRb) levels nearly fourfold in HepG2 cells (a hepatocellular carcinoma cell line) as well as in cow pulmonary artery endothelial (CPAE) cells, respectively. CONCLUSION: Taken together these results, ELF, a TGF-beta adaptor and signaling molecule, functions as a critical adaptor protein in TGF-beta modulation of angiogenesis as well as cell cycle progression. Loss of ELF in the liver leads the cancer formation by deregulated hepatocyte proliferation and stimulation of angiogenesis in early cancers. Our studies propose that ELF is potentially a powerful target for mimetics enhancing the TGF-beta pathway tumor suppression of HCC.
Hepatology 07/2008; 48(4):1128-37. · 11.66 Impact Factor
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Yi Tang, Krit Kitisin,
Wilma Jogunoori,
Cuiling Li,
Chu-Xia Deng,
Susette C Mueller,
Habtom W Ressom,
Asif Rashid,
Aiwu Ruth He,
Jonathan S Mendelson,
John M Jessup,
Kirti Shetty,
Michael Zasloff,
Bibhuti Mishra,
E P Reddy,
Lynt Johnson,
Lopa Mishra
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ABSTRACT: Cancer stem cells (CSCs) are critical for the initiation, propagation, and treatment resistance of multiple cancers. Yet functional interactions between specific signaling pathways in solid organ "cancer stem cells," such as those of the liver, remain elusive. We report that in regenerating human liver, two to four cells per 30,000-50,000 cells express stem cell proteins Stat3, Oct4, and Nanog, along with the prodifferentiation proteins TGF-beta-receptor type II (TBRII) and embryonic liver fodrin (ELF). Examination of human hepatocellular cancer (HCC) reveals cells that label with stem cell markers that have unexpectedly lost TBRII and ELF. elf(+/-) mice spontaneously develop HCC; expression analysis of these tumors highlighted the marked activation of the genes involved in the IL-6 signaling pathway, including IL-6 and Stat3, suggesting that HCC could arise from an IL-6-driven transformed stem cell with inactivated TGF-beta signaling. Similarly, suppression of IL-6 signaling, through the generation of mouse knockouts involving a positive regulator of IL-6, Inter-alpha-trypsin inhibitor-heavy chain-4 (ITIH4), resulted in reduction in HCC in elf(+/-) mice. This study reveals an unexpected functional link between IL-6, a major stem cell signaling pathway, and the TGF-beta signaling pathway in the modulation of mammalian HCC, a lethal cancer of the foregut. These experiments suggest an important therapeutic role for targeting IL-6 in HCCs lacking a functional TGF-beta pathway.
Proceedings of the National Academy of Sciences 03/2008; 105(7):2445-50. · 9.68 Impact Factor
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Yi Tang, Krit Kitisin,
Wilma Jogunoori,
Cuiling Li,
Chu-Xia Deng,
Susette C. Mueller,
Habtom W. Ressom,
Asif Rashid,
Aiwu Ruth He,
Jonathan S. Mendelson,
John M. Jessup,
Kirti Shetty,
Michael Zasloff,
Bibhuti Mishra,
E. P. Reddy,
Lynt Johnson,
Lopa Mishra
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ABSTRACT: Cancer stem cells (CSCs) are critical for the initiation, propagation, and treatment resistance of multiple cancers. Yet functional
interactions between specific signaling pathways in solid organ “cancer stem cells,” such as those of the liver, remain elusive.
We report that in regenerating human liver, two to four cells per 30,000–50,000 cells express stem cell proteins Stat3, Oct4,
and Nanog, along with the prodifferentiation proteins TGF-β-receptor type II (TBRII) and embryonic liver fodrin (ELF). Examination
of human hepatocellular cancer (HCC) reveals cells that label with stem cell markers that have unexpectedly lost TBRII and
ELF. elf
+/− mice spontaneously develop HCC; expression analysis of these tumors highlighted the marked activation of the genes involved
in the IL-6 signaling pathway, including IL-6 and Stat3, suggesting that HCC could arise from an IL-6-driven transformed stem
cell with inactivated TGF-β signaling. Similarly, suppression of IL-6 signaling, through the generation of mouse knockouts
involving a positive regulator of IL-6, Inter-alpha-trypsin inhibitor-heavy chain-4 (ITIH4), resulted in reduction in HCC
in elf
+/− mice. This study reveals an unexpected functional link between IL-6, a major stem cell signaling pathway, and the TGF-β signaling
pathway in the modulation of mammalian HCC, a lethal cancer of the foregut. These experiments suggest an important therapeutic
role for targeting IL-6 in HCCs lacking a functional TGF-β pathway.
Proceedings of the National Academy of Sciences 02/2008; 105(7):2445-2450. · 9.68 Impact Factor
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ABSTRACT: The transforming growth factor-beta (TGF-beta) superfamily comprises nearly 30 growth and differentiation factors that include TGF-betas, activins, inhibins, and bone morphogenetic proteins (BMPs). Multiple members of the TGF-beta superfamily serve key roles in stem cell fate commitment. The various members of the family can exhibit disparate roles in regulating the biology of embryonic stem (ES) cells and tumor suppression. For example, TGF-beta inhibits proliferation of multipotent hematopoietic progenitors, promotes lineage commitment of neural precursors, and suppresses epithelial tumors. BMPs block neural differentiation of mouse and human ES cells, contribute to self-renewal of mouse ES cells, and also suppress tumorigenesis. ES cells and tumors may be exposed to multiple TGF-beta members, and it is likely that the combination of growth factors and cross-talk among the intracellular signaling pathways is what precisely defines stem cell fate commitment. This Connections Map Pathway in the Database of Cell Signaling integrates signaling not only from TGF-beta and BMP but also from the ligands nodal and activin, and describes the role of the signaling pathways activated by these ligands in mammalian development. Much of the evidence for the connections shown comes from studies on mouse and human ES cells or mouse knockouts. This pathway is important for understanding not only stem cell biology, but also the molecular effectors of TGF-beta and BMP signaling that may contribute to cancer suppression or progression and thus are potential targets for therapeutic intervention.
Science s STKE 09/2007; 2007(399):cm1.
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ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Surgical intervention is the only curative option, with only a small fraction of patients being eligible. Conventional chemotherapy and radiotherapy have not been effective in treating this disease, thus leaving patients with an extremely poor prognosis. In viral, alcoholic, and other chronic hepatitis, it has been shown that there is an activation of the progenitor/stem cell population, which has been found to reside in the canals of Hering. In fact, the degree of inflammation and the disease stage have been correlated with the degree of activation. Dysregulation of key regulatory signaling pathways such as transforming growth factor-beta/transforming growth factor-beta receptor (TGF-beta/TBR), insulin-like growth factor/IGF-1 receptor (IGF/IGF-1R), hepatocyte growth factor (HGF/MET), Wnt/beta-catenin/FZD, and transforming growth factor-alpha/epidermal growth factor receptor (TGF-alpha/EGFR) in this progenitor/stem cell population could give rise to HCC. Further understanding of these key signaling pathways and the molecular and genetic alterations associated with HCC could provide major advances in new therapeutic and diagnostic modalities.
Gastrointestinal cancer research: GCR 08/2007; 1(4 Suppl 2):S13-21.
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ABSTRACT: Colorectal cancer is an ideal model in which to study malignant progression from the molecular-genetic perspective because different stages of the same malignancy coexist within each patient. Approximately 75% of colorectal cancer cases are sporadic and the remaining are familial disease, yet genetic mutations that have been identified account for only 5% to 6% of inherited cases. The two major pathways by which mutational changes leading to colorectal cancer occur are chromosomal instability and microsatellite instability. This article discusses genes and signaling pathways involved in development of inherited disease, as well as the association of some of these pathways with sporadic cases. Furthermore, therapies targeting active pathways in colorectal carcinogenesis, including the vascular endothelial growth factor and epidermal growth factor receptor tyrosine kinase, have shown promising results in clinical trials are now included in standard recommended treatment.
Seminars in Oncology 01/2007; 33(6 Suppl 11):S14-23. · 3.50 Impact Factor
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ABSTRACT: We have shown that loss of ELF, a stem cell adaptor protein, disrupts TGF-beta signaling through Smad3 and Smad4 localization. Notably elf(+/-)/smad4(+/-) mice develop gastric cancer presenting this as an important model for analyzing molecular event in gastric carcinogenesis. To gain further insight into the functional role of ELF in gastric cancer suppression, we carried out a detailed characterization of cell cycle events leading to gastric tumorigenesis. elf(-/-) cells and elf(+/-)/smad4(+/-) mice demonstrate a marked alteration of cell cycle regulators, such as Cdk4, K-Ras, and p21. Levels of Cdk4 increased compared to normal controls, suggesting loss of ELF results in functional abnormalities in cell cycle regulation. We further demonstrate that the elf(-/-) MEFs show a disruption of G1/S cell cycle transition and a significant reduction in senescence. Thus, in response to ELF deficiency, the abnormalities of G1/S checkpoint and senescence contribute their increment of susceptibility to malignant transformation.
Biochemical and Biophysical Research Communications 07/2006; 344(4):1216-23. · 2.48 Impact Factor
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ABSTRACT: We have shown that loss of ELF, a stem cell adaptor protein, disrupts TGF-β signaling through Smad3 and Smad4 localization. Notably elf+/−/smad4+/− mice develop gastric cancer presenting this as an important model for analyzing molecular event in gastric carcinogenesis. To gain further insight into the functional role of ELF in gastric cancer suppression, we carried out a detailed characterization of cell cycle events leading to gastric tumorigenesis. elf−/− cells and elf+/−/smad4+/− mice demonstrate a marked alteration of cell cycle regulators, such as Cdk4, K-Ras, and p21. Levels of Cdk4 increased compared to normal controls, suggesting loss of ELF results in functional abnormalities in cell cycle regulation. We further demonstrate that the elf−/− MEFs show a disruption of G1/S cell cycle transition and a significant reduction in senescence. Thus, in response to ELF deficiency, the abnormalities of G1/S checkpoint and senescence contribute their increment of susceptibility to malignant transformation.
Biochemical and Biophysical Research Communications 344(4):1216-1223. · 2.48 Impact Factor
