Transcatheter Arterial Chemoembolization Is a Feasible Palliative Locoregional Therapy for Breast Cancer Liver Metastases

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

Role of Transforming Growth Factor β Signaling and Expansion of Progenitor Cells in Regenerating Liver

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-β) signaling components, including the Smad3 adaptor protein β2-Spectrin (β2SP), 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-βsignaling components, especially β2SP, 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-β signaling as in the β2SP (β2SP/) knockout mouse demonstrated a striking 2 to 4-fold (P \u3c 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-βsignaling, particularly β2SP, 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. Copyright © 2010 by the American Association for the Study of Liver Diseases

TGF-β signaling pathway inactivation and cell cycle deregulation in the development of gastric cancer: Role of the β-spectrin, ELF

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. © 2006

Cost-Effectiveness Evaluation of Bariatric Surgery for Morbidly Obese with Diabetes Patients in Thailand

Background. Bariatric surgery is a choice for treatment in morbidly obese patients with type 2 diabetes mellitus (DM type 2) who have inadequate diabetes control with only medical treatment. However, bariatric surgery requires highly sophisticated equipment, and thus the cost of surgery seems to be very high following the procedure compared with the cost of conventional diabetes care. This raises the question of whether bariatric surgery is cost-effective for morbidly obese people with diabetes in Thailand. Objective. To perform a cost-effectiveness evaluation of bariatric surgery compared with ordinary treatment for diabetes control in morbidly obese DM type 2 patients in Thailand. Methods. Cost-effectiveness study was conducted, using a combination of decision tree and Markov model in analysis. Treatment outcomes and healthcare costs were incurred by data from literature review and retrospective cohort in King Chulalongkorn Memorial Hospital from September 2009 to March 2016 for the conventional and bariatric surgery group, respectively. One-way sensitivity was used for analysis of the robustness of the model. Cost-effectiveness was assessed by calculating incremental cost-effectiveness ratios (ICERs). Monetary benefits at a threshold of 150,000 to 200,000 Thai baht (THB) per quality-adjusted life-year (QALY) based on the Thailand gross domestic products (GDP) value was regarded as cost-effectiveness of bariatric surgery. Results. Bariatric surgery significantly improves the clinical outcome including long-term diabetes remission rate, hemoglobin A1C, and body mass index (BMI). The incremental cost per QALY of bariatric surgery compared with the medication control is 26,907.76 THB/QALY which can consider bariatric surgery as a cost-effective option. Conclusions. Use of bariatric surgery in morbidly obese with DM type 2 patients is a cost-effective strategy in Thailand’s context

Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling

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. © 2008 by The National Academy of Sciences of the USA

Cirrhosis is not a contraindication to laparoscopic cholecystectomy: results and practical recommendations

AbstractBackgroundGallstones 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.MethodsRetrospective 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.ResultsA 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).ConclusionsLaparoscopic cholecystectomy in patients with cirrhosis is feasible with no mortality and low morbidity, especially in patients with Child's class A cirrhosis

Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling

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. © 2008 by The National Academy of Sciences of the USA