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Programmed cell death protein-1 (PD-1) inhibitors have shown promising results for treating advanced hepatocellular carcinoma (HCC). However, the clinical utility of such inhibitors in HCC patients with vascular tumor thrombosis remains unclear. This study investigated PD-1 inhibitor efficacy in advanced HCC with macrovascular invasion in a clinical setting. Among the 110 patients with unresectable HCC treated with PD-1 inhibitors, 34 patients with vascular metastases in the portal vein and inferior vena cava were retrospectively compared with 34 patients without tumor thrombi. The vascular response and its effect on survival were assessed. Predictors of survival were identified using multivariate analysis. Among patients achieving objective response, those with and without thrombi exhibited similar response to immunotherapy and comparable survival. Among the 34 patients with tumor thrombi, including 13 receiving PD-1 inhibitors alone and 21 receiving it in combination with tyrosine kinase inhibitors, the median overall survival was 8.9 months (95% confidence interval 3.2–12.6). The objective response rate of vascular metastasis was 52.9%, and vascular responders had a significantly longer survival than did non-responders (11.1 vs 3.9 months). Failure to obtain a vascular response correlated significantly with increased post-treatment Child–Pugh score or class. Multivariate analysis showed that vascular response was a significant positive factor for longer overall survival. Treatment-related grade 3/4 adverse events occurred in 3 (8.8%) of the patients with tumor thrombi. Immunotherapy with PD-1 inhibitors may be a feasible treatment option for HCC with tumor thrombi owing to the high response rate of tumor thrombi and favorable survival outcomes. Supplementary Information The online version contains supplementary material available at 10.1007/s00262-020-02845-9.

Introduction: The tumor microenvironments of different organs often differ and thus may affect the immunotherapy response. Objective: This study elucidated that the efficacy of programmed cell death protein-1 (PD-1) inhibitors varies across different metastatic sites among individuals with advanced hepatocellular carcinoma (HCC). Methods: We retrospectively analyzed treatment outcomes in advanced HCC patients receiving PD-1 inhibitors with or without a combination of tyrosine kinase inhibitors (TKIs). Both the overall response rate (ORR) and organ-specific response rate (OSRR) were assessed using Response Evaluation Criteria in Solid Tumors 1.1 criteria. A survival analysis and its predictors were determined using a multivariate analysis. Results: We analyzed 42 advanced HCC patients (median age: 58.0 years; 78.6% males). Thirty (71.4%) patients were sorafenib-experienced and 27 (64.3%) were administered a combination of TKIs. The ORR was 14.3% and the disease control rate was 33.3%. The median overall survival (OS) and progression-free survival (PFS) were 12.0 and 2.9 months, respectively. The OSRRs were 14.7, 23.8, 28.6, and 50.0% for the liver, lungs, lymph nodes, and vascular response, respectively. The multivariate analysis indicated that the vascular response was significantly associated with PFS. ECOG performance status was a significant independent predictor of OS. Conclusions: PD-1 inhibitors improved OS and PFS in advanced HCC patients. Their efficacies varied among the metastatic locations regardless of the combination of TKIs; in particular, a higher response in vascular metastases was correlated with a longer PFS. PD-1 inhibitors may deliver a synergistic benefit in patients undergoing traditional therapy and progression in other organs in vascular responders.

Chronic and persistent inflammation is a well-known carcinogenesis promoter. Hepatocellular carcinoma (HCC) is one of the most common inflammation-associated cancers; most HCCs arise in the setting of chronic inflammation and hepatic injury. Both NF-κB and STAT3 are important regulators of inflammation. Centrosomal P4.1-associated protein (CPAP), a centrosomal protein that participates primarily in centrosome functions, is overexpressed in HCC and can increase TNF-α-mediated NF-κB activation and IL-6-induced STAT3 activation. A transgenic (Tg) mouse model with hepatocyte-specific CPAP expression was established to investigate the physiological role of CPAP in hepatocarcinogenesis. Obvious inflammatory cell accumulation and fatty change were observed in the livers of CPAP Tg mice. The alanine aminotransferase (ALT) level and the expression levels of inflammatory genes, such as IL-6, IL-1β and TNF-α, were higher in CPAP Tg mice than in wild type (WT) mice. High-dose/short-term treatment with diethylnitrosamine (DEN) increased the ALT level, proinflammatory gene expression levels, and STAT3 and NF-κB activation in CPAP Tg mice; low-dose/long-term DEN treatment induced more severe liver tumor formation in CPAP Tg mice than in WT mice. CPAP can increase the expression of chemokine (C-C motif) ligand 16 (CCL-16), an important chemotactic cytokine, in human hepatocytes. CCL-16 expression is positively correlated with CPAP and TNF-α mRNA expression in the peritumoral part of HCC. In summary, these results suggest that CPAP may promote hepatocarcinogenesis through enhancing the inflammation pathway via increasing the expression of CCL-16.

Advancement in systemic therapy, particularly immune checkpoint inhibitor (ICI)-based combination regimens, has transformed the treatment landscape for patients with advanced hepatocellular carcinoma (HCC). The advancement in systemic therapy also provides new opportunities of reducing recurrence after curative therapy through adjuvant therapy or improving resectability through neoadjuvant therapy. Improved recurrence-free survival by adjuvant or neoadjuvant ICI-based therapy has been reported in other cancer types. In this article, developments of systemic therapy in adjuvant and neoadjuvant settings for HCC were reviewed. The design of adjuvant and neoadjuvant therapy using ICI-based regimens and potential challenges of trial conduct and result analysis was discussed. Results from these trials may extend the therapeutic benefit of ICI-based systemic therapy beyond the advanced-stage disease and lead to a new era of multidisciplinary management for HCC.

Centrosomal P4.1-associated protein (CPAP) is overexpressed in hepatocellular carcinoma (HCC) and positively correlated with recurrence and vascular invasion. Here, we found that CPAP plays an important role in HCC malignancies. Functional characterization indicated that CPAP overexpression increases tumor growth, angiogenesis, and metastasis ex vivo and in vivo. In addition, overexpressed CPAP contributes to sorafenib resistance. Mechanical investigation showed that the expression level of CPAP is positively correlated with activated STAT3 in HCC. CPAP acts as a transcriptional coactivator of STAT3 by directly binding with STAT3. Interrupting the interaction between CPAP and STAT3 attenuates STAT3-mediated tumor growth and angiogenesis. Overexpression of CPAP upregulates several STAT3 target genes such as IL-8 and CD44 that are involved in angiogenesis, and CPAP mRNA expression is positively correlated with the levels of both mRNAs in HCC. Knocked-down expression of CPAP impairs IL-6-mediated STAT3 activation, target gene expression, cell migration, and invasion abilities. IL-6/STAT3-mediated angiogenesis is significantly increased by CPAP overexpression and can be blocked by decreased expression of IL-8. Our findings not only shed light on the importance of CPAP in HCC malignancies, but also provide potential therapeutic strategies for inhibiting the angiogenesis pathway and treating metastatic HCC.

The aim of the study was to use a previously proposed mask region–based convolutional neural network (Mask R-CNN) for automatic abnormal liver density detection and segmentation based on hepatocellular carcinoma (HCC) computed tomography (CT) datasets from a radiological perspective. Training and testing datasets were acquired retrospectively from two hospitals of Taiwan. The training dataset contained 10,130 images of liver tumor densities of 11,258 regions of interest (ROIs). The positive testing dataset contained 1,833 images of liver tumor densities with 1,874 ROIs, and negative testing data comprised 20,283 images without abnormal densities in liver parenchyma. The Mask R-CNN was used to generate a medical model, and areas under the curve, true positive rates, false positive rates, and Dice coefficients were evaluated. For abnormal liver CT density detection, in each image, we identified the mean area under the curve, true positive rate, and false positive rate, which were 0.9490, 91.99%, and 13.68%, respectively. For segmentation ability, the highest mean Dice coefficient obtained was 0.8041. This study trained a Mask R-CNN on various HCC images to construct a medical model that serves as an auxiliary tool for alerting radiologists to abnormal CT density in liver scans; this model can simultaneously detect liver lesions and perform automatic instance segmentation.

Background & AimsContinued limitations in hepatocellular carcinoma (HCC) screening have led to late diagnosis with poor survival, despite well-defined high-risk patient populations. Our aim is to develop a non-invasive urine circulating tumor DNA (ctDNA) biomarker panel for HCC screening to aid in early detection.MethodsCandidate ctDNA biomarkers was prescreened in urine samples obtained from HCC, cirrhosis, and hepatitis patients. Then, 609 patient urine samples with HCC, cirrhosis, or chronic hepatitis B were collected from five academic medical centers and evaluated by serum alpha feto-protein (AFP) and urine ctDNA panel using logistic regression, a Two-Step machine learning algorithm, and iterated 10-fold cross-validation.ResultsMutated TP53, and methylated RASSF1a and GSTP1, were selected for the urine ctDNA panel. The sensitivity of AFP-alone (9.8 ng/mL cut-off) to detect HCC was 71% by Two-Step. The combination of ctDNA and AFP increased the sensitivity to 81% at a specificity of 90%. The AUROC for the combination of ctDNA and AFP vs. AFP-alone were 0.925 (95% CI, 0.924-0.925) and 0.877 (95% CI, 0.876-0.877), respectively. Notably, among the patients with AFP ConclusionsThe combination of urine ctDNA and serum AFP can increase HCC detection rates including in those patients with low-AFP. Given the ease of collection, a urine ctDNA panel could be a potential non-invasive HCC screening test.

Background The superiority of anatomic resection (AR) over non-anatomic resection (NAR) for very early-stage hepatocellular carcinoma (HCC) has remained a topic of debate. Thus, this study aimed to compare the prognosis after AR and NAR for single HCC less than 2 cm in diameter. Methods Consecutive patients with single HCC of diameter less than 2 cm who underwent curative hepatectomy between 1997 and 2017 were included in this retrospective study. Results In total, 159 patients were included in this study. Of these, 52 patients underwent AR (AR group) and 107 patients underwent NAR (NAR group). No significant differences were noted in recurrence-free survival (RFS) and overall survival (OS) between the AR and NAR groups (P = 0.236 and P = 0.363, respectively). Multivariate analysis revealed that low preoperative platelet count and presence of satellite nodules were independent prognostic factors of RFS and OS. Wide surgical resection margin did not affect RFS (P = 0.692) in the AR group; however, in the NAR group, RFS was found to be higher with surgical resection margin widths ≥1 cm than with surgical resection margin widths Conclusions Prognosis was comparable between the NAR and AR groups for very early-stage HCC with well-preserved liver function. For better oncologic outcomes, surgeons should endeavor in keeping the surgical resection margin widths during NAR ≥1 cm.

BackgroundSurvival in hepatocellular carcinoma (HCC) is lower in the USA than in Taiwan. Little is known about the extent to which differences in stage at diagnosis and treatment contribute to this difference. We examined treatment patterns and survival in HCC and analyzed factors driving the difference.MethodsUsing a uniform methodology, we identified patients aged 66 years and older with newly diagnosed HCC between 2004 and 2011 in the USA and Taiwan. We compared treatment within 6 months after HCC diagnosis and 2-year stage-specific survival between the two countries.ResultsCompared with patients in Taiwan (n = 32,987), patients in the USA (n = 7,003) were less likely to be diagnosed as stage IA (4% vs 8%) and II (13% vs 22%), or receive cancer-directed treatments (41% vs 58%; all p < .001). Stage-specific 2-year survival rates were lower in the USA than in Taiwan (stage IA: 57% vs 77%; stage IB: 38% vs 63%; stage II: 40% vs 57%, stage III: 14% vs 18%; stage IV: 4% vs 5%, respectively; all p < .001 except p = .018 for stage IV). Differences in age and sex (combined), stage, and receipt of treatment accounted for 3.8%, 17.0%, and 16.8% of the survival difference, respectively, leaving 62.5% unexplained.ConclusionsDifferential stage at diagnosis and treatment were substantially associated with the survival difference, but approximately two-thirds of the difference remained unexplained. Identifying the main drivers of the difference could help improve HCC survival in the USA.

Background: Sorafenib is the standard treatment for patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC). However, the treatment outcome is not satisfactory. We retrospectively analyzed whether adding transarterial embolization/chemoembolization (TA(C)E)-based locoregional therapy to sorafenib can further improve treatment efficacy. Patients and Methods: We included 147 BCLC stage C HCC patients with Child-Turcotte-Pugh class A liver function and treated with sorafenib for analysis. Through propensity score matching, we divided patients into the combined treatment group (n = 63; patients received TA(C)E-based locoregional treatment and sorafenib) and the sorafenib monotherapy group (n = 63). We analyzed the effects of patients’ clinical and tumor-related factors on their overall survival (OS) and time to tumor progression. Results: The OS was better in the combined treatment group than in the sorafenib monotherapy group (419 vs. 223 days, p = 0.028). In the Cox regression model, combined treatment, a lower baseline α-fetoprotein (AFP) level < 400 ng/mL, tumors without main portal venous tumorous thrombosis, and age ≥60 years were identified as independent factors for OS. Subgroup analysis demonstrated that patients with a higher baseline AFP level > 400 ng/mL, age < 60 years, tumors with branched portal venous tumorous thrombosis only or without extrahepatic metastasis benefited the most from combined treatment. Conclusion: Combining TA(C)E-based locoregional treatment with sorafenib resulted in better OS in patients with BCLC stage C HCC compared with sorafenib alone. TA(C)E-based locoregional treatment can be an adjunctive treatment to sorafenib for patients with advanced HCC and a satisfactory liver functional reserve.

AIM To investigate the clinicopathological significance of progesterone receptor membrane component 1 (PGRMC1) and PGRMC2 in hepatocellular carcinoma (HCC). METHODS We performed immunohistochemical staining to evaluate the estrogen receptor (ER), progesterone receptor (PR), PGRMC1, and PGRMC2 in a clinical cohort consisting of 89 paired HCC and non-tumor liver samples. We also analyzed HCC data (n = 373) from The Cancer Genome Atlas (TCGA). We correlated the expression status of PGRMC1 and PGRMC2 with clinicopathological indicators and the clinical outcomes of the HCC patients. We knocked down or overexpressed PGRMC1 in HCC cell lines to evaluate its biological significance in HCC cell proliferation, differentiation, migration, and invasion. RESULTS We found that few HCC cases expressed ER (5.6%) and PR (4.5%). In contrast, most HCC cases expressed PGRMC1 (89.9%) and PGRMC2 (100%). PGRMC1 and PGRMC2 exhibited significantly lower expression in tumor tissue than in non-tumor tissue (P < 0.001). Lower PGRMC1 expression in HCC was significantly associated with higher serum alpha-fetoprotein expression (P = 0.004), poorer tumor differentiation (P = 0.045) and liver capsule penetration (P = 0.038). Low PGRMC1 expression was an independent predictor for worse disease-free survival (P = 0.002, HR = 2.384, CI: 1.377-4.128) in our cases, as well as in the TCGA cohort (P < 0.001, HR = 2.857, CI: 1.781-4.584). The expression of PGRMC2 did not relate to patient outcome. PGRMC1 knockdown promoted a poorly differentiated phenotype and proliferation of HCC cells in vitro, while PGRMC1 overexpression caused the opposite effects. CONCLUSION PGRMC1 is a non-classical hormonal receptor that negatively regulates hepatocarcinogenesis. PGRMC1 down-regulation is associated with progression of HCC and is a poor prognostic indicator.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. The beta-catenin gene, CTNNB1, is among the most frequently mutated in HCC tissues. However, mutational analysis of HCC tumors is hampered by the difficulty of obtaining tissue samples using traditional biopsy. Here, we explored the feasibility of detecting tumor-derived CTNNB1 mutations in cell-free DNA (cfDNA) extracted from the urine of HCC patients. Using a short amplicon qPCR assay targeting HCC mutational hotspot CTNNB1 codons 32–37 (exon 3), we detected CTNNB1 mutations in 25% (18/73) of HCC tissues and 24% (15/62) of pre-operative HCC urine samples in two independent cohorts. Among the CTNNB1-mutation-positive patients with available matched pre- and post-operative urine (n = 13), nine showed apparent elimination (n = 7) or severalfold reduction (n = 2) of the mutation in urine following tumor resection. Four of the seven patients with no detectable mutations in postoperative urine remained recurrence-free within five years after surgery. In contrast, all six patients with mutation-positive in post-operative urine recurred, including the two with reduced mutation levels. This is the first report of association between the presence of CTNNB1 mutations in pre- and post-operative urine cfDNA and HCC recurrence with implications for minimum residual disease detection.

Integrated hepatitis B virus (HBV) DNA detected in more than 85% of HBV-infected hepatocellular carcinoma (HBV-HCC) can cause insertional mutagenesis, chromosomal instability, sustained viral protein expression, and/or immune-mediated inflammation leading to HCC carcinogenesis. An opportunistic outcome of HBV DNA integration events, which occur randomly into the host genome, is the creation of a unique HBV-host junction sequence (HBV-JS) in individually infected hepatocytes representing a specific molecular signature of that cell. A noninvasive approach to detect HBV-JS's will enable frequent monitoring and aid in assessing HBV treatment efficacy and HCC disease progression. Here, we assessed the feasibility of detecting HBV-JS's in urine of HBV-infected patients as a proof-of-concept for utilizing urine as a noninvasive HBV-JS liquid biopsy for HBV-related disease monitoring. Utilizing an in-house developed HBV primer extension capture (PEC) NGS assay, we assessed early-stage HBV-patient tumor tissue and matched urine (n=8). Five of 8 urine samples contained detectable HCC tissue-derived HBV-JS's, including a TERT junction sequence. Next, we assessed 32 urine specimens collected from 28 HBV-infected patients including hepatitis (n=5), cirrhosis (n=11), HCC (n=4), and post-HCC (n=8). Interestingly, all urine samples contained HBV-JS sequences with 30 of 32 urines containing integrations in gene-coding regions. Of 351 unique HBV-JS in gene-coding regions identified in urine, 11 HBV-JS's have also been previously reported in tissue of HCC patients, including TERT. All eleven HBV-JS's were identified in cirrhosis or HCC patient cohorts. Furthermore, the distribution of urinary integrated HBV DNA in the HBV genome in all disease categories was found predominantly clustered in HBV DR1-2 (>70%), an integration hotspot, consistent with findings in tissue. Altogether this support the potential of urine as a noninvasive HBV-JS liquid biopsy to monitor HBV-infected patients for disease progression and treatment efficacy. Citation Format: Selena Lin, Yu-lan Kao, Robin Su, Ting-Tsung Chang, Yih-Jyh Lin, Yixiao Cui, Hie-Won Hann, Grace Park, Wei Song, Ying-Hsiu Su. Detection of liver-derived hepatitis B virus-host junction sequences in urine of hepatitis B infected patients for noninvasive disease monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 545.

Background Hepatocellular carcinoma (HCC) with inferior vena cava (IVC) involvement is a rare disease with poor prognosis. This study aimed to evaluate the outcome of HCC patients receiving radiotherapy (RT) to IVC tumor thrombus. Methods A total of 42 consecutive HCC patients treated with RT to IVC tumor thrombus between September 2007 and October 2018 were enrolled. Overall survival (OS), the response of IVC thrombus, prognostic factors and failure pattern were assessed. Results The median follow-up time was 4.4 months. The median RT equivalent dose in 2-Gy fractions was 48.75 Gy (range, 3.25–67.10). The objective response rate of IVC thrombus was 47.6% (95% confidence interval [CI], 33.3–64.3%). The OS rate at 1 year was 30.0%, with a median OS of 6.6 months (95% CI, 3.7–9.5) from the start of RT. On multivariate analysis, Child-Pugh class, lymph node metastasis, lung metastasis and objective response of IVC thrombus were independent predictors for OS. Lung was the most common site of first progression in 14 (33.3%) patients. For 32 patients without lung metastasis before RT, use of systemic treatment concurrent with and/or after RT was associated with a significantly longer lung metastasis-free survival (5.9 vs. 1.5 months, p = 0.0033). Conclusions RT is effective for IVC tumor thrombus of HCC with acceptable adverse effects. RT might be a treatment option incorporated into combination therapy for HCC involving IVC.

BACKGROUND: In the biliary tract cancer (BTC) cohort of KEYNOTE-158, which enrolled 104 patients with advanced BTC who had progression/intolerance to standard therapy, showed 6.6% overall response rate in the subgroup of programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 but the median progression-free survival (PFS) and overall survival (OS) were only 1.9 and 7.2 months, respectively (2018 ESMO). Of note, two patients had duration of response more than 15 months, which suggested immunotherapy might have antitumor activity in a subset of advanced BTC. Herein, we report an experience of complete response after immunotherapy in a patient of cholangiocarcinoma with obvious peritoneal metastases. METHODS: A 60-year-old male with stage IIIA hilar cholangiocarcinoma received treatment in National Cheng Kung University Hospital. Clinical characteristics are reviewed through the electronic medical records. Tumor response is evaluated by CT scan via RECIST 1.1. PD-L1 expression is evaluated through the Dako 22C3 PD-L1-IHC platform. RESULTS: Patient underwent curative extended right lobectomy in December 2016 with initial CA19-9 409.9 IU/mL. After surgery, CA19-9 decreased to 19.8 IU/mL. A half year later, CA19-9 increased to 46.3 IU/mL without CT evidence of tumor recurrence. Chemotherapy with gemcitabine and cisplatin was given. Two months later, CA19-9 increased to 657.9 IU/mL and CT scan showed peritoneal seeding. Despite the change of chemotherapy to S-1, leucovorin, oxaliplatin and gemcitabine (SLOG), follow-up CT scan 3 months later showed progression of peritoneal tumors with CA19-9 increased to 4,739 IU/mL. Biopsy of the metastatic tumor showed high PD-L1 expression (90%) on the tumor cells. Salvage immunotherapy pembrolizumab (fixed dose 100 mg, approximately equal to 1.5 mg/kg, every 3–4 weeks) has been given since December 2017. After three doses of pembrolizumab, CT scan showed complete regression of the peritoneal tumors with drastic decline of CA19-9 to 33.7 IU/mL. The patient received a total of seven doses of pembrolizumab and stopped due to financial issue. To date, 13 months after the beginning of immunotherapy, the patient is still alive without evidence of cholangiocarcinoma recurrence. CONCLUSIONS: Our experience suggested immunotherapy may have durable antitumor activity for cholangiocarcinoma with extremely high PD-L1 expression. Underlying mechanism caused such high PD-L1 expression and incredible response to immunotherapy remains unclear and further investigation is warranted.

Background/Purpose This study aims to examine the cost effectiveness of treating major cancers compared with other major illnesses in Taiwan. Methods We collected data on 395,330 patients with cancer, 125,277 patients with end-stage renal disease, and 50,481 patients under prolonged mechanical ventilation during 1998–2007. They were followed for 10–13 years to estimate lifetime survival functions using a semiparametric method. EuroQol five-dimension was used to measure the quality of life for 6189 cancer patients and 1401 patients with other illnesses. The mean utility values and healthcare costs reimbursed by the National Health Insurance were multiplied with the corresponding survival probabilities to estimate quality-adjusted life expectancies and lifetime costs, respectively. Data of 22,344 cancer patients under hospice care (considered as a comparison group) were used to conduct a cost-effectiveness analysis. Sensitivity analysis was conducted by assuming patients without treatment survived for 2 years with a quality of life value of 0.5. Results The costs of care for patients under prolonged mechanical ventilation and those with end-stage renal disease were US$41,780–53,708 per quality-adjusted life year (QALY) and US$18,222–18,465 per QALY, respectively, which are equivalent to 2.17–2.79 gross domestic product (GDP) per capita per QALY and 1.18–1.25 GDP per capita per QALY. The costs of care for the nine different cancers were less than 1 GDP per capita per QALY, with those of lung, esophagus, and liver cancers being the highest. Sensitivity analysis showed the same conclusion. Lifetime risks of six out of nine cancer sites show an increased trend. Conclusion Cancer care in Taiwan seemed cost effective compared with that of other illnesses, but prevention is necessary to make the National Health Insurance more sustainable.

Ground glass hepatocytes (GGHs) have been shown to predict the development of hepatocellular carcinoma (HCC). Type I GGH and type II GGH harbor hepatitis B virus (HBV) pre-S1 and pre-S2 deletion mutants, respectively. Whether anti-HBV therapy can inhibit the expression of GGHs and potentially reduce HCC development is explored in this study. Two sets of liver specimens were included: the first contained 31 paired biopsy specimens obtained from chronic HBV patients receiving oral nucleos(t)ide analogue (NA) treatment; the second contained 186 resected liver tissues obtained from HBV-related HCC patients receiving surgery: 82 received NA before surgery and 104 did not. Compared with the baseline biopsy specimens, type I (P=0.527) and type II GGH (P=0.077) were not significantly decreased after 48 weeks of NA treatment in the first set of patients. In the second set, despite suppression of viral load (P

CD90 is used as a marker for cancer stem cell in liver cancer. We aimed to study the mechanism by which CD90 promoted liver cancer progression and identify the new therapeutic targets on CD90 signal pathway. Ectopic expression of CD90 in liver cancer cell lines enhanced anchorage-independent growth and tumor progression. Furthermore, CD90 promoted sphere formation in vitro and upregulated the expression of the cancer stem cell marker CD133. The CD133 expression was higher in CD45-CD90+ cells in liver cancer specimen. The natural carcinogenic molecules TGF-β-1, HGF, and hepatitis B surface antigen increased the expression of CD90 and CD133. Inhibition of CD90 by either shRNA or antibody attenuated the induction of CD133 and anchorage-independent growth. Lentiviral delivery of CD133 shRNA abolished the tumorigenicity induced by CD90. Ectopic expression of CD90 induced mTOR phosphorylation and AMPK dephosphorylation. Mutation of integrin binding-RLD domain in CD90 attenuated the induction of CD133 and anchorage-independent growth. Similar results were observed after silencing β3 integrin. Signaling analyses revealed that AMPK/mTOR and β3 integrin were required for the induction of CD133 and tumor formation by CD90. Importantly, the energy restriction mimetic agent OSU-CG5 reduced the CD90 population in fresh liver tumor sample and repressed the tumor growth. In contrast, sorafenib did not decrease the CD90+ population. In conclusion, the signal axis of CD90-integrin-mTOR/AMPK-CD133 is critical for promoting liver carcinogenesis. Molecules inhibiting the signal axis, including OSU-CG5 and other inhibitors, may serve as potential novel cancer therapeutic targets in liver cancer.

Transarterial chemoembolization (TACE) is the first-line treatment in patients with unresectable hepatocellular carcinoma (HCC). In recent years, there has been increasing clinical evidence that drug-eluting beads provide a combined ischemic and cytotoxic effect that may be superior to conventional TACE, with low systemic toxicity. The therapeutic value of TACE performed using the embolic microsphere DC Bead loaded with doxorubicin (drug-eluting bead doxorubicin [DEBDOX]) has been shown by several randomized controlled trials. Since Lencioni et al. [Cardiovasc Intervent Radiol 2012; 35: 980–985] published the first widely accepted technical recommendations on HCC embolization with DEBDOX-TACE in 2012, new studies have contributed to a better understanding of when and how to apply this new therapeutic modality, and they have yet to be incorporated into an updated guideline. Additionally, differences in the underlying liver pathology and practice of transcatheter embolization between Asian and Western populations have not been adequately addressed, and there remain significant variations in the TACE protocols adopted in different parts of the world. These mainly revolve around the number and type of chemotherapeutic agents used, type of embolic material, reliance on Lipiodol, and selectivity of catheter positioning. As a result of these issues, it has been difficult to interpret and compare results obtained from different centers in a systematic fashion. To address these concerns, we convened a panel of experts specializing in different aspects of HCC treatment to craft an updated set of recommendations that better reflect recent clinical experiences and are tailored to the use of DEBDOX-TACE in Taiwan. The conclusions of this expert panel are described in the following article.

Limited access to or receipt of liver transplantation (LT) may jeopardize survival of patients with end-stage liver diseases. Taiwan launched its National Health Insurance (NHI) program in 1995, which essentially removes financial barriers to health care. This study aims to investigate where there are still demographic and urbanization disparities of LT after 15 years of NHI program implementation. Data analyzed in this study were retrieved from Taiwan’s NHI inpatient claims. A total of 3020 people aged ≥18 years received LT between 2000 and 2013. We calculated crude and adjusted prevalence rate of LT according to secular year, age, sex, and urbanization. The multiple Poisson regression model was further employed to assess the independent effects of demographics and urbanization on prevalence of LT. The biennial number of people receiving LT substantially increased from 56 in 2000–2001 to 880 in 2012–2013, representing a prevalence rate of 1.63 and 18.58 per 106, respectively. Such increasing secular trend was independent of sex. The prevalence was consistently higher in men than in women. The prevalence also increased with age in people

Interleukin (IL)-20 is a proinflammatory cytokine of the IL-10 family and involved in rheumatoid arthritis, atherosclerosis, stroke, and osteoporosis. However, the pathophysiological roles of IL-20 in liver injury have not been extensively studied. We explored the involvement of IL-20 in liver injury and the therapeutic potential of IL-20 antagonists for treating liver fibrosis. Compared with normal liver tissue from healthy individuals, the amount of IL-20 was much higher in hepatocytes and hepatic stellate cells in liver biopsies from patients with fibrosis, cirrhosis, and hepatocellular carcinoma. Carbon tetrachloride (CCl4) treatment induced IL-20 that further up-regulated the expression of transforming growth factor (TGF)-b1 and p21 WAF1 and resulted in cell cycle arrest in the Clone-9 rat hepatocyte cell line. IL-20 activated quiescent rat hepatic stellate cells (HSCs) and up-regulated TGF-b1 expression. IL-20 also increased TGF-b1, tumor necrosis factor (TNF)-a, and type I collagen (Col-I) expression, and promoted the proliferation and migration of activated HSCs. Serum IL-20 was significantly elevated in mice with short-term and long-term CCl4-induced liver injury. In mice with short-term liver injury, anti-IL-20 monoclonal antibody (7E) and anti-IL-20 receptor (IL-20R1) monoclonal antibody (51D) attenuated hepatocyte damage caused by CCl4, TGF-b1, and chemokine production. In mice with long-term liver injury, 7E and 51D inhibited CCl4-induced cell damage, TGF-b1 production, liver fibrosis, HSC activation, and extracellular matrix accumulation, which was caused by the reduced expression of tissue inhibitors of metalloproteinases as well as increased metalloproteinase expression and Col-I production. IL-20R1-deficient mice were protected from short-term and longterm liver injury. Conclusion: We identified a pivotal role of IL-20 in liver injury and showed that 7E and 51D may be therapeutic for liver fibrosis. (HEPATOLOGY 2014;00:000-000)

The development of colorectal cancer (CRC) is commonly accompanied by the overexpression of the cyclooxygenase-2 (COX-2) gene, with high levels being most common in early colorectal lesions. In the present study, we hypothesized that the expression of COX-2 in normal mucosa affects the expression of COX-2 in adjacent tumors. COX-2 protein expression levels were determined in tumor tissues and the adjacent normal mucosa of 49 paired clinical CRC specimens using western blotting and immunohistochemistry (IHC) staining. The majority of specimens exhibited an extremely low level of COX-2 expression in the tumor tissue and a markedly higher expression level in the adjacent normal tissue, however, high COX-2 expression in the tumor was shown to correlate with a high recurrence rate and poor overall survival. Of the nine CRC cell lines, HT29 showed consistently higher levels of COX-2 expression. Therefore, COX-2 expression in the normal tissue adjacent to the tumor may be involved in the tumorigenesis of CRC. These observations are likely to be useful in determining the significance of COX-2 expression in the tumorigenesis of CRC.

Summary Background Deregulation of mammalian target of rapamycin (mTOR) signalling is common in human hepatocellular carcinoma (HCC). Aim To determine the maximum tolerated dose (MTD) of the oral mTOR inhibitor everolimus in advanced HCC patients. Methods Patients with locally advanced or metastatic HCC (Child-Pugh class A or B) were enrolled in an open-label phase 1 study and randomly assigned to daily (2.5–10 mg) or weekly (20–70 mg) everolimus in a standard 3 + 3 dose-escalation design. MTD was based on the rate of dose-limiting toxicities (DLTs). Secondary endpoints included safety, pharmacokinetics and tumour response. In a post hoc analysis, serum hepatitis B virus (HBV) DNA levels were quantified. Results Thirty-nine patients were enrolled. DLTs occurred in five of 21 patients in the daily and two of 19 patients in the weekly cohort. Daily and weekly MTDs were 7.5 mg and 70 mg respectively. Grade 3/4 adverse events with a ≥10% incidence were thrombocytopenia, hypophosphataemia and alanine transaminase (ALT) elevation. In four hepatitis B surface antigen (HBsAg)-seropositive patients, grade 3/4 ALT elevations were accompanied by significant (>1 log) increases in serum HBV levels. The incidence of hepatitis flare (defined as ALT increase >100 IU/mL from baseline) in HBsAg-seropositive patients with and without detectable serum HBV DNA before treatment was 46.2% and 7.1% respectively (P

e16120Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer mortality in the United States. Due to the high prevalence of hepatitis B/C infection, HCC ranks second in can...

Strategies to increase antitumor efficacy of oncolytic adenoviruses are actively investigated. We have previously shown that E1B-55 kDa-deleted adenovirus, designated Ad5WS1, has therapeutic potential for treating hepatocellular carcinoma (HCC). To achieve HCC-restricted replication of oncolytic adenovirus, we generated Ad5WS2, an E1B-55 kDa-deleted adenovirus with its E1A gene driven by the liver-specific transthyretin promoter. Our results showed that Ad5WS2 could replicate within tumor cells where the transthyretin gene was expressed. Mouse transthyretin promoter was active in murine and human HCC cells, but relatively quiescent in cells of non-liver origin. Ad5WS2 caused severe cytolytic effect on HCC cells, but was much attenuated in non-HCC cells. Peritoneal administration of Ad5WS2 into mice bearing liver tumors grown in ascites resulted in enhanced survival. In an orthotopic HCC model, Ad5WS2, when systemically administered, exerted higher antitumor effects than Ad5WS1. Lack of viral replication in normal organs and minimal hepatic toxicity was noted after Ad5WS2 treatment. Furthermore, the antitumor effect of Ad5WS2 could be enhanced when combined with chemotherapeutic agent cisplatin in the ascites tumor model. These results suggest that E1B-55 kDa-deleted adenovirus driven by the transthyretin promoter may be a safer and more efficacious oncolytic agent for the treatment of primary and metastatic HCC.

Enzyme-linked immunosorbent assay (ELISA) and flow cytometric techniques have been introduced to overcome the limited sensitivity and specificity of the CDC assay. This retrospective study used lambda antigen tray-mixed screening and Luminex HLA class I and II specificity assays to re-examine: (1) the accuracy with which detection of HLA antibody and specificity by ELISA predicts pretransplantation National Institutes of Health (NIH)/Centers for Disease Control and Prevention (CDC) crossmatch; and (2) a comparison of Luminex and ELISA methods to detect HLA antibodies. Sera from 481 patients awaiting kidney transplantation were tested using the ELISA method lambda antigen tray-mixed and using NIH-CDC to determine how well HLA antibodies detected using ELISA predicted crossmatches using CDC. Pretransplantation sera from 48 patients with follow-up data were retested using both ELISA lambda antigen tray-mixed and Luminex to compare the efficacy of the 2 methods.

A critical element restricting the application of liver transplantation is the shortage of human deceased donor organs. Xenotransplantation using pig organs might be a solution to this shortage. Although the problems that still require resolution include the immunologic barrier, the potential risk of transferring infectious agents with the transplanted organ, and uncertainty about whether the transplanted organ will function satisfactorily in the human environment, recent progress in the genetic manipulation of pigs has led to the prospect that clinical xenografting, at least as a bridge to allotransplantation, may be possible in the foreseeable future. Experience with clinical auxiliary and orthotopic liver xenotransplantation and experimental liver xenotransplantation in nonhuman primate and other large animal models is reviewed, and the remaining immunologic problems are discussed. Evidence suggests that, in patients with hepatic failure, the pig liver may be less susceptible to antibody-mediated injury than other pig organs, such as the heart or kidney. Pig Kupffer cells and other macrophages will recognize and phagocytose primate red blood cells, but this problem should be overcome by pretransplant depletion of macrophages from the organ-source pig. From the evidence currently available, it does not seem unduly optimistic to anticipate that a liver from an α1,3-galactosyltransferase gene-knockout pig would survive at least long enough to function as a successful bridge to allotransplantation. Liver Transpl 14:425–434, 2008. © 2008 AASLD.

// Cheng-Hsun Ho 1, 2, * , Huai-Chia Chuang 3, * , I-Chin Wu 2 , Hung-Wen Tsai 4, 5 , Yih-Jyh Lin 6 , Hung-Yu Sun 7 , Kung-Chia Young 7 , Yen-Cheng Chiu 2 , Pin-Nan Cheng 2 , Wen-Chun Liu 2, 5 , Tse-Hua Tan 3, 8 , Ting-Tsung Chang 2, 5, 9 1 Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 2 Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 3 Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan 4 Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 5 Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan 6 Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 7 Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan 8 Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA 9 Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan * These authors have contributed equally to this work Correspondence to: Ting-Tsung Chang, email: ttchang@mail.ncku.edu.tw Tse-Hua Tan, email: ttan@nhri.org.tw Keywords: hepatocellular carcinoma, recurrence, GLK, NFκB Received: September 08, 2015 Accepted: June 04, 2016 Published: June 20, 2016 ABSTRACT Germinal center kinase-like kinase (GLK) is a key controller of autoimmunity. In this study, we assessed the clinical relevance and tumorigenic effects of GLK in hepatocellular carcinoma (HCC). Using immunohistochemistry, we showed that the GLK proportion score increased in both cancerous and adjacent non-cancerous liver tissue from patients with HCC recurrence. A Kaplan-Meier analysis revealed that patients with a wide distribution of GLK in non-cancerous liver tissue had a higher rate of HCC recurrence than those with very low or no GLK expression. Multivariate Cox regression analyses indicated that a high GLK proportion score in non-cancerous liver tissue was an independent predictor of early HCC recurrence after resection. Lentiviral vector-mediated overexpression of GLK activated the nuclear factor kappa B (NFκB) signaling cascade and accelerated cell cycle progression in primary human hepatocytes, thereby promoting proliferation. An increase in GLK expression coincided with NFκB activation and enhanced expression of proliferating cell nuclear antigen in HCC tissue. Our findings demonstrate a potential hepatocarcinogenic effect of GLK and the feasibility of using GLK to predict early HCC recurrence.

Recepteur d'Origine Nantais (RON) is a distinct receptor tyrosine kinase in the c-met proto-oncogene family. We examined the mutational and expression patterns of RON in eight human uroepithelial cell lines. Biological effects of RON overexpression on cancer cells were investigated in vitro, and the prognostic significance of RON and/or c-met protein (MET) expression was analysed in a bladder cancer cohort (n=183). There was no evidence of mutation in the kinase domain of RON. Overexpression of RON using an inducible Tet-off system induced increased cell proliferation, motility, and antiapoptosis. Immunohistochemical analysis showed that RON was overexpressed in 60 cases (32.8%) of primary tumours, with 14 (23.3%) showing a high level of expression. Recepteur d'Origine Nantais expression was positively associated with histological grading, larger size, nonpapillary contour, and tumour stage (all P

This retrospective study uses the LAT-M (One Lambda Inc., Calif) screen assay to reexamine the impacts (a), of pretransplant human leukocyte antigen (HLA) antibody on long-term graft survival; (b) posttransplant HLA antibody on long-term graft survival and (c) immunosuppressive regimen on posttransplant HLA antibody development.Pretransplant sera from 222 renal transplant recipients and posttransplant sera from 216 renal transplant recipients were studied for the impact of HLA antibody on long-term graft survival.Among the patients who did not display pretransplant HLA antibodies, 85% enjoyed 5-year and 59% 10-year graft survival, whereas the patients who tested positive were 83% and 83% (P = .5596). Among the patients who did not show posttransplant HLA antibodies, 99% enjoyed 5-, 91% 10-, and 65% 15-year graft survival, whereas for the 44 patients who tested positive they were 59%, 44%, and 30%, respectively (P.0001). Patients prescribed cyclosporine + myfortic (odds ratio 0.17, P = .05) or FK + Cellcept (odds ratio 0.36, P = .04) showed the lowest posttransplant HLA antibody development.Both regimens improve graft survival.

Background. Cyclosporine A (CsA) and morphine have neurotoxic and psychiatric side effects, respectively. Endogenous opiatelike peptides can elicit a number of behavioral responses that mimic the symptoms of psychiatric illness. The purpose of this study was to quantitiate the changes of Met-enkephalin (ME) and β-endorphin (BE) after administration of CsA and morphine in surgery and to assess the antinociceptive effect. Patients and materials. Pain sensitivity, an antinociceptive indicator in rats, was determined with the hotplate test. Plasma ME and BE levels were measured with radioimmunoassays. Results. In normal unoperated rats, CsA induced a profound analgesic effect concomitant with an increased plasma ME level on day 1. Morphine produced an analgesic effect on days 1 and 2, with decreased ME levels on days 2 and 3. Coadministration of CsA and morphine prolonged the analgesia from days 1 to 4 and increased the plasma ME level on day 1. No change in plasma BE level was found. In surgically operated rats, CsA induced an analgesic effect and higher ME levels than those in unoperated rats. Interestingly, the combined use of CsA and morphine prolonged the analgesia and increased plasma ME levels from days 1 to 4, with no significant change in plasma BE levels. Conclusions. Our results showed that CsA can induce antinociception and increase plasma ME levels. This induction can be potentiated by the addition of morphine. Acute neuropsychiatric manifestations in the early posttransplant period might, therefore, be due to induction of ME after coadministration of CsA and morphine.

Background Mixed chimerism is associated with donor-specific tolerance. Spleen or splenocyte allotransplantation (Tx) is recognized as potentially tolerogenic. There is no definitive report comparing chimerism levels following spleen and splenocyte Tx in a large animal model. We have compared chimerism after spleen, splenocyte, or kidney Tx in pigs. Methods Outbred (n = 5) and MHC-defined miniature (n = 1) pigs underwent orthotopic spleen Tx. Outbred pigs received splenocytes through a systemic vein (n = 1) or the portal vein (n = 3). Kidney Tx (n = 2) or concomitant Tx of spleen + kidney (n = 2) was carried out. All except one recipient pigs were irradiated (700 cGy thymic and 100–125 cGy whole body) on day − 2. Cyclosporine or tacrolimus was administered for 42 days. All donors were males and all recipients were females; chimerism in the blood was determined by Quantification-PCR for the donor Y chromosome. Mixed lymphocyte reaction (MLR) was performed before and after Tx. Results One week after spleen Tx in outbred and MHC-defined pigs, chimerism ranged between 0.8 and 22.5%, and 5.4–20.1%, respectively, and remained between 17.7 and 67.4%, and 2.2–7.4%, respectively, until day 28. One week after splenocyte Tx, chimerism ranged between 0.1 and 8.5%, and decreased to 0.1–0.8% at 3–4 weeks. There was no detectable chimerism 14 days after kidney Tx. The response on MLR of all recipient pigs to donor cells was decreased after Tx, except in one case of splenocyte Tx, indicating that this pig might have become sensitized. After discontinuation of immunosuppression, most isolated spleen or kidney grafts were not rejected, but the kidney was rejected after concomitant spleen + kidney Tx. Conclusions There was a significantly higher level of blood chimerism following spleen Tx compared to splenocyte or kidney Tx. However, concomitant Tx of spleen + kidney may be associated with accelerated kidney graft rejection.

Objectives Despite the advantages of laparoscopic living donor nephrectomy (LDN), this technique is known to have a steep learning curve that makes worldwide adoption challenging, especially in institutions without a large patients volume. Herein, we have reviewed our 5-year experience of adoption and evolution of this surgical technique, examining the donor and recipient outcomes. Methods Between September 2002 and June 2007, 40 LDNs were performed consecutively. Our surgical technique was mainly derived from the University of California San Francisco method. We retrospectively reviewed the donor demographics, operative characteristics, perioperative complication of donors/recipients, and outcomes of donors and recipients. Results Among the 40 cases, 36 (90.0%) were left-sided LDNs. Mean operative time was 335.1 ± 66.9 minutes, blood loss was 303.9 ± 333.2 mL, and warm ischemia time was 243.2 ± 127.0 seconds. Multiple renal arteries required bench arterial reconstruction in 7 (17.5%) donor kidneys. Three renovascular injuries occurred intraoperatively, and 2 (5.0%) required open conversion. The overall postoperative complication rate was 20.0%. Postoperative donor serum creatinine was 1.5 times higher than preoperative serum creatinine. All but one recipient was discharged with adequate renal function. Graft function continues in 36 of the 38 harvested kidneys (94.7%) during the follow-up period. One (2.5%) recipient developed ureteral necrosis, and no recipients developed vascular thrombosis. Conclusions LDNs can be performed with careful adoption and evolution in institutions without a large patient volume. The intraoperative complication rate of LDN can be reduced with experience.

Background Predonation kidney function may be an important factor affecting graft outcome. Increased baseline allograft function may be more effective than strategies to slow the decline in glomerular filtration rate (GFR). However, the role of donor effective renal plasma flow (ERPF) on long-term outcome is less well understood. The purpose of this study was to examine the relationship between preoperative allograft function as measured by ERPF and the decline of allograft function as defined by the annualized change in GFR among living-donor kidney transplant recipients. Methods We performed a retrospective analysis of 83 patients who underwent living donor renal transplantation at our institution from March 2001 to October 2010. A time series analysis of autoregressive integrated moving average (ARIMA) model was applied to determine the annualized change in GFR after transplantation. Univariate and stepwise multivariate analyses were performed using linear regression between preoperative ERPF and annualized change in GFR after transplantation. We also investigated the influence on annualized change in GFR of other donor or recipient variables. Results The ARIMA model revealed that the annualized change in GFR was −1.344 ± 12.476 mL/min/1.73 m 2 per year. Pearson correlation coefficient for the association between predonation ERPF of the transplanted kidney and the annualized change in GFR was 0.033 ( P = .777). Conclusions Poor predonation kidney function was not associated with an increased rate of decline of allograft function. Neither donor age nor renal function (preoperative ERPF value) was a valid predictor of change in GFR among living-donor kidney transplant recipients.

Background Mycophenolic acid (MPA) pharmacokinetics using the mycophenolate mofetil (CellCept) formulation are known to differ between patients receiving tacrolimus (FK) or cyclosporine (CyA), but only limited data exist concerning concomitant use of FK or CyA with enteric-coated mycophenolate sodium (EC-MPS; Myfortic). This retrospective study compared the drug interactions with the mycophenolic acid blood levels using different immunosuppressants and their relation to graft survival. Patients and methods We studied MPA levels in posttransplant sera from 298 renal transplant recipients. Results Patients receiving immunosuppression with CyA + Myfortic showed 94% at 5- and 10-year graft survivals, which were better than CyA + CellCept (75%, 63%). This combination suppressed posttransplant human leukocyte antigen (HLA) antibody development significantly ( P = .03) with higher MPA levels. Conclusion Patients immunosuppressed with CyA + Myfortic showed higher MPA levels and lower posttransplant HLA antibody development as well as the best graft survival. CyA + Myfortic or FK + Cellcept may be better combinations.

Purpose: To measure the CD151 expression in colorectal cancer (CRC). Methods: CD151 expression was assessed in 179 CRC patients and 39 patients with hepatic liver metastasis. Results: High CD151 expression was observed in 48% of patients with early-stage CRC versus only 33% of patients with metastatic colon cancer. A higher level of tumor invasion status correlated with a decrease in CD151 expression. Metastatic stage and advanced tumor stage correlated with a decreased CD151 expression. Twenty-seven out of the 39-paired samples had high CD151 expression in liver metastasis sites. Conclusions: CD151 expression is decreased in patients with metastatic CRC.

Allograft/xenograft rejection is associated with “passenger leukocyte” migration from the organ into recipient lymph nodes. In Study 1, we attempted to deplete leukocytes from potential kidney “donor” pigs, using two regimens of total body irradiation. A dose of 700 cGy was administered, followed by either 800 cGy (“low-dose”) or 1,300 cGy (“high dose”) with the kidneys shielded. Neither regimen was entirely successful in depleting all leukocytes, although remaining T and 8 cell numbers were negligible. Study 2 was aimed at providing an indication of whether near-complete depletion of leukocytes had any major impact on kidney allograft survival. In non-immunosuppressed recipient pigs, survival of a kidney from a donor that received high-dose irradiation was compared with that of a kidney taken from a non-irradiated donor. Kidney graft survival was 9 and 7 days, respectively, suggesting that depletion had little impact on graft survival. The lack of effect may have been related to (i) inadequate depletion of passenger leukocytes, thus not preventing a direct T cell response, (ii) the presence of dead or dying leukocytes (antigens), thus not preventing an indirect T cell response, or (iii) constitutive expression of MHC class II and B7 molecules on the porcine vascular endothelium, activating recipient T cells.

BACKGROUND: The recurrence of hepatocellular carcinoma (HCC) after hepatectomy is a serious event. It has been demonstrated that different ground-glass hepatocyte (GGH) patterns harbor specific hepatitis B virus (HBV) pre-S deletion mutants and represent preneoplastic lesions in chronic HBV infection. In the current study, the authors investigated whether a specific GGH pattern in nontumorous liver tissues was associated with the recurrence of HBV-related HCC after surgery. METHODS: Clinicopathologic data from 82 patients with HBV-related HCC were reviewed. GGH patterns were assessed on hematoxylin and eosin-stained sections. Tissue hepatitis B surface antigen (HBsAg) expression was evaluated by immunohistochemical staining. Serum profiles of pre-S status, viral load, and HBV genotype were determined and correlated with clinical recurrence and survival after surgery. RESULTS: The results indicated that the clustered pattern of GGHs or HBsAg expression was associated significantly with decreased local recurrence-free survival (LRFS) during a mean follow-up of 46.4 months (P

Objectives Predonation kidney function is supposed to be an important factor affecting graft outcome. Controversial evidence suggests that higher predonation glomerular filtration rate (GFR) positively correlated with posttransplant graft outcome. The purpose of this study was to examine the relationship between living donor graft kidney function as measured by effective renal plasma flow (ERPF) and short-term graft function. Methods We performed a retrospective analysis of 45 patients who underwent living donor renal transplantation at our institution from 2001 to 2007. The comprehensive nuclear medicine evaluation of donors' ERPF was performed before laparoscopic nephrectomy. The preoperative absolute ERPF–recipient body surface area (F/BSA) ratio and absolute ERPF–recipient body weight (F/Wt) ratio were determined for each donor–recipient pair. Posttransplant graft function was estimated by the four-variable Modification of Diet in Renal Disease (Chinese MDRD) equation. Results Estimated GFR correlated with F/BSA ratio at 3 months and 6 months (Pearson r = .495, P = .001 and r = .441, P = .012). Estimated GFR correlated with F/Wt ratio at 3 months and 6 months ( r = .567, P r = .453, P = .009). The correlations between the estimated GFR at 3 months and other variables were investigated. However, in the final multivariate model, F/BSA ratio and F/Wt ratio were the independent predictors of graft function. Conclusion Preoperative ERPF can be used to calculate F/BSA and F/Wt ratios before living donor kidney transplantation. Our study provided evidence that F/BSA and F/Wt ratios may be considered predictive indices for short-term outcomes. An extreme discrepancy should be avoided between preoperative allograft function (absolute ERPF) and recipient body surface area or body weight.

An increasing number of studies have demonstrated adverse graft survival in patients who have anti-HLA antibodies, whether preformed or developed posttransplantation. This retrospective study used Lambda antigen tray-mixed (LAT-M) screening and Luminex HLA class I and II specificity assay to re-examine the impact of pretransplantation HLA antibody on long-term graft survival. In this study, pretransplantation sera from 288 renal patients were tested using the enzyme-linked immunosorbent assay (ELISA) method, LAT-M. Among the 234 of the patients who did not have pretransplantation antibodies, 85% enjoyed 5-year functional graft survival, 76% 10-year functional graft survival, and 56% 15-year functional graft survival. The corresponding functional graft survival for the 54 patients who tested HLA antibody-positive was 65%, 53%, and 28%, respectively (P = .0021).

Streptozotocin (STZ) has been widely used to induce diabetes in rodents and nonhuman primates, but it has been found difficult to achieve a completely diabetic state in pigs in the absence of detrimental side effects. As a result, pancreatectomy has been advocated in this species. We have investigated the effects of 2 dosages of STZ to safely induce diabetes in pigs.Three pigs received Zanosar STZ at 150 mg/kg (group 1). Four pigs received Zanosar STZ at 200 mg/kg (group 2). The levels of glucose, insulin, and C-peptide when (a) fasting, (b) 30 minutes after eating, and (c) during intravenous glucose tolerance tests (IVGTTs) were measured in all pigs for 4 weeks after STZ injection. To confirm how long the diabetic state can be maintained after induction with STZ, levels were measured for 20 weeks in group 2.One to 4 weeks after STZ administration, in group 1 (150 mg/kg) pigs, insulin and C-peptide levels were detected up to 7 microIU/mL and 0.4 ng/mL, respectively, both when fasting and after a meal test or IVGTT, indicating that the pigs had failed to become fully diabetic. In group 2 (200 mg/kg) pigs, insulin and C-peptide levels were less than the 2 microIU/mL and 0.25 ng/mL respective detection levels and did not increase after a meal test or IVGTT. Group 2 remained completely diabetic for the entire 20-week period of follow-up, without STZ-related hepatic or renal dysfunction.High-dose (200 mg/kg) Zanosar STZ induces diabetes safely and completely in pigs without side effects. Pancreatectomy can, therefore, be avoided.

The aim of this article is to provide a review of six patients with the various stages of obturator hernia and a diagnostic and therapeutic strategy in suspected cases. Obturator hernia is relatively rare and is a diagnostic challenge. It is a significant cause of intestinal obstruction, especially in emaciated elderly women with chronic disease. A palpable groin mass is not common in these patients because the hernia mass is usually concealed beneath the pectineus muscle. The high mortality is directly related to the delayed recognition, with resultant ruptured gangrenous bowel, and to the high incidence of patients with concurrent medical illness. A total of six patients with obturator hernias were treated at this hospital between 1994 and 2004, and one of these patients was diagnosed and treated by elective laparoscopy. We reviewed these six cases and examined the clinical presentation, age, body weight, associated medical conditions, preoperative diagnosis, operative findings, complications, and outcome in this retrospective study. We concluded that we cannot shorten the time from onset of symptoms to admission, but what we can do is to make a rapid evaluation and surgical intervention to reduce the morbidity and mortality from obturator hernia. The approaches to different presentation of obturator hernia and diagnostic role of CT scan are also discussed.

Background. Clinically, liver dysfunction in renal transplant recipients is related to hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. The contribution of parvovirus B19 (B19) to liver disease in renal transplant recipients has not been studied. Here we present the association of liver dysfunction with or without the coinfection of B19, HBV, and HCV after renal transplantation. Methods. We used enzyme-linked immunosorbent assay to identify B19, HBV, and HCV infections in serum samples taken from 144 renal transplant recipients before transplantation and at 12 and 24 months after transplantation. After each patient had fasted for 12 hr, blood was taken for measurement of aspartate aminotransferase and alanine aminotransferase monthly for at least 6 months. Results. Liver dysfunction developed at the significantly higher incidence of 47% in the anti-HCV(+) patients compared with 6% in the noninfected group (P

Most retroperitoneal leiomyosarcomas are clinically silent and are usually detected late, so a large size main tumor accompanied by satellite lesions might be presented. We report a case of a large multicentric retroperitoneal leiomyosarcoma with satellite lesions in the left iliac region, mimicking an abscess, was found on pre-operative pelvic computed tomography (CT). Positron emission tomography (PET-CT) was performed, but revealed only focal bony destruction of the left ilium and no discernable lesions in the abdomen. After resection of the iliacus satellite lesion, CT and magnetic resonance imaging (MRI) of the abdomen revealed another huge retroperitoneal leiomyosarcoma with invasion of the left kidney and ureter, descending colon and left iliac arteries. The patient was then treated with a multidisciplinary extensive excision operation. The clinical presentation, operative findings and imaging findings were reported and related articles were reviewed.

AIM: To demonstrate that administering heparanase inhibitor PI-88 at 160 mg/d is safe and promising in reducing hepatocellular carcinoma (HCC) recurrence for up to 3 year following curative resection. METHODS: A total of 143 patients (83.1% of the 172 participants in the phase II study) participated in the follow-up study. Of these patients, 50 had received no treatment, 48 had received 160 mg/d PI-88, and 45 had received 250 mg/d PI-88 during the phase II trial. Safety parameters and the following efficacy endpoints were investigated: (1) time to recurrence; (2) disease-free survival; and (3) overall survival. RESULTS: PI-88 at 160 mg/d delayed the onset and frequency of HCC recurrence, and provided a clinically significant survival advantage for up to 3 years after treatment compared with those of the control group: (1) the recurrence-free rate increased from 50% to 63%, and (2) time to recurrence at the 36th percentile was postponed by 78%. The efficacy of administering PI-88 at 250 mg/d was confounded by a high dropout rate (11 out of 54 patients). Additionally, subgroup analyses of patients with (1) multiple tumors or a single tumor ≥ 2 cm; and (2) hepatitis B or C revealed that administering PI-88 at 160 mg/d conferred the most significant survival advantage (56.8% improvement in disease-free survival, P = 0.045) for patients with both risk factors for recurrence. CONCLUSION: Administering PI-88 at 160 mg/d is a safe and well-tolerated dosage that may confer significant clinical benefits for patients with HCC.