Surgeons' involvement in COVID-19 treatment: a practice by a regional core hospital in Japan to avoid physician burnout.

BACKGROUND: To prevent task accumulation on certain divisions, our institution developed a unique system of allocating inpatient treatment of COVID-19 patients to doctors who were not specialized in respiratory infections. The objective of this study was to investigate whether surgeons can be involved in the COVID-19 inpatient treatment without negatively affecting patient outcome, and how such involvement can affect the wellbeing of surgeons. METHODS: There were 300 patients diagnosed with COVID-19 and hospitalized from January to June 2021, and 160 of them were treated by the redeployed doctors. They were divided into 3 groups based on the affiliation of the treating doctor. Patient characteristics and outcomes were compared between the groups. In addition, the impact of COVID-19 duty on participating surgeons was investigated from multiple perspectives, and a postduty survey was conducted. RESULTS: There were 43 patients assigned to the Department of Surgery. There were no differences in the backgrounds and outcomes of patients compared with other groups. The surgeon's overtime hours were significantly longer during the duty period, despite no change in the number of operations and the complication rate. The questionnaire revealed that there was a certain amount of mental and physical burden from the COVID-19 duty. CONCLUSION: Surgeons can take part in inpatient COVID-19 treatment without affecting patient outcome. However, as such duty could negatively affect the surgeons' physical and mental wellbeing, further effort is needed to maintain the balance of fulfilling individual and institutional needs.

The safety and feasibility of laparoscopic gastrectomy for gastric cancer in very elderly patients: short-and long-term outcomes.

PURPOSE: It remains unclear whether laparoscopic gastrectomy (LG) for gastric cancer is a suitable treatment for very elderly (VE) patients. We aimed to assess the safety and feasibility of LG for gastric cancer in VE patients. METHODS: We reviewed 226 consecutive patients who underwent LG between January 2010 and December 2016. We compared VE patients (age ≥ 80, n = 38) with non-elderly patients (age ≤ 79, n = 188). RESULTS: An ASA-PS score ≥ 2 was more common in VE group (86.8 vs. 48.9%; P < 0.01). There were no significant differences in the operating time, blood loss, postoperative hospital stay, or postoperative morbidity between the groups. The 3-year survival rate and 3-year disease-specific survival rate were lower in the VE group (53.7 vs. 85.6%; P < 0.0001, 78.5 vs. 92.4%; P = 0.0116). A univariate analysis showed that PS scores ≥ 2, Charlson comorbidity index ≥ 4, and pN stage were independent predictors of decreased overall survival rates in the VE group. A multivariate analysis showed total gastrectomy, a Charlson comorbidity index ≥ 4, and the pN stage to be independent predictors in the VE group. CONCLUSION: LG for gastric cancer is, thus, considered to be safe for patients aged 80 years or older. Total gastrectomy, a Charlson comorbidity index ≥ 4, and the pN stage were independent risk factors for a poor prognosis in these patients.

Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors.

Metabolic syndrome is a newly identified risk factor for hepatocellular carcinoma (HCC); however, tumor-specific biomarkers still remain unclear. We performed cross-species analysis to compare gene signatures of HCC from human patients and melanocortin 4 receptor-knockout mice, which develop HCC with obesity, insulin resistance, and dyslipidemia. Unsupervised hierarchical clustering and principle component analysis of 746 differentially expressed orthologous genes classified HCC of 152 human patients and melanocortin 4 receptor-knockout mice into two distinct subgroups, one of which included mouse HCC and was causatively associated with metabolic risk factors. Nine genes commonly overexpressed in human and mouse metabolic disease-associated HCC were identified; fatty acid binding protein 4 (FABP4) was remarkably enriched in intratumoral activated hepatic stellate cells (HSCs). Subclones constitutively expressing FABP4 were established from a human HSC cell line in which expression levels of inflammatory chemokines, including IL-1A and IL-6, were up-regulated through NF-κB nuclear translocation, resulting in recruitment of macrophages. An immunohistochemical validation study of 106 additional human HCC samples indicated that FABP4-positive HSCs were distributed in tumors of 38 cases, and the FABP4-high group consisted of patients with nonviral and nonalcoholic HCC (P = 0.027) and with multiple metabolic risk factors (P < 0.001) compared with the FABP4-low group. Thus, FABP4 overexpression in HSCs may contribute to hepatocarcinogenesis in patients with metabolic risk factors by modulation of inflammatory pathways.

DNA methylation at hepatitis B viral integrants is associated with methylation at flanking human genomic sequences.

Integration of DNA viruses into the human genome plays an important role in various types of tumors, including hepatitis B virus (HBV)-related hepatocellular carcinoma. However, the molecular details and clinical impact of HBV integration on either human or HBV epigenomes are unknown. Here, we show that methylation of the integrated HBV DNA is related to the methylation status of the flanking human genome. We developed a next-generation sequencing-based method for structural methylation analysis of integrated viral genomes (denoted G-NaVI). This method is a novel approach that enables enrichment of viral fragments for sequencing using unique baits based on the sequence of the HBV genome. We detected integrated HBV sequences in the genome of the PLC/PRF/5 cell line and found variable levels of methylation within the integrated HBV genomes. Allele-specific methylation analysis revealed that the HBV genome often became significantly methylated when integrated into highly methylated host sites. After integration into unmethylated human genome regions such as promoters, however, the HBV DNA remains unmethylated and may eventually play an important role in tumorigenesis. The observed dynamic changes in DNA methylation of the host and viral genomes may functionally affect the biological behavior of HBV. These findings may impact public health given that millions of people worldwide are carriers of HBV. We also believe our assay will be a powerful tool to increase our understanding of the various types of DNA virus-associated tumorigenesis.

Impact of resection and ablation for single hypovascular hepatocellular carcinoma ≤2 cm analysed with propensity score weighting.

BACKGROUND AND AIMS: Small hypovascular hepatocellular carcinoma (HCC) ≤2 cm is biologically less aggressive than hypervascular one, however, the optimal treatment is still undetermined. The efficacy of surgical resection (SR), radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) was evaluated. METHODS: The 853 (SR, 176; RFA, 491; PEI, 186) patients were enrolled who met Child-Pugh A/B, single hypovascular HCC ≤2 cm pathologically proven, available tumour differentiation and absence of macrovascular invasion and extrahepatic metastasis. Overall and recurrence-free survivals were compared in original and a propensity score weighted pseudo-population with 732 patients. RESULTS: The median follow-up time and tumour size were 2.8 years and 1.47 cm respectively. In original population, multivariate Cox regression showed no significant difference for overall survival among three groups. In pseudo-population, Cox regression also revealed no significant difference for overall survival among them, although SR (HR, 0.56; 95% CI, 0.36-0.86) and RFA (HR, 0.75; 95% CI, 0.57-1.00) groups had significantly lower recurrence than PEI group. The overall survival rates at 3 and 5 years for the SR, RFA and PEI groups were 94%/70%, 90%/75% and 94%/73% respectively. Corresponding recurrence-free survival rates were 64%/54%, 59%/41% 48%/33% respectively. Subgroup analysis revealed no significant survival benefit of SR compared with non-SR. No treatment-related death occurred. CONCLUSIONS: For patients with single hypovascular HCC ≤2 cm, no significant difference for overall survival was first identified among 3 treatment groups. The SR or RFA could be recommended, and PEI would be alternative to RFA.

Novel Aurora/vascular endothelial growth factor receptor dual kinase inhibitor as treatment for hepatocellular carcinoma.

We previously identified Aurora B kinase as the only independent factor predictive of the aggressive recurrence of hepatocellular carcinoma (HCC). In this preclinical study, JNJ-28841072, a novel Aurora/vascular endothelial growth factor receptor dual kinase inhibitor, was evaluated for treatment of HCC. In vitro and in vivo effects of JNJ-28841072 were analyzed using human HCC cell cultures and xenograft models. An orthotopic liver xenograft model was used for the pharmacobiological effects on Aurora kinase and vascularization in hepatic tumors. JNJ-28841072 suppressed in vitro phosphorylation of histone H3 with induction of cell polyploidy and death in a dose-dependent manner (IC50  = 0.8-1.2 µM). In s.c. human HCC xenografts, remarkable inhibition of tumor growth was observed after JNJ-28841072 treatment (P = 0.0005). In orthotopic liver xenografts, the treatment with JNJ-28841072 significantly suppressed in vivo phosphorylation of histone H3 (P = 0.0008), vessel formation (P = 0.018), normoxic area (P = 0.0001), and hepatoma growth (P = 0.038). Our preclinical studies indicate that JNJ-28841072 is a promising novel therapeutic approach for the treatment of HCC. It might be worthy of evaluation in further studies.

EVI1, a target gene for amplification at 3q26, antagonizes transforming growth factor-ß-mediated growth inhibition in hepatocellular carcinoma.

EVI1 (ecotropic viral integration site 1) is one of the most aggressive oncogenes associated with myeloid leukemia. We investigated DNA copy number aberrations in human hepatocellular carcinoma (HCC) cell lines using a high-density oligonucleotide microarray. We found that a novel amplification at the chromosomal region 3q26 occurs in the HCC cell line JHH-1, and that MECOM (MDS1 and EVI1 complex locus), which lies within the 3q26 region, was amplified. Quantitative PCR analysis of the three transcripts transcribed from MECOM indicated that only EVI1, but not the fusion transcript MDS1-EVI1 or MDS1, was overexpressed in JHH-1 cells and was significantly upregulated in 22 (61%) of 36 primary HCC tumors when compared with their non-tumorous counterparts. A copy number gain of EVI1 was observed in 24 (36%) of 66 primary HCC tumors. High EVI1 expression was significantly associated with larger tumor size and higher level of des-γ-carboxy prothrombin, a tumor marker for HCC. Knockdown of EVI1 resulted in increased induction of the cyclin-dependent kinase inhibitor p15(INK) (4B) by transforming growth factor (TGF)-ß and decreased expression of c-Myc, cyclin D1, and phosphorylated Rb in TGF-ß-treated cells. Consequently, knockdown of EVI1 led to reduced DNA synthesis and cell viability. Collectively, our results suggest that EVI1 is a probable target gene that acts as a driving force for the amplification at 3q26 in HCC and that the oncoprotein EVI1 antagonizes TGF-ß-mediated growth inhibition of HCC cells.

Gd-EOB-DTPA-enhanced magnetic resonance imaging and alpha-fetoprotein predict prognosis of early-stage hepatocellular carcinoma.

UNLABELLED: The survival of patients with hepatocellular carcinoma (HCC) is often individually different even after surgery for early-stage tumors. Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) has been introduced recently to evaluate hepatic lesions with regard to vascularity and the activity of the organic anion transporter OATP1B3. Here we report that Gd-EOB-DTPA-enhanced MRI (EOB-MRI) in combination with serum alpha-fetoprotein (AFP) status reflects the stem/maturational status of HCC with distinct biology and prognostic information. Gd-EOB-DTPA uptake in the hepatobiliary phase was observed in ∼15% of HCCs. This uptake correlated with low serum AFP levels, maintenance of hepatocyte function with the up-regulation of OATP1B3 and HNF4A expression, and good prognosis. By contrast, HCC showing reduced Gd-EOB-DTPA uptake with high serum AFP levels was associated with poor prognosis and the activation of the oncogene FOXM1. Knockdown of HNF4A in HCC cells showing Gd-EOB-DTPA uptake resulted in the increased expression of AFP and FOXM1 and the loss of OATP1B3 expression accompanied by morphological changes, enhanced tumorigenesis, and loss of Gd-EOB-DTPA uptake in vivo. HCC classification based on EOB-MRI and serum AFP levels predicted overall survival in a single-institution cohort (n=70), and its prognostic utility was validated independently in a multi-institution cohort of early-stage HCCs (n=109). CONCLUSION: This noninvasive classification system is molecularly based on the stem/maturation status of HCCs and can be incorporated into current staging practices to improve management algorithms, especially in the early stage of disease.

A novel therapeutic combination sequentially targeting aurora B and Bcl-xL in hepatocellular carcinoma.

BACKGROUND: Effective therapeutic combinations targeting the oncogenic pathway still are unknown in human hepatocellular carcinoma (HCC). The authors previously identified aberrant expression of aurora B kinase as the independent predictor for the lethal recurrence of HCC, showing that AZD1152 induced in vitro and in vivo apoptosis with polyploidy in human HCC cells. In this preclinical study, the combined effects of molecular-targeted therapies were evaluated based on the cellular response of aurora B inhibition. METHODS: This study analyzed the expression of Bcl-2 family proteins in polyploidization induced by AZD1152 and the in vitro synergistic effects of AZD1152 with control of the Bcl-2 family pathway in human HCC cells. The in vivo effects of the combination therapy targeting the specific molecules were evaluated using subcutaneous tumor xenograft models. RESULTS: The findings showed that Bcl-xL was specifically overexpressed in AZD1152-induced polyploid HCC cells. The combination of AZD1152 followed by Bcl-xL/2 inhibitor ABT263 induced synergistically cellular apoptosis (p < 0.001) and growth inhibition (p < 0.0001). Interestingly, the reverse sequential administration of AZD1152 combined with pretreatment of ABT263 was less effective than the original one. In vivo studies using tumor xenografts of human HCC cells showed that combination therapy of ABT263 after AZD1152 pretreatment induced significant intratumoral apoptosis (p < 0.05) and remarkable anti-tumor effects (p < 0.05) without a severe adverse effect compared with the monotherapy. CONCLUSION: Based on Bcl-xL overexpression in polyploidy induced by aurora B inhibition, the rationale for therapeutic combinations targeting aurora B and Bcl-xL was demonstrated in the authors' preclinical studies, leading to a promising novel approach for the mechanism-based treatment of human HCC.

Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines).

The 3rd version of Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence-based medicine, which was published in October 2013 in Japanese. Here, we briefly describe new or changed recommendations with a special reference to the two algorithms for surveillance, diagnosis, and treatment.

Visualization of stem cell features in human hepatocellular carcinoma reveals in vivo significance of tumor-host interaction and clinical course.

UNLABELLED: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies because of recurrence and/or metastasis even after curative resection. Emerging evidence suggests that tumor metastasis and recurrence might be driven by a small subpopulation of stemness cells, so-called cancer stem cells (CSCs). Previous investigations have revealed that glioma and breast CSCs exhibit intrinsically low proteasome activity and that breast CSCs also reportedly contain a lower reactive oxygen species (ROS) level than corresponding nontumorigenic cells. Here we visualized two stem cell features, low proteasome activity and low intracellular ROS, in HCC cells using two-color fluorescence activated cell sorting to isolate cells with stem cell features. These cells were then analyzed for their division behavior in normoxia and hypoxia, expression of stem cell markers, tumorigenicity, metastatic potential, specific gene expression signatures, and their clinical implications. A visualized small subpopulation of HCC cells demonstrated asymmetric divisions. Their remarkable tumorigenicity in nonobese diabetic/severe combined immunodeficient mice suggested the cancer initiation potential of these HCC CSCs. Comprehensive gene expression analysis revealed that chemokine-related genes were up-regulated in the CSCs subpopulation. Our identified HCC CSCs facilitated the migration of macrophages in vitro and demonstrated metastatic potential by way of recruitment of macrophages in vivo. In patients who undergo curative operation for HCC, the CSC-specific gene signature in the liver microenvironment significantly correlates with recurrence. CONCLUSION: Based on these findings, the stem cell feature monitoring system proposed here is a promising tool to analyze the in vivo significance of CSC microenvironments in human HCCs.

Contrast-enhanced intraoperative ultrasonography for vascular imaging of hepatocellular carcinoma: clinical and biological significance.

UNLABELLED: Abnormal tumor vascularity is one of the typical features of hepatocellular carcinoma (HCC). In this study, the significance of contrast-enhanced intraoperative ultrasonography (CEIOUS) images of HCC vasculature was evaluated by clinicopathological and gene expression analyses. We enrolled 82 patients who underwent curative hepatic resection for HCC with CEIOUS. Clinicopathological and gene expression analyses were performed according to CEIOUS vasculature patterns. CEIOUS images of HCC vasculatures were classified as reticular HCC or thunderbolt HCC. Thunderbolt HCC was significantly correlated with higher alpha-fetoprotein levels, tumor size, histological differentiation, portal vein invasion, and tumor-node-metastasis stage, and these patients demonstrated a significantly poorer prognosis for both recurrence-free survival (P = 0.0193) and overall survival (P = 0.0362) compared with patients who had reticular HCC. Gene expression analysis revealed that a rereplication inhibitor geminin was significantly overexpressed in thunderbolt HCCs (P = 0.00326). In vitro knockdown of geminin gene reduced significantly the proliferation of human HCC cells. Immunohistochemical analysis confirmed overexpression of geminin protein in thunderbolt HCC (P < 0.0001). Multivariate analysis revealed geminin expression to be an independent factor in predicting poor survival in HCC patients (P = 0.0170). CONCLUSION: CEIOUS vascular patterns were distinctly identifiable by gene expression profiling associated with cellular proliferation of HCC and were significantly related to HCC progression and poor prognosis. These findings might be clinically useful as a determinant factor in the postoperative treatment of HCC.

FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma.

UNLABELLED: The response rate to sorafenib in hepatocellular carcinoma (HCC) is relatively low (0.7%-3%), however, rapid and drastic tumor regression is occasionally observed. The molecular backgrounds and clinico-pathological features of these responders remain largely unclear. We analyzed the clinical and molecular backgrounds of 13 responders to sorafenib with significant tumor shrinkage in a retrospective study. A comparative genomic hybridization analysis using one frozen HCC sample from a responder demonstrated that the 11q13 region, a rare amplicon in HCC including the loci for FGF3 and FGF4, was highly amplified. A real-time polymerase chain reaction-based copy number assay revealed that FGF3/FGF4 amplification was observed in three of the 10 HCC samples from responders in which DNA was evaluable, whereas amplification was not observed in 38 patients with stable or progressive disease (P = 0.006). Fluorescence in situ hybridization analysis confirmed FGF3 amplification. In addition, the clinico-pathological features showed that multiple lung metastases (5/13, P = 0.006) and a poorly differentiated histological type (5/13, P = 0.13) were frequently observed in responders. A growth inhibitory assay showed that only one FGF3/FGF4-amplified and three FGFR2-amplified cancer cell lines exhibited hypersensitivity to sorafenib in vitro. Finally, an in vivo study revealed that treatment with a low dose of sorafenib was partially effective for stably and exogenously expressed FGF4 tumors, while being less effective in tumors expressing EGFP or FGF3. CONCLUSION: FGF3/FGF4 amplification was observed in around 2% of HCCs. Although the sample size was relatively small, FGF3/FGF4 amplification, a poorly differentiated histological type, and multiple lung metastases were frequently observed in responders to sorafenib. Our findings may provide a novel insight into the molecular background of HCC and sorafenib responders, warranting further prospective biomarker studies.

EpCAM-targeted therapy for human hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies and the identification of new effective therapies for HCC is urgently needed. We have previously identified EpCAM, one of the hepatic stem/progenitor markers, as a prognostic predictor of patients who received curative hepatectomy for HCC. In this preclinical study, the effects of VB4-845, an immunotoxin targeting EpCAM, were evaluated in HCC. METHODS: In vitro effects of VB4-845 on human HCC cells, the cytotoxic activity, sphere-forming ability, and expression of hepatic stem/progenitor markers were analyzed. In vivo effects of VB4-845 were evaluated using subcutaneous and orthotopic liver xenograft models. RESULTS: In all HCC cell lines expressing EpCAM, VB4-845 showed potent cytotoxicity and was significantly effective in combination with 5-FU (p < 0.05). Although 5-FU did not affect the sphere-forming ability and increased the populations expressing other stem/progenitor markers CD133 and CD13 (p < 0.05), VB4-845 strongly suppressed the sphere-formation and decreased the population expressing CD133 and CD13 (p < 0.0005, <0.01, respectively). In subcutaneous xenograft models, the combination of VB4-845 plus 5-FU showed significant regression of tumors compared with the control (p = 0.016). Moreover, in orthotopic liver xenograft models, the combination therapy dramatically decreased the tumor volume compared with the control (p = 0.0011). CONCLUSIONS: Our preclinical investigation suggests that EpCAM-targeted therapy may offer a promising and novel approach for the treatment of HCC with a poorer prognosis.

Reduced organic anion transporter expression is a risk factor for hepatocellular carcinoma in chronic hepatitis C patients: a propensity score matching study.

OBJECTIVES: Recent reports indicated that reduced SLC22A7 (a gene-encoding organic anion transporter 2) expression in noncancerous liver tissue predicts hepatocellular carcinoma (HCC) recurrence after curative resection. Our study aimed to elucidate the association between SLC22A7 expression and HCC development in chronic hepatitis C patients. METHODS: HCC recurrence after local ablation therapy and SLC22A7 expression in noncancerous liver tissue were analyzed in 20 patients. Subsequently, the association between de novo HCC development and SLC22A7 expression was examined at baseline in 38 hepatitis C patients without HCC who subsequently developed HCC as well as in 76 hepatitis C patients who did not develop HCC and were matched for age, gender and stage of fibrosis. RESULTS: In the patients whose HCC had been cured, reduced SLC22A7 expression in noncancerous liver tissue was significantly associated with a high incidence of multifocal HCC recurrence. In patients without HCC at baseline, cumulative incidence of de novo HCC development was significantly higher with a reduced SLC22A7 expression than with a normal expression (p = 0.01). This difference remained significant among patients without known risk factors for HCC like age and advanced fibrosis. CONCLUSION: Reduced SLC22A7 expression in the liver indicates a significant risk for HCC development in chronic hepatitis C, independently of other risk factors.

Does the preoperative alpha-fetoprotein predict the recurrence and mortality after hepatectomy for hepatocellular carcinoma without macrovascular invasion in patients with normal liver function?

AIM: It has been highly controversial whether elevated serum α-fetoprotein (AFP) level before hepatectomy predicts recurrence and mortality of patients with hepatocellular carcinoma (HCC) or not. This study is to identify whether the index predicts recurrence and mortality after hepatectomy in HCC. METHODS: Of 568 consecutive patients, 342 with normal liver function (Child-Pugh score, 5) and no macrovascular invasion were enrolled between April 2000 and March 2013. Multivariate analysis was performed to identify risk factors for disease-free survival (DFS) and overall survival (OS). RESULTS: In multivariate analysis, the elevated serum AFP level was an independent risk factor for DFS (hazard ratio [HR], 1.9; P < 0.0001) and OS (HR, 2.0; P < 0.0001). Histological hepatic venous tumor thrombus was also an independent risk factor for DFS (HR, 2.6; P < 0.0001) and OS (HR, 2.5; P = 0.001). Anatomical resection decreases the risk factor for recurrence after hepatectomy (HR, 0.6; P = 0.003), though it did not decrease the risk for OS (P = 0.3). At 5 years, DFS rates were 42% and 21% (P < 0.0001) and OS rates were 75% and 46% among patients with low and high AFP levels, respectively (P < 0.0001). The area under the receiver-operator curves (AUROC) of serum AFP and des-γ-carboxy prothrombin were 0.65 and 0.58 for DFS and 0.65 and 0.57 for OS, respectively. Tumor size was the best predictor of microvascular invasion (AUROC, 0.70, P < 0.0001). CONCLUSION: Serum AFP was a highly reliable index for DFS and OS.

Nationwide survey in Japan regarding splenectomy/partial splenic embolization for interferon treatment targeting hepatitis C virus-related chronic liver disease in patients with low platelet count.

AIM: In chronic liver disease associated with hepatitis C virus (HCV), a low platelet count is a major obstacle in carrying out interferon (IFN) treatment. We used a questionnaire to clarify the extent to which splenectomy/partial splenic embolization (PSE) is performed before IFN treatment, as well as the efficacy and complications thereof. METHODS: Two questionnaires were distributed to 413 medical institutes in Japan specializing in the treatment of liver diseases, and responses were obtained from 204 institutes. Furthermore, a more detailed questionnaire was completed by 10 institutes that experienced cases of death. RESULTS: In patients with HCV genotype 1b and a high viral load (HCV1b/High), the sustained viral response (SVR) rate was 28% for the splenectomy group and 22% for the PSE group, with no significant difference between these groups. In patients that were not HCV1b/High, the SVR rate was higher in those that underwent splenectomy (71%) compared to the PSE group (56%; P = 0.025). There were cases of death in seven of 799 splenectomy cases (0.89%) and four of 474 PSE cases (0.84%). Infectious diseases were involved in nine of 11 cases of death, with a peculiar patient background of Child-Pugh B (6/10) and an age of 60 years or greater (7/11). CONCLUSION: The application of splenectomy/PSE before IFN treatment should be avoided in patients with poor residual hepatic function and/or elderly patients. In HCV1b/High patients, splenectomy/PSE should be performed only after selecting those in which IFN treatment should be highly effective.

Severe postoperative hemorrhage caused by antibody-mediated coagulation factor deficiencies: report of two cases.

Antibody-mediated coagulation factor deficiencies constitute a rare disorder that may develop in elderly patients without any history of a bleeding diathesis. Patients may present with severe and sometimes catastrophic bleeding. We report two cases of postoperative hemorrhage caused by a coagulation factor deficiency. In Case 1, massive intraabdominal bleeding occurred on day 3 after pancreaticoduodenectomy for bile duct cancer, and was caused by an acquired inhibitor of coagulation factor VIII. Hemostasis was achieved and the factor VIII inhibitor titer decreased to zero with activated prothrombin complex concentrates, prednisolone, and cyclophosphamide. In Case 2, intraabdominal bleeding occurred on day 7 after hepatectomy for hepatocellular carcinoma, and was caused by an acquired inhibitor against factors II (prothrombin) and V. This patient was treated with hemostatic agents containing bovine thrombin during surgery and also with prednisolone. We report these cases to highlight that antibody-mediated coagulation factor deficiencies should be considered when an elderly patient suffers sudden postoperative hemorrhage and to stress the importance of prompt diagnosis because of the risk of potentially life-threatening hemorrhage.

Combined resection of a tumor and the inferior vena cava: report of two cases.

Tumor resection and caval tumor thrombectomy, with or without cavotomy and inferior vena cava (IVC) replacement are sometimes performed in patients with renal cell carcinoma (RCC) extending into the IVC or liver tumors invading the IVC. Two such cases were treated. Case 1: a 68-year-old female was transferred with a diagnosis of right RCC with tumor thrombus extending into the IVC. A plication was performed to prevent extension into the right atrium before the nephrectomy and cavotomy with removal of the tumor thrombus was accomplished, because the IVC was almost completely obstructed and the hemodynamics were stable during cross-clamping of the IVC. Case 2: a 37-year-old female was transferred with a diagnosis of a giant metastatic liver tumor. A trisegmentectomy with resection of the invaded IVC and IVC replacement was performed while the abdominal aorta was cross-clamped to maintain the hemodynamics. Therefore, abdominal aortic cross-clamping was convenient to maintain the hemodynamics when the IVC replacement was performed during IVC cross-clamping.

[Curative resection of stage IV advanced gallbladder cancer following combined treatment with gemcitabine and CDDP].

A 74-year-old woman was referred to our hospital following the diagnosis of advanced gallbladder cancer with para-aortic lymph node metastasis. Combination treatment involving gemcitabine(1,000mg/m / 2 body surface area)and CDDP(50mg/ m2 body surface area)was initiated and repeated for 4 courses; gemcitabine was administrated on day 1 and day 8, whereas CDDP was administrated on day 8, followed by 1 week of no treatment. After 4 courses, abdominal computed tomography (CT)indicated a reduction in size of the main lesion and disappearance of para -aortic lymph nodes. The remarkable response to the chemotherapy, which resulted in tumor downstaging, enabled us to perform the curative surgery procedure. Thus, cholecystectomy with resection of the hepatic bed and lymph node dissection were performed. The resected specimens indicated papillary adenocarcinoma of the gallbladder infiltrating the muscular wall of the gallbladder. In addition, the resected para-aortic lymph nodes indicated hyalinization and fibrosis as a result of the chemotherapy. Moreover, the pericholedocal lymph nodes were necrotic and no viable tumor was noted, thus indicating the excellent response to the chemotherapy.