Safety/efficacy of atezolizumab + bevacizumab during anti-platelet/anticoagulation therapy in unresectable hepatocellular carcinoma.

BACKGROUND AND AIMS: This study aimed to determine the safety and efficacy of atezolizumab + bevacizumab therapy in hepatocellular carcinoma patients receiving anti-platelet agents or anticoagulants. METHODS: Patients were divided into those using (IM out) and those not using (IM in) anti-platelet agents or anticoagulants, who violated the exclusion criteria of the IMbrave150 trial, and were retrospectively examined. RESULTS: The study included 185 patients (IM in: 157; IM out: 28). For first-line treatment, progression-free survival was 184 days for IM in and 266 days for IM out (p = .136). Overall survival was 603 days for IM in and not reached for IM out (p = .265), with no significant between-group difference. Similarly, there were no significant between-group differences in progression-free survival or overall survival for later-line treatment. Haemorrhagic adverse events of ≥grade 3 were observed in 11 IM in patients and 3 IM out patients. No significant factors associated with haemorrhagic adverse events of ≥grade 3 were identified in the multivariate analysis including IM out classification, whose p value was .547. Regarding thrombotic/embolic adverse events in the IM out group, one case of exacerbation of portal vein thrombosis was observed. No deaths were directly attributable to bleeding events or exacerbations of thrombosis. CONCLUSION: Atezolizumab + bevacizumab therapy shows similar safety and efficacy in patients receiving and those not receiving anti-platelet agents or anticoagulants; therefore, it can be considered for patients with hepatocellular carcinoma receiving anti-platelet agents or anticoagulants.

Rosuvastatin ameliorates high-fat and high-cholesterol diet-induced nonalcoholic steatohepatitis in rats.

BACKGROUND/AIMS: Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibit endogenous cholesterol synthesis, possess pleiotropic activities, such as anti-inflammatory, anti-oxidative and antifibrotic effects. Here, we investigated whether statins ameliorate steatohepatitis using a high-fat and high-cholesterol (HFHC) diet-induced rat model. METHODS: Eight-week-old male Sprague-Dawley rats were fed control chow or HFHC diet. Half of the HFHC diet-fed rats were orally administered 2 mg/kg/day rosuvastatin for 12 weeks. Hepatic injury, steatosis, fibrosis and markers of lipid peroxidation/oxidant stress were evaluated. RESULTS: As previously reported, HFHC diet induced steatohepatitis in rat livers with hypercholesterolaemia. Rosuvastatin decreased Oil Red O stained-positive areas, liver/body weight ratio, serum total cholesterol levels and hepatic free fatty acid contents in HFHC diet-fed rats. Further study revealed that rosuvastatin significantly decreased hepatic mRNA expression of tumour necrosis factor-α and interleukin-6, serum alanine aminotransferase levels and hepatic lobular inflammation grade. Hepatic fibrosis was also ameliorated by rosuvastatin with decreases in hepatic mRNA expression of transforming growth factor-ß, connective tissue growth factor and type-1 procollagen. Similarly, hepatic Sirius red stained or α-smooth muscle actin stained-positive areas and expression of markers of lipid peroxidation/oxidant stress [hepatic 8-hydroxy-oxyguanosine and hepatic 4-hydroxy-2-nonenal] were decreased. Interestingly, whereas the expression of carnitine palmitoyltransferase-1 and long-chain acyl-CoA dehydrogenase was not affected, that of catalase and acyl-coA oxidase was restored. CONCLUSIONS: These data suggest that rosuvastatin improved not only hepatic steatosis but also hepatic injury and fibrosis via improved peroxisomal ß-oxidation in this rat HFHC model.

Selective synthesis of tightly- and loosely-twisted metallomacrocycle isomers towards precise control of helicity inversion motion.

Molecular twist is a characteristic component of molecular machines. Selectively synthesising isomers with different modes of twisting and controlling their motion such as helicity inversion is an essential challenge for achieving more advanced molecular systems. Here we report a strategy to control the inversion kinetics: the kinetically selective synthesis of tightly- and loosely-twisted isomers of a trinuclear PdII-macrocycle and their markedly different molecular behaviours. The loosely-twisted isomers smoothly invert between (P)- and (M)-helicity at a rate of 3.31 s-1, while the helicity inversion of the tightly-twisted isomers is undetectable but rather relaxes to the loosely-twisted isomers. This critical difference between these two isomers is explained by the presence or absence of an absolute configuration inversion of the nitrogen atoms of the macrocyclic amine ligand. Strategies to control the helicity inversion and structural loosening motions by the mode of twisting offer future possibilities for the design of molecular machines.

Greater age and hepatocellular aging are independent risk factors for hepatocellular carcinoma arising from non-B non-C non-alcoholic chronic liver disease.

We previously reported that hepatocellular aging can be assessed by measuring the nuclear size of hepatocytes. We attempted to elucidate whether this method is useful to identify the high risk group of hepatocellular carcinoma (HCC) in the patients with non-B non-C non-alcoholic liver injury. Fourteen patients with HCC and 78 without HCC, both of whom presented with non-B non-C non-alcoholic chronic liver injury and underwent liver biopsy, were selected. Twelve histologically normal liver tissues were selected as controls. The relative nuclear size (RNS) was calculated as the average nuclear size of the hepatocytes divided by that of lymphocytes. Multiple clinicopathological parameters were studied. The RNS values of normal livers ranged from 1.32 to 2.10, showing a gradual increase in an age-dependent manner. The RNS values of the injured livers without HCC increased after middle age. Univariate analysis identified greater age, existence of diabetes and RNS, as significantly positive contributors and ALT value and the degree of steatosis as negative contributors for the occurrence of HCC. Only age and RNS retained significance in multivariate analysis. All of the HCC patients were older than 50 and showed RNS values higher than 2.00. Therefore, such patients are classified as a high risk group of HCC.

The ultrasonographic assessment of the morphologic changes in the ulnar nerve at the cubital tunnel in Japanese volunteers: relationship between dynamic ulnar nerve instability and clinical symptoms.

BACKGROUND: We investigated the differences in the prevalence of ulnar nerve instability (UNI) by hand dominance and evaluated the relationship between UNI and morphologic changes in the ulnar nerve and the clinical findings and upper limb function. METHODS: This study examined 153 healthy participants (n = 306 elbows; 44 men, 112 women; mean age 65.4 years) who underwent ultrasonography to assess the ulnar nerve cross-sectional area (UNCSA) at three points of the bilateral cubital tunnel at 30° of elbow flexion. Participants were divided into three groups based on the ultrasonography findings of UNI: no instability (type N), subluxation (type S), and dislocation (type D). For the dominant and nondominant sides, we assessed the relationship between the UNCSA and clinical factors, including the age, gender, height, weight, body mass index, fat mass, grip strength, key pinch strength, UNCSA, and Patient-Rated Elbow Evaluation score. RESULTS: We identified 75 cases without instability in both elbows and 78 cases with some instability. The prevalence of UNI was 51%. No significant difference was found between hand dominance and the prevalence of UNI. The UNCSA at 1 cm proximal to the medial epicondyle on the bilateral sides in type S was the most increased among three types. CONCLUSION: UNI was identified in almost half of the participants, with no marked difference found in the hand dominance. The UNCSA at 1 cm proximal to the medial epicondyle was significantly increased the most in type S. UNI does not appear to be associated with elbow symptoms in the general population.

Eosinophilic Cholangitis with Poor Prognosis after Corticosteroid- and Ursodeoxycholic Acid-Related Remission of Peripheral and Peribiliary Eosinophilia.

A 79-year-old man presented with high fever, marked eosinophilia, altered biochemical liver function tests (LFT) with predominance of biliary enzymes, and severe wall thickening of the gallbladder. Magnetic resonance cholangiopancreatography (MRCP) suggested cholecystitis, without signs of biliary strictures. Laparoscopic cholecystectomy and exploratory liver excision revealed eosinophilic cholangitis and cholecystitis, complicated with hepatitis and portal phlebitis. Prednisolone monotherapy rapidly improved peripheral eosinophilia, but not LFT. Liver biopsy showed that infiltrating eosinophils were replaced by lymphocytes and plasma cells. Treatment with ursodeoxycholic acid improved LFT abnormalities. Nevertheless, after 2 months, transaminase-dominant LFT abnormalities appeared. Transient prednisolone dose increase improved LFT, but biliary enzymes' levels re-elevated and jaundice progressed. The second and third MRCP within a 7-month interval showed rapid progression of biliary stricture. The repeated liver biopsy showed lymphocytic, not eosinophilic, peribiliary infiltration and hepatocellular reaction to cholestasis. Eighteen months after the first visit, the patient died of hepatic failure. Autopsy specimen of the liver showed lymphocyte-dominant peribiliary infiltration and bridging fibrosis due to cholestasis. Though eosinophil-induced biliary damage was an initial trigger, repeated biopsy suggested that lymphocytes played a key role in progression of the disease. Further studies are needed to elucidate the relationship between eosinophils and lymphocytes in eosinophilic cholangitis.

Nuclear size measurement is a simple method for the assessment of hepatocellular aging in non-alcoholic fatty liver disease: Comparison with telomere-specific quantitative FISH and p21 immunohistochemistry.

Telomere-specific quantitative fluorescent in situ hybridization (Q-FISH) accurately evaluates hepatocellular aging on histological sections, but it requires appropriate tissue processing. To establish a more simple method for the assessment of hepatocellular aging, the usefulness of nuclear size measurement was clarified using biopsy liver samples from 64 patients with non-alcoholic fatty liver disease (NAFLD), a model for oxidative stress-associated hepatocellular aging, and 11 control individuals. Relative telomere intensity (RTI) was measured on Q-FISH, and the relative nuclear size (RNS) was calculated as the average nuclear size of the hepatocytes divided by that of lymphocytes. In normal individuals and NAFLD patients, the RTI and RNS were negatively correlated. The degree of nuclear enlargement in NAFLD patients was larger than that in normal individuals with the same telomere length, possibly reflecting telomere-independent senescence. In NAFLD patients with RNS >2.0, the regenerative responses, indicated by the ratio of Ki-67-positive index to serum alanine aminotransferase level, were significantly reduced. The RNS positively correlated with the p21 expression, another marker of senescence. This all indicates that nuclear enlargement progresses in parallel with reduced regenerative responses, telomere shortening, and p21 upregulation. Nuclear size measurement is an effective method for estimation of hepatocellular aging.

Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis.

We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of target lesions' longest diameters from baseline according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 5.0 months. The receiver operating characteristic curve analysis in differentiating long-term responders (PFS ≥ 5.0 months) from short-term responders (PFS < 5.0 months) revealed an ETS cut-off value of 10%. ETS ≥ 10% was significantly correlated with better PFS and OS compared with ETS < 10%. Additionally, ETS ≥ 10% showed a better discrimination ability on prognosis compared with modified RECIST-based objective response at the first evaluation. Multivariate analysis confirmed ETS ≥ 10% as an independent predictor of better OS, as well as a Child-Pugh score of 5 and macrovascular invasion. In conclusion, ETS ≥ 10% was strongly associated with outcome in patients treated with LEN. This biomarker could allow earlier assessment of the treatment response and guide treatment decision-making for HCC.

Association of gankyrin protein expression with early clinical stages and insulin-like growth factor-binding protein 5 expression in human hepatocellular carcinoma.

UNLABELLED: Gankyrin (also known as PSMD10) is a liver oncoprotein that interacts with multiple proteins including MDM2 and accelerates degradation of the tumor suppressors p53 and Rb. We produced a monoclonal anti-gankyrin antibody and immunohistochemically assessed the clinicopathological significance of gankyrin overexpression in 43 specimens of human hepatocellular carcinoma (HCC). Specific cytoplasmic staining for gankyrin was observed in 62.8% (27/43) of HCCs, which was significantly associated with low TNM stage (P = 0.004), no capsular invasion (P = 0.018), no portal venous invasion (P = 0.008), and no intrahepatic metastasis (P = 0.012). The cumulative survival rate of patients with gankyrin-positive HCC was significantly higher than that with gankyrin-negative HCC (P = 0.037). p53 and MDM2 were positively stained by antibodies in 30.2% and 23.3%, respectively, of HCCs, but neither was inversely associated with gankyrin expression. In the Huh-7 human HCC cell line, overexpression of gankyrin up-regulated expression of insulin-like growth factor binding protein 5 (IGFBP-5), whereas suppression of gankyrin expression by siRNA down-regulated it. Supression of IGFBP-5 expression inhibited proliferation of Huh-7 cells as well as U-2 OS osteosarcoma cells. In HCC specimens, positive staining for IGFBP-5 was observed by immunohistochemistry in 41.9% (18/43), and the level of expression was significantly correlated with that of gankyrin (rho = 0.629, P < 0.001). CONCLUSION: These results suggest that gankyrin plays an oncogenic role(s) mainly at the early stages of human hepatocarcinogenesis, and that IGFBP-5 inducible by gankyrin overexpression may be involved in it.

Oxidative stress may enhance the malignant potential of human hepatocellular carcinoma by telomerase activation.

BACKGROUND/AIMS: Continuous oxidative stress (OS) plays an important role in the progression of chronic liver diseases and hepatocarcinogenesis through telomere shortening in hepatocytes. However, it has not been established how the OS influences the progression of human hepatocellular carcinomas (HCCs). We examined the correlations of OS with telomere length of cancer cells, telomerase activity and other clinicopathological factors in 68 HCCs. METHODS: The level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a marker of OS was examined immunohistochemically and OS was scored in four grades (0-3). The telomere length of cancer cells was measured by quantitative fluorescence in situ hybridization. Telomerase activity was measured by (i) immunodetection of human telomerase reverse transcriptase (hTERT) and (ii) telomere repeat amplification protocol (TRAP) assay. Telomerase related proteins, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Akt, and other clinicopathological factors were also evaluated. RESULTS: As the OS grade increased, the average telomere length became significantly shorter in HCCs, especially in the hTERT-negative group. In the state of high-grade OS, hTERT-positive HCC cells showed more proliferative and less apoptotic features compared with hTERT-negative HCC cells. Telomerase activity, as measured by the TRAP assay, was strongly correlated with OS grade in HCCs. Furthermore, a high OS grade was correlated with the downexpression of PTEN and the activation of Akt. CONCLUSIONS: Oxidative stress enhanced the malignant potential of HCCs through the activation of telomerase, which raises the possibility of using OS as a marker for assessing the clinical state of HCCs.

Impact of Relative Dose Intensity of Early-phase Lenvatinib Treatment on Therapeutic Response in Hepatocellular Carcinoma.

BACKGROUND: Factors associated with response to lenvatinib have not been clarified in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: This study retrospectively analyzed 50 patients treated with lenvatinib as first-line therapy between March 2018 and March 2019. Patients were divided into two groups by the Modified Response Evaluation Criteria in Solid Tumours (mRECIST) (responders and non-responders, whose best overall responses were complete (CR)/partial response (PR) and stable (SD)/progressive disease (PD), respectively). Factors associated with response were assessed, including the relative dose intensity 8 weeks after lenvatinib induction (8W-RDI). RESULTS: The best overall responses were 0/22/14/14 of CR/PR/SD/PD. Multivariate analysis revealed that only 8W-RDI was significantly associated with response. The receiver operating characteristic curve for 8W-RDI in differentiating responders from non-responders revealed a cut-off value of 75%. Patients with 8W-RDI ≥75% experienced a higher response rate and longer progression-free survival than patients with 8W-RDI <75%. CONCLUSION: Our results suggest that maintaining an RDI ≥75% during the initial 8 weeks of lenvatinib treatment has a favorable impact on response.

Hepatitis B virus-related insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis.

Growing evidence demonstrates that hepatitis B virus (HBV) integration and resulting insertional mutagenesis play an important role in cell growth or maintenance in hepatocellular carcinomas (HCCs). To determine if HBV integration occurs and affects cellular genes at such a stage of infection, we analysed viral-host junctions in chronic hepatitis tissues without HCC using PCR amplification with primers specific to human Alu-repeat and HBV. We obtained 42 independent viral-host junctions from six patients examined and identified chromosomal locations for 20 of the 42 junctions. In six clones, each integration apparently affected a single gene. These six candidate genes included one known tumor suppressor gene, three human homologs of drosophila genes that are critical for organ development, one putative oncogene and one recently found chemokine. Our data, together with previously reported HBV integrants in HCCs, suggested preferential HBV integration into chromosome 3 (P = 0.022). Our virus-tagging approach provided (a) firm evidence of HBV integration in hepatocytes at an early stage of chronic infection and (b) revealed cellular genes possibly affected by HBV integration and potentially involved in early steps of the process leading to carcinogenesis.

First phase viral kinetic parameters and prediction of response to interferon alpha-2b/ribavirin combination therapy in patients with chronic hepatitis C.

The aim of the present study was to assess parameters in early phase HCV dynamics for predicting the outcome of interferon (IFN)/ribavirin combination therapy in patients with chronic hepatitis C (CH-C). Sixty-five CH-C patients who received IFN alpha-2b/ribavirin combination therapy were enrolled. The serum levels of HCV RNA 0h and 3 months after commencing therapy were serially quantified. HCV kinetic parameters such as quantity, ratio of decline, and half-life were analyzed. In genotype 1 patients, both the quantity and the ratio of decline of HCV RNA 24h after the start of therapy were useful predictors of a poor response. No patients who had serum HCV RNA above 200KIU/ml 24h after the start of therapy achieved a sustained viral response (SVR). In genotype 2 patients, conversely, these two parameters were predictors of a sustained viral response. The efficacy of these parameters in predicting the outcome of therapy was comparable to that of the disappearance of HCV RNA from sera at 4 weeks. These results demonstrate that parameters of HCV kinetics 24h after the start of therapy are useful for the early prediction of outcome in response to IFN alpha-2b/ribavirin combination therapy.

Multifocal intraportal invasion of breast carcinoma diagnosed by laparoscopy-assisted liver biopsy.

Hepar lobatum carcinomatosum (HLC) is defined as an acquired hepatic deformity consisting of an irregularly lobulated hepatic contour caused by intravascular infiltration of metastatic carcinoma. To date, only nine cases of HLC have been reported in the literature. We report a case of a 68-year-old woman showing hepatic metastasis of breast carcinoma in radiologically unidentified form. Initially, she received left partial mastectomy for breast cancer but solid hepatic metastases were identified in S(2) and S(6), 9 mo after surgery. Then, they responded to chemotherapy and radiologically disappeared. After radiological disappearance of the liver tumors, the patient's blood chemistry showed abnormal liver function. A CT scan demonstrated heterogeneous enhancement effect in the liver in the late phase, suggesting uneven hepatic blood supply. Hepatic deformity was not obvious. Laparoscopy revealed a slightly deformed liver surface with multiple indentations and shallow linear depressions. Furthermore, a wide scar was observed on the surface of S(2) possibly at the site where the metastatic tumor existed before chemotherapy. Liver biopsy from the wide scar lesion showed intraportal tumor thrombi with desmoplastic change. Because of its similarity to the histology of the original breast cancer, we concluded that the hepatic functional abnormalities and slightly deformed liver surface were derived from the circulatory disturbance caused by microscopic tumor thrombi. Besides, since the wide scar was located at the site of the pre-existing tumor, it is probable that chemotherapy was an important cause of fibrous scarring as a result of tumor regression. These morphologic findings are compatible with those of HLC. Laparoscopy-assisted liver biopsy was useful to make definite diagnosis, even though the hepatic deformity was radiologically undetectable.

Loss of p53 transcriptional activity in hepatocellular carcinoma evaluated by yeast-based functional assay: comparison with p53 immunohistochemistry.

We studied the transcriptional activity of p53 protein in 50 tissues of hepatocellular carcinoma (HCC) using a yeast functional assay. In this assay, red yeast colonies indicate that p53 protein cannot bind to its specific domain and has lost its transcriptional activity. We also clarified whether mutant p53 protein could inactivate wild-type p53 protein in a transdominant manner using a modified yeast assay. In addition, we examined whether immunohistochemically detectable p53 protein was functionally inactive. The incidence of p53 inactivation was significantly higher in tumors with capsular invasion. Out of 21 tumors diagnosed with p53 mutations, 11 exhibited >75% red colonies, and all contained missense mutations. In these tumors, p53 function was lost because there was supposedly no intact p53 gene on either allele. One missense mutant produced <60% red colonies, but it was also considered inactive as a p53 protein heterotetramer because of its transdominant activity. In 7 of the remaining 9 tumors, p53 was considered to be mutated on one allele and intact on the other. All of these 7 tumors contained nonsense or frameshift mutations and had no transdominant activity, which suggested that p53 function remained intact. Alternately, immunohistochemical analysis demonstrated that all of the tumors with missense mutations were positively immunostained, whereas those that contained nonsense or frameshift mutations were negatively stained. Consequently, positively immunostaining tumors mostly coincided with p53-inactive tumors. These yeast-based assays suggested that p53 function was retained in some mutant cases. Immunohistochemistry was helpful in screening functionally inactive p53 protein in HCCs.

Simple tumor profile chart based on cell kinetic parameters and histologic grade is useful for estimating the natural growth rate of hepatocellular carcinoma.

Thirty-four untreated hepatocellular carcinomas (HCCs) with known growth rates were classified into 5 groups on a tumor profile chart based on their doubling time (DT), Ki-67-positive index (Ki-67-PI), apoptotic index (Apo-I), and histologic grade. The slow-growing HCCs (DT > 100 days) consisted of well-differentiated tumors with slight cell kinetic imbalance and were divided into groups A and B. Group A had Apo-I values <3%, and most tumors had Ki-67-PI values <10%, whereas group B had Apo-I values of 3 per thousand to 10 per thousand and Ki-67-PI values of 10% to 20%. The HCCs with intermediate growth rates, which had Ki-67-PI values similar to those of the tumors in group B, were divided into groups C and D based on differences in cell kinetics: group C consisted of well-differentiated tumors, most of which had Apo-I values <3 per thousand, and group D consisted of moderately or poorly differentiated tumors with Apo-I values between 10 per thousand and 20 per thousand. The rapidly growing tumors (DT < 50 days, group E) had higher Ki-67-PI values than other groups and a wide range of Apo-I values. Rapidly growing tumors were mostly moderately or poorly differentiated, with a large cell kinetic imbalance in favor of cell production. This grouping system is useful for approximating the growth rate of HCCs in a clinical setting, even when only histologic parameters are available.

Transient biochemical response in interferon therapy decreases the development of hepatocellular carcinoma for five years and improves the long-term survival of chronic hepatitis C patients.

The development of hepatocellular carcinoma (HCC) was significantly reduced in both sustained responders (SR) and transient biochemical responders (TR) in chronic hepatitis C (CH-C) patients who received interferon (IFN) therapy. However, the long-term clinical outcome of TR remains unclear. One thousand three hundred and seventy CH-C Japanese patients who received IFN therapy and 54 control cirrhotic patients were enrolled. TR were defined as those patients who showed a normal serum alanine aminotransferase level (<==30 IU/l) at the end of therapy and then relapsed. Mean follow-up period was 5.6 years (6.1 years in 48 cirrhotic patients) in the IFN group and 8.3 years in the 54 control cirrhotic patients. HCC was detected in 114 patients in the IFN group among whom 4 were in the 425 SR, 21 were in the 359 TR and 89 were in the 586 non-responders (NR). The cumulative incidence of HCC was significantly (P=0.0001) inhibited in both SR and TR compared with NR. Its inhibitory effect in TR was within 5 years. Platelet count did not significantly decrease for 2-4 years after IFN therapy in TR, but it significantly decreased in NR 2 years after IFN therapy. The cumulative survival in both SR and TR was significantly higher than NR (SR vs NR; P=0.0001, TR vs NR; P=0.0305). These results indicate that IFN therapy lowers the rate of the progression of HCC and improves the long-term survival even in CH-C patients who transiently respond to IFN therapy.

Recurrence of hepatocellular carcinoma with rapid growth after spontaneous regression.

We report an 80-year-old man who presented with spontaneous regression of hepatocellular carcinoma (HCC). He complained of sudden right flank pain and low-grade fever. The level of protein induced by vitamin K antagonist (PIVKA)-II was 1 137 mAU/mL. A computed tomography scan in November 2000 demonstrated a low-density mass located in liver S4 with marginal enhancement and a cystic mass of 68 mmX55 mm in liver S6, with slightly high density content and without marginal enhancement. Angiography revealed that the tumor in S4 with a size of 25 mmX20 mm was a typical hypervascular HCC, and transarterial chemoembolization was performed. However, the tumor in S6 was hypovascular and atypical of HCC, and thus no therapy was given. In December 2000, the cystic mass regressed spontaneously to 57 mmX44 mm, and aspiration cytology revealed bloody fluid, and the mass was diagnosed cytologically as class I. The tumor in S4 was treated successfully with a 5 mm margin of safety around it. The PIVKA-II level normalized in February 2001. In July 2001, the tumor regressed further but presented with an enhanced area at the posterior margin. In November 2001, the enhanced area extended, and a biopsy revealed well-differentiated HCC, although the previous tumor in S4 disappeared. Angiography demonstrated two tumor stains, one was in S6, which was previously hypovascular, and the other was in S8. Subsequently, the PIVKA-II level started to rise with the doubling time of 2-3 wk, and the tumor grew rapidly despite repeated transarterial embolization with gel foam. In February 2003, the patient died of bleeding into the peritoneal cavity from the tumor that occupied almost the entire right lobe. Considering the acute onset of the symptoms, we speculate that local ischemia possibly due to rapid tumor growth, resulted in intratumoral bleeding and/or hemorrhagic necrosis, and finally spontaneous regression of the initial tumor in S6.

Successful treatment of a previously healthy woman with Pseudomonas aeruginosa community-acquired pneumonia with plasmapheresis.

A previously healthy 39-year-old woman with severe chest pain presented at our hospital. She was diagnosed with bacterial pneumonia by chest X-ray and computed tomography. Despite adequate antimicrobial treatment, she had to undergo intubation for respiratory distress and was treated with mechanical ventilation 42 hours after admission. However, her condition improved markedly after plasmapheresis. Bacterial culture specimens from the sputum, blood, and pleural fluid were positive for Pseudomonas aeruginosa (P. aeruginosa). Pseudomonas aeruginosa community-acquired pneumonia (CAP) in previously healthy individuals is very rare, rapidly progressive, and often fatal. This is the first report of the successful treatment of this life-threatening pneumonia with plasmapheresis.

High expression of p300 in HCC predicts shortened overall survival in association with enhanced epithelial mesenchymal transition of HCC cells.

P300 impacts the transcription of several genes involved in biological behavior of human malignancies including hepatocellular carcinomas (HCC). We found p300 is highly expressed in 47% of surgically resected HCC specimens by immunohistochemistry, which correlated with advanced TNM staging (P = 0.034), vascular invasion (P = 0.036), intrahepatic metastasis (P = 0.001) and shortened overall survival (P = 0.028). In vitro study, knocking down of p300 expression in hepatoma cells recovered E-cadherin expression, inhibited the translocation of beta (ß)-catenin into the nuclei, decreased cyclin D1 activity and suppressed the migration/invasion of HCC cells. Furthermore, suppression of p300 led to down-regulation of epithelial-mesenchymal transition (EMT)-related molecules such as Snail, Twist and HIF-1 alpha. These observations suggest that p300 contributes to the EMT-related progression of HCCs.