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A woman in her 70s was diagnosed with a protruding mucosa-associated lymphoid tissue (MALT) lymphoma during a secondary health examination. After eradication of Helicobacter pylori, a biopsy revealed gastric follicular lymphoma (FL) and the lesion was still protruding one year later.

407 Background: Several new combination therapies, including GEM plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX) has been developed for treating pancreatic ductal adenocarcinoma (PDAC) in these ten years. We investigated trends in characteristics, treatment patterns, and outcomes of unselected patients with unresectable PDAC in real-life practice in Japan. Methods: We retrospectively reviewed the medical records of 1917 patients diagnosed as having unresectable or recurrent PDAC in multiple centers in our local area between January 2009 and April 2018. Results: The median age was 74, and 53.1% were men; 27.2% had locally advanced and 67.2% metastatic disease, and 5.6% had recurrences. Oncological therapy was administered to 1295 patients (67.6%): chemotherapy (n = 1161), chemo-radiotherapy (n = 117), or radiotherapy (n = 17); the remaining patients were treated with best supportive care. Of 100 patients diagnosed in 2009, 62.0% received GEM as first-line chemotherapy; whereas 56.8% of the 266 patients diagnosed in 2017 or 2018 received GnP, 20.3% GEM, and 15.4% FFX. The objective response rates of patients treated with GnP, FFX and GEM were 16.8%, 17.6%, and 5.1%, respectively. The median time to treatment failures were 3.9, 3.6, and 2.8 months, and the overall survivals were 11.5, 11.7, and 6.5 months after GnP, FFX, and GEM, respectively. Grade 3 or greater any hematological toxicity occurred in 53.7%, 64.7%, and 34.6% of the patients treated with GnP, FFX, and GEM, respectively. The treatment discontinuation rates due to adverse events were 17.2%, 14.9% and 22.9% in the patients treated with GnP, FFX and GEM, respectively. Conclusions: Chemotherapeutic protocols changed dramatically between 2009 and 2018 in Japan. Both GnP and FFX are well-tolerable and effective in real-life practice despite high frequent adverse events.

Consensus has been reached that diabetes is a risk factor for development of HCC, but the impact on postoperative recurrence is still controversial. To clarify this point, we analyzed the relationship of postoperative recurrence rate of HCC and coexistence of diabetes in the patients with viral hepatitis.A total of 90 patients who had undergone curative resection for HCC were analyzed. They were divided into two groups with and without diabetes, and the recurrence-free survival rates after surgical treatment and the factors contributing to recurrence were examined.Kaplan-Meier survival analysis showed the recurrence-free survival rates in the diabetic group were significantly lower than those in the nondiabetic group (P= 0.005) and overall survival rates in the diabetic group were significantly lower than those in the nondiabetic group (P= 0.005). These results were emphasized in the analysis of patients infected with hepatitis C virus. Univariate and multivariate analyses showed diabetes was a significant factor contributing to HCC recurrence after treatment. Furthermore, multivariate analysis in HCC patients with diabetes showed Child-Pugh classification B (P= 0.001) and insulin therapy (P= 0.049) were significant factors contributing to HCC recurrence after treatment.The results of the present study suggest that diabetes is a risk factor for the recurrence of HCV-related HCC and decreases the overall survival rates after surgical treatment. HCV-related HCC patients with diabetes should be closely followed for postoperative recurrence.

症例は60歳男性. 1990年より糖尿病と肝機能障害を指摘され, 他院にて経過観察されていた. 2003年10月に心窩部痛のため当院初診, 上部消化管内視鏡検査で十二指腸乳頭部からの出血を認め入院となった. 背景にアルコール性肝硬変があり, AFP, PIVKA-II, AFP-L3分画の上昇に加え肝右葉に多発する腫瘤と門脈腫瘍塞栓を認めることから, 胆道出血を合併した肝細胞癌と診断した. インターフェロン併用肝動注化学療法を開始し, 2クール目からは外来にて化学療法を継続した. 4クール施行途中から胆道感染の悪化を認め, 胆道出血・閉塞性黄疸を最初に発症してから約8カ月後に死亡した. 胆道出血を契機に発見される肝細胞癌は比較的少なく, その予後は不良とされているが, 本症例は画像上腫瘍縮小効果はないものの, 他の報告に比較してインターフェロン併用肝動注化学療法によって延命が得られた1例と考えられた.

p14(ARF), a product of the INK4A/ARF locus, induces p53 upregulation by neutralizing the effects of MDM2, a transcriptional target of p53 that antagonizes its function. Here we report that adenovirus-mediated p14(ARF) gene transfer leads to the accumulation of ectopically transduced p53 and to apoptosis in human cancer cells. We constructed an adenoviral vector expressing p14(ARF) (Ad-ARF) and examined its synergistic effect with p53-expressing adenovirus (Ad5CMV-p53 or Ad-p53) in human lung and esophageal cancer cells. Simultaneous Ad-ARF and Ad-p53 infection increased p53 protein levels not only in a wild-type p53-expressing cell line, but also in cell lines with deleted p53. This resulted in a significant in vitro cytotoxicity compared with Ad-p53 infection alone. Coinfection of Ad-ARF and Ad-p53 also resulted in an increase in expression of p53-inducible genes, including p21(WAF-1/Cip1), p53R2, and Noxa. In addition, the growth of human lung cancer tumors subcutaneously implanted into nu/nu mice was inhibited significantly by intratumoral injection with Ad-ARF and Ad-p53. Our data demonstrate that overexpression of ectopic p14(ARF) may render cells more sensitive to p53-mediated apoptosis, an outcome that has important implications for the treatment of human cancers.

Myeloid-derived suppressor cells (MDSCs) are known as key immune regulators in various human malignancies, and it is reported that CD14(+)HLA-DR(-/low) MDSCs are increased in hepatocellular carcinoma (HCC) patients. However, the host factors that regulate the frequency and the effect on the prognosis of HCC patients are still unclear. We investigated these issues and clarified the relationships between a feature of MDSCs and host factors in HCC patients. We examined the frequency of MDSCs in 123 HCC patients, 30 chronic liver disease patients without HCC, and 13 healthy controls by flow cytometric analysis. The relationships between the clinical features and the frequency of MDSCs were analyzed. In 33 patients who received curative radiofrequency ablation (RFA) therapy, we examined the impact of MDSCs on HCC recurrence. The frequency of MDSCs in HCC patients was significantly increased. It was correlated with tumor progression, but not with the degree of liver fibrosis and inflammation. In terms of serum cytokines, the concentrations of IL-10, IL-13, and vascular endothelial growth factor were significantly correlated with the frequency of MDSCs. In HCC patients who received curative RFA therapy, the frequency of MDSCs after treatment showed various changes and was inversely correlated with recurrence-free survival time. The frequency of MDSCs is correlated with tumor progression, and this frequency after RFA is inversely correlated with the prognosis of HCC patients. Patients with a high frequency of MDSCs after RFA should be closely followed and the inhibition of MDSCs may improve the prognosis of patients.

An outbreak of enterohemorrhagic Escherichia coli (EHEC) occurred in Toyama and other prefectures in Japan during 2011. Some patients, including adults, showed complications such as encephalopathy, disseminated intravascular coagulation, and hemolytic–uremic syndrome, and the disease course was extremely aggressive. This report describes the clinical features of four patients infected with Escherichia coli (E. coli) O111 who developed very severe to fatal complications. The initial symptoms in all patients included abdominal pain, diarrhea, and bloody stools, and neurological abnormalities started to appear from 1 to 3 days after admission. Vomiting and pyrexia developed in three patients. Leukocyte counts, lactate dehydrogenase (LDH), and fibrin/fibrinogen degradation products were elevated, and thrombocytopenia was evident. Extremely elevated LDH and severe thrombocytopenia were characteristic at the time encephalopathy became apparent. All patients received oral fosfomycin, intravenous antibiotics, and anticoagulant therapy, three received gamma globulin, plasma exchange, and blood transfusion, and two received steroids and dialysis. Three patients required mechanical ventilation, and two adult patients died. E. coli O111 positive for Shiga toxin 2 was detected in stool culture in two patients, and serological tests for E. coli O111 were positive in the other two patients. In conclusion, EHEC O111 can cause severe illness in children and adults, and the prognosis becomes poorer as the severity of complications increases. Close monitoring including platelet counts and LDH are useful. Once these clinical parameters change, intensive treatment should be provided to prevent the development of severe complications.

金沢大学先進予防医学研究センター / 金沢大学医薬保健研究域医学系, The purpose of this study was to assess the properties of CD4+CD25high/low/negative T cell subsets and analyze their relation with dendritic cells (DCs) in patients with hepatocellular carcinoma (HCC). In HCC patients, the prevalence of CD45RO+ cells in CD4+CD25high T cells was increased and associated with higher frequencies of plasmacytoid DCs. Larger proportions of this T cell subset were detected in the patients with larger tumor burdens. These results suggest that increased frequencies of the CD45RO+ subset in CD4+CD25high Tregs in HCC patients may establish the immunosuppressive environment cooperatively with tolerogenic plasmacytoid DCs to promote disease progression of liver cancer. © 2011.

Diabetes is a risk factor for the progression of liver fibrosis and development of hepatocellular carcinoma in chronic hepatitis C. However, the impact of diabetes on the long-term prognosis and the synergistic interactions of various host factors for diabetes to the progression of liver fibrosis are unknown. In the present study, we examined the host factors associated with the progression of hepatitis C in 68 patients with a posttransfusion hepatitis (PTH) and analyzed the relationships. Multivariate analysis showed that age of PTH, being male, and type 2 diabetes mellitus were risk factors for the progression of liver fibrosis. By the Kaplan-Meier method, the cirrhosis-free survival rates after the onset of PTH were significantly lower in the diabetic group than in the nondiabetic group (P.01). Diabetes also had a great impact on the long-term prognosis of chronic hepatitis C by reducing the time from PTH to the occurrence of hepatocellular carcinoma (P.01) and to liver-related death (P.05). Coexistence of obesity (body mass indexor =25 kg/m(2)) or hypertriglyceridemia (or =150 mg/dL) with diabetes had a synergistic effect on liver fibrosis progression in patients with chronic hepatitis C. Thus, the treatment of diabetes, obesity, and hypertriglyceridemia may hold the key to improving the prognosis of chronic hepatitis.

Apoptosis is a morphologically distinct form of programmed cell death that plays a major role in cancer treatments. This cellular suicide program is known to be regulated by many different signals from both intracellular and extracellular stimuli. Here we report that p53 suppressed expression of the cellular FLICE-inhibitory protein (FLIP) that potentially blocks apoptotic signaling in human colon cancer cell lines expressing mutated and wild-type p53. In contrast, the expression of the death receptor KILLER/DR5 (TRAIL-R2) had no effect on FLIP expression, although exogenous p53 is known to induce KILLER/DR5 expression. In line with these observations, FLIP-negative cancer cells were sensitive to both p53- and KILLER/DR5-mediated apoptosis, whereas cells containing high levels of FLIP underwent apoptotic cell death when triggered by ectopic p53 expression but not by KILLER/DR5 expression. Treating the cells with a specific inhibitor of the proteasome inhibited the decrease of FLIP by p53, suggesting that p53 enhances the degradation of FLIP via a ubiquitin-proteasome pathway. Thus, the data indicate that p53-mediated downregulation of FLIP may explain the potent sensitization of human cancer cells to the apoptotic suicide program induced by wild-type p53 gene transfer.

Cardiac myocytes and vascular endothelial cells produce endothelin (ET)-1, which has potent hypertrophic effects on cardiac myocytes. Although in cultured cardiomyocytes, angiotensin II (Ang II) was reported to enhance ET-I production in vitro, it is not known whether ET- I production is enhanced by Ang II in vivo. We investigated the production and pathophysiologic roles of ET-1 in 20-week-old male transgenic hypertensive mice (THM), in which the renin-angiotensin system (RAS) was markedly activated because of the presence of both human renin and angiotensinogen genes. Systolic blood pressure and the ratio of left ventricular weight to body weight were significantly higher in the THM than in control mice. indicating that THM developed cardiac hypertrophy. ET-1 production was significantly increased in the heart of THM because both ET-1 mRNA expression and peptide levels were significantly higher than in controls. However, circulating plasma ET-I levels did not differ between the groups, and blood pressure did not change after i.v. injection with a high dose (3 mg/kg) of the ET A/B -nonselective receptor antagonist SB209670. These findings suggest that increased cardiac ET-I production may contribute to the progression of cardiac hypertrophy and that endogenous ET-I may not be involved in the short-term modulation of blood pressure in THM of this age.