Exploring Predictors of Hypertension Development With Pazopanib and Examining Predictive Performance Over Time.

BACKGROUND/AIM: Hypertension occurs frequently in patients taking pazopanib. Therefore, this study aimed to clarify the predictive factors for pazopanib-induced hypertension. PATIENTS AND METHODS: In total, 47 patients who started pazopanib treatment for renal cell carcinoma or soft tissue sarcoma during hospitalization at Kurume University Hospital from November 2012 to February 2020 were included in the study. Patient background factors associated with pazopanib-induced hypertension were analyzed using a logistic regression model. Subsequently, a time-dependent receiver operating characteristic (ROC) analysis was performed to evaluate changes in the predictive performance of predictors of pazopanib-induced hypertension over time. RESULTS: Logistic regression analysis showed that total bilirubin (t-bil) and sex are predictors of pazopanib-induced hypertension, along with systolic blood pressure (SBP) before pazopanib introduction. Additionally, evaluation of area under the curve (AUC) changes over time during the first 20 days of pazopanib treatment using time-dependent ROC showed that the AUC tended to be higher in the first half for SBP and in the second half for t-bil. Moreover, models including these two factors (SBP+t-bil and SBP+t-bil+sex) maintained a higher AUC from the early to late stages of the treatment period. CONCLUSION: Total bilirubin and sex can serve as predictors of pazopanib-induced hypertension. Total bilirubin may contribute to the prediction of the development of hypertension after day 5.

Successful Superficial Blood Sampling to Localize a Fibroblast Growth Factor-23-Producing Tumor.

BACKGROUND Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome caused by aberrant fibroblast growth factor-23 (FGF-23)-producing tumors. Early surgical resection is the optimal strategy for preventing TIO progression. Thus, tumor localization is a priority for successful treatment. A simple and safe examination method to identify functional endocrine tumors is essential to achieve better outcomes in patients with TIO. CASE REPORT A 64-year-old Japanese man with recurrent fractures, hypophosphatemia, and elevated alkaline phosphatase and FGF-23 levels (109 pg/mL) was admitted to our university hospital and was diagnosed with FGF23-related hypophosphatemic osteomalacia. Notably, the superficial dorsal vein in the patient's left foot exhibited a high FGF-23 level (7510 pg/mL). Octreotide and ¹8F-fluorodeoxyglucose (FDG) scintigraphy and systemic venous sampling revealed that the tumor in the third basal phalanx of the left foot was responsible for FGF-23 overproduction. Tumor resection resulted in a rapid decrease in serum FGF-23 levels and an increase in serum phosphorus levels. CONCLUSIONS Octreotide scintigraphy, FDG-positron emission tomography, and systemic venous sampling are the standard methods for localizing functional endocrine tumors. However, the limited availability and invasive nature of these examinations hinder effective treatment. Here, we highlight the importance of peripheral superficial blood sampling as an alternative to conventional systemic methods for confirming the presence of FGF-23-producing tumors. Clinicians should consider TIO as a potential cause of acquired hypophosphatemic osteomalacia. Furthermore, peripheral superficial vein blood sampling may be useful for confirming the localization of FGF-23-producing tumors.

Protocol for the 2ND-STEP study, Japan Clinical Oncology Group study JCOG1802: a randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib.

BACKGROUND: Soft tissue sarcomas (STS) are a rare type of malignancy comprising a variety of histological diagnoses. Chemotherapy constitutes the standard treatment for advanced STS. Doxorubicin-based regimens, which include the administration of doxorubicin alone or in combination with ifosfamide or dacarbazine, are widely accepted as first-line chemotherapy for advanced STS. Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD), which is the empirical standard therapy in Japan, are major candidates for second-line chemotherapy for advanced STS, although clear evidence of the superiority of any one regimen is lacking. The Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group (JCOG) conducts this trial to select the most promising regimen among trabectedin, eribulin, and pazopanib for comparison with GD as the test arm regimen in a future phase III trial of second-line treatment for patients with advanced STS. METHODS: The JCOG1802 study is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 intravenously, every 3 weeks), eribulin (1.4 mg/m2 intravenously, days 1 and 8, every 3 weeks), and pazopanib (800 mg orally, every day) in patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. The principal eligibility criteria are patients aged 16 years or above; unresectable and/or metastatic STS; exacerbation within 6 months prior to registration; histopathological diagnosis of STS other than Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, well-differentiated liposarcoma and myxoid liposarcoma; prior doxorubicin-based chemotherapy for STS, and Eastern Cooperative Oncology Group performance status 0 to 2. The primary endpoint is progression-free survival, and the secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. The total planned sample size to correctly select the most promising regimen with a probability of > 80% is 120. Thirty-seven institutions in Japan will participate at the start of this trial. DISCUSSION: This is the first randomized trial to evaluate trabectedin, eribulin, and pazopanib as second-line therapies for advanced STS. We endeavor to perform a subsequent phase III trial comparing the best regimen selected by this study (JCOG1802) with GD. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials ( jRCTs031190152 ) on December 5, 2019.

Phase equilibria among η-Fe2Al5 and its higher-ordered phases.

Phase equilibria among the η-Fe2Al5 phase and its higher-ordered phases with the η framework structure were determined experimentally. The solubility range of the η phase at elevated temperature does not differ remarkably from that in previous studies, but this phase is found to undergo complicated phase transformations upon cooling. Four phases are present, namely η', η", η"' and η m, with higher-order atomic orderings in the c-axis chain sites of the orthorhombic crystal structure of the parent η phase. The η" and η"' phases form on the Al-poor and Al-rich sides, respectively, in equilibrium with the ζ-FeAl2 phase below ~415°C and θ-Fe4Al13 phase below ~405°C. The η' and η m phases become stable below 312°C and 343°C with the peritectoid reactions η' → η m + Î·"' and η m → η + Î·", respectively. The η phase is not stable below 331°C with the eutectoid reaction of η m + Î·"' → η. On the basis of these findings, we unraveled the phase equilibria among the η-Fe2Al5 phase and its higher-ordered phases with the η framework structure.

Clinicopathological and immunohistochemical analysis of autoimmune regulator expression in patients with osteosarcoma.

Autoimmune regulator (AIRE) is a transcription factor that is expressed in medullary thymic epithelial cells. It plays an essential role in central tolerance by eliminating self-reactive T cells. Recently, extrathymic AIRE-expressing cells have been revealed, which are associated with peripheral tolerance. Moreover, AIRE expression has been demonstrated in skin tumors and breast cancer. However, the expression of AIRE in osteosarcoma is unknown. We used immunohistochemistry to investigate AIRE expression in biopsy samples from 43 patients with conventional osteosarcoma and statistically analyzed the association between AIRE expression and clinicopathological characteristics. High AIRE expression was detected in 25 patients (58.1%), and significantly associated with the presence of lung metastasis (P = 0.014) and an increased number of forkhead box P3-positive tumor-infiltrating lymphocytes (regulatory T cells) (P = 0.014). The overall survival rate for all osteosarcoma patients with high AIRE expression was significantly shorter than that for those with low AIRE expression (P = 0.046). In a subgroup analysis of American Joint Committee on Cancer stage II patients who underwent complete surgical resection and conventional chemotherapy, the overall survival and metastasis-free survival rates were significantly shorter for patients with high AIRE expression than for those with low AIRE expression (P = 0.019 and P < 0.01, respectively). High AIRE expression was confirmed to be an independent poor prognostic factor for both overall survival (hazard ratio: 3.841, P = 0.038) and metastasis-free survival (hazard ratio: 4.348, P = 0.022) in the multivariate analysis. The evaluation of AIRE expression may be useful for stratifying osteosarcoma patients for more effective clinical follow-up.

Elevated Expression of Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) Is Associated With a Poor Prognosis in Osteosarcoma.

BACKGROUND: Transforming acidic coiled-coil containing protein 3 (TACC3) is expressed during the mitotic phase of nuclear division and regulates microtubules. Recently, high TACC3 expression in tumor cells of various cancers including soft tissue sarcoma has been reported. However, its role in osteosarcoma remains unknown. Because we have few prognostic markers for survival in osteosarcoma, we wanted to investigate the potential role of TACC3 in human osteosarcoma and determine if it is associated with survival. QUESTIONS/PURPOSES: (1) Is there a relationship between TACC3 expression and clinicopathologic characteristics such as sex, age (< 20 or ≥ 20 years), histologic type (osteoblastic or others), tumor location (femur or others), American Joint Committee on Cancer staging system (AJCC stage IIA or IIB), tumor necrosis percentage after chemotherapy (< 90% or ≥ 90%), p53 expression (low or high), and Ki-67 expression (low or high)? (2) Is TACC3 expression associated with event-free and overall survival in patients with osteosarcoma? METHODS: Forty-six conventional patients with osteosarcoma were treated at our institution from 1989 to 2013. Patients were excluded because of unresectable primary site (two patients) and no chemotherapy (two patients). Patients with metastasis at the initial visit (five patients), without pretreatment biopsy samples (two patients), or clinical charts (two patients) were also excluded. The left 33 patients who received neoadjuvant and adjuvant chemotherapy, which consisted of cisplatin/doxorubicin/methotrexate or cisplatin/doxorubicin/methotrexate/ifosfamide, and completed surgical resection with histologic wide tumor margins. Primary tumor samples before chemotherapy were used in this study. We investigated TACC3 expression using immunohistochemical staining and statistically analyzed the TACC3 expression, clinicopathologic characteristics, and event-free and overall survival in patients with osteosarcoma. RESULTS: High TACC3 expression was observed in 19 of 33 osteosarcoma specimens (58%), and this was associated with larger tumor size (ie, AJCC stage IIB in this study; p = 0.002), higher p53 expression (p = 0.007), and higher Ki-67 expression (p = 0.002). The estimated metastasis-free survival at 5 years was 21% (95% confidence interval [CI], 7%-41%) in patients with high TACC3 expression and 79% (95% CI, 47%-93%) in patients with low TACC3 expression (p < 0.001), and the estimated overall survival at 5 years was 34% (95% CI, 13%-56%) in patients with high TACC3 expression and 86% (95% CI, 54%-96%) in patients with low TACC3 expression (p < 0.001). Furthermore, high TACC3 expression was an independent poor prognostic factor for metastasis-free survival with a hazard ratio of 3.89 (95% CI, 1.07-19.78; p = 0.039) as well as overall survival with 4.41 (95% CI, 1.01-32.97; p = 0.049). CONCLUSIONS: High TACC3 expression was associated with aggressive clinicopathologic features and unfavorable prognosis in these patients with osteosarcoma. Our preliminary results suggest that further analysis about mutation or an inactive form of TACC3 would be useful to understand the mechanism of abnormal TACC3 expression in patients with osteosarcoma. If these findings are substantiated in larger studies, TACC3 might be useful for predicting survival and a potential therapeutic target for osteosarcoma. LEVEL OF EVIDENCE: Level III, therapeutic study.

Clinicopathological value of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression in synovium of patients with rheumatoid arthritis.

The etiology of rheumatoid arthritis (RA) is thought to involve dysfunction of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway; PD-1 negatively regulates autoimmunity by interacting with its ligand, PD-L1. We therefore investigated PD-1/PD-L1 expression in synovial tissue of patients with RA. We immunohistochemically stained synovial specimens from 51 patients with RA and assessed the association between PD-1/PD-L1 expression and rheumatoid factor (RF), the total count of infiltrating T cells, C-reactive protein (CRP), and Krenn's synovitis score. PD-1 expression on infiltrating lymphocytes was detected in 34/51 RA cases (66.7%), while PD-1 expression was very mildly correlated only with the number of total infiltrating T cells (R2 = 0.1011, P = 0.0230). On the other hand, PD-L1 expression on synovial lining cells was observed in 37/51 RA cases (72.5%). Furthermore, a higher PD-L1 expression was significantly associated with RF positive state (P = 0.0454), and the correlations between PD-L1 expression and the number of infiltrating T cells (R2 = 0.5571, P < 0.0001), CRP (R2 = 0.4060, P < 0.0001), and Krenn's synovitis score (R2 = 0.7785, P < 0.0001) were confirmed. PD-1 was expressed on infiltrating lymphocytes, while PD-L1 was expressed on synovial lining cells; the expression of PD-L1 on synovial lining cells was significantly correlated with the active state of the disease. These data suggest that PD-1/PD-L1 pathway may have an important role in the pathogenesis of RA.

Clinicopathological and prognostic value of transforming acidic coiled-coil-containing protein 3 (TACC3) expression in soft tissue sarcomas.

Transforming acidic coiled-coil-containing protein 3 (TACC3), a microtubule regulator, is associated with various cancers. However, the relationship between TACC3 and soft tissue sarcomas (STS) remains unclear. We investigated the expression of TACC3 in 136 STS patient samples using immunohistochemical (IHC) staining, and the statistical associations between TACC3 expression and clinicopathological characteristics were evaluated. Additionally, the expression levels of the tumor suppressor p53 and of the cell proliferation marker Ki-67 were also assessed by IHC. High TACC3 expression was detected in 94/136 of STS cases (69.1%), and significantly correlated with higher grade according to the French Fédération Nationale des Centres de Lutte Contre le Cancer system (P<0.0001), poorer tumor differentiation (P<0.0001), increased mitotic counts (P<0.0001), advanced stage per American Joint Committee on Cancer guidelines (P<0.0001), higher p53 expression (P = 0.0487), higher Ki-67 expression (P<0.0001), and undergoing postoperative therapy (P = 0.0001). Disease-free survival (DFS) and overall survival (OS) of patients with high TACC3 expression were significantly shorter (P<0.0001 and P<0.0001, respectively). On multivariate analyses, high TACC3 expression was an independent negative prognostic factor for both DFS and OS (hazard ratio [HR]: 3.074; P = 0.0235 and HR: 8.521; P = 0.0415, respectively). Our results suggest that TACC3 is an independent prognostic factor and may be a novel therapeutic target for the treatment of STS.

GATA3 Expression Is a Poor Prognostic Factor in Soft Tissue Sarcomas.

OBJECTIVE: Recent studies have investigated the significance of GATA3 expression in patients with various malignant tumors. However, no previous studies have evaluated the clinicopathological importance of GATA3 expression in soft tissue sarcomas (STS) patients. METHODS: We evaluated GATA3 expression in 76 STS cases using immunohistochemical analysis, and statistically compared clinicopathological characteristics between GATA3-positive and GATA3-negative cases. RESULT: GATA3-positive expression was significantly associated with a higher mitotic count (P < 0.0001). Disease-free survival (DFS) of GATA3-positive cases was significantly shorter than that of cases without GATA3 expression (P = 0.0104). Overall survival (OS) of GATA3-positive cases was significantly shorter than that of cases without GATA3 expression (P = 0.0006). GATA3-positive expression was significantly associated with shorter DFS in both univariate analysis (hazard ratio [HR], 2.719; P = 0.012) and multivariate analysis (HR, 2.711; P = 0.014). GATA3-positive expression was also significantly associated with worse OS in both univariate analysis (HR, 5.730; P = 0.0007) and multivariate analysis (HR, 5.789; P = 0.0008). CONCLUSION: These results indicate that GATA3 is an independent prognostic factor and suggest that evaluation of GATA3 expression might enable more effective clinical follow-up using prognostic stratification of STS patients.

Anaplastic lymphoma kinase protein expression, genetic abnormalities, and phosphorylation in soft tissue tumors: Phosphorylation is associated with recurrent metastasis.

Gene and protein abnormalities of anaplastic lymphoma kinase (ALK) play an important role in the pathogenesis of various cancers and serve as important therapeutic targets. We investigated ALK protein expression, phosphorylation, and genetic aberrations using fluorescence in situ hybridization (FISH) in 81 soft tissue tumor samples: inflammatory myofibroblastic tumor, n=1; alveolar soft part sarcoma, n=2; leiomyosarcoma, n=10; well-differentiated liposarcoma, n=7; pleomorphic liposarcoma, n=2; extraskeletal osteosarcoma, n=1; epithelioid sarcoma, n=1; synovial sarcoma, n=4; malignant peripheral nerve sheath tumor, n=4; undifferentiated pleomorphic sarcoma, n=19; rhabdomyosarcoma, n=6; myxofibrosarcoma, n=8; myxoid liposarcoma, n=11; fibrosarcoma, n=4; and desmoid-type fibromatosis, n=1. ALK protein expression, gene signal gain (without translocation), and phosphorylation were observed in 33/81 (40.7%), 55/81 (67.9%), and 30/81 (37.0%) tumor samples, respectively. ALK protein expression was statistically associated with phosphorylation, but not with gene signal gain. ALK phosphorylation-positive cases showed a statistically worse metastasis-free survival compared with phosphorylation-negative cases (P=0.0215). Particularly, metastasis of myxoid liposarcoma was associated with ALK phosphorylation (P=0.0019), but not with ALK protein expression or gene signal gain. However, the prognosis had no association with ALK protein expression, gene signal gain, or phosphorylation. ALK protein expression and phosphorylation play an important role in tumor biology and provide potential therapeutic targets for soft tissue tumors. Future research should focus on the oncogenic role and the efficacy of potential inhibitors of ALK.

Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma.

Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is extremely rare, and the etiology of disease is not fully understood. We present herein the case of a primary hepatic MALT lymphoma with Helicobacter pylori and hepatitis C virus infection. A 71-year-old male was admitted to our institution to undergo a precise evaluation of a hepatic tumor incidentally detected during a computed tomography (CT) scan for chest examination. Dynamic CT showed faint enhancement during the arterial phase. The gadoxetate disodium-enhanced magnetic resonance imaging showed a hyper-intensity on the arterial phase and low intensity during the late and hepatocyte phases. Liver biopsy specimen showed small to intermediate size atypical lymphocytes with positive CD20 immunohistochemical staining. It was finally diagnosed as primary hepatic MALT lymphoma. FDG-PET/CT showed faintly increased uptake with a maximum standardized uptake value of 4.6, and did not show other pathological uptake. We present the rare case of primary hepatic MALT lymphoma and discussed the etiology of this disease.

Multicentric extra-abdominal desmoid tumors arising in bilateral lower limbs.

Extra-abdominal desmoid tumors preferentially affect the shoulders, arms, backs, buttocks, and thighs of young adults. Multicentric occurrence is rather rare but seems to be another distinctive feature of extra-abdominal desmoid tumors. In this article we report a rare case of multicentric extra-abdominal desmoid tumors arising in bilateral lower limbs.

Hyaluronan modulates proliferation and migration of rabbit fibroblasts derived from flexor tendon epitenon and endotenon.

PURPOSE: There is a growing body of evidence supporting the use of hyaluronan (HA) for treatment of injured tendons, although the mechanism of the healing effect has not yet been clarified. We therefore investigated the effects of HA on the proliferation and migration of tendon fibroblasts derived from rabbit flexor tendon epitenon and endotenon. METHODS: From explanted rabbit intrasynovial flexor tendons (n = 5), we cultured tendon fibroblasts derived from the epitenon and endotenon. CD44 expression on the tendon fibroblasts was detected by flow cytometric analysis. Various concentrations of HA (0.1-5.0 mg/mL) were added to monolayer-cultured tendon fibroblasts. We evaluated cell proliferation by recording changes in cell number, and measured cell migration by wound-healing assay. RESULTS: Flow cytometric analysis detected CD44 expression on the tendon fibroblasts. Treatment with HA at various concentrations notably and dose dependently inhibited cell proliferation and promoted cell migration. CONCLUSIONS: Hyaluronan modulates the proliferation and migration of rabbit fibroblasts derived from the flexor tendon epitenon and endotenon.

Pure red cell aplasia accompanied by autoimmune hemolytic anemia in a patient with type A viral hepatitis.

A rare case of acute hepatitis A associated with autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) is reported. A 55-year-old woman consulted a doctor because of common cold-like symptoms and she was referred to our hospital in January 2007. Laboratory findings showed a marked elevation of serum transaminase and total bilirubin levels (AST 9,605 IU/l, ALT 5,546 IU/l and T-bil 4.14 mg/dl), and prolonged prothrombin time, findings which suggested the risk of progression to fulminant hepatitis, and she was treated with plasmapheresis and hemodialysis filtration on the first and second hospital days. She was diagnosed with severe acute hepatitis A based on the elevation of serum IgM anti-hepatitis A virus. On the 20th hospital day, her hemoglobin level began to decrease in spite of improving transaminase levels without any signs of gastrointestinal bleeding. Bilirubin and LDH elevation, haptoglobin decline and a positive direct Coombs test were detected and these findings indicated AIHA complication; however, the reticulocyte count decreased and bone marrow showed marked erythroid hypoplasia so the co-existence of PRCA was diagnosed. After oral prednisolone administration (1 mg/kg/day), her hemolytic anemia rapidly improved.

Copper-catalyzed aerobic oxidative amidation of terminal alkynes: efficient synthesis of ynamides.

A copper-catalyzed method for the preparation of ynamides has been identified that proceeds via aerobic oxidative coupling of terminal alkynes with various nitrogen nucleophiles, including cyclic carbamates, amides and ureas, and N-alkyl-arylsulfonamides and indoles.

[Clinical study of low-dose cisplatin and 5-fluorouracil chemotherapy via implanted fusion port in 20 patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis].

We experienced 20 cases of advanced hepatocellular carcinoma with portal vein tumor thrombosis treated with low-dose cisplatin and 5-fluorouracil (5-FU) chemotherapy via implanted fusion port between August 1999 and September 2003. A fusion port was implanted by inserting an intraarterial catheter into the hepatic artery. Cisplatin (10 mg/day, 5 times/week, 4 weeks) and 5-FU (250 mg/day, 5 times/week, 4 weeks) were administered for one cycle. The treatment was performed repeatedly until the patient showed progressive disease (PD) with an off period of 4 to 12 weeks. The average number of cycles was 1.7+/-0.73. Responses were complete response (CR) 0/20, partial response (PR) 6/20, no change (NC) 8/20, and PD 6/20, and the overall response rate was 30%. The 1-year survival rate was 48.5%, and the average observation period was 357 days. The toxicities of grade 3 and above were leukocytopenia (2 cases; 10%), thrombocytopenia (2 cases; 10%), nausea (1 case; 5%), and epigastralgia (1 case; 5%). Complications with reservoir implantation included 2 cases of catheter dislocation, 1 case of wound separation,1 case of bleeding from the port implantation site, 1 case of development of collateral circulation,and 1 case of catheter occlusion. The outcomes were survival in 5 cases (25%) and death in 15 cases (75%). The causes of death included cancer (12 cases; 60%), varices rupture (2 cases; 10%),and hemoptysis (1 case; 5%). The group with a CLIP score of 3 or less showed a significantly higher survival rate than the group with a CLIP score of 4 or more (survival rates were 80% and 12.5%, respectively; p=0.0032, logrank test). Among CLIP score factors, tumor morphology (TM) was particularly related to life convalescence,and TM 1 group with the tumor occupying less than half of the liver showed a significantly higher survival rate than the TM 2 group with the tumor occupying more than half of the liver (p=0.0003, logrank test) with one-year survival rates of 88.9% and 10.9%, respectively. CLIP score and TM were also significantly reflected in life convalescence on multivariate analysis. While low-dose cisplatin and 5-FU chemotherapy via an implanted fusion port were regarded as a useful therapeutic regimen to improve life convalescence for cases of progressive hepatocellular carcinoma with portal vein tumor thrombosis (Vp 3/4), life convalescence in those with a CLIP score of 3 and above,particularly in the TM 2 group, was poor. We consider that treatment in such cases should be decided carefully, taking into consideration their quality of life.

Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection.

BACKGROUND: Despite the progression of therapeutic approaches, a high frequency of recurrence is what determines the long-term prognosis of patients with hepatocellular carcinoma (HCC). In this study, the chemopreventive effects of vitamin K2 on the recurrence and survival of patients with HCC after curative therapy were evaluated. METHODS: Sixty patients who were diagnosed to be free of HCC after radiofrequency ablation therapy or surgery were randomly assigned to either the vitamin K2 group (n = 30 patients) or the control group (n = 30 patients). All patients were positive for the hepatitis C virus (HCV) antibody and hepatitis B surface antigen positive patients were excluded from this study. Patients in the vitamin K2 group received an oral dose of menatetrenone at 45 mg per day. Disease recurrence and the survival rates were analyzed in patients with HCC. RESULTS: The cumulative recurrence-free rates in the vitamin K2 group were 92.3% at 12 months, 48.6% at 24 months and 38.8% at 36 months; and those in the control group were 71.7%, 35.9% and 9.9%, respectively (P = 0.045). The cumulative survival rates in the vitamin K2 group were 100% at 12 months, 95.0% at 24 months and 77.5% at 36 months; and those in the control group were 95.8%, 90.2% and 66.4%, respectively (P = 0.70). CONCLUSIONS: Vitamin K2 may have a suppressive effect on the recurrence of HCC and a beneficial effect on tumor recurrence. However, there was no significant difference in the survival rates. The chemopreventive effects of vitamin K2 are not sufficient. The development of a further regimen such as combination therapy is required.

Suppression of IL-6 production and proliferation by blocking STAT3 activation in malignant soft tissue tumor cells.

There is no established optimum treatment for malignant fibrous histiocytoma (MFH) at present, and few MFH cell lines are established. In the present study, we established new MFH cell lines, KHZ-MFH and SFT85-03, and investigated the JAK/STAT (Janus kinase/signal transducer and activator of transcription) signaling pathway. We found that MFH cells secreted high levels of IL-6 and that STAT3 was constitutively activated in these cells. The JAK2 kinase inhibitor, tyrphostin AG490, suppressed the growth of MFH cells and inhibited the secretion of IL-6. Furthermore, blockade of activated STAT3 by forced expression of a cytokine signaling repressor, SOCS3 gene as well as a dominant-negative STAT3 in these cells significantly suppressed their growth. These results indicated that an autocrine mechanism of the JAK/STAT3 signaling pathway could promote the growth of MFH cells and that this pathway could be a therapeutic target of MFH.

Hepatocellular carcinoma in extremely elderly patients: an analysis of clinical characteristics, prognosis and patient survival.

AIM: To identify the clinical and prognostic features of patients with hepatocellular carcinoma (HCC) aged 80 years or more. METHODS: A total of 1310 patients with HCC were included in this study. Ninety-one patients aged 80 years or more at the time of diagnosis of HCC were defined as the extremely elderly group. Two hundred and thirty-four patients aged > or = 50 years but less than 60 years were regarded as the non-elderly group. RESULTS: The sex ratio (male to female) was significantly lower in the extremely elderly group (0.90:1) than in the non-elderly group (3.9:1, P < 0.001). The positive rate for HBsAg was significantly lower in the extremely elderly group and the proportion of patients negative for HBsAg and HCVAb obviously increased in the extremely elderly group (P < 0.001). There were no significant differences in the following parameters: diameter and number of tumors, Child-Pugh grading, tumor staging, presence of portal thrombosis or ascites, and positive rate for HCVAb. Extremely elderly patients did not often receive surgical treatment (P < 0.001) and they were more likely to receive conservative treatment (P < 0.01). There were no significant differences in survival curves based on the Kaplan-Meier methods in comparison with the overall patients between the two groups. However, the survival curves were significantly worse in the extremely elderly patients with stage I/II, stage I/II and Child-Pugh grade A cirrhosis in comparison with the non-elderly group. The causes of death did not differ among the patients, and most cases died of liver-related diseases even in the extremely elderly patients. CONCLUSION: In the patients with good liver functions and good performance status, aggressive treatment for HCC might improve the survival rate, even in the extremely elderly patients.

A case of metachronous cholangiocellular and hepatocellular carcinoma with good prognosis.

A 63-year-old man was treated for 6 months with interferon (IFN) for chronic hepatitis C but the treatment failed to eradicate hepatitis C virus. Six months after completion of IFN therapy, cholangiocellular carcinoma (CCC) was detected in the posterior inferior segment and was resected surgically. He had been in good condition except for diabetic nephropathy progressing to renal failure at 3 years after the resection of CCC. Seven years after the resection of CCC, hepatocellular carcinoma (HCC) was detected in the posterior superior segment of the liver. The tumor was pathologically confirmed by fine needle aspiration biopsy. The patient was successfully treated with two courses of percutaneous ethanol injection and has been well 1 year after the treatment. HCV status did not change as genotype 1b with moderate viral load (300 to 500 kilo copies/mL by amplicore monitoring) during the follow-up. Thus, even though the patient was treated with IFN, hepatitis C could progress to not only HCC but also CCC in the same patient. Our patient is still alive, 9.5 years after detection of the first tumor.