[Successful treatment of myelomatous pleural effusion with daratumumab administration before autologous peripheral stem cell transplantation].

A 50-year-old woman diagnosed with surgically resected plasmacytoma of the ovaries and uterus presented with another plasmacytoma in the pancreas with positive uptake on positron emission tomography (PET) and massive right pleural effusion with plasma cell infiltration (myelomatous pleural effusion). After four courses of the bortezomib, lenalidomide, and dexamethasone regimen as induction therapy, partial response was achieved with reduced myelomatous pleural effusion and negative uptake on PET in the pancreatic plasmacytoma. However, soon after she received bortezomib and high-dose cyclophosphamide for peripheral blood stem cell harvesting, right myelomatous pleural effusion increased without signs of heart failure or infection. Because of the progressive nature of the disease, daratumumab was introduced as 2 courses of daratumumab, lenalidomide, and dexamethasone (DLd) regimen, after which she achieved complete response with disappearance of the pleural effusion. After autologous peripheral blood stem cell transplantation, she received an additional four courses of the DLd regimen as consolidation therapy. She maintained relapse-free survival for two years with maintenance therapy containing daratumumab and dose-reduced lenalidomide. Our case may suggest the usefulness of daratumumab before autologous peripheral stem cell transplantation for relapsed/refractory myelomatous pleural effusion.

Efficacy of on-demand intrahepatic arterial therapy in combination with sorafenib for advanced hepatocellular carcinoma.

PURPOSE: The purpose of this study was to evaluate the effectiveness and tolerability of "on-demand" combination therapy with sorafenib and hepatic arterial treatments, such as transarterial chemoembolization and hepatic arterial infusion chemotherapy, in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Eighty consecutive patients with advanced HCC, 58 administered sorafenib monotherapy and 22 administered on-demand combination therapy, were retrospectively evaluated. RESULTS: The disease control rate was significantly higher in the combination group than in the monotherapy group (86.3% vs 51.7%, p=0.01). Elevated alanine aminotransferase levels were significantly more frequent in the combination group (40.9% vs 12.1%, p=0.01), but it was tolerable. Progression-free survival (180 vs 45 days, p=0.045) and overall survival (983 vs 452 days, p=0.004) were significantly longer in the combination group, as was the duration of sorafenib treatment (367 vs 66 days, p<0.001). Multivariate analysis showed that hepatitis C virus infection, disease control, and combination therapy were positive independent prognostic factors for survival, whereas alpha-fetoprotein >400 ng/mL was negatively prognostic. In patients receiving combination therapy, male sex, hepatitis B virus infection, performance status deterioration, Barcelona clinic liver cancer-B, and major vascular invasion were prognostic of survival. CONCLUSION: On-demand combination therapy was tolerated and may be a therapeutic option for patients with advanced HCC.

Combined hepatocellular-cholangiocarcinoma successfully treated with sorafenib: case report and review of the literature.

Sorafenib, a multiple kinase inhibitor, has been established as first-line standard systemic chemotherapy for patients with advanced hepatocellular carcinoma (HCC). We encountered a patient with combined hepatocellular and cholangiocarcinoma (CHC) who achieved complete remission in response to sorafenib treatment. A 58-year old man with hepatitis C virus (HCV)-induced liver cirrhosis was diagnosed with CHC in segments 6th and 7th of the liver and underwent partial surgical resection. Three months later, CHC recurred as metastases at multiple intrahepatic sites, lymph nodes, and bones, making surgery impossible. Treatment with sorafenib was initiated at 400 mg b.i.d., later reduced to 400 mg/day. After 6 months of sorafenib administration, he no longer showed abnormal uptake on fluorodeoxyglucose positron emission tomography. He was continued on sorafenib for 2.5 years, but later discontinued due to adverse events. He has shown no evidence of tumor recurrence more than 1 year after sorafenib discontinuation. His HCV was eradicated by direct-acting antivirals, and he remains in good health.

Survival Benefit of Tolvaptan for Refractory Ascites in Patients with Advanced Cirrhosis.

AIMS: The study aimed to evaluate the effects of tolvaptan treatment on survival of patients with decompensated liver cirrhosis with refractory ascites. METHODS: This multicenter, retrospective, observational study included patients with cirrhosis who were treated with tolvaptan for hepatic ascites refractory to conventional diuretics. Patients who could and could not decrease accompanying diuretics within 1 month after tolvaptan administration were defined as the "Decreased" and "Not-decreased" groups, respectively. RESULTS: Median body weight change 1 week after tolvaptan treatment was -1.95 kg, with the 50% of patients experiencing a 2 kg/week reduction. Spot urinary sodium was found to be a better predictor of tolvaptan response than liver function and liver fibrosis markers. Median survival was significantly longer (not reached versus 116 days, p = 0.005) and serum creatinine concentrations 12 weeks after tolvaptan administration significantly lower (0.99 vs. 1.55 mg/dL, p < 0.05) in the Decreased than in the Not-decreased group. Multivariate analysis showed that the presence of viable hepatocellular carcinoma (hazards ratio [HR] 2.14, p = 0.02) and a decrease in diuretics were independently prognostic of survival (HR 0.36, p < 0.01). CONCLUSIONS: The maintenance of renal function is essential in enhancing survival of patients with cirrhosis. Doses of diuretics should be adjusted appropriately during tolvaptan treatment.

A Patient with Non-alcoholic Steatohepatitis Complicated by Multiple Myeloma.

A 68-year-old woman with liver dysfunction was diagnosed with nonalcoholic steatohepatitis (NASH) stage 1. Three years later, she showed massive ascites and jaundice. A trans-jugular liver biopsy confirmed advanced cirrhosis, suggesting that her liver fibrosis had progressed rapidly. At the same time, she was diagnosed with multiple myeloma (MM). In this case, the plasma levels of osteopontin (OPN), a proinflammatory cytokine that promotes liver fibrosis progression through the hedgehog pathway and is increased in patients with MM, were increased. This increased OPN expression was accompanied by the upregulation of the hedgehog pathway in this patient, suggesting that the MM-associated increase in OPN had promoted the progression of liver fibrosis through the hedgehog pathway. The progression of liver fibrosis should be monitored in patients with NASH if other diseases, such as MM, are present.

Neutrophil-to-lymphocyte ratio predicts recurrence after radiofrequency ablation in hepatitis B virus infection.

BACKGROUND AND AIM: Radiofrequency ablation (RFA) is an established treatment for small hepatocellular carcinoma (HCC) wherein non-recurrence is essential for long-term survival. Recently, neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation that is associated with tumor-associated macrophages (TAMs), was suggested to be a prognostic marker of HCC treated with RFA. Therefore, we evaluated predictive factors, including NLR, associated with recurrence after curative RFA. METHODS: A total of 163 patients initially diagnosed with HCC and treated with RFA were enrolled. We retrospectively analyzed factors associated with recurrence and survival after RFA. Furthermore, TAMs were evaluated using surgically resected specimens. RESULTS: Hepatitis C virus (HCV) infection was the most frequent cause of HCC in this population (111 cases, 68.1%), whereas hepatitis B virus (HBV) infection accounted for 26 cases (16.0%). Recurrence, mostly intrahepatic distant recurrence, was found in 101 cases (61.9%). Recurrence and posttreatment NLR were independent prognostic factors related to survival, and male sex, HCV infection, serum des-γ-carboxy prothrombin >  40 AU/L, and posttreatment NLR were associated with recurrence. Pretreatment NLR showed no association with recurrence, whereas posttreatment NLR showed prognostic value. Interestingly, pretreatment NLR >  2.5 was significantly associated with recurrence in HBV-HCC patients (odds ratio 3.439, P = 0.037) not but HCV-HCC (odds ratio 1.430, P = 0.17). Furthermore, TAMs were increased in the peripheral area of HCCs with HBV infection compared with those with HCV. CONCLUSIONS: Recurrence of HCC after RFA was strongly associated with survival. NLR is useful as a predictive marker of recurrence, especially in HBV-HCC patients.

Neutrophil/lymphocyte ratio as a prognostic indicator of hepatic arterial infusion chemotherapy with arterial cisplatin plus continuous 5-fluorouracil.

AIM: Hepatic arterial infusion (HAIC) therapy may be a therapeutic option for advanced hepatocellular carcinoma (HCC) in addition to administration of sorafenib, which is the only currently established standard regimen for this disease. Survival benefit of HAIC has been reported in patients positive for antitumor response. Therefore, the prediction of antitumor response is important in decision-making for HAIC treatment. METHODS: Twenty-six consecutive patients with advanced HCC treated by HAIC using arterial cisplatin plus continuous 5-fluorouracil were retrospectively analyzed in this study. Neutrophil/lymphocyte ratio (NLR) was assessed to determine its effectiveness as a prognostic indicator of HAIC. RESULTS: The median time to progression and overall survival time (OS) were 5.0 and 17.0 months, respectively. The overall response rate (RR) among the 26 patients was 42.3%, and RR was independent of liver function. Interestingly, RR was significantly lower in patients with NLR of 4 or more (odds ratio, 0.49; P = 0.04). When we investigated factors that influenced OS, treatment effect and NLR of less than 4 were associated with prolonged OS. No serious adverse events were found in treatment with HAIC. CONCLUSION: HAIC is a candidate for treatment of advanced HCC, and NLR may be a useful prognostic indicator for suitability of HAIC.

Repeated sauna therapy improves myocardial perfusion in patients with chronically occluded coronary artery-related ischemia.

BACKGROUND: Repeated low-temperature sauna (Waon) therapy relieves ischemic symptoms in patients with peripheral arterial disease. We investigated whether Waon therapy could improve myocardial perfusion in patients with ischemia related to chronic total occlusion (CTO) of coronary arteries. METHODS: Twenty-four patients who had ischemia in the CTO-related area were examined. The severity of ischemia was quantified by thallium-201 myocardial perfusion scintigraphy with adenosine. The Waon group (n=16) was treated daily for three weeks with a 60 °C far infrared-ray dry sauna bath for 15 min and then kept in a bed covered with blankets for 30 min. The control group (n=8) underwent myocardial perfusion scintigraphy twice with a three-week interval. RESULTS: In the control group, neither summed stress score (SSS) nor summed difference score (SDS) of myocardial scintigraphy changed. However, Waon therapy improved both SSS (16 ± 7 to 9 ± 6, p<0.01) and SDS (7 ± 4 to 3 ± 2, p<0.01), and the improvement was greater in patients with higher SSS and SDS scores at the baseline. Waon therapy extended treadmill exercise time (430 ± 185 to 511 ± 192s, p<0.01) and improved flow-mediated dilation of the brachial artery (4.1 ± 1.3 to 5.9 ± 1.8%, p<0.05), but tended to decrease the number of circulating CD34-positive bone marrow-derived cells. CONCLUSIONS: Waon therapy improves CTO-related myocardial ischemia in association with improvement of vascular endothelial function. This therapy could be a complementary and alternative tool in patients with severe coronary lesions not suitable for coronary intervention.

[A case of pancreatic acinar cell carcinoma with a giant liver metastasis successfully treated with combination of gemcitabine and peroral S-1].

Pancreatic acinar cell carcinoma is rare, and its incidence is less than 1% of all the malignant pancreatic tumors. Little is reported on effectiveness of chemotherapy. We report a 64-year-old male patient with pancreatic acinar cell carcinoma and a giant metastatic liver tumor, which responded to combination chemotherapy with gemcitabine(GEM)and peroral S-1 administration. The patient had upper abdominal pain and hypervascular tumors in liver(15 cm in diameter)and pancreas tail (3 cm in diameter), which were detected by an enhanced abdominal computed tomography(CT)scan, and was admitted for further examination. Abdominal angiography, FDG-positron emission tomography(PET), and liver tumor biopsy led to a diagnosis of pancreatic acinar cell carcinoma in the pancreas tail with liver metastasis. The patient was then treated with combination chemotherapy, which consisted of intravenous infusion of GEM and peroral administration of S-1, and the metastatic liver tumor was markedly reduced(partial response in RECIST). Although the prognosis of patients with unresectable pancreatic acinar cell cancers is generally unfavorable, it is suggested that the GEM/S- 1 combination chemotherapy is effective for these patients' treatment.

Development of osteomalacia in a post-liver transplant patient receiving adefovir dipivoxil.

We report the case of a patient treated with living donor-related liver transplantation who suffered from osteomalacia during adefovir dipivoxil (ADV)-containing antiviral therapy for lamivudine-resistant hepatitis B virus infection. The patient had generalized bone pain, with severe hypophosphatemia after 20 mo of ADV therapy. Radiographic studies demonstrated the presence of osteomalacia. The peak plasma ADV level was 38 ng/mL after administration of ADV at 10 mg/d. It was also found that ADV affected the metabolism of tacrolimus, a calcineurin-inhibitor, and caused an increase in the plasma levels of tacrolimus. The disability was reversed with the withdrawal of ADV and with mineral supplementation. ADV can cause an elevation of plasma tacrolimus levels, which may be associated with renal dysfunction. High levels of ADV and tacrolimus can cause nephrotoxicity and osteomalacia. This case highlights the importance of considering a diagnosis of osteomalacia in liver transplantation recipients treated with both ADV and tacrolimus.

Docetaxel inhibits progression of human hepatoma cell line in vitro and is effective in advanced hepatocellular carcinoma.

BACKGROUND: Current chemotherapy for advanced hepatocellular carcinoma (HCC) is insufficient; only sorafenib has been proven to provide a modest survival benefit. A future direction of chemotherapy is to tailor treatment based on the chemosensitivity of each individual tumor. By doing so, only patients who stand to benefit from therapy will be exposed to potential side-effects and morbidity. Although the use of docetaxel (DTX) for the treatment of lung, breast and gastric cancer has been reported, there are few reports about its use in the setting of HCC. METHODS: To examine the efficacy of DTX for HCC, we established a human hepatoma cell line (TK cell) from the patient's malignant ascites from peritoneal carcinomatosis and treated it with DTX in vitro. RESULTS: After we confirmed the efficacy of DTX in vitro, we treated our patient with DTX with positive results. CONCLUSION: In this study, we present a therapeutic approach by using DTX that supports the potential usefulness of personalized medicine in vitro and demonstrates it clinically.

[A case of hepatocellular carcinoma rapidly progressing after percutaneous radiofrequency ablation successfully treated with low-dose 5-FU and CDDP].

A 65-year-old Japanese man was admitted to our hospital for treatment of hepatocellular carcinoma (HCC) with alcoholic liver cirrhosis. He had been treated by transarterial chemoembolization (TACE) in another hospital before this admission. In our hospital, percutaneous radiofrequency ablation (PRFA) to HCC (2.5 cm diameter) in hepatic S8 was done, and the tumor was ablated completely with the treated margin. After 8 months of the PRFA procedure, abdominal CT revealed diffused-type HCC located in contact with the post RFA area and was diagnosed as a local recurrence of HCC. He was then treated with hepatic arterial infused chemotherapy, low-dose 5-FU and CDDP (FP); one course consisted of (5-FU 250 mg/day + CDDP 10 mg/day) x 5 days/w x 4 wks using a port-infusion system. He was treated with 3 courses of low-dose FP, and the diffuse-type HCC was completely diminished. No recurrence was seen 22 months after chemotherapy. Although rapidly progressing recurrent HCC after PRFA is potentially fatal and useful treatments have only rarely been reported, hepatic arterial infusion chemotherapy including low-dose FP should be considered a possible treatment.

Fas-associated phosphatase-1 promotes Fas-mediated apoptosis in human colon cancer cells: novel function of FAP-1.

BACKGROUND AND AIM: Fas-associated phosphatase-1 (FAP-1) has been thought as an inhibitor in Fas-mediated apoptosis. Here, we investigated the role of FAP-1 in Fas-mediated apoptosis of human colon cancer cells. METHOD: The viability of four colon cancer cell lines treated with agonistic anti-Fas antibody was determined using WST-1 assay and cell death detection ELISA. pRc/CMV-FAP-1 was transfected to a FAP-1-negative, Fas-resistant colon cancer cell line SW480 by lipofection and the clones expressing FAP-1 protein were selected by limiting dilution. In the clones, expression of 550 genes was analyzed by cDNA microarrays. Protein expression of FAP-1 and molecules related to apoptosis was examined by western blot. RESULTS: We obtained two FAP-1 overexpressed clones which were much more susceptible to Fas-mediated apoptosis than control cells. In the clones, caspase 8 and caspase 3 were fully activated by agonistic anti-Fas antibody treatment. Bcl-2 family proteins were not related to the high susceptibility of these clones, because caspase 9 was not activated. Transfection of FAP-1 did not suppress the survival actions of insulin-like growth factor (IGF-1) which enhanced survival signal through Akt phosphorylation. Upregulation in 21 genes and downregulation in 29 genes was revealed by cDNA arrays. We confirmed protein expression of p21 and phosphorylated p21 were much more enhanced in the clones than in control cells. CONCLUSIONS: Overexpression of FAP-1 enhanced susceptibility to Fas-mediated apoptosis in SW480 and upregulation of p21 may contribute to this phenomenon. Our results indicate a novel function of FAP-1 in Fas-mediated apoptosis of human colon cancer cells.

Immature NK cells suppress dendritic cell functions during the development of leukemia in a mouse model.

To analyze the mechanisms by which cancer cells escape from hosts' immune surveillance, we investigated the changes in immune status during the progression of leukemia induced by injecting mice with WEHI-3B cells. In the bone marrow (BM) of leukemic mice, only DX5(+)CD3(-) cells were continuously increased, despite the progression of leukemia. In addition, DX5(+)CD3(-) cells were rapidly increased in peripheral blood (PB) 20 days after inoculation. We also found that myeloid dendritic cells (DCs) expressing low levels of I-A(d) and having low allo-T cell stimulatory activity were markedly increased in PB and spleen. The increase in DX5(+) cells in BM was thought to be induced by soluble factors from leukemic cells. DX5(+) cells from leukemic mice were CD3(-), B220(-), Gr-1(-), CD14(-), CD94(-), Ly-49C/F(-), asialo GM1(+), CD25(+), CD122(+), Thy-1(bright), and c-kit(dim) and showed low killing activity against YAC-1 cells, suggesting that those DX5(+) cells were immature NK cells. NK cells from leukemic PB down-regulated the expression of I-A(d) on DCs, an effect mediated by TGF-beta. Moreover, these NK cells significantly suppressed the allo-T cell stimulatory activity of DCs, an effect requiring cell-to-cell contact between NK cells and DCs and thought to involve CD25. Importantly, NK cells from leukemic PB inhibited generation of autotumor-specific CTL induced by DCs in primary MLR or by DC immunization. In conclusion, we identified circulating immature NK cells with immunosuppressive activities. These cells may be important for understanding the involvement of the host immune system during the development of leukemia.

Overexpression of granulocyte-macrophage colony-stimulating factor in mouse liver enhances the susceptibility of lipopolysaccharide leading to massive apoptosis of hepatocytes.

BACKGROUND/AIMS: We examined whether antigen-nonspecific accumulation of dendritic cells (DCs) and macrophages in the liver by the overexpression of granulocyte macrophage-colony stimulating factor (GM-CSF) could prime severe liver injury after LPS injection. METHODS: We injected a recombinant adenovirus encoding GM-CSF intravenously (AdGM), and LPS was administered 7 days later. Liver histology, serum alanine aminotransferase (ALT) levels and apoptosis of hepatocytes were examined. RESULTS: Liver histology of the AdGM-primed mice showed marked infiltrates of mononuclear cells (DCs and macrophages) without granuloma formation on day 7. Expression of toll-like receptor-4 on intrahepatic mononuclear cells isolated from AdGM-primed mice was up-regulated. After LPS injection, serum ALT levels in AdGM-primed mice reached about 6000 IU/l at 12 h, and all those mice died within 24 h. Hemorrhagic liver injury with massive apoptosis of hepatocytes was histologically recognized. When AdGM and LPS were injected in FasL-deficient C57BL/6J-gld/gld mice, serum ALT levels were not elevated by the pretreatment with a neutralizing anti-TNF-alpha antibody. CONCLUSIONS: Our present study provides a new model of severe liver injury, in which antigen-nonspecific accumulation of DCs and macrophages in the liver by overexpressing GM-CSF enhances the susceptibility to LPS, leading to hemorrhagic liver injury with massive hepatocyte apoptosis after LPS injection.

Sodium butyrate enhances Fas-mediated apoptosis of human hepatoma cells.

BACKGROUND/AIMS: Human hepatoma cells have been reported to be resistant to Fas-mediated apoptosis. Sodium butyrate (SB) induced apoptosis of several cancer cells. We investigated the effects of SB on Fas-mediated apoptosis of hepatoma cells. METHODS: In hepatoma cells (HuH-6, HuH-7, Hep-G2, and PLC/PRF/5), susceptibility to Fas-mediated apoptosis and Fas expression were assessed. Caspase-3 activation and cell cycle progression were evaluated in HuH-6. A cDNA microarray assay was performed to screen the changes in the expression of mRNAs. RESULTS: Pretreatment with SB caused an enhancement of the sensitivity to anti-Fas-mediated cytotoxicity, though it did not increase the expression of Fas. The cDNA microarray assay revealed up-regulation of pro-apoptotic Bik, Bak, Bid and c-Jun N-terminal protein kinase-1, and down-regulation of anti-apoptotic Bag-1 and cellular Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitor protein. In some molecules, expression of the proteins was confirmed by Western blotting. An increase in truncated-Bid accompanying the reduction in Bid was also observed. CONCLUSIONS: SB enhances the susceptibility of hepatoma cells to anti-Fas-mediated cytotoxicity by altering the mRNA and protein expression and/or the activation status of proteins that could be involved in the Fas signaling pathway. SB may have an important role in the elimination of hepatoma cells.

Transcription starting from an alternative promoter leads to the expression of the human ABO histo-blood group antigen.

BACKGROUND: Using the 5'-rapid amplification of cDNA ends technique with the ex vivo culture of AC133-CD34+ cells, a transcription start site was recently identified approximately 0.7 kb upstream from the transcription start sites previously determined. The transcripts from the alternative starting exon 1a were demonstrated in the cells of both erythroid and epithelial lineages. Because the nucleotide sequence of exon 1a does not contain an ATG codon, we examined whether transcription starting from exon 1a leads to production of a functional glycosyltransferase. STUDY DESIGN AND METHODS: Stable transfection experiments into the human gastric cancer MKN28 cells were performed using the various A transferase expression plasmids. RESULTS: Large amounts of A antigens were demonstrated on the cells transfected with the A transferase expression plasmid containing the entire cDNA from exon 1a or the 5'-truncated cDNA leading to the production of the N-truncated protein with deletion of the cytoplasmic tail and a portion of the transmembrane domain. However, negligible amounts of A antigens were observed on the cells transfected with the A transferase expression plasmids containing the 5'-truncated cDNA leading to the production of the N-truncated proteins without the cytoplasmic tail and the transmembrane domain. CONCLUSION: This study suggests that a functional A transferase could be produced by the transcription from exon 1a.