The occurrence of hepatocellular carcinoma (HCC) is closely associated with viral hepatitis or alcoholic hepatitis. Although active surveillance is ongoing in Korea, advanced or metastatic HCC is found at initial presentation in many patients. Metastatic HCC presents with a hypervascular intrahepatic tumor and extrahepatic lesions such as lung or lymph node metastases. Cases of HCC presenting as carcinoma of unknown primary have been rarely reported. The authors experienced a case of metastatic HCC in a patient who presented with a metastatic bone lesion but no primary intrahepatic tumor. This case suggests that HCC should be considered as a differential diagnosis when evaluating the primary origin of metastatic carcinoma.
Antineoplastic Agents/therapeutic use ; Bone Neoplasms/*diagnosis/diagnostic imaging/secondary ; Carcinoma, Hepatocellular/*diagnosis/drug therapy ; Cervical Cord/pathology ; Chemoembolization, Therapeutic ; Gamma Rays ; Humans ; Liver Neoplasms/*diagnosis/drug therapy ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Neoplasms, Unknown Primary/pathology ; Niacinamide/analogs & derivatives/therapeutic use ; Pelvic Bones/pathology ; Phenylurea Compounds/therapeutic use ; Tomography, X-Ray Computed

Antineoplastic Combined Chemotherapy Protocols ; Arsenicals ; administration & dosage ; Carcinoma, Hepatocellular ; drug therapy ; secondary ; Chemoembolization, Therapeutic ; methods ; Humans ; Liver Neoplasms ; Lung Neoplasms ; drug therapy ; secondary ; Niacinamide ; administration & dosage ; analogs & derivatives ; Oxides ; administration & dosage ; Phenylurea Compounds ; administration & dosage

3-Bromopyruvate (3BP) is a new, promising anticancer alkylating agent with several notable functions. In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase (LDH), 3BP also selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells. Moreover, 3BP induces hydrogen peroxide generation in cancer cells (oxidative stress effect) and competes with the LDH substrates pyruvate and lactate. There is only one published human clinical study showing that 3BP was effective in treating fibrolamellar hepatocellular carcinoma. LDH is a good measure for tumor evaluation and predicts the outcome of treatment better than the presence of a residual tumor mass. According to the Warburg effect, LDH is responsible for lactate synthesis, which facilitates cancer cell survival, progression, aggressiveness, metastasis, and angiogenesis. Lactate produced through LDH activity fuels aerobic cell populations inside tumors via metabolic symbiosis. In melanoma, the most deadly skin cancer, 3BP induced necrotic cell death in sensitive cells, whereas high glutathione (GSH) content made other melanoma cells resistant to 3BP. Concurrent use of a GSH depletor with 3BP killed resistant melanoma cells. Survival of melanoma patients was inversely associated with high serum LDH levels, which was reported to be highly predictive of melanoma treatment in randomized clinical trials. Here, we report a 28-year-old man presented with stage IV metastatic melanoma affecting the back, left pleura, and lung. The disease caused total destruction of the left lung and a high serum LDH level (4,283 U/L). After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions (1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level. This may have been due to high tumor GSH content. On combining oral paracetamol, which depletes tumor GSH, with 3BP treatment, serum LDH level dropped maximally. Although a slow intravenous infusion of 3BP appeared to have minimal cytotoxicity, its anticancer efficacy via this delivery method was low. This was possibly due to high tumor GSH content, which was increased after concurrent use of the GSH depletor paracetamol. If the anticancer effectiveness of 3BP is less than expected, the combination with paracetamol may be needed to sensitize cancer cells to 3BP-induced effects.
Acetaminophen ; therapeutic use ; Adult ; Carcinoma, Hepatocellular ; Disease Progression ; Drug Therapy, Combination ; Enzyme Inhibitors ; Glutathione ; Glycolysis ; Hexokinase ; Humans ; L-Lactate Dehydrogenase ; Lactic Acid ; Lung Neoplasms ; secondary ; Male ; Melanoma ; drug therapy ; Necrosis ; Neovascularization, Pathologic ; Pleural Neoplasms ; secondary ; Prognosis ; Pyruvates ; adverse effects ; therapeutic use ; Treatment Outcome

Transarterial chemoembolization (TACE) is one of the most effective therapies for unresectable hepatocelluar carcinoma or metastatic hypervascular tumors. Abscess occurring in the other organs beside the liver after TACE is a complication that often occurs, sometimes potentially fatal. We report a case of spinal epidural abscess occurred after liver abscess complicated by TACE in a patient with metastatic neuroendocrine tumors to the liver. A 67-year-old female underwent TACE first for the metastatic lesions to liver, with a history of pancreatoduodenectomy for the primary pancreatic neuroendocrine tumor. Four days after TACE, sudden high fever occurred, and liver abscess was found on abdominal CT. Two days later, back pain and radiating pain to the right leg occurred, and lumbar spine MRI showed spinal epidural abscess. After intravenous antibiotics for 8 weeks and partial laminectomy, the patient recovered and was discharged without complications.
Aged ; Anti-Bacterial Agents/therapeutic use ; Carcinoma, Hepatocellular/secondary/*therapy ; Chemoembolization, Therapeutic/*adverse effects ; Epidural Abscess/*etiology/microbiology/surgery ; Escherichia coli/isolation & purification ; Escherichia coli Infections/drug therapy ; Female ; Humans ; Laminectomy ; Liver Abscess/*etiology ; Liver Neoplasms/secondary/*therapy ; Lumbar Vertebrae/microbiology/radiography ; Magnetic Resonance Imaging ; Neuroendocrine Tumors/pathology/surgery ; Pancreaticoduodenectomy ; Tomography, X-Ray Computed

Hepatoid adenocarcinoma (HAC) is a rare type of extrahepatic carcinoma whose morphology is similar to that of hepatocellular carcinoma (HCC). Metachronous HCC and HAC in the same patient is extremely rare. The case of a 68-year-old man with chronic hepatitis B infection who had both HCC and HAC of the stomach is reported herein. Nine years previously this patient had been diagnosed with HCC and received a right lobectomy. HCC that recurred at the caudate lobe at 6 months after the operation was successfully treated with transarterial chemoembolization. The patient was followed up regularly thereafter without evidence of tumor recurrence for 9 years. In July 2010 his serum alpha-fetoprotein (AFP) level elevated from 6.5 ng/mL to 625.4 ng/mL, and he developed a probable single metastatic lymph node around the hepatic artery without intrahepatic lesions. Subsequent evaluation with upper endoscopy revealed a 4-cm ulcerative lesion on the antrum of the stomach. Subtotal gastrectomy was performed with lymph-node dissection. Histologic examination revealed a special type of extrahepatic AFP-producing adenocarcinoma-HAC with lymph-node metastasis-which indicates that HAC can be a cause of elevated AFP even in patients with HCC. HAC should be considered if a patient with stable HCC exhibits unusual elevation of AFP.
Adenocarcinoma/*diagnosis/drug therapy/secondary ; Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Camptothecin/analogs & derivatives/therapeutic use ; Carcinoma, Hepatocellular/*diagnosis/drug therapy/pathology ; Chemoembolization, Therapeutic ; Chemotherapy, Adjuvant ; Fluorouracil/therapeutic use ; Gastroscopy ; Humans ; Leucovorin/therapeutic use ; Liver Neoplasms/*diagnosis/drug therapy/pathology ; Lymph Nodes/surgery ; Lymphatic Metastasis ; Male ; Recurrence ; Silicates/therapeutic use ; Stomach Neoplasms/*diagnosis/drug therapy/secondary ; Titanium/therapeutic use ; Tomography, X-Ray Computed ; alpha-Fetoproteins/*analysis

OBJECTIVETo investigate the effects of a Chinese herbal extract Songyou Yin on residual hepatocellular carcinoma after chemotherapy in nude mice and the relevant mechanisms.

METHODSOrthotopic nude mouse models bearing residual hepatocellular carcinoma after chemotherapy was established using human liver carcinoma MHCC97L cells. Three different doses of Songyon Yin (2.1 g/kg, 4.2 g/kg and 8.4 g/kg) were administered to the mice in the trial groups by intragastric gavage, respectively. The mice in the control group were administered physiological saline. The tumor growth, metastasis and survival in the mice of each group were recorded. The corresponding mechanisms were studied.

RESULTSThe pulmonary metastasis rates of the control group and 2.1g/kg, 4.2g/kg, 8.4g/kg Songyou Yin treatment group were 86.7%, 73.3%, 40.0%, and 20.0%, respectively, and the survivals of these groups were 53.83 ± 4.71, 56.50 ± 6.09, 66.67 ± 5.61, 81.17 ± 7.36 days, respectively. Compared with the mice in the control group, mice in the 4.2 g/kg, 8.4 g/kg Songyou Yin treatment groups had a lower pulmonary metastasis rate (P = 0.021 and P = 0.001, respectively) and longer survival (P = 0.002 and P = 0.001, respectively). A restoration of E-cadherin expression and a concomitant reduction of N-cadherin expression were detected in the tumors of the 4.2 g/kg and 8.4 g/kg Songyou Yin treatment groups.

CONCLUSIONSSongyou Yin effectively inhibits the invasion and metastasis of the residual hepatocellular carcinoma after chemotherapy in nude mice through attenuating the epithelia-mesenchymal transition and prolongs the survival. Songyon Yin may have potential to promote the efficacy of chemotherapy in hepatocellular carcinoma.

Animals ; Antineoplastic Agents ; therapeutic use ; Antineoplastic Agents, Phytogenic ; isolation & purification ; pharmacology ; Cadherins ; metabolism ; Carcinoma, Hepatocellular ; drug therapy ; metabolism ; pathology ; Cell Line, Tumor ; Drug Combinations ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Epithelial-Mesenchymal Transition ; drug effects ; Humans ; Liver Neoplasms ; drug therapy ; metabolism ; pathology ; Lung Neoplasms ; secondary ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Neoplasm, Residual ; metabolism ; pathology ; Organoplatinum Compounds ; therapeutic use ; Plants, Medicinal ; chemistry ; Random Allocation ; Survival Rate ; Tumor Burden ; drug effects ; Xenograft Model Antitumor Assays

Chronic hepatitis C infection is an important cause of cirrhosis and hepatocellular carcinoma (HCC). Antiviral therapy (AVT) for patients with cirrhosis due to hepatitis C may retard the progression of cirrhosis and prevent both the development of HCC as well as the recurrence of hepatitis C following liver transplantation. This review highlights the issues associated with AVT for patients with compensated and decompensated cirrhosis due to hepatitis C virus.
Antiviral Agents ; therapeutic use ; Carcinoma, Hepatocellular ; prevention & control ; virology ; Disease Progression ; Hepacivirus ; Hepatitis C, Chronic ; complications ; drug therapy ; Humans ; Liver Cirrhosis ; drug therapy ; virology ; Liver Neoplasms ; prevention & control ; virology ; Liver Transplantation ; Secondary Prevention

OBJECTIVETo explore the changes of metastatic potential of residual hepatocellular carcinoma (HCC) after in vivo chemotherapy and its mechanism.

METHODSNude mouse models of orthotopic HCC in the nude mouse livers was established using human hepatocellular carcinoma cell line MHCC97L cells. Oxaliplatin (10 mg/kg, once per week) was administered intraperitoneally (i.p.) to mice in the trial group. Mice in the control group received 0.2 ml of 0.9% sodium chloride on the same days. On day 7 after the third injection, all mice were sacrificed and tumor fragments of equal volume (2 mm×2 mm×2 mm) from each mouse of the oxaliplatin-treated and untreated groups were reinoculated into the livers of each new recipient mouse correspondingly. The growth, metastasis and molecular phenotype of the reinoculated tumors in both groups were determined.

RESULTSIn the new recipient mice, compared with untreated tumors, oxaliplatin pre-treated tumors grew significantly slower [(2624.59 ± 491.60) mm(3) vs. (3849.72 ± 827.09) mm(3), P < 0.001], but gave more spontaneous metastasis to the lung (10/12 vs. 3/12, P = 0.012). A decreased expression of E-cadherin and increased expression of N-cadherin, vimentin and transcription factor Snail were detected in the oxaliplatin pre-treated tumors by immunohistochemistry, which provided the evidence of epithelial mesenchymal transition (EMT) in these tumors.

CONCLUSIONResidual hepatocellular carcinomas after in vivo chemotherapy grow slower but gain enhanced metastatic potential to the lung, associated with epithelial mesenchymal transition.

Animals ; Antineoplastic Agents ; therapeutic use ; Apoptosis ; drug effects ; Cadherins ; metabolism ; Carcinoma, Hepatocellular ; drug therapy ; metabolism ; secondary ; Cell Line, Tumor ; Epithelial-Mesenchymal Transition ; Humans ; Liver Neoplasms ; drug therapy ; metabolism ; pathology ; Lung Neoplasms ; drug therapy ; secondary ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Metastasis ; Neoplasm Transplantation ; Neoplasm, Residual ; drug therapy ; metabolism ; secondary ; Organoplatinum Compounds ; therapeutic use ; Snail Family Transcription Factors ; Transcription Factors ; metabolism ; Tumor Burden ; Vimentin ; metabolism ; Xenograft Model Antitumor Assays

Transcatheter arterial chemoembolization (TACE) has been used widely to treat patients with unresectable hepatocellular carcinoma. However, this method can induce various adverse events caused by necrosis of the tumor itself or damage to nontumor tissues. In particular, neurologic side effects such as cerebral infarction and paraplegia, although rare, may cause severe sequelae and permanent disability. Detailed information regarding the treatment process and prognosis associated with this procedure is not yet available. We experienced a case of paraplegia that occurred after conducting TACE through the intercostal artery to treat hepatocellular carcinoma that had metastasized to the rib. In this case, TACE was attempted to relieve severe bone pain, which had persisted even after palliative radiotherapy. A sudden impairment of sensory and motor functions after TACE developed in the trunk below the level of the sternum and in both lower extremities. The patient subsequently received steroid pulse therapy along with supportive care and continuous rehabilitation. At the time of discharge the patient had recovered sufficiently to enable him to walk by himself, although some paresthesia and spasticity remained.
Antiviral Agents/therapeutic use ; Bone Neoplasms/radiography/secondary ; Carcinoma, Hepatocellular/diagnosis/pathology/*therapy ; Catheter Ablation ; Chemoembolization, Therapeutic/*adverse effects ; Hepatitis B/complications/drug therapy ; Humans ; Liver Cirrhosis/etiology ; Liver Neoplasms/diagnosis/pathology/*therapy ; Male ; Middle Aged ; Positron-Emission Tomography ; Soft Tissue Neoplasms/secondary ; Spinal Cord Injuries/*etiology ; Tomography, X-Ray Computed

Although continuous low-dose (metronomic [MET]) therapy exerts anti-cancer efficacy in various cancer models, the effect of long-term MET therapy for hepatocellular carcinoma (HCC) remains unknown. This study assessed the long-term efficacy of MET on suppression of tumor growth and spontaneous metastasis in a rat model of HCC induced by administration of diethylnitrosamine for 16 wk. The rats were divided into 3 groups: MTD group received intraperitoneal (i.p.) injections of 40 mg/kg cyclophosphamide on days 1, 3, and 5 of a 21-day cycle; Control and MET groups received i.p. injections of saline and 20 mg/kg cyclophosphamide twice a week, respectively. Anti-tumor and anti-angiogenic effects and anti-metastatic mechanisms including matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were evaluated. Twelve wk of MET therapy resulted in a significant reduction in intrahepatic tumors than control or MTD therapy. The MET group had fewer proliferating cell nuclear antigen-positive cells and decreased hypoxia-inducible factor-1alpha levels and microvessel density. Lung metastases were detected in 100%, 80%, and 42.9% in the control, MTD, and MET groups, respectively. MET therapy significantly decreased expression of TIMP-1, MMP-2 and -9. For mediators of pro-MMP-2 activation, MET therapy induced significant suppression in the TIMP-2 and MMP-14 level. The survival in the MET group was significantly prolonged compared to the control and MTD groups. Long-term MET scheduling suppresses tumor growth and metastasis via its potent anti-angiogenic properties and a decrease in MMPs and TIMPs activities. These results provide a rationale for long-term MET dosing in future clinical trials of HCC treatment.
Animals ; Antineoplastic Agents/*administration & dosage/*pharmacology ; Carcinoma, Hepatocellular/chemically induced/*drug therapy/mortality/pathology ; Cell Proliferation/drug effects ; Cyclophosphamide/*administration & dosage/*pharmacology ; Diethylnitrosamine ; Disease Models, Animal ; Gene Expression Regulation, Neoplastic/*drug effects ; Liver Cirrhosis/chemically induced ; Liver Neoplasms/chemically induced/*drug therapy/mortality/pathology ; Lung Neoplasms/drug therapy/pathology/secondary ; Male ; Matrix Metalloproteinases/metabolism ; Neovascularization, Pathologic/enzymology/physiopathology ; Rats ; Rats, Sprague-Dawley ; Survival Analysis ; Tissue Inhibitor of Metalloproteinases/metabolism ; Tumor Burden/drug effects