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Undifferentiated sarcoma of the liver is rare, especially in adults, and is an aggressive malignancy that originates from the primary mesenchymal tissues. A 53-year-old man was referred to our hospital for further evaluation of a low-grade fever. Contrast-enhanced CT revealed an 18-cm tumor in the right lobe of the liver. The tumor was characterized by low-density areas suspected of cystic components, a high-density area suspected of hemorrhage, and contrast enhancement in the thickened marginal and internal septa. MRI revealed a high-intensity tumor with a heterogeneous structure on T2-weighted images. Angiosarcoma of the liver with intratumoral hemorrhage was suspected, and right hepatectomy was performed. The pathological diagnosis was an undifferentiated sarcoma based on the presence of undifferentiated mesenchymal tumor cells with a stellate to spindle-shaped pleomorphism. Following a multidisciplinary discussion, 4 courses of the AI regimen (doxorubicin and ifosfamide)were administered as adjuvant chemotherapy, and no recurrence was confirmed at 2 years and 6 months follow-up. Our case suggests that radical resection followed by adjuvant chemotherapy may contribute to a favorable prognosis for undifferentiated sarcoma of the liver.

Purpose: Liver metastasis (LM) is associated with poor prognosis in patients with metastatic colorectal cancer (mCRC). Here, we investigated the prognostic utility of several serum factors in mCRC patients with or without LM who were treated with anti-angiogenic agents in first-line (FL) or salvage-line (SL) settings., Methods: A combined cohort of 125 patients was analyzed in this single institute pooled analysis: FL cohort receiving bevacizumab (n = 71) and SL cohort receiving regorafenib (n = 54). Blood samples were obtained at baseline (BL) and during treatment, and serum factors were measured by ELISA. Overall survival (OS) was analyzed using Kaplan-Meier curves, the log-rank test, and Cox proportional hazard regression methods., Results: In univariate analysis of the combined cohort, right-sided CRC, primary unresected tumor, wild-type KRAS, LM, ≥ 2 metastatic sites, and SL were associated with shorter OS; in multivariable analysis, LM and SL remained significant. Serum angiopoietin-2 (Ang-2) levels ≥ 2190.3 pg/ml and interleukin (IL)-8 levels ≥ 15.1 pg/ml at BL were significantly associated with LM. Using these cut-off values, patients with higher Ang-2 or IL-8 levels at BL had shorter OS than those with lower BL levels (Ang-2: hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.47-4.51, P = 0.001; IL-8: HR 4.31, 95%CI 2.11-8.79, P < 0.001). High serum IL-8 level remained a significant predictor of shorter OS in multivariable analysis (HR 3.24, 95%CI 1.47-7.16, P = 0.004)., Conclusion: Circulating IL-8 and Ang-2 levels are associated with LM in mCRC patients. IL-8 may be a prognostic marker of response to anti-angiogenic therapy, regardless of the treatment timing.

Background: This study aimed to evaluate the efficacy and the safety of polyethylene glycol conjugated granulocyte colony-stimulating factor (PEG-G-CSF) for preventing neutropenia in metastatic colorectal cancer (mCRC) patients that received fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab (Bev) in clinical practice., Methods: We retrospectively analyzed mCRC patients who received FOLFOXIRI plus Bev between December 2015 and December 2017. We evaluated the efficacy of PEG-G-CSF as preventing or treating grade 3 or 4 neutropenia, the overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival (PFS), overall survival (OS), and adverse events of FOLFOXIRI plus Bev based on the Common Terminology Criteria for Adverse Events version 4.0., Results: A total of 26 patients (median age 53.5 years) were included. The ORR rate was 65.3%, the median PFS was 9.6 months (7.2-16.9), and the median OS was 24.2 months (13.6-NA). Grade 3 or 4 neutropenia occurred in 53.8% of the patients, and febrile neutropenia occurred in 7.7%. PEG-G-CSF was given to 77.0% of the patients, including prophylactically (n = 9) and after the development of grade 3 or 4 neutropenia (n = 11). No patients experienced grade 3 or 4 neutropenia after the administration of PEG-G-CSF. In seven of the nine patients who received PEG-G-CSF prophylactically (77.8%), no dose adjustment was required., Conclusions: PEG-G-CSF is useful in preventing severe neutropenia in mCRC patients treated with FOLFOXIRI plus Bev.

Background The effectiveness of reintroducing oxaliplatin for metastatic colorectal cancer (mCRC) refractory to both oxaliplatin and irinotecan was previously reported in a phase II study (RE-OPEN). We conducted a phase I study to determine the maximum tolerated dose of oxaliplatin plus trifluridine/tipiracil (FTD/TPI) in patients with refractory mCRC. Patients and Methods Three dosages of intravenous oxaliplatin (50, 65 and 85 mg/m 2 ) on days 1 and 15 and a fixed dose of FTD/TPI 35 mg/m 2 twice daily (bid) on days 1-5 and 15-19 every 4 weeks were investigated in patients with refractory mCRC using a 3 + 3 design. Eligible patients had received prior oxaliplatin-based treatment that achieved a response or stable disease followed by confirmed disease progression at least 6 months before entering the study. Results Twelve patients were enrolled in the study. Three of six patients in the oxaliplatin 85 mg/m 2 cohort had dose-limiting toxicities (DLTs) with treatment delays during the second cycle at ≥8 days due to grade ≥ 2 neutropenia or grade 2 AST/ALT increased. No DLTs were observed in the other cohorts. Grade ≥ 3 AEs were neutropenia (n = 3), thrombocytopenia (n = 1), anorexia (n = 1), and nausea (n = 1). There was no evidence of allergic reaction to oxaliplatin or severe peripheral sensory neuropathy. Conclusions A combination of FTD/TPI 35 mg/m 2 bid on days 1-5 and 15-19 and oxaliplatin 85 mg/m 2 on days 1 and 15 every 4 weeks could be a suitable regimen for the recommended dose of FTD/TPI plus oxaliplatin in patients with refractory mCRC.

Background: The detection of molecules and mechanisms affecting the malignant phenotype of gastric cancer cells may contribute to the identification of biomarkers for metastasis and recurrence, and such molecules may serve as targets of therapy. For this purpose, in this study transcriptome analysis was performed using surgically resected specimens from patients with gastric cancer with synchronous metastasis. We identified homeobox C10 (HOXC10) as the most highly expressed gene in gastric cancer tissues compared with the adjacent noncancerous gastric mucosa., Methods: Polymerase chain reaction (PCR) array analysis was performed to identify genes coordinately expressed with HOXC10. The effects of inhibiting HOXC10 on malignant phenotype was evaluated using HOXC10 knockout gastric cancer cell lines, and antibody array analysis was performed to assess the effect of HOXC10 knockout on intracellular signaling. We used a mouse subcutaneous xenograft model to evaluate the tumorigenicity. HOXC10 expression was determined in gastric cancer tissues acquired from 300 patients with gastric cancer., Results: PCR array analysis revealed that the levels of HOXC10 messenger RNA positively correlated with those of FGFBP1 and SOX10. The phosphorylation of ERK1/2 was decreased in HOXC10 knockout cells. HOXC10 knockout significantly suppressed proliferation by increasing apoptosis and reducing the migration and invasiveness of gastric cancer cells. Mouse xenograft models revealed that the tumorigenicity of HOXC10 knockout cells was attenuated compared with the parental cells. The relatively high expression levels of HOXC10 in gastric cancer tissues were significantly associated with hepatic and peritoneal recurrence, as well as worse prognosis., Conclusions: Our results indicated that HOXC10 enhances the malignant phenotype of gastric cancer cells. The expression levels of HOXC10 may therefore serve as a prognostic biomarker and the products of HOXC10 may provide targets of therapy.

Hepatic recurrence of gastric cancer (GC) is uncontrollable. Discovery of causative oncogenes and the development of sensitive biomarkers to predict hepatic recurrence are required to improve patients' outcomes. In this study, recurrence pattern-specific transcriptome analysis of 57 749 genes was conducted to identify mRNAs specifically associated with hepatic metastasis of patients with stage III GC who underwent curative resection. GC cell lines were subjected to mRNA expression analysis, PCR array analysis, and siRNA-mediated knockdown. The expression levels of primary cancer tissues from 154 patients with resectable GC were determined and correlated with clinicopathological variables. Among 21 genes significantly overexpressed specifically in patients with hepatic recurrence, Sushi domain containing 2 (SUSD2) was selected as a promising target. PCR array analysis revealed that SUSD2 mRNA levels positively correlated with those of FZD7, CDH2, TGFB1, SPARC, ITGA5, and ZEB1. Functional analysis revealed that knockdown of SUSD2 significantly reduced the proliferation, migration, and invasiveness GC cell lines. Patients with high SUSD2 expression were more likely to experience shorter disease-free and overall survival. Analysis of the relation between disease recurrence pattern and SUSD2 levels revealed that significantly more patients with hepatic metastases expressed higher levels of SUSD2 mRNA. The cumulative incidence of hepatic recurrence was greater in patients with high SUSD2 expression. In conclusion, SUSD2 likely contributes to the malignant potential of GC and may serve as a novel biomarker that predicts hepatic recurrence after curative resection., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Liver metastasis remains a serious problem in the management of gastric cancer (GC). Our aims were to identify through transcriptome analysis a molecule that mediates hepatic metastasis in GC, and to evaluate its potential as a diagnostic marker and a therapeutic target. The effects of knocking out a relevant molecule using genome editing were evaluated in vitro experiments and in mouse xenograft models. Expression levels of candidate molecule in 300 pairs of gastric tissues were determined to assess whether differentially expressed genes predicted hepatic recurrence, metastasis, or both. Transcriptome data identified the overexpression of synaptotagmin VII (SYT7) in GC tissues with hepatic metastasis. Its expression in the GC cell lines was high, particularly in those that exhibited a differentiated phenotype, and positively correlated with the expression of SNAI1 and TGFB3, and inversely with RGS2. SYT7 knockout inhibited the proliferation of GC cells, indicated by increased apoptosis with activated caspase and loss of mitochondria membrane potential, G2/M cell-cycle arrest and attenuated cell migration, invasion, and adhesion. The tumorigenicity of SYT7-knockout cells was moderately reduced in a mouse model of subcutaneous metastasis in which the levels of BCL2 and HIF1A were decreased and was more strikingly attenuated in a model of hepatic metastasis. The SYT7 levels in the primary GC tissues were significantly associated with hepatic recurrence, metastasis, and adverse prognosis. SYT7 represents a tool for prediction and monitoring of hepatic metastasis from GC as well as being a promising therapeutic target.

In the present study, we investigated the role of lysyl oxidase‑like 2 (LOXL2), the correlation between LOXL2 and epithelial to mesenchymal transition (EMT) and the effects of using β‑aminopropionitrile (BAPN) to inhibit LOXL2 with the aim of reducing tumor progression in hepatocellular carcinoma (HCC). The expression level of LOXL2 was evaluated in HCC and adjacent non‑cancerous tissues using quantitative reverse transcription polymerase chain reaction and clinicopathological analyses. The effects of BAPN on cell proliferation, migration and invasion were investigated in vitro. Additionally, LOXL2 expression was assessed in the culture supernatants of HCC cell lines. Our results revealed that LOXL2 expression was higher in HCC cell lines and tissues. There was a significant correlation between EMT status and LOXL2 levels (P=0.004). BAPN reduced migration and invasion in HCC cells. HCC patients with high levels of LOXL2 expression had relatively shorter disease‑free survival (P=0.009) and overall survival (P=0.035). The expression level of LOXL2 was similar between cell supernatants and HCC cell lines. A multivariate analysis demonstrated that portal vein invasion (P=0.015), venous invasion (P=0.026), serum AFP (α‑fetoprotein) levels (P=0.019) and LOXL2 expression (P=0.009) were independent prognostic factors. Our results indicated that a higher level of LOXL2 may contribute to tumor progression, indicating that LOXL2 has clinical value as a therapeutic target in HCC.

Background: Tri-phosphorylated trifluridine (FTD) incorporation into DNA is TAS-102's main anti-tumor action. We tested whether genetic polymorphisms in homologous recombination (HR) and cell cycle checkpoint pathway for DNA repair is associated with outcomes in refractory metastatic colorectal cancer (mCRC) patients treated with TAS-102., Patients and Methods: We analyzed genomic DNA extracted from 233 samples of three cohorts: an evaluation cohort of 52 patients receiving TAS-102, a validation cohort of 129 patients receiving TAS-102 and a control cohort of 52 patients receiving regorafenib. Single nucleotide polymorphisms of genes involved in HR (ATM, BRCA1, BRCA2, XRCC3, FANCD2, H2AX, RAD51) and cell cycle checkpoint (ATR, CHEK1, CHEK2, CDKN1A, TP53, CHE1, PIN1, PCNA) were analyzed by PCR-based direct sequencing., Results: In univariate analysis for the evaluation cohort, patients with any G allele in ATM rs609429 had longer overall survival (OS) than those with the C/C variant (8.7 vs. 4.4 months, HR 0.37, 95% CI: 0.14-0.99, P = 0.022). Patients carrying any A allele in XRCC3 rs861539 had significantly longer progression-free survival (PFS) (3.8 vs. 2.3 months, HR 0.44, 95% CI: 0.21-0.92, P = 0.024) and OS (15.6 vs. 6.3 months, HR 0.25, 95% CI: 0.08-0.79, P = 0.012) than those with the G/G variant. In multivariable analysis, ATM rs609429 remained significant for OS (P = 0.020). In the validation cohort, patients having ATM rs609429 with any G allele showed longer OS and PFS; the G/A variant in XRCC3 rs861539 showed longer OS, though without statistical significance., Conclusion: Genetic variants in the HR pathway may predict clinical outcome in mCRC patients receiving TAS-102., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: After analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies. However, it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first-line treatment for metastatic colorectal cancer., Methods: Of the 1001 consecutive colorectal cancer patients examined for RAS, PIK3CA, and BRAF tumor mutations using a multiplex kit (Luminex®), we studied 90 patients who received combination chemotherapy with bevacizumab as first-line treatment for metastatic colorectal cancer. The objective response rate (ORR) and progression-free survival (PFS) were evaluated according to mutational status., Results: The ORR was higher among patients with wild-type tumors (64.3%) compared to those with tumors that were only wild type with respect to KRAS exon 2 (54.8%), and the differences in ORR between patients with wild-type and mutant-type tumors were greater when considering only KRAS exon 2 mutations (6.8%) rather than RAS/PIK3CA/BRAF mutations (18.4%). There were no statistically significant differences in ORR or PFS between all wild-type tumors and tumors carrying any of the mutations. Multivariate analysis revealed that liver metastasis and RAS and BRAF mutations were independent negative factors for disease progression after first-line treatment with bevacizumab., Conclusions: Patient selection according to RAS/PIK3CA/BRAF mutations could help select patients who will achieve a better response to bevacizumab treatment. We found no clinical benefit of restricting combination therapy with bevacizumab for metastatic colorectal cancer patients with EGFR-wild type tumors.

Purpose: Surgery is the only potentially curative strategy for patients who have Stage IV colorectal cancer (CRC) with resectable metastases, but relapse is common. Randomized trials of adjuvant 5-FU-based systemic chemotherapy have not demonstrated any benefit after resection of liver metastases. We evaluated the efficacy, safety, and tolerability of oxaliplatin-based adjuvant chemotherapy after curative resection of hepatic or extrahepatic metastases of CRC., Methods: We retrospectively studied data for 88 consecutive patients with Stage IV CRC who underwent curative resection of metastases followed by oxaliplatin-based adjuvant chemotherapy between March 2007 and June 2013., Results: The 3-year relapse-free survival (RFS) rate was 54.0 %. There was no significant difference in 3-year RFS between patients with metastases confined to the liver (52.7 %) and patients with extrahepatic metastases (57.2 %). Multivariate analysis revealed that the site of the primary tumor (right-sided colon or left-sided colon/rectum) and the number of metastases (solitary or multiple) were predictors of RFS. Scheduled courses were completed in 80.7 % of the patients. Except for neutropenia (47.7 %), severe adverse events were observed in <5 % of patients., Conclusions: Oxaliplatin-based adjuvant chemotherapy could be an effective option for selected patients with Stage IV CRC after curative resection of hepatic or extrahepatic metastases, and is both safe and tolerable.

Background/aims: The aim of this study was to evaluate patterns of the initial recurrence after pancreatectomy for pancreatic cancer and risk factors in each pattern., Methodology: This study included 209 pancreatic cancer patients who underwent pancreatectomy and of whom the detailed information on the first recurrent lesions detected by imaging during postoperative followup were available. Relapse patterns were classified into 4 groups: liver, peritoneal, local and extra-abdominal recurrences. We evaluated their associations with prognosis and various clinicopathological factors to identify relevant risk factors., Results: Cumulative numbers of patients with liver, peritoneal, local, and extra-abdominal recurrences were 81, 70, 98 and 22, respectively, for the first recurrences. Hepatic relapse was associated with significantly shorter overall survival than other sites (p<0.001) and was an independent prognostic factor in multivariate analysis (p<0.001). Pathological portal vein invasion was the only independent risk factor for hepatic relapse (p=0.045). There was no significant correlation between the depth of invasion and prevalence of hepatic relapse., Conclusions: Hepatic relapse was associated with a dismal prognosis and with pathological portal vein invasion. Novel therapeutic strategies are therefore required to reduce the incidence of hepatic relapse, especially in patients with portal vein invasion.

Patients with hepatocellular carcinoma (HCC) have a poor prognosis, and novel molecular targets for treating recurrence and progression of the disease along with associated biomarkers are urgently required. In the present study, expression and the regulatory mechanism of TUSC1 (tumor suppressor candidate 1) were investigated to determine if it is a candidate tumor suppressor gene for HCC, which shows repressed transcription that involves aberrant DNA methylation. TUSC1 mRNA expression levels in HCC cell lines and 94 pairs of surgical specimens were determined using quantitative real-time reverse transcription polymerase chain reaction assay. Methylation status of HCC cell lines and clinical samples were analyzed to investigate the regulatory mechanism of TUSC1 transcription and the relationship between the methylation status of the TUSC1 gene and clinicopathological factors. The expression and distribution of the TUSC1 protein in liver tissues were determined using immunohistochemistry. A majority of HCC cell lines (89%) and surgical specimens (84%) demonstrated reduced expression levels of TUSC1 mRNA compared with paired non-cancerous liver tissues. The mean mRNA expression level in HCC was significantly lower than in corresponding non-cancerous liver. In contrast, no significant difference was found in TUSC1 mRNA expression level between adjacent normal and cirrhotic liver tissue from HCC patients. The TUSC1 protein expression pattern in HCC and liver tissues was consistent with TUSC1 mRNA expression. Twenty-nine (31%) of 94 patients showed intragenic hypermethylation of the TUSC1 gene in HCC, and hypermethylation was significantly associated with advanced pathological stage. Subsequently, patients with hypermethylation of the TUSC1 gene had a significantly poorer prognosis than patients without hypermethylation. Our results suggest that TUSC1 is a candidate tumor suppressor gene and intragenic hypermethylation is one of the suppressive mechanisms that regulate TUSC1 transcription in HCC. Intragenic methylation of the TUSC1 gene may serve as a novel prognostic marker of HCC.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and its prognosis is poor. Novel targets for treating recurrence and progression along with associated biomarkers are urgently required. In this study, the expression and regulatory mechanism of DENN/MADD domain containing 2D (DENND2D) were investigated in an attempt to identify a tumor suppressor gene for HCC regulated by silencing through promoter hypermethylation. The levels of DENND2D expression in HCC cell lines and surgical specimens were determined using a quantitative polymerase chain reaction assay and the relationship between the expression levels of DENND2D mRNA and clinicopathological factors was evaluated. The expression and distribution of DENND2D were determined using immunohistochemistry. DNA methylation analysis was performed to determine the regulatory mechanisms of DENND2D expression in HCC. Most HCC cell lines (89%) and surgical specimens (78%) expressed lower levels of DENND2D mRNA compared with normal liver tissue. In contrast, there was no significant difference in the expression levels of DENND2D mRNA between normal tissues of HCC patients with and without cirrhosis. The expression patterns of DENND2D protein and mRNA were consistent. Patients with significantly lower levels of DENND2D mRNA in HCC tissues had remarkably earlier recurrences after hepatectomy and their prognosis worsened. The DENND2D promoter was methylated in eight out of nine HCC cell lines and DNA demethylation reactivated DENND2D mRNA expression. Hypermethylation of DENND2D was frequently detected in HCC tissues (75%) and was significantly associated with downregulation of DENND2D mRNA expression. DENND2D is a candidate tumor suppressor gene that is inactivated by promoter hypermethylation in patients with HCC and may serve as a novel biomarker of early recurrence of HCC.

Background and Objectives: Though Melanoma-associated antigen (MAGE) family genes have received lots of attention as cancer-related genes and targets for immunotherapy, MAGE-D4 expression in hepatocellular carcinoma (HCC) has not yet been evaluated., Methods: MAGE-D4 mRNA expression was assayed in nine HCC cell lines and 94 HCC surgical specimens obtained from Japanese patients by quantitative real-time reverse transcription polymerase chain reaction, and the correlations between MAGE-D4 mRNA expression and clinicopathological factors were evaluated. The expression and distribution of MAGE-D4b protein were evaluated immunohistochemically., Results: MAGE-D4 mRNA was overexpressed in five of nine HCC cell lines and 34 of 94 primary HCCs (36.2%). Median overall survival (14.8 vs. 118 months, P < 0.001) and relapse-free survival (2.7 vs. 18.3 months, P < 0.001) were significantly shorter in patients with high than with low-moderate MAGE-D4 expression. Multivariate analysis for overall survival showed that MAGE-D4 overexpression was independently prognostic for survival (hazard ratio 2.88, P = 0.009) and significantly associated with high alpha-fetoprotein concentration (P < 0.001), poor tumor differentiation (P = 0.003) and vascular invasion (P = 0.021). MAGE-D4b protein expression patterns were consistent with those of MAGE-D4 mRNA., Conclusions: Overexpression of MAGE-D4 may be a predictive marker of early recurrence and mortality in patients with HCC., (© 2013 Wiley Periodicals, Inc.)

A 70-year-old woman was referred to our hospital because of abdominal pain. Abdominal computed tomography(CT)and colonoscopy revealed transverse colon cancer with multiple liver metastases, with involvement of the hepatic pedicle and superior mesenteric artery lymph nodes. The patient received eight courses of XELOX plus bevacizumab, and CT showed a decrease in the size of the liver metastases and hepatic pedicle lymphadenopathy. Right hemicolectomy, partial hepatectomy, and hepatic pedicle lymph node resection were performed. Histopathological examination of the resected tissue revealed no residual cancer cells, suggesting a pathological complete response. The patient remains well 7 months after operation, without any signs of recurrence. Surgical resection should be considered for patients with initially unresectable colon cancer with liver metastases and hepatic pedicle lymph nodes involvement if systemic chemotherapy is effective.

Unlabelled: Most colorectal cancer patients with liver metastases are not resectable upon initial diagnosis. Recently, chemotherapy improves overall survival of initially unresectable patients by allowing tumor downstaging and complete resection. We report a FOLFOX-refractory rectal cancer patient with unresectable multiple liver metastases, whose tumors could be downstaged and completely resected after initiation of FOLFIRI with cetuximab., Case: A 41-year-old male demonstrated rectal cancer with unresectable multiple liver metastases. He was treated by FOLFOX4 therapy as first-line chemotherapy. After initiating 14 courses, he was treated by FOLFIRI with cetuximab because of disease progression. After initiation of chemotherapy, radiographic examination demonstrated remarkable reduction of primary rectal tumor and metastatic liver tumors. He underwent complete rectal tumor resection after 13 courses of chemotherapy, and metastatic liver tumor resection after 18 courses of chemotherapy.

A 12-year-old boy was referred to our hospital suffering from severe anemia and liver dysfunction. The laboratory data on admission confirmed severe anemia and an elevated alpha-fetoprotein level. Abdominal ultrasonography revealed a mass measuring 51 x 49 mm in size, and abdominal computed tomography showed a low-density mass in S8 of Couinaud's segment and a low-density area in S7, thus suggesting bleeding in the tumor. Right subphrenic fluid collection and perirectal fluid collection were also observed. Celiac arteriography showed a faint tumor stain fed by A5-8 but no evidence of any extravasation. A diagnosis of pediatric liver carcinoma was made, and the case was classified as T2 C3 V0 N0 M0 Stage IIIA. Although there was no evidence of bleeding during angiography, because of the high risk of rebleeding, a laparotomy was performed before chemotherapy. At operation, the tumor rupture site and hematoma appeared to be in S7, and a right lobectomy was thus performed. Ascitic fluid cytology was class V. The cut surface of the resected specimen showed a tumor measuring 51 x 49 mm located in S8 and a hematoma located in S7. Histologically, the tumor was a well-differentiated hepatoblastoma. The patient was transferred to the pediatric department and treated with six courses of intravenous chemotherapy followed by peripheral blood stem cell transplantation. The outcome has been favorable, with no recurrence as of 25 months after the operation.

Although in recent years hepatic resection has become a safe procedure, there are few data on repeat liver resection for hepatic metastases from gastrointestinal stromal tumor. A 60-year-old Japanese man underwent partial gastrectomy and extended right hepatectomy for gastrointestinal stromal tumor of the stomach with liver metastasis. However, liver metastasis recurred at the interval of less than 1 year. Therefore, the patient underwent a total of six liver resections. The liver resections comprised four R0, one R1 and one R2 resection. To our knowledge, six times for liver resection performed on one patient is a maximum. This patient survived 43 months after the first surgery. Despite frequent recurrence of hepatic metastasis from gastrointestinal stromal tumor, repeated hepatectomy provides a survival benefit if complete removal of all tumorous masses appears possible.

Hepatocellular carcinoma is a refractory cancer for the following two reasons: the tumor characteristics, including formation of tumor thrombus in the portal vein, metastasis within the liver and multicentricity of growth; and liver function disturbance due to cirrhotic change by B- or C-type viral infection. The most desirable treatment is hepatic resection, the only method producing a disease-free condition. However, there are not many cases that meet the indications for hepatic resection, since they have advanced lesions and/or liver dysfunction. If one cannot perform a hepatic resection, other suitable therapies should be selected, including transcatheter arterial embolization, percutaneous ethanol injection therapy, ligation of hepatic artery, irradiation, chemotherapy from hepatic artery via reservoir and so on. Combined therapy may sometimes be necessary for satisfactory efficacy. For long-term survival it is very important to do a close follow-up study over a long period. This encourages us to detect new lesions earlier and then perform suitable therapy again. Notifying patients of the disease and obtaining informed consent are needed for this long-term follow-up and treatment. When patients were examined who had first undergone hepatic resection and then hepatic re-resection for recurrence, we found that their survival rate was not different from that in the non-recurrent cases. This result indicates that overcoming refractory hepatocellular carcinoma requires a multidisciplinary treatment in which hepatic resection is the main means.

Background: Although intrahepatic recurrence after hepatic resection for hepatocellular carcinoma is the most significant cause of death, very few reports are available for hepatic re-resection as a radical treatment for recurrence., Methods: Eighteen patients who underwent repeated hepatic resections for hepatocellular carcinoma were evaluated. Most of the patients regularly received measurement of alpha-fetoprotein level once a month and examination by ultrasonography and/or computed tomography scanning once every 3 to 4 months., Results: No operative deaths occurred. The alpha-fetoprotein levels of 9 of the 18 patients were within the normal range. Most patients underwent limited hepatic resection to maintain the remaining hepatic function. The 1-, 3-, and 5-year cumulative survival rates after repeated resection were 88%, 37%, and 37%, respectively. The 3-, 5-, and 7-year survival rates after the first resection were 88%, 68%, and 45%, respectively. These showed no significant difference from the survival rates of patients with no recurrences after hepatic resection., Conclusions: Careful follow-up examinations after hepatic resection are needed for early detection of recurrences, and efforts should be made for repeated hepatic resection, which leads to satisfactory outcome.

One hundred and eighteen patients underwent hepatic resection for hepatocellular carcinoma from 1979 to 1987. Ninety-eight of these patients had co-existing cirrhosis of the liver; 18 patients underwent lobectomy, 28 patients had segmentectomy, and 52 patients had subsegmentectomy. In the 21 non-cirrhotic patients, 11 patients underwent lobectomy, 5 patients had segmentectomy, and 5 patients had subsegmentectomy. The operative mortality rate of patients with cirrhosis was 11% and of patients without cirrhosis was 5%. There was no significant difference in hepatic function tests between survivors and nonsurvivors. Lobectomy of < 55% of the parenchymal hepatic resection rate was well tolerated in the patients with cirrhosis. One-year, 3-year, and 5-year survival rates of patients with hepatocellular carcinoma and co-existing cirrhosis were 57.9%, 36.8% and 20.0% following lobectomy, 82.8%, 82.8% and 57.6% following segmentectomy, and 72.0%, 46.2% and 24.0% following subsegmentectomy. The tumor recurrence rate appeared to be lower after segmentectomy than subsegmentectomy. Multiple gross lesions, tumors > 5 cm, and presence of gross vascular invasion were poor prognostic signs in terms of survival rates as well as recurrence rates. Of the 51 patients with tumor recurrence limited to the residual liver, 13 patients underwent repeat resection, and 23 patients were treated by transcatheter arterial chemoembolization. The survival rates of the patients undergoing repeat resection were significantly better than those of other groups.

Unlabelled: UFT is a preparation consisting of tegafur and uracil at the molar ratio 1 : 4. In 22 resected patients with hepatocellular carcinoma (HCC), the concentrations of 5-fluorouracil (5-FU), tegafur and uracil were estimated in the serum, liver and cancer tissues after oral administration of UFT (tegafur, 300mg) before operation. The concentrations of 5-FU, tegafur and uracil in the serum were highest at 2 hours, and reduced thereafter. The maximum 5-FU level was 0.040 +/- 0.034 microgram/ml. The concentrations of 5-FU in the cancer tissue were 0.101 +/- 0.070 microgram/g in all patients, 0.085 +/- 0.050 microgram/g in cirrhotic patients and 0.144 +/- 0.105 microgram/g in non-cirrhotic patients. These concentrations were significantly higher than those in the liver tissue. In 10 out of 13 patients, 5-FU concentrations was higher than 0.056 microgram/g which was reported as minimum effective concentration., Conclusion: the concentration of 5-FU after oral administration of UFT prior to resection of HCC was estimated in the serum, liver and cancer tissues. The concentration of 5-FU in cancer tissues was satisfactorily higher regardless of cirrhotic or non-cirrhotic conditions UFT seemed to be a safe and useful drug since tissue 5-FU concentration was higher than those in the serum and liver.

Before proceeding with a resection of a hepatocellular carcinoma (HCC) in patients, the concentrations of 5-FU and 1-Hexylcarbamoyl-5-fluorouracil (HCFU) have been measured in the serum, the liver, and in the cancer tissue after an oral administration of HCFU (300 mg). The maximum 5-FU value was found to be 3.45 +/- 3.21 micrograms/ml (n = 22) at 2 hours, and this value decreased linearly. The concentrations of 5-FU in the liver tissues were 0.02 +/- 0.01 micrograms/g (n = 16) and the concentrations of 5-FU in cancer tissues were 0.03 +/- 0.01 micrograms/g (n = 16). There were no statistical differences found between cirrhotic patients and non-cirrhotic patients. These results indicate that the concentrations of HCFU in the serum and tissues were not influenced by liver damage.