Endoscopic submucosal dissection in a patient with esophageal adenoid cystic carcinoma.

We report the first use of endoscopic submucosal dissection (ESD) for the treatment of a patient with adenoid cystic carcinoma of the esophagus (EACC). An 82-year-old woman visited our hospital for evaluation of an esophageal submucosal tumor. Endoscopic examination showed a submucosal tumor in the middle third of the esophagus. The lesion partially stained with Lugol's solution, and narrow band imaging with magnification showed intrapapillary capillary loops with mild dilatation and a divergence of caliber in the center of the lesion. Endoscopic ultrasound imaging revealed a solid 8 mm × 4.2 mm tumor, primarily involving the second and third layers of the esophagus. A preoperative biopsy was non-diagnostic. ESD was performed to resect the lesion, an 8 mm submucosal tumor. Immunohistologically, tumor cells differentiating into ductal epithelium and myoepithelium were observed, and the tissue type was adenoid cystic carcinoma. There was no evidence of esophageal wall, vertical stump or horizontal margin invasion with pT1b-SM2 staining (1800 µm from the muscularis mucosa). Further studies are needed to assess the use of ESD for the treatment of patients with EACC.

Liver injury after aluminum potassium sulfate and tannic acid treatment of hemorrhoids.

We are reporting a rare case of acute liver injury that developed after an internal hemorrhoid treatment with the aluminum potassium sulfate and tannic acid (ALTA) regimen. A 41-year-old man developed a fever and liver injury after undergoing internal hemorrhoid treatment with a submucosal injection of ALTA with lidocaine. The acute liver injury was classified clinically as hepatocellular and pathologically as cholestastic. We could not classify the mechanism of injury. High eosinophil and immunoglobulin E levels characterized the injury, and a drug lymphocyte stimulation test was negative on postoperative day 25. Fluid replacement for two weeks after hospitalization improved the liver injury. ALTA therapy involves injecting chemicals into the submucosa, from the rectum to the anus, and this is the first description of a case that developed a severe liver disorder after this treatment; hence, an analysis of future cases as they accumulate is desirable.

A case of adenosquamous cell carcinoma of the gallbladder with markedly elevated PTHrP and G-CSF levels.

A 76-year-old woman was referred to our hospital with anorexia. Computed tomography revealed a tumor lesion measuring 110mm in the liver at S4/5 with calcification and swelling of a paraaortic lymph node. The gallbladder was not visualized. Histological examination of a biopsy specimen from the liver tumor revealed squamous cell and undifferentiated carcinomas, and several tumor markers were elevated. Therefore, we diagnosed the patient with gallbladder adenosquamous cell carcinoma T3N2M0 stage III. Because the serum parathyroid hormone-related protein (PTHrP) and granulocyte-colony stimulating factor (G-CSF) levels were significantly elevated, we suspected that PTHrP and G-CSF production occurred because of adenosquamous cell carcinoma in the gallbladder. We initiated chemotherapy with S-1.

Clinical characteristics and survival outcomes of super-elderly hepatocellular carcinoma patients not indicated for surgical resection.

AIM: Considering the dramatic increase in average life expectancy during the 20th century throughout the world, the management of elderly patients with cancer has become a global issue. We herein investigated the clinical characteristics and outcomes of super-elderly hepatocellular carcinoma (HCC) patients over 80 years old not indicated for surgical resection. METHODS: We retrospectively evaluated 206 newly diagnosed HCC patients. The patients were divided into two groups according to their age at inclusion; a super-elderly group (n = 37, ≥80 years) and a younger group (n = 169, <80 years). We compared the clinical characteristics, overall survival (OS) and disease-specific survival (DSS) rates among the two groups. Both univariate and multivariate analyses were performed to identify the factors associated with the OS and DSS. RESULTS: The proportion of women was higher in the super-elderly group than in the younger group (P = 0.017). There were no significant differences in the OS (P = 0.171) or DSS (P = 0.176) between the two groups. The multivariate analysis revealed that only the Cancer Liver Italian Program score (hazard ratio [HR], 2.972; P < 0.0001; HR, 3.694; P < 0.0001) was independently associated with the OS and DSS. Age was not found to be associated with the OS or DSS according to either the univariate or multivariate analysis. CONCLUSION: There were no significant differences in the OS and DSS rates among the super-elderly HCC patients and younger HCC patients not indicated for surgical resection. An advanced age itself does not restrict the therapeutic approach, even in super-elderly HCC patients not indicated for surgical resection.

Staging systems for hepatocellular carcinoma: Current status and future perspectives.

Hepatocellular carcinoma (HCC) is a major health concern worldwide and the third cause of cancer-related death. Despite advances in treatment as well as careful surveillance programs, the mortality rates in most countries are very high. In contrast to other cancers, the prognosis and treatment of HCC depend on the tumor burden in addition to patient's underlying liver disease and liver functional reserve. Moreover, there is considerable geographic and institutional variation in both risk factors attributable to the underlying liver diseases and the management of HCC. Therefore, although many staging and/or scoring systems have been proposed, there is currently no globally accepted system for HCC due to the extreme heterogeneity of the disease. The aim of this review is to focus on currently available staging systems as well as those newly reported in the literatures since 2012. Moreover, we describe problems with currently available staging systems and attempts to modify and/or add variables to existing staging systems.

The C-reactive protein/albumin ratio, a novel inflammation-based prognostic score, predicts outcomes in patients with hepatocellular carcinoma.

BACKGROUND: The C-reactive protein/albumin (CRP/Alb) ratio is associated with outcomes in septic patients. We investigated the prognostic value of the CRP/Alb ratio in patients with hepatocellular carcinoma (HCC). METHODS: We retrospectively evaluated 186 newly diagnosed HCC patients and investigated the correlations among the pretreatment CRP/Alb ratio, clinicopathological parameters, and overall survival (OS). Multivariate analyses were performed to identify the clinicopathological parameters associated with OS. Subsequently, we evaluated the prognostic value of the CRP/Alb ratio compared with other inflammation-based prognostic scores [Glasgow Prognostic Score (GPS), modified GPS (mGPS), and neutrophil lymphocyte ratio (NLR)] using the area under the curve (AUC). RESULTS: The optimal cutoff level for the CRP/Alb ratio was 0.037. An elevated CRP/Alb ratio (≥0.037) was associated with tumor progression and reduced liver functional reserve. In the multivariate analysis, the CRP/Alb ratio [hazard ratio (HR) 3.394; p < 0.0001], Cancer Liver Italian Program score (HR 2.686; 95% CI 2.122-3.401; p < 0.0001), and vascular invasion (HR 3.376; 95% CI 1.594-7.151; p = 0.001) were independently associated with OS (HR 3.394; p < 0.0001). The CRP/Alb ratio had higher AUC values at 6 months (0.844), 12 months (0.863), and 24 months (0.82) compared with the GPS, mGPS, and NLR. CONCLUSION: The CRP/Alb ratio might be an independent prognostic marker in patients with HCC, and may have comparable prognostic ability to other established inflammation-based prognostic scores. The prognostic value of this novel inflammation-based prognostic score needs to be verified in patients with other types of cancer.

The addition of C-reactive protein to validated staging systems improves their prognostic ability in patients with hepatocellular carcinoma.

OBJECTIVES: C-reactive protein (CRP) is a practical prognostic marker in patients with hepatocellular carcinoma (HCC). We investigated the prognostic value of adding the CRP level to other validated staging systems (Cancer Liver Italian Program, Japan Integrated Staging, Barcelona Clinic Liver Cancer classification system, Tokyo score and tumor node metastasis classification) in HCC patients. METHODS: One hundred and eighty-six newly diagnosed HCC patients were retrospectively evaluated. A multivariate analysis identified the clinicopathological variables associated with overall survival; the variables identified were then added to each staging system and compared to those without the additional variable. RESULTS: In multivariate analysis, an elevated serum CRP level was independently associated with a poor prognosis (hazard ratio 3.792, p < 0.0001). The addition of the CRP level to each of the established staging systems provided a higher linear χ(2) value and a lower -2 log likelihood than those without the addition of the term. Moreover, the area under the receiver-operating characteristic curve (AUC) analysis showed that the addition of CRP improved the AUC of each staging system. CONCLUSIONS: This study demonstrates that an elevated serum CRP level is independently associated with a poor prognosis in HCC patients, and the addition of the CRP level to the validated staging systems could improve the prognostic ability of each staging system.

The Glasgow Prognostic Score accurately predicts survival in patients with biliary tract cancer not indicated for surgical resection.

The Glasgow Prognostic Score (GPS) and neutrophil to lymphocyte ratio (NLR) are associated with the survival in patients with various types of malignancy. The aim of this study was to investigate the prognostic value of the GPS and NLR in patients with biliary tract cancer (BTC) undergoing palliative chemotherapy or best supportive care (BSC). Fifty-two patients with newly diagnosed BTC were retrospectively evaluated. We investigated the correlation between the GPS, NLR, and the overall survival rates. The area under the receiver operating characteristics curve (AUC) was calculated to compare the predictive ability of each score. Both the univariate and multivariate analyses were performed to identify clinicopathological variables associated with the overall survival. There were significant differences between the GPS groups regarding the neutrophil levels (p < 0.0001), Hb (p = 0.024), Alb (p < 0.0001) and CRP (p < 0.0001). A significant difference in the overall survival was found between the groups stratified based on the GPS, NLR (p < 0.001). The GPS had a higher AUC value (0.905) in comparison to the NLR (0.648). In the multivariate analysis, the sex (p = 0.002), CA19-9 (p < 0.0001) and the GPS (p < 0.0001) were found to be independently associated with the overall survival. Our results demonstrate that the GPS is an independent marker of the prognosis in patients with BTC undergoing palliative chemotherapy or BSC, and is superior to the NLR in terms of its prognostic ability.

Elevated plasma fibrinogen levels are associated with a poor prognosis in patients with hepatocellular carcinoma.

OBJECTIVES: Elevated plasma fibrinogen levels are associated with tumor progression and poor outcomes in cancer patients. We investigated the prognostic value of pretreatment plasma fibrinogen levels in patients with hepatocellular carcinoma (HCC). METHODS: One hundred and thirteen patients with newly diagnosed HCC were retrospectively evaluated. We investigated the correlation between pretreatment plasma fibrinogen levels, clinicopathological parameters and overall survival. Both univariate and multivariate analyses were performed to identify the clinicopathological parameters associated with overall survival. RESULTS: The median value of the pretreatment plasma fibrinogen level was 279 mg/dl. Elevated plasma fibrinogen levels were associated with larger tumor size, the presence of vascular invasion and higher Cancer Liver Italian Program scores. Lower plasma fibrinogen levels were associated with higher Child-Pugh grades. The overall survival rates in patients with pretreatment plasma fibrinogen levels ≥ 315 mg/dl were significantly lower than those with a pretreatment plasma fibrinogen level <315 mg/dl (p = 0.016). On multivariate analysis, the plasma fibrinogen levels (per 100 mg/dl) were found to be independently associated with overall survival (hazard ratio 1.236; p = 0.046). CONCLUSIONS: This study demonstrates that elevated pretreatment plasma fibrinogen levels are associated with tumor progression and are independently associated with a poor prognosis in patients with HCC.

Genetic polymorphisms of enzymes related to oral tegafur/uracil therapeutic efficacy in patients with hepatocellular carcinoma.

Oral tegafur/uracil therapy has been indicated for patients with hepatocellular carcinoma (HCC) and is often used as a single-agent treatment. However, how the treatment efficacy is related to 5-fluorouracil (5-FU) metabolic enzymes is unclear. We investigated genetic polymorphisms of the 5-FU metabolic enzymes in Japanese patients with HCC. We examined two genetic polymorphisms of the metabolic enzymes cytochrome P450 2A6 (CYP2A6) and dihydropyrimidine dehydrogenase (DPD) in 58 Japanese hepatitis C virus-seropositive HCC patients. To measure efficacy, we investigated genetic polymorphisms of the variable number of tandem repeats (VNTRs) of thymidylate synthase (TS) and classified the genotypes as high or low expression types. The frequency of the CYP2A6*4 allele (no-activity allele) among 58 HCC patients was 0.233 and a homozygous genotype (*4/*4) was found in five patients. The heterozygous genotype (T/C) of DPYD*9 (T85C) was detected in eight patients and the frequency of the DPYD*9 allele among 58 HCC patients was 0.069. Of 58 patients, 42 were classified as high expression type and 16 as low expression type for TS VNTR. Fifteen of these 16 patients appeared to have normal CYP2A6 metabolic activity and 13 of these 15 patients likely had normal DPD metabolic activity. Only 13 of 58 HCC patients (22.4%) tested may respond positively to treatment with oral tegafur/uracil. Therefore, when administering oral 5-FU in patients with HCC, it is important to consider three genetic polymorphisms (CYP2A6, DPYD, and TS) associated with 5-FU metabolic enzymes.

The Glasgow Prognostic Score, an inflammation based prognostic score, predicts survival in patients with hepatocellular carcinoma.

BACKGROUND: Elevated Glasgow Prognostic Score (GPS) has been related to poor prognosis in patients with hepatocellular carcinoma (HCC) undergoing surgical resection or receiving sorafenib. The aim of this study was to investigate the prognostic value of GPS in patients with various stages of the disease and with different liver functional status. METHODS: One hundred and fifty patients with newly diagnosed HCC were prospectively evaluated. Patients were divided according to their GPS scores. Univariate and multivariate analyses were performed to identify clinicopathological variables associated with overall survival; the identified variables were then compared with those of other validated staging systems. RESULTS: Elevated GPS were associated with increased asparate aminotransferase (P<0.0001), total bilirubin (P<0.0001), decreased albumin (P<0.0001), α-fetoprotein (P=0.008), larger tumor diameter (P=0.003), tumor number (P=0.041), vascular invasion (P=0.0002), extra hepatic metastasis (P=0.02), higher Child-Pugh scores (P<0.0001), and higher Cancer Liver Italian Program scores (P<0.0001). On multivariate analysis, the elevated GPS was independently associated with worse overall survival. CONCLUSIONS: Our results demonstrate that the GPS can serve as an independent marker of poor prognosis in patients with HCC in various stages of disease and different liver functional status.

Pretreatment serum C-reactive protein level predicts poor prognosis in patients with hepatocellular carcinoma.

C-reactive protein (CRP) is known to be associated with poor prognosis in patients with various malignancies. We investigated the relationship between the pretreatment serum CRP level and survival in patients with hepatocellular carcinoma (HCC) in various stages of the disease. A cohort of 133 patients with newly diagnosed HCC was prospectively evaluated. The patients were divided into two groups: high-CRP group (n=27) with the pretreatment serum CRP level≧1.0 mg/dl and low-CRP group (n=106) with the CRP level<1.0 mg/dl. They were followed 22 months in average (1-69 months) and clinicopathological variables, and overall survivals between the two groups were compared at the end of the follow-up period. There was a significant difference between the two groups in aspartate aminotransferase, alanine aminotransferase, total serum bilirubin, albumin, α-fetoprotein level, maximal tumor diameter, frequency of vascular invasion and extrahepatic metastases. Patients in the high-CRP group had higher Child-Pugh scores, higher Cancer of the Liver Italian Program scores and higher Japan Integrated Staging scores than patients in the low-CRP group. The overall survival rates in the high-CRP group were significantly lower than those in the low-CRP group. Survival rates were similar in tumor stage and liver function-matched patients. On multivariate analysis, pretreatment serum CRP level was independently associated with overall survival. Our results demonstrate that the pretreatment serum CRP level is associated with tumor progression and reduced liver function and is an independent poor prognostic marker in patients with HCC.

Useful detection of CD147 (EMMPRIN) for pathological diagnosis of early hepatocellular carcinoma in needle biopsy samples.

AIM: To make clear whether CD147 (EMMPRIN) expression in pathological tumor samples with a fine-needle aspiration biopsy is useful for pathological diagnosis of early hepatocellular carcinoma (HCC). METHODS: Twenty-two patients (15 men and 7 women; median age 68 years, range 56-81 years) underwent a liver tissue biopsy in order to make a diagnosis of HCC. Paraffin-embedded liver biopsy tissue samples from 22 patients were stained with anti-CD147 antibody, murine monoclonal antibody 12C3 (MAb12C3) for immunohistochemical analysis. An immunohistochemical analysis of CD147 was performed and the degree of staining compared between tumor and non-tumor tissue. In addition, the degree of staining within tumor tissue was compared according to a number of clinicopathological variables. RESULTS: The degree of staining of CD147 was significantly higher in tumor tissues than non-tumor tissues, even in tumors less than 15 mm in diameter. The expression of this protein was significantly elevated in HCC tissue specimens from patients with a low value of serum AST and gamma-GTP. CONCLUSION: CD147 serves potentially as a pathological target for cancer detection of early HCC.