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.

[A Case of Primary Cancer of the Pancreas and Colon Treated with the Combination of Gemcitabine and TS-1].

The patient was a 74-year-old man. A medical examination for diabetes revealed a hypovascular tumor in the pancreatic head. A heterogeneously enhanced tumor in the ascending colon with wall thickening was observed on enhanced CT of the abdomen. He was diagnosed with multiple primary cancers of the pancreas and colon. He received 12 courses of chemotherapy with gemcitabine (1,000 mg/m 2) and TS-1 (60 mg/m2). After 12 courses of chemotherapy, the size of the pancreatic tumor was slightly decreased and the size of the tumor in the colon was significantly decreased. The tumor marker level was also significantly decreased. The combination of gemcitabine and TS-1 is a promising treatment regimen for patients with primary cancer of the pancreas and colon.

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.

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.

C-Reactive Protein as a Prognostic Marker in Patients with Hepatocellular Carcinoma.

C-reactive protein (CRP) is an acute phase reactant synthesized by hepatocytes that is regulated by pro-inflammatory cytokines, particulary interleukin-6 (IL-6). Over the last decade, CRP has been reported to be associated with a poor prognosis in patients with various types of cancer. Although the mechanisms by which the systemic inflammatory response reflected by an elevated serum CRP level influences survival in patients with cancer have not been fully elucidated, several possibilities involving the activation of IL-6, thereby elevating the CRP level, in cancer patients have been proposed. With regard to hepatocellular carcinoma (HCC), since Hashimoto et al. first demonstrated that the preoperative serum CRP level is an independent and significant factor predictive of a poor prognosis in patients undergoing surgical resection, several investigators have identified an elevated serum CRP level to be an indicator of poor outcomes in HCC patients undergoing transplantation, transarterial chemoembolization, radiofrequency ablation, percutaneous ethanol injection and best supportive care. Recently, the CRP level has been reported to be clinically applicable as a marker of treatment outcomes in HCC patients. However, large-scale, prospective validation studies are needed to confirm these results.

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.

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.

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.

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.

[Case of lymphangioleiomyomatosis associated with protein-losing gastroenteropathy].

A 29-year-old woman was referred to our hospital for the intensive examination of leg edema and hypoproteinemia. CT scan of showed multiple thin-walled cysts in both lungs, suggesting lymphangioleiomyomatosis. CT scan of the abdomen, lymphoscintigraphy showed enlarged abdominal lymph nodes. Protein loss from the gastrointestinal tract was documented by measurement of the clearance of alpha-1 antitrypsin from the plasma using a 72 h stool collection and (99m)Tc human serum albumin scintigraphy. We thought that secondary lymphangiectasia with lymphangioleiomyomatosis caused protein-losing gastroenteropathy. Dietary therapy resulted in symptomatic improvement.

Clinical features and prognosis of elderly patients with hepatocellular carcinoma not indicated for surgical resection.

Hepatocellular carcinoma (HCC) is a major health problem worldwide. The average life expectancy during the 20th century has increased in many parts of the world, and therefore the opportunities to examine elderly HCC patients have significantly increased worldwide. Many elderly patients develop HCC with intermediate to advanced stages of disease at the initial diagnosis, and have more comorbidities and compromised liver regeneration compared with younger patients. These circumstances show that elderly patients with HCC are poorer candidates for surgical resection or transplantation. The aim of the present review was to focus on the clinical features and prognosis of elderly HCC patients not indicated for surgical resection including multimodal treatment. Although the chronological age of 60 or 65 years as the definition of an elderly person is accepted in most countries, many studies in our review article define elderly as those aged 75 years or older. Geriatr Gerontol Int 2017; 17: 189-201.

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.

[Role of immunological disorders in the pathophysiology of severe acute pancreatitis].

Severe acute pancreatitis is a disease associated with high mortality, causes of which are multiple organ failure(MOF) in the early course and the development of bacterial infections in the later course. Inflammatory response leading to organ failure continues to be one of the major problem after acute pancreatitis. This review summarizes recent studies that demonstrate the critical role played by inflammatory mediators in acute pancreatitis. Immunological disorder, immune suppression, also plays a role at high risk of sepsis in the development of severe acute pancreatitis. We have to clarify the mechanism of immunological suppression in the development of bacterial infections in severe acute pancreatitis. It is important that the elucidation of key mediators in MOF and the mechanism of immune suppression in the development of bacterial infection could be improved by the prognosis of severe acute pancreatitis.

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.

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.