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Nitric oxide (NO) is an essential signaling molecule in biological systems. Soluble guanylate cyclase (sGC), composing of α1 and β1 subunit, is the receptor for NO. Using radioimmunoassay, we discovered that activation of sGC by treatment with bradykinin or sodium nitroprusside (SNP) is impaired in MCF-7 and MDA-MB-231 breast cancer cells as compared to normal breast epithelial 184A1 cells. The 184A1 cells expressed both sGC α1 and sGCβ1 mRNAs. However, levels of sGCβ1 mRNAs were relatively lower in MCF-7 cells while both mRNA of sGC subunits were absent in MDA-MB-231 cells. Treatment with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) increased mRNA levels of both sGCα1 and sGCβ1 in MDA-MB-231 cells but only sGCβ1 mRNAs in MCF-7 cells. The 5-aza-dC treatment increased the SNP-induced cGMP production in MCF-7 and MDA-MB-231, but not in 184A1 cells. Bisulfite sequencing revealed that the promoter of sGCα1 in MDA-MB-231 cells and promoter of sGCβ1 in MCF-7 cells were methylated. Promoter hypermethylation of sGCα1 and sGCβ1 was found in 1 out of 10 breast cancer patients. Over-expression of both sGC subunits in MDA-MB-231 cells induced apoptosis and growth inhibition in vitro as well as reduced tumor incidence and tumor growth rate of MDA-MB-231 xenografts in nude mice. Elevation of sGC reduced protein abundance of Bcl-2, Bcl-xL, Cdc2, Cdc25A, Cyclin B1, Cyclin D1, Cdk6, c-Myc, and Skp2 while increased protein expression of p53. Our study demonstrated that down-regulation of sGC, partially due to promoter methylation, provides growth and survival advantage in human breast cancer cells.

Brain metastasis is a major complication of breast cancer. This study aimed to analyze the effect of age and biological subtype on the risk and timing of brain metastasis in breast cancer patients. We identified subtypes of invasive ductal carcinoma of the breast by determining estrogen receptor, progesterone receptor and HER2 status. Time to brain metastasis according to age and cancer subtype was analyzed by Cox proportional hazard analysis. Of the 2248 eligible patients, 164 (7.3%) developed brain metastasis over a median follow-up of 54.2 months. Age 35 or younger, HER2-enriched subtype, and triple-negative breast cancer were significant risk factors of brain metastasis. Among patients aged 35 or younger, the risk of brain metastasis was independent of biological subtype (P = 0.507). Among patients aged 36-59 or >60 years, those with triple-negative or HER2-enriched subtypes had consistently increased risk of brain metastasis, as compared with those with luminal A tumors. Patients with luminal B tumors had higher risk of brain metastasis than luminal A only in patients >60 years. Breast cancer subtypes are associated with differing risks of brain metastasis among different age groups. Patients age 35 or younger are particularly at risk of brain metastasis independent of biological subtype.

Background The Model for End-Stage Liver Disease (MELD) score is currently used as a disease severity index of cirrhotic patients awaiting liver transplantation. This study evaluated the usefulness of the MELD score in predicting mortality and morbidity of patients with hepatocellular carcinoma (HCC) undergoing hepatic resection. Methods The study cohort consisted of 1,017 patients who underwent hepatic resection for HCC between 1991 and 2005. Patient variables were examined by univariate and multivariate analyses to identify risk factors for morbidity and mortality. Accuracy in predicting mortality was assessed with the area under the receiver operator characteristic curve (AUC) analysis. Results The morbidity and mortality rates were 30.7% and 1.9%, respectively. Age, liver cirrhosis, operation time, and MELD score were risk factors for mortality, whereas indocyanine green retention rate at 15-min value, operation time, blood loss, and Child-Turcotte-Pugh score were risk factors for morbidity. Patients with MELD score >8 had higher mortality (4.0% vs. 0.6%, p  = 0.004) and higher liver-related morbidities (16.1% vs. 4.3%, p  < 0.001), including massive ascites, intra-abdominal hemorrhage, and hepatic failure, compared with patients with MELD score <6. High MELD score also was related to longer postoperative hospital stay (score >8, 14.5 days vs. score <6, 12.6 days, p  = 0.015). The AUC for MELD score as a predictor of mortality was 0.718, indicating high clinical usefulness. Conclusions The MELD score relates with mortality and liver-related morbidities in HCC patients who undergo hepatic resection. A MELD sore >8 represents the trigger for intensive treatment to improve patient outcome.

Hepatocellular carcinoma (HCC) is a hypervascular malignancy. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin (ANG) are important angiogenic factors of neoangiogenesis. This study investigated the predictive value of serum VEGF, bFGF, and ANG in tumor recurrence, disease-free survival (DFS), and overall survival (OS) in HCC patients. Preoperative serum VEGF, bFGF, and ANG were measured in 98 patients with resectable HCC and in 15 healthy controls. The median follow-up time was 43 months. Preoperative serum VEGF was increased in patients with resectable HCC compared with healthy controls (P <.05). Increased serum VEGF was correlated with tumor recurrence (P =.001). Univariate analysis showed that serum VEGF, tumor-node-metastasis stage, tumor size and number, macroscopic portal vein invasion, and microscopic vascular invasion were correlated with OS and DFS. Serum bFGF and ANG were not associated with survival. Multivariate analysis showed that serum VEGF was the most significant predictor of DFS (relative risk, 2.35; 95% confidence interval, 1.26-4.39; P =.007) and OS (relative risk, 3.44; 95% confidence interval, 1.81-6.57; P <.001) in HCC patients after surgical resection. Preoperative serum VEGF is a significant independent predictor of tumor recurrence, DFS, and OS in patients with resectable HCC.

Reducing blood loss during resection of hepatocellular carcinoma (HCC) in patients with impaired liver function is important. This study evaluated the effect and safety of inflow occlusion (hemihepatic vascular occlusion and the Pringle maneuver) in reducing blood loss during hepatectomy. A total of 120 HCC patients with impaired liver function (with a preoperative indocyanine green retention rate at 15 minutes > 10%) who underwent hepatectomy were included in this retrospective study. Patients were divided into three groups, no‐occlusion (n = 30), hemihepatic vascular occlusion (n = 49), and Pringle maneuver (n = 41). There was one hospital death in each group. Of all three groups, 50 patients (41.7%) had blood loss less than 1000 ml. The three groups were similar in terms of clinocopathological features. All patients underwent minor resection. Blood loss was significantly greater in the no‐occlusion group; there was no difference between the hemihepatic group and the Pringle group. Multivariate analysis revealed that risk factors related to blood loss included no inflow occlusion [odds ratios (ORs), 2.93; 95% confidence intervals (CIs) 1.13–7.59], tumor centrally located (ORs, 3.85; 95% CIs, 1.50–9.90), serum albumin level < 3.5 gm/dl (ORs, 5.15; 95% CIs, 1.20–22.07), and serum alanine aminotransferase >120 U/l (ORs, 3.58; 95% CIs, 1.19–10.80). For patients with occlusion time ≥ 45 minutes, postoperative serum total bilirubin and aspartate aminotransferase levels in the Pringle group were significantly higher than those in the hemihepatic and no‐occlusion groups (P < 0.05). In HCC patients with impaired liver function undergoing hepatectomy, both hemihepatic vascular occlusion and the Pringle maneuver are safe and effective in reducing blood loss. Patients subjected to hemihepatic vascular occlusion responded better than those subjected to the Pringle maneuver in terms of earlier recovery of postoperative liver function, especially when occlusion time was ≥ 45 minutes.

The postresectional tumor recurrence rate is high in patients with hepatocellular carcinoma (HCC). Tumor portal venous invasion is the most important factor related to recurrence. Adjuvant intraportal infusion chemotherapy (IPIC) was used in HCC patients to improve the outcomes. Between June 1998 and May 1999, 28 HCC patients (IPIC group) underwent postresectional IPIC daily for 2 days with 5-fluorouracil (650 mg/m(2)), leucovorin (45 mg/m(2)), doxorubicin (10 mg/m(2)), and cisplatin (20 mg/m(2)). Treatment was repeated every 3 weeks for six cycles. Patient outcomes were compared with those of 66 matched HCC patients (control group) who underwent hepatectomy without adjuvant therapy. The IPIC group received an average of 5.2 cycles of chemotherapy, starting 5 to 24 days after surgery. The most frequent IPIC-related adverse events were upper abdominal pain, vomiting, and myelosuppression. Five-year disease-free and overall survival rates for the IPIC group were 44.6% and 60.7%, respectively. Subgroup analysis of patients with tumor-node-metastasis stage I and II disease identified significantly lower recurrence rates for the IPIC group (33.3%) than the control group (65.0%; P = .025). For patients with stage I and II disease, 5-year disease-free and overall survival rates for the IPIC group (70.6% and 83.3%, respectively) were significantly higher than those of the control group (33.4% and 46.9%, respectively; P < .05). Patients with stage III disease do not benefit from IPIC. Postoperative IPIC benefits HCC patients with tumor-node-metastasis stage I and II disease. The survival advantages demonstrated justify a selection of patients for future trials.

We analyzed the changes in mitochondrial DNA (mtDNA) copy numbers and the shifting of mtDNA D310 sequence variations (D310 mutation) with their relationships to pathological status and the expression levels of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER-2/neu), tumor-suppressor protein p53 and cellular proliferation protein Ki-67 in breast invasive ductal carcinoma (BIDC), respectively. Fifty-one paraffin-embedded BIDCs and their paired non-cancerous breast tissues were dissected for DNA extraction. The mtDNA copy number and mtDNA D310 sequence variations were determined by quantitative real-time polymerase chain reaction (q-PCR) and PCR-based direct sequencing, respectively. The expression levels of ER, PR, HER-2/neu, p53 and Ki-67 were determined by immunohistochemical (IHC) staining. Compared to the paired non-cancerous breast tissues, 24 (47.1%) BIDCs had elevated mtDNA copy numbers and 29 (56.9%) harbored mtDNA D310 mutations. Advanced T-status (p=0.056), negative-ER (p=0.005), negative-PR (p=0.007), positive-p53 (p=0.050) and higher Ki-67 (p=0.004) expressions were related to a higher mtDNA copy ratio. In addition, advanced T-status (p=0.019) and negative-HER-2/neu expression (p=0.061) were associated with mtDNA D310 mutations. In conclusion, higher mtDNA copy ratio and D310 mutations may be relevant biomarkers correlated with pathological T-status and the expression levels of ER, PR, HER-2/neu, p53 and Ki-67 in BIDCs.

Hepatocellular carcinoma (HCC) is frequently associated with liver cirrhosis. Patients with HCCs undergoing surgical resection may have declining hepatic functional reserve over time. However, the incidence and risk factors of hepatic decompensation, and its relation to postoperative tumor recurrence are unknown. This study investigated 241 HCC patients (208 male; age 61 ± 13 years) undergoing resection with a long‐term follow‐up. The Child‐Pugh scoring system was used to evaluate the postoperative deterioration of liver reserve, defined as a sustained increment in the Child‐Pugh score by 2 or more. The 1‐, 3‐, and 5‐year cumulative probabilities of postoperative decompensation were 14%, 32%, and 56%, respectively, during a follow‐up period of 27 ± 18 months (range 3‐75 months). The average increment in Child‐Pugh score was 1.4 ± 1.1 in 2.3 ± 1.5 years, or 0.6 point per year. Altogether, 74 (31%) patients developed postoperative hepatic decompensation during the follow‐up period, 43 (58%) of whom had decompensation within 2 years of resection. Large (> 3 cm) tumor size was the only independent predictor associated with hepatic decompensation (relative risk 1.7, 95% confidence interval 1.1–2.8, p = 0.041) and was a significant risk factor for intrahepatic tumor recurrence (p = 0.018). Patients with tumor recurrence more frequently (40% of 109 patients vs. 23% of 132 patients, p = 0.005) and more rapidly (0.8 vs. 0.4 point per year) developed hepatic decompensation than those without recurrence. In conclusion, large HCCs are closely associated with hepatic decompensation in patients after resection. Tumor recurrence may predispose to the development of hepatic decompensation in these patients.

Hepatic resection for small hepatocellular carcinomas (HCCs) offers patients a chance of cure but is associated with a significant tumor recurrence rate. We characterized 145 resected small HCCs and defined patients who would most benefit from hepatic resection. A retrospective study was conducted of 485 HCC patients who had undergone curative resection. The clinical features and survival rates of patients with HCCs ≤ 3 cm (group 1, n = 145) were compared with those of patients with HCCs > 3 cm (group 2, n = 340). Compared with group 2 patients, group 1 had worse liver function, a higher frequency of hepatitis C infection, and a lower α‐fetoprotein level. The 1‐, 3‐, and 5‐year disease‐free survival rates of group 1 were better than those of group 2 (82%, 59%, and 42% vs. 56%, 39%, and 31%, respectively) (p < 0.001). From the sixth postoperative year onward, the proportions of disease‐free survivors were not significantly different between the two groups (32% vs. 31%). By multivariate analysis, factors influencing small‐HCC patients’ outcomes were tumor centrally located (p = 0.003), indocyanine green retention rate > 10% (p = 0.017), and albumin level < 3.7 g/dl (p = 0.004). A clinical risk scoring system incorporating these factors correlated closely with the patients’ outcomes and it may be used to select patients who would most benefit from hepatic resection.

. Recurrence of hepatocellular carcinoma (HCC) after curative hepatic resection is frequent and is an important factor adversely influencing long‐term survival. The role of postoperative chemotherapy in the reduction of tumor recurrence rate is still controversial. During the period of 1992–1995 a series of 49 patients who underwent curative resection of HCC and had at least one risk factor of tumor recurrence were followed in this prospective study. Patients were allocated to adjuvant chemotherapy and control groups. Twenty‐four patients received a combination of low dose intravenous epirubicin (20 mg/m2) and mitomycin (5 mg) monthly for seven courses starting 5 to 6 weeks after surgery. Twenty‐five patients had no adjuvant treatment. The disease‐free and overall survivals were compared for the two groups. A total of 154 courses of chemotherapy were given to the 24 patients. The chemotherapy‐related side effects were mild and tolerable with no mortality. At a median follow‐up of 39 months (range 9–71 months), 9 patients in the adjuvant chemotherapy group and 16 patients in the control group developed tumor recurrence. The respective 1‐, 2‐, 3‐, and 5‐year disease‐free survival rates were 75%, 67%, 63%, and 63% for patients in the adjuvant chemotherapy group and 68%, 42%, 37%, and 32% for patients in the control group (p= 0.0575). The 1‐, 2‐, 3‐, and 5‐year overall survival rates were 100%, 96%, 77%, and 72% in the adjuvant chemotherapy group and 92%, 67%, 63%, and 51% in the control group (p= 0.0746). In conclusion, postoperative adjuvant chemotherapy using the present regimen has a tendency to reduce tumor recurrence rate and may improve long‐term survival for high risk patients.