BACKGROUNDThe prognosis of hepatocellular carcinoma (HCC) invading into the major branches of the portal vein (Vp3) is extremely poor.METHODSEleven consecutive patients with HCC and Vp3 were treated with 2–6 cycles of a “basic” combination therapy consisting of continuous arterial infusion of 5‐fluorouracil (450–500 mg/day, for the initial 2 weeks) and subcutaneous injection of interferon‐α (5 million international units, 3 times/week, 4 weeks). In the first 3 patients, methotrexate (90 mg/day 1 of every week), cisplatin (10 mg/day), and leucovorin (30 mg/days 2 and 3 of every week) also were administered for the initial 2 weeks (“full” regimen).RESULTSIn 8 (73%) of 11 patients, an objective response (complete response [CR] or partial response [PR]) was observed with marked regression of tumor and decrease in tumor markers. The use of the full regimen was associated with objective response in all patients; instead, they developed thrombocytopenia or leukopenia. In the subsequent 8 patients with basic regimen, 5 patients showed CR (2 cases) or PR (3 cases; objective response rate, 63%), and leukopenia was observed only in 1 patient.CONCLUSIONSSimple combination therapy with subcutaneous interferon‐α and intraarterial 5‐fluorouracil therefore is a promising treatment modality for intractable HCC with Vp3. Cancer 2002;94:435–42. © 2002 American Cancer Society.
We previously reported the beneficial effects of combination therapy of interferon (IFN)-a/5-fluorouracil (FU) for advanced hepatocellular carcinoma (HCC) with tumour thrombi in the major portal branches. This report describes the results of longer follow-up and includes more than double the number of patients relative to the original report, and evaluates the role of IFN-a/type 2 interferon receptor (IFNAR2) expression on the response to the combination therapy. The study subjects were 55 patients with advanced HCC and tumour thrombi in the major branches of the portal vein (Vp3 or 4). They were treated with at least two courses of IFN-a/5-FU without major complication. In the 55 patients, 24 (43.6%) showed objective response (eight (14.5%) showed complete response, 16 (29.1%) partial response), four (7.3%) showed no response, and 27 (49.1%) showed progressive disease. Immunohistochemically, IFNAR2 expression was detected in nine out of 13 (69.2%) patients. There was significant difference in the time-to-progression survival (P ¼ 0.0002) and the overall survival (Po0.0001) between IFNAR2-positive and -negative cases. There was a significant correlation between IFNAR2 expression and response to IFN-a/5-FU combination therapy in univariate analysis (P ¼ 0.0070). IFN-a/5-FU combination therapy is a promising modality for advanced HCC with tumour thrombi in the major portal branches and could significantly depend on IFNAR2 expression.
Pancreatic cancer is the most lethal of all solid tumors partially because of its chemoresistance. Although gemcitabine is widely used as a first selected agent for the treatment of this disease despite low response rate, molecular mechanisms of gemcitabine resistance in pancreatic cancer still remain obscure. The aim of this study is to elucidate the mechanisms of gemcitabine resistance. The 81-fold gemcitabine resistant variant MiaPaCa2-RG was selected from pancreatic cancer cell line MiaPaCa2. By microarray analysis between MiaPaCa2 and MiaPaCa2-RG, 43 genes (0.04%) were altered expression of more than 2-fold. The most upregulated gene in MiaPaCa2-RG was ribonucleotide reductase M1 subunit (RRM1) with 4.5-fold up-regulation. Transfection with RRM1-specific RNAi suppressed more than 90% of RRM1 mRNA and protein expression. After RRM1-specific RNAi transfection, gemcitabine chemoresistance of MiaPaCa2-RG was reduced to the same level of MiaPaCa2. The 18 recurrent pancreatic cancer patients treated by gemcitabine were divided into 2 groups by RRM1 levels. There was a significant association between gemcitabine response and RRM1 expression (p 5 0.018). Patients with high RRM1 levels had poor survival after gemcitabine treatment than those with low RRM1 levels (p 5 0.016). RRM1 should be a key molecule in gemcitabine resistance in human pancreatic cancer through both in vitro and clinical models. RRM1 may have the potential as predictor and modulator of gemcitabine treatment. ' 2006 Wiley-Liss, Inc.Key words: gemcitabine; pancreatic cancer; drug resistance; RRM1; microarray Pancreatic cancer remains one of the most malignant cancers. Although surgery is the only curative treatment currently available, over 80% of patients have advanced regional disease or distant metastasis at the time of diagnosis and less than 20% of the patients are candidates for resection.1 Therefore, chemotherapy, radiation or a combination of these therapies most commonly plays an important role in pancreatic cancer treatment. They have not had a significant impact on survival rates in recent decades, however, despite many clinical trials.
Purpose: Akt is a serine/threonine kinase that plays a central role in tumorigenesis. Among the members of Akt family, Akt2 is associated with the development of human cancers. The present study was designed to clarify the prognostic significance of Akt2 and activated Akt expression in pancreatic ductal adenocarcinoma (PDAC). In addition, activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) and the proliferation activity of tumor cells detected by Ki-67 immunohistochemistry were examined.Experimental Design: Immunohistochemical analysis was performed on paraffin-embedded specimens from 65 patients with PDAC; 36 males and 29 females with ages ranging from 48 to 79 years (median, 66 years) of age. Expression levels of Akt2, phosphorylated Akt (p-Akt), and phosphorylated ERK 1/2 (p-ERK 1/2) were categorized as either weaker (low intensity) or equal to stronger (high intensity) compared with those in the endothelial cells of the same specimens. For Ki-67 immunohistochemistry, cases were divided into two groups: level 1, Ki-67 labeling index (LI), <20%; level 2, Ki-67 LI, >20%.Results: Twenty-six (42.6%), 28 (45.9%), 39 (63.9%), and 46 (75.4%) of the tumors showed high intensity of Akt2, p-Akt, and p-ERK 1/2 expression, and Ki-67 LI level 2, respectively. A significant positive correlation was observed between Akt2 and p-Akt expression (P < 0.01). Multivariate analysis revealed that p-Akt expression, Ki-67 LI, and histological differentiation are independent prognosticators for PDAC.Conclusions: p-Akt expression is a significant prognostic indicator for PDAC. Inhibition of Akt is a possible molecular approach for treatment of PDAC.
Surgical margin, ie, the area of possible local intrahepatic metastasis, is controversial in hepatectomy for hepatocellular carcinoma. Design: The blood drainage area of tumor was identified preoperatively by abdominal helical computed tomographic scan under hepatic arteriography and excised as surgical margin. The specimens were pathologically examined on the basis of the corresponding computed tomographic images. Setting: University hospital.
Expression of cell-cycle modulators at the G 1 -S boundary, retinoblastoma gene product (pRb), p21, p16, p27, p53, cyclin D 1 , and cyclin E was investigated with 104 hepatocellular carcinomas (HCC), as well as 90 of their adjacent noncancerous lesions and 9 normal liver control specimens. The labeling indices (LI) of pRb, p21, p16, and p27 were higher in HCC lesions than in the adjacent noncancerous lesions and normal controls. Especially, p27 LI in noncancerous lesions was significantly higher than that in normal livers (P ؍ .011). Aberrant p53 expression and cyclin D 1 and E overexpression were observed exclusively in HCC lesions. pRb was positive in 85.6% of the HCC cases and was not related to any clinicopathological parameters. The p21 LI was generally low (average, 5.5 ؎ 9.8). Although a negative regulator, p21 LI was higher in cases with intrahepatic metastasis (P ؍ .0359). The p16 LI was significantly decreased (P ؍ .0121) in cases with advanced stage. p27 LI was significantly decreased in cases with portal invasion (P ؍ .0409), poor differentiation (P F .0001), larger size (P ؍ .0421), and intrahepatic metastasis (P ؍ .0878, borderline significance). On the other hand, aberrant p53 expression showed positive relationships with poor differentiation (P ؍ .0004) and Ki-67 LI (P ؍ .0047). Cyclin D 1 overexpression was found in 32.6% of the cases and occurred more frequently in those with high Ki-67 LI (P ؍ .0032), pRb expression (P ؍ .0202), poor differentiation (P ؍ .0612, borderline significance), and intrahepatic metastasis (P ؍ .0675, borderline significance). Cyclin E was overexpressed in 35.5% and had positive relationships with Ki-67 LI (P ؍ .0269) and stage (P ؍ .0125). In univariate analysis, cases with p27 LI F 50 (P ؍ .0004), cyclin D 1 overexpression (P ؍ .0041), and cyclin E overexpression (P ؍ .0572, borderline significance) showed poorer outcomes for disease-free survival (DFS). In multivariate analysis, p27 expression could be recognized as an independent prognostic marker for DFS. These findings suggest that in HCC: 1) p27 is active against HCC progression in early phases and, possibly, hepatocarcinogenesis as a negative regulator and can be a novel prognostic marker for DFS; and 2) cyclin D 1 predominantly works for cell-cycle progression at the G 1 -S boundary. (HEPATOLOGY 1999;30:90-99.)
The identification of molecular markers, useful for therapeutic decisions in pancreatic cancer patients, is crucial for advances in disease management. Gemcitabine, although a cornerstone of current therapy, has limited efficacy. RRM1 is a key molecule for gemcitabine efficacy and is also involved in tumor progression. We determined in situ RRM1 and excision repair cross complementation group 1 (ERCC1) protein levels in 68 pancreatic cancer patients. All had R0 resections without preoperative therapy. Protein levels were determined by automated quantitative analysis (AQUA), a fluorescence-based immunohistochemical method. The relationship between protein expressions and clinical outcomes, including response to gemcitabine at the time of disease recurrence, was determined. Patients with high RRM1 showed significantly better overall survival than patients with low expression (P=0.0196). There was a trend toward better overall survival for patient with high ERCC1 (P=0.0552). When both markers were considered together, patients with both high RRM1 and ERCC1 faired the best in terms of overall and disease-free survival (P=0.0066, P=0.0127). In addition, treatment benefit from gemcitabine in patients with disease recurrence was observed only in patients with low RRM1. The combination of RRM1 and ERCC1 expression is prognostic in pancreatic cancer patients after a complete resection. On disease recurrence, only patients with low RRM1 derive benefit from gemcitabine.
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