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Brian I Carr

Publications and source records attributed to Brian I Carr.

At least 19 recordsLinked to original sources
PubMed2006

Health-related quality of life: Hepatocellular carcinoma, chronic liver disease, and the general population.

Health related quality of life (HRQL) has become an important endpoint in testing the efficacy of treatments for chronic liver disease (CLD) and the consequences of CLD which include hepatocellular carcinoma (HCC) and liver failure. However, a paucity of research on HRQL has been conducted with these patient populations. The aims of the present study were to compare persons diagnosed with HCC to persons diagnosed with CLD as well as with the general population (GP) on a disease-specific instrument measuring HRQL. If significant and clinically meaningful differences in HRQL exist, HRQL may be used as a corroborative indicator of disease progression in patients with CLD. Two hundred and seventy-two people participated in the present study. Of these participants, 83 were diagnosed with HCC, 51 with CLD, and 138 were from the GP. None of the patients in the HCC or CLD samples were actively receiving chemotherapeutic treatments for the CLD or HCC. A sociodemographic questionnaire and the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) was administered to participants. The results of the study suggested that people diagnosed with HCC, prior to treatment, had a poorer overall HRQL when compared to those persons with CLD and the general population, as expected. The differences in HRQL were statistically significant as well as clinically meaningful. People diagnosed with CLD and HCC respectively, reported better social and family well-being than the general population. Furthermore, people with CLD reported equivalent emotional well-being as the general population sample. HRQL subscale scores, with the exception of social and family well-being, discriminated group membership.

Adolescent↗
PubMed2006

H32, a non-quinone sulfone analog of vitamin K3, inhibits human hepatoma cell growth by inhibiting Cdc25 and activating ERK.

We previously synthesized a K-vitamin derivative, Cpd 5, which was a potent growth inhibitor of human tumor cells, including Hep3B hepatoma cells. However, being a quinone compound, Cpd 5 has the potential for generating toxic reactive oxygen species (ROS). We therefore synthesized a nonquinone sulfone derivative, H32, which has a sufone group substituting the quinone. The IC50 of H32 for Hep3B cells was found to be 2.5 microM, which was 2.5 and 3.2 times more potent than Cpd 5 and vitamin K3 respectively. It induced apoptosis in Hep3B cells but did not generate ROS when compared to Cpd 5. Interestingly, under similar culture conditions, normal rat hepatocytes were 14-fold more and 7-fold more resistant to the growth inhibitory effects of H32 than Hep3B and PLC/PRF5 cells respectively. H32 preferentially inhibited the activities of the cell cycle controlling Cdc25A phosphatase likely by binding to its catalytic cysteine. As a consequence, it induced inhibitory tyrosine phosphorylation of the Cdc25 substrate kinases Cdk2 and Cdk4 in Hep3B cells and the cells undergo an arrest in the G1 phase of the cell cycle. H32 also induced persistent phosphorylation of the MAPK protein ERK1/2, but marginal JNK1/2 and p38 phosphorylation. The ERK inhibitor U0126, added at least 30 min prior to H32, antagonized the growth inhibition induced by H32. However, the JNK and p38 inhibitors, JNKI-II and SB203580, were not able to antagonize H32 induced growth inhibition. Thus, H32 differentially inhibited growth of normal and liver tumor cells by preferentially inhibiting the actions of Cdc25 phosphatases and inducing persistent ERK phosphorylation.

Animals↗
PubMed2006

Fluorinated Cpd 5, a pure arylating K-vitamin derivative, inhibits human hepatoma cell growth by inhibiting Cdc25 and activating MAPK.

We previously synthesized several K-vitamin derivatives, which are potent growth inhibitors of human tumor cells, including Hep3B human hepatoma cells. Among these, Cpd 5 was the most potent. However, being a quinone derivative, Cpd 5 has the potential for generating toxic reactive oxygen species (ROS). We therefore synthesized a fluorinated derivative of Cpd 5, F-Cpd 5. The calculated reduction potential of F-Cpd 5 was much higher than that for Cpd 5 and it was not predicted to generate ROS. This was supported by our observation that F-Cpd 5 generated significantly lower ROS than Cpd 5. F-Cpd 5 was three times more potent than Cpd 5 in inhibiting Hep3B cell growth. Interestingly, under identical culture conditions, F-Cpd 5 inhibited mitogen-induced DNA synthesis in normal rat hepatocytes 12-fold less potently than Hep3B cells. F-Cpd 5 was found to induce caspase-3 cleavage and nuclear DNA laddering, evidences for apoptosis. It preferentially inhibited the activities of the cell cycle controlling phosphatases Cdc25A and Cdc25B, by binding to their catalytic cysteines. Consequently, inhibitory tyrosine phosphorylation of the Cdc25 substrate kinases Cdk2 and Cdk4 were induced. F-Cpd 5 also induced phosphorylation of the MAPK proteins ERK1/2, JNK1/2 and p38 in Hep3B cells and the MAPK inhibitors (U0126, JNKI-II, and SB 203580) antagonized its growth inhibition. F-Cpd 5 inhibited the action of cytosolic ERK phosphatase activity, which likely caused the ERK phosphorylation. F-Cpd 5 thus differentially inhibited growth of normal and tumor cells by preferentially inhibiting the actions of Cdc25A and Cdc25B phosphatases and inducing MAPK phosphorylation.

Animals↗
PubMed2006

Antitumor activity of JS-K [O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] and related O2-aryl diazeniumdiolates in vitro and in vivo.

The literature provides evidence that metabolic nitric oxide (NO) release mediates the cytotoxic activities (against human leukemia and prostate cancer xenografts in mice) of JS-K, a compound of structure R(2)N-N(O)=NO-Ar for which R(2)N is 4-(ethoxycarbonyl)piperazin-1-yl and Ar is 2,4-dinitrophenyl. Here we present comparative data on the potencies of JS-K and 41 other O(2)-arylated diazeniumdiolates as inhibitors of HL-60 human leukemia cell proliferation, as well as in the NCI 51-cell-line screen for six of them. The data show JS-K to be the most potent of the 42 in both screens and suggest that other features of its structure and metabolism besides NO release may contribute importantly to its activity. Results with control compounds implicate JS-K's arylating ability, and the surprisingly low IC(50) value of the N-(ethoxycarbonyl)piperazine byproduct of NO release suggests a role for the R(2)N moiety. In addition to the above-mentioned in vivo activities, JS-K is shown here to be carcinostatic in a rat liver cancer model.

Animals↗
PubMed2006

Phosphorylation regulates Myc expression via prolonged activation of the mitogen-activated protein kinase pathway.

We previously showed that prolonged and strong ERK phosphorylation induced by Compound 5 (Cpd 5), a Cdc25A protein phosphatase inhibitor, was involved in its mechanism of cell growth inhibition. To study the relationship between ERK phosphorylation and cell growth inhibition, we used Cpd 5 as a tool to investigate ERK-regulated c-Myc expression in Hep3B hepatoma cells. We found that ERK phosphorylation caused by Cpd 5 induced c-Myc phosphorylation, but suppressed c-Myc expression at the mRNA and protein levels. Furthermore, Cpd 5 inhibited c-Myc transcriptional activity and DNA binding ability, and this inhibition was antagonized by ERK kinase (MEK) inhibitor U-0126, implying that the ERK pathway was involved in regulating c-Myc expression. Since the participation of c-Myc protein in transcription requires its dimerization with Max protein, we examined the Myc-Max association in Cpd 5-treated cells and found that Cpd 5 suppressed Myc-Max dimerization. Transfection of Hep3B cells with mutated ERK (T188A/Y190F), which has lost its dual-phosphorylation sites, attenuated the actions of Cpd 5 on Myc-Max association. To further demonstrate whether Myc phosphorylation by Cpd 5-induced ERK activation was able to directly regulate c-myc gene expression, a chromatin immunoprecipitation (ChIP) assay was used to examine the binding of phospho-Myc to the c-myc promoter region. We found that phospho-Myc induced by Cpd 5 had lost its ability to bind to the c-myc promoter, whereas MEK inhibitor U-0126 antagonized this inhibitory effect. These data suggest that an increase in c-Myc phosphorylation in response to prolonged ERK phosphorylation negatively auto-regulates c-Myc gene expression, leading to the suppression of its target gene expression and cell cycle block.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed2006

Outcome of 1000 liver cancer patients evaluated at the UPMC Liver Cancer Center.

We evaluated 1000 consecutive patients with liver tumors at the University of Pittsburgh Medical Center (UPMC) Liver Cancer Center over the 4-year period from August 2000 to August 2004. Of the 1000 patients seen, 573 had primary liver cancer and 427 had metastatic cancer to the liver. The mean age of the patients evaluated was 62.2 years, and 61% were male. Treatment consisted of a liver surgical procedure (resection or radiofrequency ablation) in 369 cases (36.9%), hepatic intra-arterial regional therapy (transarterial chemoembolization or (90)yttrium microspheres) in 524 cases (52.4%), systemic chemotherapy in 35 cases (3.5%), and palliative care in 72 patients (7.2%). For treated patients, median survival was 884 days for those undergoing resection/radiofrequency ablation, compared to 295 days with regional therapy. These data indicate that over 90% of patients with liver cancer evaluated at a tertiary referral center can be offered some form of therapy. Survival rates are superior with a liver resection or ablation procedure, which is likely consistent with selection bias. Hepatocellular carcinoma was the most common tumor seen due to referral pattern and screening of hepatitis patients at a major liver transplant center. The most common reason for offering palliative care was hepatic insufficiency usually associated with cirrhosis.

Age Factors↗
PubMed2006

PM-20, a novel inhibitor of Cdc25A, induces extracellular signal-regulated kinase 1/2 phosphorylation and inhibits hepatocellular carcinoma growth in vitro and in vivo.

We have synthesized several new phenyl maleimide compounds, which are potent growth inhibitors of several human tumor cell lines. Among these, PM-20 was the most potent with an IC50 of 700 nmol/L for Hep3B human hepatoma cell growth. Two other derivatives, PM-26 and PM-38, did not inhibit Hep3B cell growth even at 100 micromol/L. Interestingly, under identical experimental conditions, PM-20 inhibited DNA synthesis of primary cultures of normal hepatocytes at a 10-fold higher concentration than that needed to inhibit the DNA synthesis of the Hep3B hepatoma cells. PM-20 affected two cellular signaling pathways in Hep3B cells: Cdc25 phosphatase and extracellular signal-regulated kinase (ERK) 1/2. It competitively inhibited the activity of Cdc25 (preferentially Cdc25A) by binding to the active site, likely through the catalytic cysteine, but did not inhibit PTP1B, CD45, or MKP-1 phosphatases. As a result of its action, tyrosine phosphorylation of the cellular Cdc25A substrates Cdk2 and Cdk4 was induced. It also induced strong and persistent phosphorylation of the Cdc25A substrate ERK1/2. Hep3B cell lysates were found to contain ERK2 phosphatase(s) activity, which was inhibited by the actions of PM-20. However, activity of exogenous dual-specificity ERK2 phosphatase MKP1 was not inhibited. Induction of ERK1/2 phosphorylation correlated with the potency of growth inhibition in tumor cell lines and inhibition of ERK1/2 phosphorylation by the mitogen-activated protein kinase (MAPK)/ERK kinase 1/2 inhibitor U0126 or overexpression of the cdc25A gene in Hep3B cells antagonized the growth inhibitory actions of PM-20. Growth of transplantable rat hepatoma cells in vivo was also inhibited by PM-20 action with a concomitant induction of pERK in the tumors. The mechanism(s) of growth inhibition of Hep3B hepatoma cells by the phenyl maleimide PM-20 involves prolonged ERK1/2 phosphorylation, likely resulting from inhibition of the ERK phosphatase Cdc25A. PM-20 thus represents a novel class of tumor growth inhibitor that inhibits mainly Cdc25A, is dependent on ERK activation, and has a considerable margin of selectivity for tumor cells compared with normal cells.

Animals↗
PubMed2005

Sexual functioning in patients with hepatocellular carcinoma.

BACKGROUND: The objectives of the current study were to assess the rates of sexual dysfunction in patients with hepatocellular carcinoma (HCC) and compare the rates of sexual morbidity with a sample of patients diagnosed with chronic liver disease (CLD) and the general population. It was expected that patients diagnosed with HCC would have a greater prevalence of sexual dysfunction than those diagnosed with CLD and the general population, respectively. Furthermore, those patients who reported a sexual dysfunction would also have a poorer quality of life (QOL). METHODS: Twenty-one men diagnosed with HCC and 23 men diagnosed with CLD completed a battery of questionnaires that included the Sexual History Questionnaire and the Functional Assessment of Cancer Therapy-Hepatobiliary. RESULTS: Results indicated that 41% of patients reported a current sexual problem (29% of HCC patients and 71% of patients with CLD) and 43% met the Diagnostic and Statistical Manual of Mental Disorders-4th edition (DSM-IV) criteria for at least 1 type of sexual dysfunction (25% of patients with HCC and 75% of patients with LD). Of the total sample, 68% reported being diagnosed with a comorbid medical condition or taking a medication that had potential sexual side effects. After eliminating cases with comorbid medical conditions and/or who were taking medications that contributed to sexual morbidity, the rate of sexual problems were found to be similar to that of the general population. Clinically significant differences were found with regard to the QOL. People who were experiencing sexual problems also reported a poorer QOL. CONCLUSIONS: Although a large percentage of sexual dysfunction may have been secondary to comorbid medical problems and medications, treatment of the sexual dysfunction is still warranted.

Carcinoma, Hepatocellular↗
PubMed2005

90Y microsphere treatment of unresectable liver metastases: changes in 18F-FDG uptake and tumour size on PET/CT.

PURPOSE: The intra-arterial administration of 90Y microspheres is a new palliative treatment option for unresectable liver metastases. The aim of this study was to quantitatively assess changes in FDG uptake and tumour size following 90Y microsphere treatment (SIR-Spheres) using 18F-fluorodeoxyglucose (FDG) PET/CT imaging. METHODS: Five patients with unresectable liver metastases who had failed multiple prior chemotherapy regimens received seven 90Y microsphere treatments to a single liver lobe. All patients underwent a baseline PET/CT scan prior to treatment, as well as up to four follow-up PET/CT scans. The tumour area of 30 liver metastases was measured on CT and the FDG uptake was semiquantitatively assessed by calculation of standardised uptake values (SUVs). A total of 18 FDG-PET/CT scans were performed. RESULTS: The SUVs in the 30 treated liver metastases decreased from 6.5+/-2.3 at baseline to 4.2+/-1.8 after the first follow-up PET/CT scan (p=0.001). In contrast, the SUVs of untreated metastases increased slightly from 7.2+/-2.3 to 8.0+/-0.8. There was no difference in FDG uptake in treated versus untreated normal liver tissue. Using a previously defined threshold of 20% decrease in SUV from baseline to determine response, 20 out of 30 liver metastases were considered to have responded at the first follow-up PET/CT scan approximately 1 month after treatment. In these metastases, the SUV decreased by 47+/-12%, compared with a slight increase by 5.9+/-19% in ten non-responding metastases (p=0.0001). The changes in tumour size did not correlate with changes in FDG uptake. On the first follow-up PET/CT scan, the tumour area on CT increased by 3.1+/-57% in treated metastases compared with 23.3+/-32% in untreated metastases. A wide range of post-treatment changes of target lesions was observed on CT, including an increase in the size of hypodense lesions, necrotic features and complete resolution of CT abnormalities. CONCLUSION: The metabolic information obtained from FDG-PET/CT seems to provide a more accurate and earlier assessment of therapy response following 90Y microsphere treatment than does the anatomical CT information.

Adult↗
PubMed2005

Hepatocyte growth factor enhances protein phosphatase Cdc25A inhibitor compound 5-induced hepatoma cell growth inhibition via Akt-mediated MAPK pathway.

We have previously shown that Compound 5 (Cpd 5), an inhibitor of protein phosphatase Cdc25A, inhibits Hep3B human hepatoma cell growth. We now show that hepatocyte growth factor (HGF), a hepatocyte growth stimulant, can strongly enhance Cpd 5-induced growth inhibition in Hep3B cells, and this enhancement in cell growth inhibition is correlated with a much stronger ERK phosphorylation when compared to cells treated with Cpd 5 or HGF separately. We found that HGF/Cpd 5-induced ERK phosphorylation and cell growth inhibition were mediated by Akt (protein kinase B) pathway, since combination HGF/Cpd 5 treatment of Hep3B cells inhibited Akt phosphorylation at Ser-473 and its kinase activity, which led to the suppression of Raf-1 phosphorylation at Ser-259. The suppression of Raf-1 Ser-259 phosphorylation caused the induction of Raf-1 kinase activity, as well as hyper-ERK phosphorylation. Transient transfection of Hep3B cells with dominant negative Akt c-DNA further enhanced both Cpd 5- and HGF/Cpd 5-induced ERK phosphorylation, while over-expression of wild-type Akt c-DNA diminished their effects. In contrast, HGF antagonized the growth inhibitory actions of Cpd 5 on normal rat hepatocytes, thus showing a selective effect on tumor cells compared to normal cells. Our data suggest that Akt kinase negatively regulates MAPK activity at the Akt-Raf level. Suppression of Akt activity by either combination HGF/Cpd 5 treatment or by dominant negative Akt c-DNA transfection antagonizes the Akt inhibitory effect on Raf-1, resulting in an enhancement of Cpd 5-induced MAPK activation and cell growth inhibition.

Animals↗
PubMed2005

Cdc25A and ERK interaction: EGFR-independent ERK activation by a protein phosphatase Cdc25A inhibitor, compound 5.

Extracellular signal-regulated kinase (ERK) plays a central role in regulating cell growth, differentiation, and apoptosis. We previously found that 2-(2-mercaptoethanol)-3-methyl-1,4-napthoquinone or Compound 5 (Cpd 5), is a Cdc25A protein phosphatase inhibitor and causes prolonged, strong ERK phosphorylation which is triggered by epidermal growth factor receptor (EGFR) activation. We now report that Cpd 5 can directly cause ERK phosphorylation by inhibiting Cdc25A activity independently of the EGFR pathway. We found that Cdc25A physically interacted with and de-phosphorylated phospho-ERK both in vitro and in cell culture. Inhibition of Cdc25A activity by Cpd 5 resulted in ERK hyper-phosphorylation. Transfection of Hep3B human hepatoma cells with inactive Cdc25A mutant enhanced Cpd 5 action on ERK phosphorylation, whereas over-expression of Cdc25A attenuated this Cpd 5 action. Furthermore, endogenous Cdc25A knock-down by Cdc25A siRNA resulted in a constitutive-like ERK phosphorylation and Cpd 5 treatment further enhanced it. In EGFR-devoid NR6 fibroblasts and MEK (ERK kinase) mutated MCF7 cells, Cpd 5 treatment also resulted in ERK phosphorylation, providing support for the idea that Cpd 5 can directly act on ERK phosphorylation by inhibiting Cdc25A activity. These data suggest that phospho-ERK is likely another Cdc25A substrate, and Cpd 5-caused ERK phosphorylation is probably regulated by both EGFR-dependent and EGFR-independent pathways.

Cell Line, Tumor↗
PubMed2005

The effects of hepatic artery chemotherapy on viral hepatitis in patients with hepatocellular carcinoma.

Transcatheter arterial chemoembolization (TACE) or arterial Yttrium-90 (90Y) microspheres are used to treat unresectable hepatocellular carcinoma (HCC), but little is known about their effects on viral hepatitis. The aim of this study was to determine their effect on viral hepatitis in patients with HCC. We carried out a retrospective review of patients treated for HCC. Worsening of viral hepatitis was determined by serum chemistry and viral loads where available. Fifty-two patients treated with TACE were followed for a mean of 22.0 months. Thirty-nine patients (75%) had decreased/stable tumor. Two of the 39 (5%) patients with decreased/stable tumor burden had a sustained increase in bilirubin. None had a sustained ALT elevation or significant increase in viral load after TACE. Twenty-four patients treated with 90Y microspheres were followed for a mean of 12.0 months. Twenty-two of these had a decreased/stable tumor burden and no patient had a significant elevation of ALT. However, 7 of the 22 had a sustained bilirubin elevation. We conclude that neither TACE nor 90Y treatment was associated with worsening viral hepatitis in this group of HCC patients. The presence of chronic viral hepatitis with normal bilirubin should not exclude the use of these therapies in patients with unresectable HCC.

Adult↗
PubMed2005

Phase I trial of menadiol diphosphate (vitamin K3) in advanced malignancy.

Based on the activity of menadione (M) in the human tumor stem cell assay, we conducted a phase I trial of M in patients with advanced cancer. Forty patients (19 men, 21 women) were treated with 90 courses of M; 82 treatment courses are evaluable for toxicity. The median patient age, Karnofsky performance status, and number of prior chemotherapy regimens were 61 years (range 32-74 years), 80% (range 50-100%), and two, respectively. M was given by a short (1-5 h) intravenous infusion every 3 weeks, starting at 40 mg/m2 and escalating by modified Fibonacci scheme to 1360 mg/m2. Toxicity was graded according to the Southwest Oncology Group toxicity scale with defined hypersensitivity reaction (HSR) scales. No grade > or =2 hematologic toxicity was observed. Non-hematologic toxicity consisted of a HSR syndrome of paresthesiae of the extremities, facial flushing, burning of the eyes and mucous membranes, chest pain and dyspnea. HSR was defined as Grade I toxicity by the presence of facial numbness, flushing, and/or a tingling sensation or burning of the eyes and mucous membranes. Grade II toxicity was defined as the presence of the same above symptoms plus chest tightness, paresthesiae of extremities and/or dyspnea and chest pain. These toxicities were grade 1 in 3 of 4 patients at a dose of 840 mg/m2. At 1360 mg/m2, 2 of 13 patients suffered grade 1 HSR and 7 of 13 grade 2 HSR. No objective partial or complete responses were observed. Plasma menadione concentrations peaked at 1.9-7.4 microM during the infusion in 3 patients receiving 1360 mg/m2. Further phase 1 and 2 combination trials using longer infusion durations have resulted from this trial.

Adult↗
PubMed2005

Proxy ratings of health related quality of life in patients with hepatocellular carcinoma.

The present study prospectively assessed consistency of ratings of health-related quality of life between patients with hepatocellular carcinoma and two types of proxy raters, family caregivers and oncologist care providers. Patients and proxies completed the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) at baseline prior to treatment (82 patients plus proxies), at 3-months (32 patients plus proxies), and 6-months follow up (16 patients plus proxies) after diagnosis. Patient and proxy demographic data and patient medical data were also collected. At baseline, significant intra-class correlations (ICC) were found for patient--caregiver ratings of physical, social/family, and functional well-being, additional concerns (symptoms, side effects), and overall health related quality of life (HRQL); for patient--care provider ratings of physical well-being; and for caregiver--care provider ratings of physical and emotional well-being. At 3-months follow-up, the most significant number of ICCs were recorded across all three rater pairs. Significant consistencies were found for overall HRQL, and all subscale scores except for social and family well-being. The fewest significant ICCs were found at the 6-month follow-up, and were for patient--caregiver ratings of physical and functional well-being, and additional concerns; and for caregiver--care provider ratings on overall HRQL. These results suggest that family caregivers are adequate proxies of patient physical and functional well-being and additional concerns throughout the patient's illness, more so than oncologist care providers. Further research is warranted with larger samples.

Adult↗
PubMed2005

Vitamin K analog (compound 5) induces apoptosis in human hepatocellular carcinoma independent of the caspase pathway.

A systemic vitamin K analog, compound 5 (Cpd 5), possesses the ability to inhibit cell growth of tumor cells. Therefore, we investigated the effect of Cpd 5 in human hepatocellular carcinoma (HCC) cell lines and evaluated its role in apoptosis. Human HCC cell lines were cultured and treated with Cpd 5. Apoptosis was assessed using DAPI staining and Annexin-V membrane staining. The expression of caspases, XIAP and Bcl-xL was also investigated. Cpd 5 decreased cell viability in a dose-dependent manner in two HCC cells (HLE and SK-Hep1) containing mutant p53, but not in the HepG2 cell line, which contained wild-type p53. Cpd 5-treated HLE and SK-Hep1 cells showed typical apoptotic features, nuclear condensation and nuclear fragmentation upon DAPI staining. Positive membranous staining for Annexin-V was also seen in these cells. Both caspase-8 and caspase-3 activities were up-regulated slightly. Pro-caspase-8 protein levels decreased slightly in both cells. Although the expression of Bcl-xL was not influenced by Cpd 5, that of XIAP decreased in HLE cells. However, the pan-caspase inhibitor, zVAD, could not significantly prevent Cpd 5-induced apoptosis and Cpd 5 could not augment TRAIL-induced apoptosis. These results demonstrate that Cpd 5 induced apoptosis in human HCC cell lines, mainly independently of caspase activities. This may contribute to its highly potent cytotoxicity toward HCC cells.

Apoptosis↗
PubMed2005

Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: factors associated with liver toxicities.

PURPOSE: Intraarterial injection of yttrium 90 microspheres (TheraSpheres) is used in the treatment of hepatocellular carcinoma (HCC). This article presents an analysis of the incidence of liver toxicities (liver-related events) and pretreatment factors associated with liver toxicities after TheraSphere treatment. PATIENTS AND METHODS: Eighty-eight TheraSphere-treated patients with low 90-day mortality risk were selected for analysis, with liver toxicities coded with use of standard oncology criteria. Descriptive and inferential statistical methods were applied to estimate the incidence of liver toxicities and to evaluate the influence of liver radiation dose and various pretreatment factors on the risk of their occurrence. RESULTS: Sixty-eight liver toxicities occurred in 37 of the 88 patients (42%). Thirty-two patients (36%) experienced 50 liver toxicities after the first treatment and nine of 23 patients (39%) who received a second treatment experienced 18 liver toxicities. Pretreatment total bilirubin and liver radiation dose were found to be associated with the risk of at least one liver toxicity and with the time to first occurrence of a liver toxicity after first treatment. Pretreatment total bilirubin also was associated with liver toxicities after the second treatment. Most of the toxicities resolved; however, those that did not resolve were attributed to tumor progression or advancing cirrhosis. CONCLUSIONS: The risk of liver toxicities in patients with unresectable HCC treated with TheraSpheres increases with increasing pretreatment total bilirubin level and liver radiation dose to a maximum of 150 Gy for a single administration. The toxicities attributed to treatment resolved over time, and none of the patients studied had confirmed radiation-induced liver disease. Consequently, doses as high as 150 Gy on a single administration and as high as 268 Gy on repeated administrations were well tolerated.

Aged↗
PubMed2005

Treatment of unresectable hepatocellular carcinoma with intrahepatic yttrium 90 microspheres: a risk-stratification analysis.

PURPOSE: To present the findings of a risk-stratification survival analysis with use of data collected on a heterogeneous group of patients with hepatocellular carcinoma (HCC) treated with TheraSphere. MATERIALS AND METHODS: Baseline, treatment, and follow-up data were collected and analyzed from 121 TheraSphere-treated patients. Survival analyses were performed to identify those variables most strongly associated with 3-month mortality. The presence of any of the identified risk variables resulted in the assignment of a patient to the high-risk category. RESULTS: Five liver reserve and two non-liver reserve variables were identified and used to stratify patients into low- or high-risk groups. Sixteen of the 33 patients assigned to the high-risk group (49%) did not survive the first 3 months after treatment, compared with six of the 88 patients assigned to the low-risk group (7%; Fisher exact test, P < .0001). Median survival for the low- and high-risk groups were 466 days and 108 days, respectively (hazard ratio, 6.0; P < .0001). Eleven of 12 patients who experienced a treatment-related major complication ending in death were included in the high-risk group. No single variable explained the major complication relationship to treatment. CONCLUSION: Patients with HCC who are being considered for treatment with TheraSpheres should be evaluated for the presence of the risk variables described herein. The absence of these variables is predictive of improved survival (median of 466 days) compared with patients at high risk (median of 108 days).

Aged↗