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PURPOSE - Transarterial chemoembolization regimens for hepatocellular carcinoma (HCC) vary, without a gold-standard method. The present study was performed to evaluate outcomes in patients with HCC treated with doxorubicin/ethiodized oil (DE), cisplatin/doxorubicin/mitomycin-c/ethiodized oil (CDM), or doxorubicin drug-eluting beads (DEBs).
MATERIALS AND METHODS - Patients received the same regimen at all visits, without crossover. Groups were compared based on Child-Pugh disease status, tumor/node/metastasis stage, and Barcelona Clinic Liver Cancer stage. Imaging outcomes were assessed based on modified Response Evaluation Criteria in Solid Tumors to calculate tumor response (ie, sum of complete and partial response), progressive disease (PD), and time to progression (TTP).
RESULTS - A total of 228 infusions were performed in 122 patients: 59 with DE, 30 with CDM, and 33 with DEBs. The groups had similar Child-Pugh status (P = .45), tumor/node/metastasis stages (P = .5), and Barcelona Clinic Liver Cancer scores (P = .22). Follow-up duration was similar among groups (P = .24). Patients treated with DE underwent significantly more treatments (2.3 ± 1.4) than those treated with CDM (1.6 ± 0.7; P = .004) or DEBs (1.4 ± 0.6; P<.0001). Compared with DE (51%), tumor response was significantly more common with CDM (84%; P = .003) or DEBs (82%; P = .004). PD was significantly more likely with DE (37%) than with CDM (13%; P = .02) or DEBs (9%; P = .004). TTP was similar between groups (P = .07). CDM and DEBs were similar in regard to disease progression (P = .6) and response (P = .83).
CONCLUSIONS - During a similar follow-up period, patients treated with CDM or DEB chemoembolization showed a significantly higher response rate and a lower incidence of tumor progression, with fewer required treatment sessions, than those treated with DE chemoembolization.
Copyright © 2013 SIR. Published by Elsevier Inc. All rights reserved.
PURPOSE - Perioperative intravesical chemotherapy following transurethral resection of bladder tumor has been underused despite level 1 evidence supporting its performance. The primary objective of this study was to estimate the economic and humanistic consequences associated with preventable recurrences in patients initially diagnosed with nonmuscle invasive bladder cancer.
MATERIALS AND METHODS - Using population based estimates of nonmuscle invasive bladder cancer incidence, a 2-year model was developed to estimate the number of preventable recurrences in eligible patients untreated with perioperative intravesical chemotherapy. Therapy utilization rates were obtained from a retrospective database analysis and a chart review study of 1,010 patients with nonmuscle invasive bladder cancer. Recurrence rates of nonmuscle invasive bladder cancer were obtained from a randomized clinical trial comparing transurethral resection of bladder tumor with or without perioperative mitomycin C. Costs were estimated using prevailing Medicare reimbursement rates. Quality adjusted life-year estimates and disutilities for complications were obtained from the literature.
RESULTS - The model estimated that 7,827 bladder recurrences could be avoided if all patients received immediate intravesical chemotherapy. It estimated an economic savings of $3,847 per avoidable recurrence, resulting in an aggregate savings of $30.1 million. The model also estimated that 1,025 quality adjusted life-years are lost every 2 years due to preventable recurrences, resulting in 0.13 quality adjusted life-years (48 quality adjusted days) lost per avoidable recurrence. This translates into 0.02 quality adjusted life-years (8.1 quality adjusted days) lost per patient not receiving immediate intravesical chemotherapy.
CONCLUSIONS - Greater use of immediate intravesical chemotherapy in the United States has the potential to substantially decrease the economic and humanistic burdens of nonmuscle invasive bladder cancer.
Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
OBJECTIVE - To identify clinical features associated with survival after hepatic arterial chemoembolization (HACE) for uveal melanoma metastasis.
METHODS - Retrospective case series including 11 men and 10 women with uveal melanoma metastasis.
RESULTS - The hepatic angiographic pattern of metastasis was infiltrative in 12 patients (57%) and nodular in 9 patients (43%). The infiltrative pattern was associated with ciliary body involvement by the primary tumor (Fisher exact test, P = .01) and extrascleral tumor extension (Fisher exact test, P = .01). Mean survival after the first HACE treatment was 7.6 months overall, 3.7 months for the patients with the infiltrative pattern, and 12.7 months for those with the nodular pattern. This difference was highly significant (Kaplan-Meier, P < .001). Chromosome 8p was found to be deleted in 4 patients with the infiltrative pattern and in no patients with the nodular pattern.
CONCLUSIONS - The hepatic metastasis pattern can be used to predict response to and survival after HACE. Loss of chromosome 8p may be a biomarker for the infiltrative metastasis pattern. Hepatic arterial chemoembolization may play an important role in the treatment of hepatic metastasis from uveal melanoma in patients with the nodular metastatic pattern. Regular screening for hepatic metastasis in patients with uveal melanoma may be beneficial in identifying those who would benefit from HACE.
PURPOSE - The optimal embolic agent for transhepatic arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) has not been identified. This study reports outcomes of TACE for HCC with Gelfoam powder and polyvinyl alcohol (PVA).
MATERIALS AND METHODS - Eighty-one patients underwent 152 TACE sessions with Gelfoam powder (n = 41) or polyvinyl alcohol (PVA) and Ethiodol (n = 40) as the embolic agent. Chemotherapeutic drugs were the same for all patients (50 mg cisplatin, 20 mg doxorubicin, 10 mg mitomycin-c). The groups were compared based on number of TACE sessions, maximum tumor size, bilirubin level, aspartate and alanine aminotransferase levels, Child-Pugh score, Model for End-stage Liver Disease score, and hepatitis B or C virus positivity. The number of cases of each Child class in each group was also evaluated. Survival starting from the first TACE session was calculated according to Kaplan-Meier analysis. Forty-eight patients died during the study period, 19 received transplants, and 14 were alive at the end of the study period.
RESULTS - The groups were statistically similar in all categories regarding liver function, Child-Pugh score, tumor size, hepatitis status, and percentage of patients with Child class A, B, and C disease. The number of TACE sessions was significantly greater for the Gelfoam powder group (mean, 2.2) versus the PVA group (mean, 1.6; P = .01). Overall survival was similar between groups whether patients who received transplants were included in the analysis (mean, 659 days +/- 83 with Gelfoam powder vs 565 days +/- 71 with PVA; P = .42) or were excluded (mean, 519 days +/- 80 with Gelfoam powder vs 511 days +/- 75 with PVA; P = .93).
CONCLUSION - In similar patient groups, survival after treatment of HCC with TACE with Gelfoam powder or PVA and Ethiodol was similar.
PURPOSE - To compare the value of the Child-Pugh and Model for End-stage Liver Disease (MELD) scores to predict patient survival rates after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).
MATERIALS AND METHODS - Eighty-seven patients underwent 169 TACE sessions. Child-Pugh and MELD values were calculated before initial treatment. Survival length was tracked from the date of the first TACE procedure. Transplant recipients were censored from the study at the time of surgery. Child-Pugh and MELD scores as well as bilirubin and albumin levels and International Normalized Ratio were placed in high and low categories defined by their respective medians. Patient survival was compared at 3 months, 6 months, 12 months, and 24 months, and patterns were tested with chi2 or Fisher exact tests. Survival over the entire period was examined with Kaplan-Meier analysis and differences were tested with log-rank tests.
RESULTS - Mean and median survival times for all patients were 24 and 17 months, respectively. Sixteen patients were censored for transplantation at a mean of 12.9 months. MELD and Child-Pugh scores correlated well with each other (r = 0.68). Child-Pugh score (r = -0.35, P = .04) correlated more strongly with 12-month survival than did MELD score (r = -0.26, P = .12). After high/low score category division, a significantly greater survival difference was predicted by Child-Pugh score (27.2 months vs 10.3 months; P = .03) versus MELD score (27.5 months vs 15.8 months; P = .19). An albumin level greater than 3.4 g/dL was also associated with significantly improved survival (29.3 months vs 10.1 months; P = .0032). Survival differences between high-risk and low-risk groups at the 3-, 6-, 12-, and 24-month intervals were significant for low Child-Pugh scores and for albumin levels greater than 3.4 g/dL. Statistical significance was not approached at any of the time lengths with MELD scores.
CONCLUSIONS - Child-Pugh score correlates better than MELD score to overall patient survival and is a better predictor than MELD score of survival at specific time points. Of the components of the Child-Pugh and MELD systems, albumin level is the most useful predictor of survival.
Mutational studies of human DNA helicase B (HDHB) have suggested that its activity is critical for the G1/S transition of the cell cycle, but the nature of its role remains unknown. In this study, we show that during G1, ectopically expressed HDHB localizes in nuclear foci induced by DNA damaging agents and that this focal pattern requires active HDHB. During S and G2/M, HDHB localizes primarily in the cytoplasm. A carboxy-terminal domain from HDHB confers cell cycle-dependent localization, but not the focal pattern, to a reporter protein. A cluster of potential cyclin-dependent kinase phosphorylation sites in this domain was modified at the G1/S transition and maintained through G2/M of the cell cycle in vivo, coincident with nuclear export of HDHB. Serine 967 of HDHB was the major site phosphorylated in vivo and in vitro by cyclin-dependent kinases. Mutational analysis demonstrated that phosphorylation of serine 967 is crucial in regulating the subcellular localization of ectopically expressed HDHB. We propose that the helicase of HDHB operates primarily during G1 to process endogenous DNA damage before the G1/S transition, and it is largely sequestered in the cytoplasm during S/G2.
High risk strains of human papillomavirus (HPV), such as HPV 16, cause human cervical carcinoma. The E6 protein of HPV 16 mediates the rapid degradation of p53, although this is not the only function of E6 and cannot completely explain its transforming potential. Previous work in our laboratory has demonstrated that transfection of HPV 16 E6 into the tumor necrosis factor (TNF)-sensitive LM cell line protects expressing cells from TNF-induced apoptosis in a p53-independent manner, and the purpose of this study was to determine the molecular mechanism underlying this protection. Caspase 3 and caspase 8 activation were significantly reduced in E6-expressing cells, indicating that E6 acts early in the TNF apoptotic pathway. In fact, E6 binds directly to TNF R1, as shown both by co-immunoprecipitation and mammalian two-hybrid approaches. E6 requires the same C-terminal portion of TNF R1 for binding as does TNF R1-associated death domain, and TNF R1/TNF R1-associated death domain interactions are decreased in the presence of E6. HA-E6 also blocked cell death triggered by transfection of the death domain of TNF R1. Together, these results provide strong support for a model in which HPV E6 binding to TNF R1 interferes with formation of the death-inducing signaling complex and thus with transduction of proapoptotic signals. They also demonstrate that HPV, like several other viruses, has developed a method for evading the TNF-mediated host immune response.
The matrix metalloproteinase matrilysin (MMP-7) has been demonstrated to contribute to tumor development. We have shown previously that members of the TNF family of apoptosis-inducing proteins are substrates for this enzyme, resulting in increased death pathway signaling. The goal of the current study was to reconcile the proapoptotic and tumor-promoting functions of matrilysin. In the human HBL100 and murine NMuMG cell lines that represent early stages of tumor progression and that express both Fas ligand and its receptor, exposure to matrilysin results in cell death that can be blocked by FasL neutralizing antibodies. Constitutive expression of matrilysin in these cell lines selects for cells with reduced sensitivity to Fas-mediated apoptosis as demonstrated both with a receptor-activating antibody and with in vitro activated splenocytes. Matrilysin-expressing cells are also significantly less sensitive to chemical inducers of apoptosis. We propose that the expression of matrilysin that has been reported at early stages in various tumor types can act to select cells with a significantly decreased chance of removal due to immune surveillance. As a result, these cells are more likely to acquire additional genetic modifications and develop further as tumors.
OBJECTIVE - To evaluate the functional and histological effects of a single application of topical mitomycin-C after laser injury in the posterior canine glottis.
STUDY DESIGN - A prospective, randomized study of 16 canines.
METHODS - A supersaturated (1%) solution of topical mitomycin-C was applied to a unilateral, laser-induced injury near the cricoarytenoid joint in eight dogs. The mitomycin-soaked pledget was placed immediately after induction of the injury and was left in contact with exposed cartilage for 3 minutes. The opposite side was not injured to provide an internal control. In eight additional dogs, the same laser injury was allowed to heal untreated. After 6 weeks, the animals were sacrificed and their larynges harvested. Arytenoid adduction sutures were placed bilaterally, and the force required to bring the vocal folds to midline was measured for each side using tensiometry. Gross and microscopic histological analysis was performed. Statistical analysis was accomplished using a two-tailed Student t test of unpaired samples, and the Wilcoxon Signed Rank Test where appropriate.
RESULTS - The mitomycin-C treated larynges demonstrated improved cricoarytenoid joint mobility (P = .007), decreased granulation tissue development (P = .03), and complete prevention of secondary "vocal granuloma" formation (P = .0004) when compared with eight dogs with identical laser injuries allowed to heal untreated. No complications were noted.
CONCLUSIONS - This study demonstrates functional preservation and improved histological appearance of the injured glottis after a single treatment with topical mitomycin-C. Potential applications of these findings include prophylactic use of topical mitomycin-C on glottic insults that commonly progress from granulation tissue formation to scarring and decreased vocal fold function.
PURPOSE - The authors develop a simple and economical method of applying reproducible intraoperative doses of mitomycin C for glaucoma filtering surgery.
METHODS - A three-part protocol was developed to study several properties of half corneal light shields (HCLSs). Part A tested the amount of mitomycin C (0.4 mg/ml) absorbed, the expansion dimensions attained, and the amount released to filter paper. In part B, the in vitro release of mitomycin C to an enucleated pig eye was examined. In part C, the in vivo release during intraoperative filtering surgery was tested.
RESULTS - The amount of mitomycin C solution absorbed by the HCLSs ranged from 1.07 x 10(-2) mg to 1.19 x 10(-2) mg; expansion width ranged from 6.8 mm to 7.0 mm; expansion height ranged from 3.6 mm to 3.8 mm; expansion thickness was constant at 0.6 mm. The amount of solution released to filter paper ranged from 6.8 x 10(-3) mg to 8.6 x 10(-3) mg. The amount of solution transferred to the pig eye ranged from 1.0 x 10(-3) mg to 2.7 x 10(-3) mg. The amount of solution released in filtering surgery ranged from 2.0 x 10(-3) mg to 4.8 x 10(-3) mg.
CONCLUSIONS - The contact surface area, the amount absorbed, and the amount released by each HCLS was reproducible. The uniform thickness theoretically provides a uniform distribution of mitomycin C. This method may allow standardization of intraoperative mitomycin C application, and may reduce the incidence of complications.