Significant Difference In Tumor Volume Research Articles

PET imaging of early response to the tyrosine kinase inhibitor ZD4190.

We evaluated noninvasive positron emission tomography (PET) imaging for monitoring tumor response to the VEGFR-2 tyrosine kinase (TK) inhibitor ZD4190 during cancer therapy. Orthotopic MDA-MB-435 tumor-bearing mice were treated with ZD4190 (100 mg/kg orally per day for three consecutive days). Tumor growth was monitored by caliper measurement. During the therapeutic period, longitudinal PET scans were acquired using (18)F-FDG, (18)F-FLT and (18)F-FPPRGD2 as imaging tracers to evaluate tumor glucose metabolism, tumor cell proliferation, and angiogenesis, respectively. Imaging metrics were validated by immunohistochemical analysis of Ki67, GLUT-1, F4/80, CD31, murine integrin β3, and human integrin αvβ3. Three consecutive daily oral administrations of 100 mg/kg of ZD4190 were effective in delaying MDA-MB-435 tumor growth. A significant difference in tumor volume was observed on day 7 between the treatment group and the control group (p < 0.01). After the final treatment, tumor growth resumed after a short delay. In the control tumors, (18)F-FPPRGD2 uptake was stable between days 0 and 7. In ZD4190-treated tumors, (18)F-FPPRGD2 uptake had decreased significantly relative to baseline by 26.74 ± 8.12% (p < 0.05) on day 1 and by 41.19 ± 6.63% (p < 0.01) on day 3, then had returned to baseline on day 7. Tumor uptake of (18)F-FLT had also decreased on both day 1 and day 3 after initiation of ZD4190 treatment. No significant change in (18)F-FDG uptake in ZD4190-treated tumors was observed, however, compared with the control group. All of the imaging findings were supported by ex vivo analysis of related biomarkers. The longitudinal imaging results demonstrated the usefulness of quantitative (18)F-FLT and (18)F-FPPRGD2 PET imaging in evaluating the early antiproliferative and antiangiogenic effects of ZD4190. The quantification data from the PET imaging were consistent with the pattern of initial growth inhibition with treatment, followed by tumor relapse after treatment cessation.

18F-FPPRGD2 and 18F-FDG PET of Response to Abraxane Therapy

Abraxane (nanoparticle albumin-bound paclitaxel) is an anticancer drug approved by the Food and Drug Administration. However, the mechanism of action of Abraxane is complex, and no established biomarker is available to accurately monitor its treatment outcomes. The aim of this study was to investigate whether the integrin-specific PET tracer 18F-FPPRGD2 (investigational new drug 104150) can be used to monitor early response of tumors to Abraxane therapy. Orthotopic MDA-MB-435 breast cancer mice were treated with Abraxane (25 mg/kg every other day, 3 doses) or phosphate-buffered saline. Tumor volume was monitored by caliper measurement. PET scans were obtained before and at different times after the start of treatment (days 0, 3, 7, 14, and 21) using 18F-FPPRGD2 and 18F-FDG. The tumoricidal effect was also assessed ex vivo by immunohistochemistry. Abraxane treatment inhibited the tumor growth, and a significant difference in tumor volume could be seen at day 5 after the initiation of treatment. The tumor uptake of 18F-FPPRGD2 in the Abraxane-treated group was significantly lower on days 3 and 7 than at baseline but returned to the baseline level at days 14 and 21, indicative of relapse of the tumors after the treatment was halted. Immunohistologic staining confirmed that the change of 18F-FPPRGD2 uptake correlated with the variation of integrin level in the tumor vasculature induced by Abraxane treatment. No significant change of tumor (rather than vascular) integrin expression was observed throughout the study. No significant decrease of 18F-FDG uptake was found between the treated and the control tumors on days 3, 14, and 21, although an increase in 18F-FDG tumor uptake of treated mice, as compared with the control mice, was found on day 7. The increase of 18F-FDG on day 7 was related to the inflammatory response during therapy. Abraxane-mediated downregulation of integrin αvβ3 expression on tumor endothelial cells can be quantitatively visualized by PET. The change of integrin expression precedes that of tumor size. Consequently, 18F-FPPRGD2 PET is superior to 18F-FDG PET in monitoring early response to treatment, favoring its potential clinical translation.

Local regulation of human breast xenograft models

Breast cancer studies implant human cancer cells under the renal capsule, subcutaneously, or orthotopically and often use estrogen supplementation and immune suppressants (etoposide) in xenograft mouse models. However, cell behavior is significantly impacted by signals from the local microenvironment. Therefore, we investigated how the combinatorial effect of the location of injection and procedural differences affected xenograft characteristics. Patient-derived breast cancer cells were injected into mouse abdominal or thoracic mammary glands +/- estrogen and/or etoposide pretreatment. Abdominal xenografts had increased tumor incidence and volume, and decreased latency (P < 0.001) compared to thoracic tumors. No statistically significant difference in tumor volume was found in abdominal xenografts treated +/- estrogen or etoposide; however, etoposide suppressed tumor volume in thoracic xenografts (P < 0.02). The combination of estrogen and etoposide significantly decreased tumor incidence in both sites. In addition, mice treated +/- estradiol were injected orthotopically or subcutaneously with well-characterized breast cancer cell lines (MCF7, ZR75-1, MDA MB-231, or MCF10Ca1h). Orthotopic injection increased tumor volume; growth varied with estrogen supplementation. Location also altered methylation status of several breast cancer-related gene promoters. Lastly, vascularization of orthotopic tumors was significantly enhanced compared to subcutaneous tumors. These data suggest that optimal xenograft success occurs with orthotopic abdominal injections and illustrate molecular details of the compelling influence of the local microenvironment on in vivo models.

Abstract 3243: Differential effects of caloric and carbohydrate restriction upon prostate cancer tumor growth in a mouse model

Abstract Background: Caloric restriction (CR) has been shown to be anti_cancer. However, whether these effects are the result of generalized reduction in overall caloric intake or reduced intake of macronutrients (i.e. carbohydrates) are unknown. We sought to investigate the differential effects of caloric and carbohydrate restriction upon prostate cancer tumor growth in a xenograft model. Materials and Methods: A total of 100 male SCID mice were injected subcutaneously with the LAPC-4 cell line. Mice were randomized to 1 of 4 diets: ad libitum Western diet (WD, 49% carbohydrates, 35% fat, and 16% protein), pair-fed No Carbohydrate Ketogenic Diet (NCKD; 1% carbohydrates, 83% fat, 16% protein), Western diet calorically restricted (WD-CR), and NCKD calorically restricted (NCKD-CR). Calorically restricted arms were fed 75% of the calories of their reference diet group. Tumor volumes and body weights were measured twice weekly. Mice were sacrificed when tumor volumes reached 1,000 mm3. Results: Relative to WD, there was a suggestion of smaller body weights in both NCKD-CR and WD-CR arms (rank-sum, p≤0.06). There was trend for heavier mice in the NCKD group (rank-sum, p=0.09). By day 50, median tumor volumes for NCKD, WD-CR, and NCKD-CR were 45, 51, and 62% smaller than WD (rank-sum, all p≤0.001). At any time point, there were no significant differences in tumor volume among the NCKD, NCKD-CR, and WD-CR arms. However, there was a suggestion of smaller tumors in the NCKD-CR arm by day 42 relative to NCKD and WD-CR (p&amp;lt;0.11). Diet was significantly associated with mouse survival (log_rank, p=0.004). In 2_way comparisons, NCKD, NCKD-CR, and WD-CR had significantly prolonged survival relative to WD (log_rank, all p≤0.02). However, no difference in survival was seen among any caloric or carbohydrate restricted arms (log rank, p≤0.16). A total of 34 mice died due to infection prior to their tumors reaching 1,000mm3 and therefore were not included in the survival analyse (WD-CR, n=14; NCKD, n=5; NCKD-CR, n =15). Conclusions: Both CR and carbohydrate restriction without weight loss are effective in delaying tumor growth and improving mouse survival. We found no differences between caloric and carbohydrate restricted arms, though this may relate to loss of study power due to mouse infections. CR may further weaken the immune system of immunocompromised mice subjecting them to increased risk of infections. A confirmatory study is underway in a high-level barrier facility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3243.

Abstract 2816: Low-carbohydrate diets and prostate cancer growth: How low is “low enough”

Abstract Introduction: Previous dietary studies indicate carbohydrate intake may influence prostate cancer biology, as LAPC-4 and LNCaP xenograft mice fed a no-carbohydrate ketogenic diet (NCKD; 84% fat-0% carbohydrate-16% protein kcal) had significantly smaller tumors and longer survival times compared to mice fed a Western diet (40% fat-44% carbohydrate-16% protein kcal). The NCKD mice were also found to have higher levels of circulating IGFBP-3 and the lowest levels of insulin, IGF-1, and IGF-1:IGFBP-3 ratio despite consuming more calories than the Western group. As it is nearly impossible for a human to consume and maintain a no-carbohydrate diet similar to that in the previous xenograft studies, we sought to determine whether diets containing 10% or 20% kcal from carbohydrates could slow tumor growth in a similar manner to the NCKD in a xenograft model. METHODS: A total of 150 male SCID mice were injected with LAPC-4 cells and placed on a Western diet (35% fat-49% carbohydrate-16% protein kcal) ad libitum. Two weeks post-injection, all mice were randomized to one of three arms: NCKD, 10% carbohydrate, or 20% carbohydrate. Ten mice not injected with tumor were fed an ad libitum low-fat diet (12% fat-72% carbohydrate-16% protein kcal) and served as the reference group in a modified-paired feeding protocol for the other three groups. Calorie intake and body weights were measured thrice weekly and tumor volumes twice per week. Mice were sacrificed when tumors reached 1,000mm3. RESULTS: Despite consuming 5-10% extra calories on average, all mice receiving low-carbohydrate diets were significantly lighter than the mice consuming the low-fat diet (p&amp;lt;0.04). Overall, the mice fed a NCKD were significantly lighter than the other two arms at multiple time points (p&amp;lt;0.05). There were no significant differences in tumor volumes among groups at any time except at Day 52 and 59, where 10% carbohydrate mice had larger tumors (p&amp;lt;0.05). However, after adjusting for the fact that tumor volumes were compared at multiple time points (i.e. multiple comparisons), these were no longer significant. Dietary treatment did not impact overall survival (p=0.34). NCKD mice had significantly higher glucose levels at sacrifice compared to the mice fed 10% and 20% carbohydrates (p=0.001), but similar levels of urinary ketones (p=0.37). CONCLUSIONS: LAPC-4 xenograft mice fed a low-carbohydrate diet (10-20% carbohydrate kcal) had similar survival to mice consuming a NCKD (0% carbohydrate kcal). Thus, the survival benefit of a NCKD may be achievable with less restrictive low-carbohydrate diets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2816.

1437 LOW-CARBOHYDRATE DIETS AND PROSTATE CANCER GROWTH: HOW LOW IS “LOW ENOUGH”?

You have accessJournal of UrologyProstate Cancer: Basic Research VIII1 Apr 20101437 LOW-CARBOHYDRATE DIETS AND PROSTATE CANCER GROWTH: HOW LOW IS “LOW ENOUGH”? Elizabeth Masko, Jean-Alfred Thomas, Jodi A. Antonelli, Jessica C. Lloyd, Tameika E. Phillips, Susan H.M. Poulton, Salvatore V. Pizzo, and Stephen J. Freedland Elizabeth MaskoElizabeth Masko More articles by this author , Jean-Alfred ThomasJean-Alfred Thomas More articles by this author , Jodi A. AntonelliJodi A. Antonelli More articles by this author , Jessica C. LloydJessica C. Lloyd More articles by this author , Tameika E. PhillipsTameika E. Phillips More articles by this author , Susan H.M. PoultonSusan H.M. Poulton More articles by this author , Salvatore V. PizzoSalvatore V. Pizzo More articles by this author , and Stephen J. FreedlandStephen J. Freedland More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1130AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Previous dietary studies indicate carbohydrate intake may influence prostate cancer biology, as LAPC-4 and LNCaP xenograft mice fed a no-carbohydrate ketogenic diet (NCKD; 84% fat-0% carbohydrate-16% protein kcal) had significantly smaller tumors and longer survival times compared to mice fed a Western diet (40% fat-44% carbohydrate-16% protein kcal). The NCKD mice were also found to have higher levels of circulating IGFBP-3 and the lowest levels of insulin, IGF-1, and IGF-1:IGFBP-3 ratio despite consuming more calories than the Western group. As it is nearly impossible for a human to consume and maintain a no-carbohydrate diet similar to that in the previous xenograft studies, we sought to determine whether diets containing 10% or 20% kcal from carbohydrates could slow tumor growth in a similar manner to the NCKD in a xenograft model. METHODS A total of 150 male SCID mice were injected with LAPC-4 cells and placed on a Western diet (35% fat-49% carbohydrate-16% protein kcal) ad libitum. Two weeks post-injection, all mice were randomized to one of three arms: NCKD, 10% carbohydrate, or 20% carbohydrate. Ten mice not injected with tumor were fed an ad libitum low-fat diet (12% fat–72% carbohydrate–16% protein kcal) and served as the reference group in a modified-paired feeding protocol for the other three groups. Calorie intake and body weights were measured thrice weekly and tumor volumes twice per week. Mice were sacrificed when tumors reached 1,000mm3. RESULTS Despite consuming 5-10% extra calories on average, all mice receiving low-carbohydrate diets were significantly lighter than the mice consuming the low-fat diet (p<0.04). Overall, the mice fed a NCKD were significantly lighter than the other two arms at multiple time points (p<0.05). There were no significant differences in tumor volumes among groups at any time except at Day 52 and 59, where 10% carbohydrate mice had larger tumors (p<0.05). However, after adjusting for the fact that tumor volumes were compared at multiple time points (i.e. multiple comparisons), these were no longer significant. Dietary treatment did not impact overall survival (p=0.34). NCKD mice had significantly higher glucose levels at sacrifice compared to the mice fed 10% and 20% carbohydrates (p=0.001), but similar levels of urinary ketones (p=0.37). CONCLUSIONS LAPC-4 xenograft mice fed a low-carbohydrate diet (10-20% carbohydrate kcal) had similar survival to mice consuming a NCKD (0% carbohydrate kcal). Thus, the survival benefit of a NCKD may be achievable with less restrictive low-carbohydrate diets. Durham, NC© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e554 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Elizabeth Masko More articles by this author Jean-Alfred Thomas More articles by this author Jodi A. Antonelli More articles by this author Jessica C. Lloyd More articles by this author Tameika E. Phillips More articles by this author Susan H.M. Poulton More articles by this author Salvatore V. Pizzo More articles by this author Stephen J. Freedland More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Antiangiogenic Tumor Treatment: Noninvasive Monitoring with Contrast Pulse Sequence Imaging for Contrast-Enhanced Grayscale Ultrasound

This study was designed to test the feasibility of contrast pulse sequencing imaging for contrast-enhanced grayscale ultrasound in assessing the effects of antiangiogenic therapy. Mice with subcutaneously implanted H22 mouse hepatoma were treated with thalidomide or placebo by oral gavage over 7 days, starting at 24 hours after implantation. Contrast pulse sequencing ultrasound imaging was performed on day 8 to evaluate maximal cross-sectional area and nonenhanced area. Immediately after imaging, mice were euthanized, and tumor tissue was removed for fixation in a 10% formalin solution. The section equivalent to the ultrasound imaging plane was stained with hematoxylin and eosin to allow for the assessment of the largest cross-sectional area and necrotic area. There was no significant difference in tumor volume between the two groups. The difference of largest cross-sectional area determined by the two methods was not significant between control and treated tumors (P > .05). The nonenhanced area and its percentage evaluated by ultrasound were significantly larger in treated tumors than in control tumors (P < .05). The necrotic area and its percentage estimated by pathology slice were also significantly larger in treated tumors than in control tumors (P < .05). The largest cross-sectional area determined by the two methods was well correlated (r = 0.815, P < .001). There was good correlation between the nonenhanced area on ultrasound and the necrotic area on pathology slides (r = 0.909, P < .001). The percentage of nonenhanced area was well correlated with the percentage of necrotic area (r = 0.910, P < .001). Contrast-enhanced grayscale ultrasound with contrast pulse sequencing imaging provides a tool for early monitoring of antiangiogenic treatment of tumors, before apparent change in tumor size.

Defining hepatoblastoma responsiveness to induction therapy as measured by tumor volume and serum α-fetoprotein kinetics

Purpose Hepatoblastoma is commonly unresectable at presentation, necessitating induction chemotherapy before definitive resection. To refine the paradigm for timing of resection, we questioned whether a plateau in hepatoblastoma responsiveness to neoadjuvant therapy could be detected by calculating tumor volume (TV) and serum α-fetoprotein (sAFP) kinetics. Methods To calculate TV and sAFP as measures of treatment responsiveness over time, infants having initially unresectable epithelial-type hepatoblastomas were identified at a single institution (1996-2008). Effects of therapy type, therapy duration, and lobe of liver involvement on TV, sAFP, margin status, and toxicity were analyzed. Results Of 24 infants treated for epithelial-type hepatoblastoma during this interval, 5 were resected primarily, and 15 had complete digital films for kinetics analysis. Both TV and sAFP decreased dramatically over time ( P < .0001). No statistically significant difference in mean TV or sAFP was detected after chemotherapy cycle 2. Left lobe tumors had greater presenting levels of and significantly slower decay in sAFP compared with right lobe tumors ( P = .005), although no statistically significant differences in TV existed between liver lobes. Resection margins did not change with therapy duration. Conclusions Measuring TV and sAFP kinetics accurately reflects hepatoblastoma responsiveness to induction therapy. Treatment toxicities may be reduced by earlier resection and tailoring of chemotherapeutic regimens.

Feasibility of chemohyperthermia with docetaxel‐embedded magnetoliposomes as minimally invasive local treatment for cancer

Hyperthermia is a minimally invasive approach to cancer treatment, but it is difficult to heat only the tumor without damaging surrounding tissue. To solve this problem, we studied the effectiveness of chemohyperthermia with docetaxel-embedded magnetoliposomes (DMLs) and an applied alternating current (AC) magnetic field. Human MKN45 gastric cancer cells were implanted in the hind limb of Balb-c/nu/nu mice. Various concentrations of docetaxel-embedded DMLs were injected into the tumors and exposed to an AC magnetic field (n = 6, each). For comparison with hyperthermia alone, magnetite-loaded liposome (ML)-injected tumors were exposed to an AC magnetic field. Furthermore, the results of DML without AC treatment and docetaxel diluted into PBS with AC treatment were also compared (n = 10, each). Tumor surface temperature was maintained between 42 and 43 degrees C. Tumor volume was reduced in the DML group with a docetaxel concentration > 56.8 microg/ml, while a docetaxel concentration > 568.5 microg/ml was required for tumor reduction without hyperthermia. Statistically significant differences in tumor volume and survival rate were observed between the DML group exposed to the magnetic field and the other groups. The tumor disappeared in 3 mice in the DML group exposed to the magnetic field; 2 mice survived over 6 months after treatment, whereas all mice of the other groups died by 15 weeks. Histologically, hyperthermia with DML damaged tumor cells and DML diffused homogeneously. To the best of our knowledge, this is the first report to show that hyperthermia using chemotherapeutic agent-embedded magnetoliposomes has an anticancer effect.

Inhibitory Effects of Liposomal Honokiol On the Lymphoma.

Abstract 4788 ObjectiveFHonokiol(HNK),an active component purified from the bark of Magnolia officianlis, consists of biphenyl skeleton with phenolic and allylic functionalities. It has showed a variety of pharmacological effects. Most attraction to us among them is antitumor effect including cytotoxicity, inducing cell differentiation and apoptosis, anti-angiogenisis, inhibiting activity of enzyme and synthesis of DNA and RNA. However, the extrem water insolubility hampers it's delivering to the tumor at an effective concentration. Liposomes have previously been used as carriers for delivery of a variety of drugs and they can improve water solubility, biodistribution and metabolism of those drugs. In the present study, we encapsulated honokiol in the non-aqueous interior of the polyethyleng glycolliposome. The antitumor efficacy and its mechanism of liposomal honokiol was investigated in vivo. MethodsFThe honokiol encapsulated by liposomes was preparated in our laboratory. The tumor model was established in C57BL/6 mice by injection of EL-4 lymphoma cells. When tumor became visible about seven days after injection, the mice were randomized into six groups (10 mice each group) and treated with different doses of liposomal honokiol(LH), empty liposome, Normal Saline(NS) and Adriamycin(ADM), respectively. Tumor volume and survival time were observed. Antiangiogenesis, antilymphangiogenesis and tumor proliferative index of the tumor tissues were determined by CD31, D2-40 and Ki-67 immunohistochemistry staining, meanwhile the tumor apoptosis index was measured by TUNEL method. ResultsFIn mouse lymphoma model liposomal honokiol obviously inhibited the growth of tumor in dose-dependent manner. After treatment, the tumor growth inhibition rate in 10mg/kg LH group was 49.54%,meanwhile the one in 20mg/kg LH group was 66.47%.The tumor volumes in 10mg/kg LHA20mg/kg LH and 5mg/kg ADM groups were significantly different compared with NS and LIP groups(P<0.05).No difference were observed in the tumor volumes between the 5mg/kg LHANS and LIP groups(P>0.05).There is significant difference in tumor volumes between 20mg/kg LH and 5mg/kg LH groups(P<0.05).In terms of survival investigation, the median survival time in NS and LIP groups were 30 days. No mice in these two groups were alive after the completion of study. Meanwhile the median survival time in 20mg/kg LH group was 36 days, with the survival time of 33% of mice in this group was longer than 60 days. The survival times in 10mg/kg LHA20mg/kg LH and 5mg/kg ADM groups were significantly different compared with NS and LIP groups(P<0.05).No intolerant sideeffects in liposomal honokiol-treated groups were observed in the present study. Compared with NS group, the MVD, LMVD, apoptosis index and proliferative index in 20mg/kg LH group were significantly different(P<0.05). ConclusionsFIn mouse lymphoma model liposomal honokiol markedly inhibited the growth of tumor, prolonged the survival time in dose-dependent manner. Liposomal honokiol exerted its inhibitory effect by blocking angiogenesis and lymphangiogenesis, inducing tumor cell apoptosis and suppressing tumor proliferation. These findings may be of importance for further exploration of the potential application of liposomal honokiol in the treatment of lymphoma. Disclosures:No relevant conflicts of interest to declare.

Silencing of signal transducer and activator of transcription 3 gene expression using RNAi enhances the efficacy of radiotherapy for laryngeal carcinoma in vivo

To study the inhibitory effect of signal transducer and activator of transcription 3 (STAT3) shRNA generated by vector pSilence in conjunction with radiotherapy on laryngeal squamous cell carcinoma of nude mice xenograft tumor. The animal models of xenotransplanted human laryngeal carcinoma cell line Hep-2 were set up in 28 nude mice which were divided into 4 groups at random: the negative plasmid control group, the group that received pshSTAT3 (pGPU6/GFP/NeoshSTAT3) transfection, the radiation group, and the group of pshSTAT3 transfection combined with irradiation. Tumor volume was determined regularly. On the fifteenth day after termination of radiation treatment, the mice were sacrificed, the tumor weight was measured in all the groups, the inhibition rate for tumor growth was calculated and tumor growth curve was plotted. Meanwhile, the expressions of p-STAT3, B cell lymphoma 2 (bcl-2), p53, vascular endothelial growth factor (VEGF) protein and intratumor microvessel density (MVD) were observed by immunohistochemistry. Computer-assisted image analysis was used to obtain the results. Flow cytometry was used to detect the cell apoptosis rate. There was a significant difference in tumor volume among the groups (P<0.01). The rate of tumor inhibition in the pshSTAT3 group, radiation group and pshSTAT3 plus radiation group was 19.68%, 34.76% and 67.70%, respectively. The p-STAT3 protein expression decreased significantly in the group of pshSTAT3 plus simple radiotherapy (P<0.01). The intratumoral MVD in the group of pshSTAT3 plus simple radiotherapy was significantly lower compared to the negative plasmid control group and the radiotherapy group (P<0.01), while the apoptosis rate was much higher (P<0.01). There was a positive correlation between the expressing of p-STAT3 and bcl-2, p53, VEGF and MVD (r value was 0.738, 0.727, 0.735, 0.691, all P<0.01), and there was a negative correlation concerning cell apoptosis rate. Moreover, a statistically positive association was present between MVD and p53, VEGF protein expression, respectively (r value was 0.784, 0.641, all P<0.01); and the correlation was negative between expression of bcl-2 and apoptosis rate (r=-0.883, P<0.01). Using pshSTAT3 in conjunction with radiotherapy can significantly inhibit the growth of laryngeal carcinoma.

Clinical Characteristics of Wilms' Tumor according to Age

Purpose: Wilms' tumor typically affects young children, with more than 80% of patients identified before 5 years of age. We evaluated the clinical features of Wilms' tumor according to age. Materials and Methods: According to their age, 27 patients with Wilms' tumor who underwent radical nephrectomy were classified into group I (under 24 months: n=15), group II (24-48 months: n=4), and group III (over 48 months: n=8), respectively. We retrospectively reviewed tumor size, pathologic features, renal vein invasion, renal capsule invasion, bilaterality, lymphovascular invasion, stage, complete resection, and survival rate. Results: The mean age of groups I, II, and III was 12.5±7.0 (range, 1-20), 33.3±5.7 (range, 24-39) and 126.9±89.1 (range, 54-300) months, respectively. Bilaterality (p<0.001) and male sexuality (p=0.039) were significantly related to early diagnostic age. Tumor stage (p=0.036) and blastema component (p=0.027) increased with age. Bilaterality and incomplete resection of Wilms' tumor were related to larger size (p<0.001) and vessel/lymph node invasion (p=0.02), respectively. There were no significant differences in tumor volume, anaplasia, capsule invasion, lymph node invasion, vessel invasion, complete resection, laterality, or recurrence according to age. There was also no significant difference in the survival rate according to age. Conclusions: Tumor stage and blastema component of Wilm's tumor increased with age. Bilaterality and male sexuality were related to an early diagnostic age. There was no significant difference in the survival rate according to age. (Korean J Urol 2009;50:1188-1192) 󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏

Volume Determination of Oral Cavity Tumors by 3-Dimensional Ultrasonography

With the help of 3-dimensional (3D) ultrasound, the ultrasonographic determination of tumor volumes offers a new view of tumors in the oral cavity. These are classified according to their maximal diameter in TNM classification whereby the possibility exists in the high T category of overestimating small tumors that have spread into surrounding structures, and in the low T of underestimating large volume tumors that do not extend into surrounding structures. We analyzed a group of 49 patients with tumors of the oral cavity, all of whom underwent surgery. Tumor volumes were determined before surgery with 3D ultrasound aided by 3D View program software. After excision, the tumors were classified in pT categories based on pathologic findings. N stage was determined after neck dissection and correlation to tumor volume were performed. The average volume of T1 tumors was 1.74 cm(3); T2 was 5.21 cm(3); T3 was 23.36 cm(3), and T4 was 13.53 cm(3). There were significant differences in tumor volumes between all T categories except T3 and T4. Tumor volumes in our patients did not correlate with N stage. Volume determination of tumors with the help of 3D View software may categorize small tumors better and perhaps become a new refinement in TNM tumor classification. Results show that although T category in oral cavity tumors is determined by diameter in T1 to T3, the volumes match with T category. By using this method, a successful follow-up can be performed and the effects of radiotherapy or chemotherapy can be evaluated.

MR Diffusion Weighted Imaging for Evaluation of Radiotherapeutic Effects on Rabbit VX2 Tumor Model

To investigate the feasibility of magnetic resonance (MR) diffusion weighted imaging (DWI) for evaluation of radiotherapeutic effects on rabbit VX2 tumor model. Sixteen New Zealand white rabbits received a subcutaneous implantation of VX2 tumor cell suspension 0.5 mL (4 x 10(7) cells/mL) in their right thighs to set up tumor model. And 2 weeks later they were randomly divided into therapy group (Group T, n = 10) and control group (Group C, n = 6). Group T received radiotherapy at a single dose of 10 Gy. MR imaging (MRI) scan including short TI inversion recovery echo-planar imaging DWI, T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI) sequences were performed 1 day prior to as well as 1 day, 2 days, 3 days and 7 days after radiotherapy. Group C received only MRI scan at the same time points without any treatment. MRI appearance on T2WI, T1WI, and DWI images was compared and tumor volume was calculated. Apparent diffusion coefficient (ADC) values of the tumor were evaluated in all cases. HE staining was used for pathological study. Necrosis (n = 8) and hemorrhage (n = 2) were seen gradually on T2WI and T1WI images of Group T after time point of day 2 after irradiation. In Group C, no obvious necrosis was found until day 7. There was no significant difference in tumor volume between the two groups before radiotherapy. After radiotherapy, tumors in Group T showed a gradual growth but not as obvious as Group C. There was a significant difference in tumor volume between the two groups from day 2 on (P < 0.05). ADC value changed dramatically right from the 1st day after radiotherapy in Group T [(0.99 +/- 0.15) x 10(-3) mm2/s for 1 day before radiotherapy, (1.23 +/- 0.08) x 10(-3), (1.45 +/- 0.07) x 10(-3), (1.63 +/- 0.06) x 10(-3), and (2.02 +/- 0.18) x 10(-3) mm2/s for day 1, 2, 3, and 7]; and ADC value had no significant changes after radiotherapy in Group C except day 7 [(1.07 +/- 0.08) x 10(-3) mm2/s for 1 day before radiotherapy, (1.03 +/- 0.04) x 10(-3), (1.05 +/- 0.02) x 10(-3), (1.05 +/- 0.05) x 10(-3), and (0.95 +/- 0.07) x 10(-3) mm2/s for day 1, 2, 3, and 7]. There was significant difference in ADC value between the two groups for each time point after radiotherapy (P < 0.01). Pathological study showed that the number of viable tumor cells in Group T decreased 1 day after radiotherapy, and the inflammatory cell infiltration was marked and almost all viable tumor cells disappeared by day 7 after radiotherapy. DWI is a new promising technique for monitoring radiotherapy outcomes. ADC value may give a prior clue on physiological changes of radiotherapy before routine MRI could tell.

The Effect of Hyperbaric Oxygen Treatment on Squamous Cell Cancer Growth and Tumor Hypoxia

Anecdotal studies have reported explosive tumor growth in patients with a history of squamous cell carcinoma after hyperbaric oxygen (HBO) treatment. Conflicting experimental results have followed. In this study, squamous cancer cells were subjected to daily HBO treatment. No difference in cellular proliferation was noted in vitro when comparing HBO and control treated cells (P = 0.534). Similarly, immunostaining for in vivo DNA synthesis failed to demonstrate any significant difference in the number of proliferating cells after treatment with HBO (P = 0.388). No significant difference in tumor volume or mass was found after in vivo implantation (P = 0.471). HBO was found to reduce tumor hypoxia, which trended towards significance when compared with controls (P = 0.057); however, there was no difference in serum VEGF levels or vessel ingrowth. Thus, even though HBO may reduce the levels of hypoxia within squamous cell tumors, it does not appear to enhance short-term growth or promote cellular proliferation or angiogenesis.

Effect of antidepressants on body weight, ethology and tumor growth of human pancreatic carcinoma xenografts in nude mice

To investigate the effects of mirtazapine and fluoxetine, representatives of the noradrenergic and specific serotonergic antidepressant (NaSSA) and selective serotonin reuptake inhibitor (SSRI) antidepressant respectively, on body weight, ingestive behavior, locomotor activity and tumor growth of human pancreatic carcinoma xenografts in nude mice. A subcutaneous xenograft model of human pancreatic cancer cell line SW1990 was established in nude mice. The tumor-bearing mice were randomly divided into mirtazapine group (10 mg/kg per day), fluoxetine group (10 mg/kg per day) and control group (an equivalent normal saline solution) (7 mice in each group). Doses of all drugs were administered orally, once a day for 42 d. Tumor volume and body weight were measured biweekly. Food intake was recorded once a week. Locomotor activity was detected weekly using an open field test (OFT). Compared to the fluoxetine, mirtazapine significantly increased food intake from d 14 to 42 and attenuated the rate of weight loss from d 28 to 42 (t = 4.38, P < 0.05). Compared to the control group, food intake was significantly suppressed from d 21 to 42 and weight loss was promoted from d 35 to 42 in the fluoxetine group (t = 2.52, P < 0.05). There was a significant difference in body weight of the mice after removal of tumors among the three groups. The body weight of mice was the heaviest (13.66 +/- 1.55 g) in the mirtazapine group and the lightest (11.39 +/- 1.45 g) in the fluoxetine group (F( (2,12) ) = 11.43, P < 0.01). The behavioral test on d 7 showed that the horizontal and vertical activities were significantly increased in the mirtazapine group compared with the fluoxetine and control groups (F( (2,18) ) = 10.89, P < 0.01). These effects disappeared in the mirtazapine and fluoxetine groups during 2-6 wk. The grooming activity was higher in the mirtazapine group than in the fluoxetine group (10.1 +/- 2.1 vs 7.1 +/- 1.9 ) (t = 2.40, P < 0.05) in the second week. There was no significant difference in tumor volume and tumor weight of the three groups. Mirtazapine and fluoxetine have no effect on the growth of pancreatic tumor. However, mirtazapine can significantly increase food intake and improve nutrition compared with fluoxetine in a pancreatic cancer mouse model.

An Anti-VEGF Antibody, in Combination with Bortezomib, Markedly Inhibits Tumor Growth in SCID-hu Models of Human Multiple Myeloma.

Vascular endothelial growth factor (VEGF) is an important signaling protein that plays a critical role in vasculogenesis and angiogenesis, and serves as one of the contributors to physiological or pathological conditions that can stimulate the formation of new blood vessels. The uncontrolled growth of new blood vessels is an important contributor to a number of pathological conditions, including multiple myeloma (MM). In support of this, bone marrow angiogenesis has been shown to correlate with disease status and poor prognosis in MM. VEGF also directly induces myeloma cell proliferation. We previously evaluated the effects of single agent mouse/human anti-VEGF antibody G6.31 (Campbell et al, Blood (ASH Annual Meeting Abstracts), Nov 2006) in several of our mouse models of human MM. In this study, we evaluated the effects of the same anti-VEGF antibody in combination with bortezomib or lenalidomide. Severe combined immunodeficient (SCID) mice were implanted into the left superficial gluteal muscle with either a 2.0 – 4.0 mm3 fragment from a patient when she was bortezomib-sensitive, LAGκ-1A, or resistant, LAGκ-1B. The tumors were allowed to grow for 21 days at which time human IgG levels were detectable in the mouse serum, and mice were blindly assigned into treatment groups (n=10 mice/group). Treatment groups consisted of a control IgG antibody or anti-VEGF antibody administered via i.p. injection twice weekly at a dose of 2 mg/kg, bortezomib administered via intravenous injection at a dose of 0.25 or 0.5 mg/kg twice weekly, lenalidomide administered via i.p. injection at a dose of 50 mg/kg daily × 5 per week, anti-VEGF antibody (2 mg/kg) + bortezomib (0.25 or 0.5 mg/kg), and anti-VEGF (2 mg/kg) + lenalidomide (50 mg/kg). Mice receiving the combination therapy of anti-VEGF + bortezomib (0.5 mg//kg) antibody showed marked inhibition of tumor growth and reduction of paraprotein levels compared to mice receiving control antibody. Notably, this combination also produced much more marked anti-MM effects compared to bortezomib treatment alone, anti-VEGF antibody alone, or vehicle alone. This combination was well tolerated. In contrast, mice receiving the combination of anti-VEGF antibody + lenalidomide showed no significant differences in tumor volume or hIgG levels compared to single agent treatment or vehicle alone. The markedly improved anti-MM effects of the combination of bortezomib and anti-VEGF antibody compared to single agent treatment in this in vivo study of human MM is promising, and these results have provided the preclinical rationale for an ongoing randomized multi-center Phase II trial.

Lack of effect of palifermin on the anti-tumor activity of cisplatin, cetuximab or panitumumab in the FaDu human head and neck carcinoma model

6060 Background: The FaDu human pharyngeal carcinoma cell line expresses the receptors for both KGF and EGF. Palifermin is a recombinant form of human KGF. The objective of this study was to determine whether the combination of palifermin with cisplatin and the EGFR inhibitors cetuximab or panitumumab interferes with the anti-tumor activities of these agents in the FaDu head and neck xenograft model. Methods: FaDu tumor cells were implanted subcutaneously in CD1 nude mice. For the combination of palifermin with cetuximab and cisplatin, treatment began on day 9 and for the combination of palifermin with panitumumab and cisplatin, treatment began on day 10. The primary endpoint was the measure of tumor volume. Results: There was no statistically significant difference in tumor volume between the control arm and palifermin alone (p = 0.9993, 0.9831). Neither was there a statistically significant difference between the combination of palifermin, cisplatin and cetuximab compared to the combination of cisplatin and cetuximab (p = 0.7730). Similarly, there was no significant difference between the combination of palifermin, cisplatin and panitumumab compared to the combination of cisplatin and panitumumab (p = 0.9739). Conclusions: In drug combination settings, the addition of palifermin did not affect the therapeutic efficacy of cisplatin, cetuximab or panitumumab in any of the two- or three-way drug combinations. When used alone, palifermin did not promote the growth of the FaDu human xenograft despite the fact that these tumors express KGFR. The lack of interference of palifermin with the anti-tumor activity of cisplatin and the anti-EGFR target therapeutics suggests it is appropriate to move forward clinically investigating the use of palifermin in solid tumor settings in which these therapeutic modalities are used. No significant financial relationships to disclose.

Iodine-125 interstitial brachytherapy for experimental liver cancer

Objective To study the effect of iodine-125 interstitial brachytherapy on liver cancer. Methods Animal model of human liver cancer was established by injecting SMMC-7721 cells cultivated in vitro subcutaneously into the flank of BALB/c nude mice. Nude mice with tumor of 5 mm in diameter were randomly divided into 2 groups ( n=10). One iodine-125 seed of apparent activity 0.8 mCi was implanted into the center of tumor in treatment group, whereas an inactive seed was implanted in control group. The other 20 nude mice with tumor reaching 10 mm in diameter were also treated as above. The size of tumor was determined weekly after implantation, and pathological examination and blood routine were taken on the 28th day. Results Tumor growth was obviously inhibited in treatment group of tumor of 5 mm in diameter, and there was statistically significant difference in tumor volume between treatment and control groups ( P<0.01). Around iodine-125 seed, apparent necrosis of tumor was shown in treatment group, accompanied by karyopyknosis and reduced plasma in residual tumor cells microscopically. Tumor growth was not inhibited in either treatment or control group of tumor of 10 mm in diameter. There was no obvious adverse effect except for decreased white blood cells in treatment groups. Conclusion There is certain effect of iodine-125 interstitial brachytherapy on liver cancer, which is associated with the size of tumor.

Comparison of expandable electrodes in percutaneous radiofrequency ablation of renal cell carcinoma

Objective To compare two different expandable electrodes in radiofrequency ablation of renal cell carcinoma. Methods Percutaneous ablation was performed at two centers using either an expandable 7F umbrella-shaped LeVeen™ probe (diameter 2–4 cm) and a 200-W generator (group A), or an expandable Starburst XL™ electrode with a 150-W generator (group B). From each center, eight patients with one tumor each were matched retrospectively with regard to tumor volume, which was 9.71 ± 6.43 cm 3 for group A and 8.74 ± 4.35 cm 3 for group B (mean tumor diameter: 2.47 ± 0.9 cm versus 2.50 ± 0.4 cm, respectively). An unpaired t-test showed no significant difference in tumor volume between the two groups ( p = 0.820). Results Sixteen patients with 16 tumors were treated. The primary technical success of radiofrequency ablation was 94% (15 of 16 patients). After retreatment of residual tumor in one patient from group B, secondary technical success was 100%. No major complications were observed. The resulting mean volume of the almost spherical necroses was 21.1 ± 9.1 cm 3 versus 14.6 ± 6.7 cm 3 for groups A and B (diameter of necrosis: 3.5 ± 0.7 cm versus 3.1 ± 0.6 cm, respectively). A Mann–Whitney U-test showed no significant difference in necrosis volume between the two groups (CI [−0.215; 0.471]; p = 0.2892). The calculated shape value of S (ratio of length to height of the coagulation necrosis) was 0.9 ± 0.1 and 1.0 ± 0.1 for groups A and B, respectively. No local recurrence was observed during a mean follow-up of 14.8 ± 11.6 months, while extrarenal tumor progression occurred in three patients. Conclusions No significant differences in coagulation volume and shape were found after RF ablation of renal cell carcinoma using two different expandable electrodes. To avoid local recurrence, however, accurate placement of probes and appropriate expansion of the electrode is necessary.