Showing papers by "Hebron University published in 2009"

Novel anticancer targets: revisiting ERBB2 and discovering ERBB3

Abstract: Aberrant receptor expression or functioning of the epidermal growth factor receptor (Erbb) family plays a crucial part in the development and evolution of cancer. Inhibiting the signalling activity of individual receptors in this family has advanced the treatment of a range of human cancers. In this Review we re-evaluate the role of two important family members, ERBB2 (also known as HER2) and ERBB3 (also known as HER3), and explore the mechanisms of action and preclinical and clinical data for new therapies that target signalling through these pivotal receptors. These new therapies include tyrosine kinase inhibitors, antibody-chemotherapy conjugates, heat-shock protein inhibitors and antibodies that interfere with the formation of ERBB2-ERBB3 dimers.

Phase II Randomized Study of Neoadjuvant Everolimus Plus Letrozole Compared With Placebo Plus Letrozole in Patients With Estrogen Receptor–Positive Breast Cancer

Abstract: Purpose Cross-talk between the estrogen receptor (ER) and the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways is a mechanism of resistance to endocrine therapy, and blockade of both pathways enhances antitumor activity in preclinical models. This study explored whether sensitivity to letrozole was enhanced with the oral mTOR inhibitor, everolimus (RAD001). Patients and Methods Two hundred seventy postmenopausal women with operable ER-positive breast cancer were randomly assigned to receive 4 months of neoadjuvant treatment with letrozole (2.5 mg/day) and either everolimus (10 mg/day) or placebo. The primary end point was clinical response by palpation. Mandatory biopsies were obtained at baseline and after 2 weeks of treatment (ie, day 15). Samples were assessed for PI3K mutation status (PIK3CA) and for pharmacodynamic changes of Ki67, phospho-S6, cyclin D1, and progesterone receptor (PgR) by immunohistochemistry. Results Response rate by clinical palpation in the everol...

The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer.

Abstract: An inherited variant on chromosome 8q24, rs6983267, is significantly associated with cancer pathogenesis. We present evidence that the region harboring this variant is a transcriptional enhancer, that the alleles of rs6983267 differentially bind transcription factor 7-like 2 (TCF7L2) and that the risk region physically interacts with the MYC proto-oncogene. These data provide strong support for a biological mechanism underlying this non-protein-coding risk variant.

Genetic structure of Europeans: a view from the North-East

Abstract: Using principal component (PC) analysis, we studied the genetic constitution of 3,112 individuals from Europe as portrayed by more than 270,000 single nucleotide polymorphisms (SNPs) genotyped with the Illumina Infinium platform. In cohorts where the sample size was >100, one hundred randomly chosen samples were used for analysis to minimize the sample size effect, resulting in a total of 1,564 samples. This analysis revealed that the genetic structure of the European population correlates closely with geography. The first two PCs highlight the genetic diversity corresponding to the northwest to southeast gradient and position the populations according to their approximate geographic origin. The resulting genetic map forms a triangular structure with a) Finland, b) the Baltic region, Poland and Western Russia, and c) Italy as its vertexes, and with d) Central- and Western Europe in its centre. Inter- and intra- population genetic differences were quantified by the inflation factor lambda (lambda) (ranging from 1.00 to 4.21), fixation index (F(st)) (ranging from 0.000 to 0.023), and by the number of markers exhibiting significant allele frequency differences in pair-wise population comparisons. The estimated lambda was used to assess the real diminishing impact to association statistics when two distinct populations are merged directly in an analysis. When the PC analysis was confined to the 1,019 Estonian individuals (0.1% of the Estonian population), a fine structure emerged that correlated with the geography of individual counties. With at least two cohorts available from several countries, genetic substructures were investigated in Czech, Finnish, German, Estonian and Italian populations. Together with previously published data, our results allow the creation of a comprehensive European genetic map that will greatly facilitate inter-population genetic studies including genome wide association studies (GWAS).

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

Abstract: Lapatinib is a human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor (TKI) that has clinical activity in HER2-amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially non-overlapping mechanisms of action. To dissect these mechanisms, we have studied the effects of lapatinib and trastuzumab on receptor expression and receptor signaling and have identified a new potential mechanism for the enhanced antitumor activity of the combination. Lapatinib, given alone or in combination with trastuzumab to HER2-overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation, prevented receptor ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modeling techniques we have shown that the lapatinib-induced HER2 accumulation at the cell surface also results in the stabilization of inactive HER2 homo- (HER2/HER2) and hetero- (HER2/EGFR and HER2/HER3) dimers. Lapatinib-induced accumulation of HER2 and trastuzumab-mediated downregulation of HER2 was also observed in vivo, where the combination of the two agents triggered complete tumor remissions in all cases after 10 days of treatment. Accumulation of HER2 at the cell surface by lapatinib enhanced immune-mediated trastuzumab-dependent cytotoxicity. We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors.

A naturally occurring HER2 carboxy-terminal fragment promotes mammary tumor growth and metastasis.

Abstract: HER2 is a tyrosine kinase receptor causally involved in cancer. A subgroup of breast cancer patients with particularly poor clinical outcomes expresses a heterogeneous collection of HER2 carboxy-terminal fragments (CTFs). However, since the CTFs lack the extracellular domain that drives dimerization and subsequent activation of full-length HER2, they are in principle expected to be inactive. Here we show that at low expression levels one of these fragments, 611-CTF, activated multiple signaling pathways because of its unanticipated ability to constitutively homodimerize. A transcriptomic analysis revealed that 611-CTF specifically controlled the expression of genes that we found to be correlated with poor prognosis in breast cancer. Among the 611-CTF-regulated genes were several that have previously been linked to metastasis, including those for MET, EPHA2, matrix metalloproteinase 1, interleukin 11, angiopoietin-like 4, and different integrins. It is thought that transgenic mice overexpressing HER2 in the mammary glands develop tumors only after acquisition of activating mutations in the transgene. In contrast, we show that expression of 611-CTF led to development of aggressive and invasive mammary tumors without the need for mutations. These results demonstrate that 611-CTF is a potent oncogene capable of promoting mammary tumor progression and metastasis.

Business ethics in Islam: the glaring gap in practice

Abstract: – The purpose of this paper is to examine and discuss business ethics from an Islamic perspective., – Descriptive, analytical, and comparative analyses are used., – The study reveals several factors that affect Muslims' ethical behavior, including legal, organizational, and individual factors. However, there are factors that affect manager's unethical behavior; for example, stage of moral development, family influence and peer influence. The paper outlines some of the ethical guidelines that should be manifested in a Muslim manager, such as being trustful, honest, and consultative. Finally, the paper highlights some of the moral issues that seem to be common between Islam and other religions such as no lying, stealing, fraud, or deceit., – The paper provides insights into Islamic work ethics for Western managers and employees, enabling them to work more effectively with Islamic managers, employees, and business partners. It is believed that the paper will provide a better understanding of Muslim societies in general and Islamic managers in particular. It also has some implications for Islamic managers and employees who have to deal with ethical dilemmas as well as situations that offer potential benefits or gains and are considered unethical on a daily basis. It is also hoped that this paper will reinforce managers' Islamic behavior and make them more aware of the code of conduct on business., – The findings presented in this research can be used by Western managers, employees, business partners, and academicians as a guide to Islamic work ethics in Muslim societies., – The paper makes a contribution to the literature on Islamic work ethics. It is believed to be one of few studies investigating the issue of management ethics in Islam. The findings presented will be of genuine interest to Western and non‐Western managers, employees, and academicians.

Predicting responders to therapies for multiple sclerosis

Abstract: Therapies for relapsing-remitting multiple sclerosis (RRMS) are only partially effective, and, in most patients receiving such treatment, clinical activity persists. Accurately assessing the treatment response to disease-modifying agents enables non-responder patients to be identified at an early stage into therapy. Patients can then be switched to another, potentially more effective, therapy before too much neurological damage has occurred. Several criteria based on relapses, disability progression or both have been proposed for clinical evaluation of the treatment response to disease-modifying agents. These criteria have not been independently validated, however, and no consensus over which are the best to use currently exists among investigators. MRI can also be employed to detect disease activity in patients treated with disease-modifying agents. Changes on MRI can provide subclinical data relating to disease activity that can be of great benefit in patients monitoring, as inflammatory events occur more often than clinical events. Pharmacogenomic approaches are in the early stages of development for MS, but hold great promise for the eventual development of individually tailored therapies. In this Review, we discuss the proposed approaches for monitoring and predicting treatment responses to disease-modifying agents in patients with RRMS. We evaluate the roles of clinical measures, MRI and pharmacogenomics in these processes.

Phase II Genomics Study of Ixabepilone as Neoadjuvant Treatment for Breast Cancer

Abstract: Purpose This phase II study evaluated the efficacy and safety of ixabepilone as neoadjuvant therapy for invasive breast cancer not amenable to breast conservation surgery. Gene expression studies were undertaken using genes that were identified as potentially associated with sensitivity/resistance to ixabepilone in prior preclinical investigations. Patients and Methods Patients with invasive breast cancer ≥ 3 cm were eligible. Ixabepilone 40 mg/m2 was administered as a 3-hour intravenous infusion on day 1 of a 21-day cycle for four or fewer cycles. Results One hundred sixty-one patients were treated. The overall complete pathologic response (pCR) rate was 18% in breast and 29% in estrogen receptor (ER) –negative patients. Gene expression data were available for 134 patients. ER gene expression (ER1) was inversely related to pCR in breast and had a positive predictive value (PPV) of 37% and negative predictive value (NPV) of 92%. A 10-gene penalized logistic regression (PLR) model developed from 200 genes ...

The Effect of Water Harvesting Techniques on Runoff, Sedimentation, and Soil Properties

Abstract: This study addressed the hydrological processes of runoff and sedimentation, soil moisture content, and properties under the effect of different water harvesting techniques (treatments). The study was conducted at three sites, representing environmental condition gradients, located in the southern part of the West Bank. For each treatment, the study evaluated soil chemical and physical properties, soil moisture at 30 cm depth, surface runoff and sedimentation at each site. Results showed that runoff is reduced by 65-85% and sedimentation by 58-69% in stone terraces and semi-circle bunds compared to the control at the semi-humid site. In addition, stone terraces and contour ridges significantly reduced the amount of total runoff by 80% and 73%, respectively, at the arid site. Soil moisture content was significantly increased by water harvesting techniques compared to the control in all treatments at the three study sites. In addition, the difference between the control and the water harvesting structures were higher in the arid and semi-arid areas than in the semi-humid area. Soil and water conservation, via utilization of water harvesting structures, is an effective principle for reducing the negative impact of high runoff intensity and subsequently increasing soil moisture storage from rainfall. Jessour systems in the valley and stone terraces were effective in increasing soil moisture storage, prolonging the growing season for natural vegetation, and decreasing the amount of supplemental irrigation required for growing fruit trees.

Seroprevalence and associated risk factors of toxoplasmosis in pregnant women in Hebron district, Palestine.

Abstract: To measure the prevalence of toxoplasmosis, we tested 204 pregnant women for IgG and IgM antibodies to Toxoplasma gondii using an enzyme-linked immunoassay. The study was conducted in Hebron district during the year 2005. The seroprevalence of IgG antibodies to T. gondii was 27.9% from rural areas (36.8%) had IgG antibodies to T. gondii than urban women (21.4%). Possible routes of infection were contaminated soil, drinking rainwater and eating raw vegetables rather than eating uncooked meat or contact with cats. The prevalence of previous abortion was 37.3%, with a slight (but not statistically significant) association with toxoplasmosis.

Nonpegylated liposomal doxorubicin (TLC-D99), paclitaxel, and trastuzumab in HER-2-overexpressing breast cancer: a multicenter phase I/II study.

Abstract: Purpose: To determine the recommended dose, cardiac safety, and antitumor activity of nonpegylated liposomal doxorubicin (TLC-D99), paclitaxel, and the anti-HER-2 monoclonal antibody trastuzumab in patients with HER-2-overexpressing locally advanced nonoperable breast cancer (LABC) and metastatic breast cancer (MBC). Experimental Design: Women with measurable, previously untreated, HER-2-overexpressing LABC and MBC with a baseline left ventricular ejection fraction (LVEF) >50% received weekly trastuzumab in combination with escalating doses of weekly paclitaxel and TLC-D99 every 3 weeks for 6 cycles. LVEF monitoring was done every 3 weeks for the first 18 weeks and every 8 weeks thereafter. Results: Sixty-nine patients participated, 15 in the dose escalating part and 54 at the recommended phase II dose (28 patients with LABC and 26 patients with MBC). The recommended doses of TLC-D99 and paclitaxel were 50 mg/m 2 every 3 weeks and 80 mg/m 2 /wk, respectively. Twelve (17%) patients developed asymptomatic declines in LVEF. In 8 of these patients, LVEF recovered to ≥50% after a median time of 9 weeks (range, 3-38 weeks). In the rest of patients, LVEF ranged from 44% to 49%. No patients developed symptomatic cardiac heart failure. The overall response rate was 98.1% (95% confidence interval, 90.1-99.9) with a median time to progression not reached in LABC and of 22.1 months (95% confidence interval, 16.4-46.3) in MBC patients. Conclusions: Nonpegylated doxorubicin, paclitaxel, and trastuzumab combination is safe, does not result in clinically manifest cardiac toxicity, and has a high rate of durable responses in HER-2-overexpressing breast cancer patients. Further exploration of this combination is warranted.

Proteomic approach to ETV5 during endometrial carcinoma invasion reveals a link to oxidative stress

Abstract: Endometrial cancer, the most common gynecological malignancy in western countries, is characterized by a favorable prognosis. Nonetheless, deep myometrial invasion correlates with more undifferentiated tumors, lymph-vascular invasion, node involvement and decreased global survival. We have described previously the Ets family member ERM/ETV5 specifically upregulated in endometrial endometrioid carcinoma (EEC) associated with myometrial infiltration. To understand the role of this transcription factor during myometrial infiltration, we analyzed by two-dimension differential gel electrophoresis (2D-DIGE) technology those proteins whose expression was altered in endometrial cell lines stably overexpressing ERM/ETV5. Pathway analysis pointed to actin regulation and transforming growth factor beta and progesterone signaling as processes regulated by ERM/ETV5. In addition, we characterized the specific upregulation of the nuclear dehydrogenase/reductase Hep27 as well as its ERM/ETV5-dependent mitochondrial localization. Further functional studies demonstrated a protective role of Hep 27 against apoptosis induced by oxidative stress. Overall, the ETV5-related proteomic approach performed in the Hec-1A cell line reinforces a role of this transcription factor in the regulation of the migratory and invasive tumor behavior and points to a modulated response to oxidative stress associated with the promotion of invasion in endometrial cancer. Unraveling the molecular events in EEC associated with the initiation of tumor invasion would represent an obvious improvement in the pursuit of rational targets for the onset of metastasis. This knowledge would also be a valuable tool for the molecular stratification of patients since myometrial affectation determines an increase in the rate of recurrence after a first surgical treatment and a decrease in 5 year survival.

Gene expression of paired abdominal adipose AQP7 and liver AQP9 in patients with morbid obesity: relationship with glucose abnormalities.

Abstract: The trafficking of glycerol from adipose and hepatic tissue is mainly mediated by 2 aquaporin channel proteins: AQP7 and AQP9, respectively. In rodents, both aquaporins were found to act in a coordinated manner. The aim was to study the relationship between adipose AQP7 and hepatic AQP9 messenger RNA expression and the presence of glucose abnormalities simultaneously in morbid obesity. Adipose tissue (subcutaneous [SAT] and visceral [VAT]) and liver biopsies from the same patient were obtained during bariatric surgery in 30 (21 male and 9 female) morbidly obese subjects. Real-time quantification of AQP7 in SAT and VAT and hepatic AQP9 gene expression were performed. A 75-g oral glucose tolerance test was performed in all subjects. The homeostasis model assessment of insulin resistance and lipidic profile were also determined. Visceral adipose tissue AQP7 expression levels were significantly higher than SAT AQP7 (P = .009). Subcutaneous adipose tissue AQP7 positively correlated with both VAT AQP7 and hepatic AQP9 messenger RNA expression (r = 0.44, P = .013 and r = 0.45, P = .012, respectively). The correlation between SAT AQP7 and liver AQP9 was stronger in intolerant and type 2 diabetes mellitus subjects (r = 0.602, P = .011). We have found no differences in compartmental AQP7 adipose tissue distribution or AQP9 hepatic gene expression according to glucose tolerance classification. The present study provides, for the first time, evidence of coordinated regulation between adipose aquaglyceroporins, with a greater expression found in visceral fat, and between subcutaneous adipose AQP7 and hepatic AQP9 gene expression within the context of human morbid obesity.

Elderly patients with advanced colorectal cancer derive similar benefit without excessive toxicity after first-line chemotherapy with oxaliplatin-based combinations: comparative outcomes from the 03-TTD-01 phase III study.

Abstract: Purpose Healthy elderly patients with metastatic colorectal cancer may benefit from chemotherapy as much as the younger population. This analysis compares the outcomes of first-line oxaliplatin plus fluoropyrimidines in elderly versus young patients. Patients and methods 348 patients were randomized to capecitabine 1000mg/(m 2 12h), days 1–14 plus oxaliplatin 130mg/m 2 day 1, every 3 weeks or weekly infusional 5-FU 2250mg/m 2 over 48h plus bimonthly oxaliplatin 85mg/m 2 . We evaluated response rate, time to progression, overall survival and toxicity according to age. Results ORR for elderly and young patients were 34.9% and 44.7%, respectively ( p =0.081). Median TTP did not differ between the two groups: 8.3 months for patients ≥70 years and 9.6 months for those p =0.114). Median OS was 16.8 months and 20.5 months for the ≥70 and p =0.74). With XELOX, mild paresthesia and an increase in transaminase levels were more frequent for young patients, whereas grade 3/4 diarrhea was higher in those ≥70 years (25% vs. 8%, p =0.005). For FUOX, only paresthesia was significantly lower in patients ≥70 years (53% vs. 71%, p =0.032). Conclusion Elderly patients with MCRC benefit from first-line oxaliplatin–fluoropyrimidine combinations as much as younger patients, without increased toxicity.

An orthotopic endometrial cancer mouse model demonstrates a role for RUNX1 in distant metastasis.

Abstract: Endometrial carcinoma is the most common malignancy of the female genital tract in industrialized countries. Metastasis is the major cause of endometrial cancer deaths. Therefore, there is a vital need for clinically relevant in vivo models allowing the elucidation of the molecular and cellular mechanisms underlying metastatic behavior. In this study, we describe an innovative experimental orthotopic model of human endometrial carcinoma. Implantation in the bifurcation of the uterine horns resulted in tumors integrated into the myometrial compartment, which can be used and further exploited for the study of in vivo angiogenesis, myometrial invasion, and the metastatic capacity of endometrial cancer cells. This orthotopic model also represents a suitable tool to analyze how tumorigenesis and distant metastasis of endometrial cancer might be influenced by gene alteration, by modulating its expression in the original cancer cell line. One of the candidate genes implicated in endometrial cancer is the transcription factor RUNX1. The over-expression of RUNX1 in the endometrial cancer cell line HEC1A and the transplantation of these cells to the uterus of nude mice were associated specifically with distant metastasis in the lung. RUNX1 plays a role in the establishment of metastases in endometrial cancer. Translated to the clinics, these models would be equivalent to an advanced undifferentiated carcinoma with node affectation (stage IIIC) and distant metastasis (stage IVB). These patients would be candidates for adjuvant therapy, not efficient until today, and therefore, our models are actually suitable for the design and evaluation of experimental therapies.

Updated Survival Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab Therapy.

Abstract: Background: The synergistic interaction of lapatinib combined with trastuzumab was established in HER2-positive preclinical models, hence providing the rationale to evaluate this combination in a clinical setting Progression-free survival (PFS) from study EGF104900 revealed the combination of lapatinib plus trastuzumab was superior to lapatinib alone in women with HER2-positive metastatic breast cancer (MBC) that progressed on multiple lines of trastuzumab-based therapy Preliminary data showed a trend in overall survival (OS) favoring the combination therapy; however, data were not mature Updated OS analyses are reportedMethods: Women with HER2-positive MBC progressing on prior trastuzumab-containing regimens were randomized to receive either lapatinib 1500 mg once daily or lapatinib 1000 mg once daily in combination with trastuzumab 2 mg/kg (after a 4-mg/kg loading dose) If objective disease progression occurred on or after 4 weeks of lapatinib alone, crossover to the combination arm was permitted OS was summarized using Kaplan-Meier curves and compared between treatment arms using stratified log-rank tests Analyses adjusting for baseline prognostic factors and crossover were also performedResults: 296 women were randomized (148 per arm) The median number of prior trastuzumab-containing regimens for MBC treatment was 3 Of the women randomized to lapatinib alone, 52% (77/148) crossed over to the combination arm At data cut-off for updated OS, 218 deaths (74%) had occurred Median OS following treatment with lapatinib plus trastuzumab was 607 weeks compared with 414 weeks for lapatinib alone A significant improvement in OS was demonstrated with combination therapy compared with lapatinib monotherapy (HR: 074; 95% CI: 057, 097; P=026) The survival benefit was maintained after adjusting for baseline prognostic factors (HR: 071; 95% CI: 054, 093; P=012) A trend toward a clinically relevant 25% reduction in risk of death (P=080) was also observed after adjusting for crossoverConclusion: A statistically significant OS benefit was observed in women with heavily pretreated, HER2-positive MBC treated with lapatinib in combination with trastuzumab compared with those treated with lapatinib alone The actual survival benefit of the combination therapy may be underestimated due to the high frequency of crossover Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 61

Delayed immune-mediated adverse effects related to polyacrylamide dermal fillers: clinical findings, management, and follow-up.

Abstract: BACKGROUNDIt has been thought that polyacrylamide (PA) injections do not have inflammatory side effects. Recent evidence shows that local and regional delayed adverse effects may appear with its use.OBJECTIVETo evaluate the clinical complaints and follow-up of patients with delayed immune-mediated a

Phase II trial of preoperative irinotecan-cisplatin followed by concurrent irinotecan-cisplatin and radiotherapy for resectable locally advanced gastric and esophagogastric junction adenocarcinoma.

Abstract: Purpose To determine in a Phase II trial whether preoperative irinotecan–cisplatin (IC) followed by concurrent IC therapy and radiotherapy (IC/RT) improved outcome in patients with resectable, locally advanced gastric adenocarcinoma (GC) or esophagogastric junction cancer (EGJC). Patients and Methods Patients with resectable Stage II–IV, M0 GC or EGJC made up the study population. The primary endpoint was pathologic complete response (pCR). Two courses of IC (irinotecan, 65mg/m 2 ; cisplatin, 30mg/m 2 on Days 1 and 8 every 21 days) were given. Patients without progression then received IC/RT, consisting of daily radiotherapy (45Gy) with concurrent IC (irinotecan, 65mg/m 2 ; cisplatin, 30mg/m 2 on Days 1, 8, 15, and 22). Surgical resection was performed, if feasible, 5–8 weeks after the end of radiotherapy. Results Twenty-three patients were included in the study: 10 with EGJC and 13 with GC. Two patients (9%) achieved pCR. The incidences of Grade 3–4 toxicities were as follows: IC: neutropenia 35% (febrile 13%), anemia 22%, diarrhea 22%, emesis 8%; IC/RT: neutropenia 52% (febrile 5%), asthenia 19%, anemia 9%, emesis 9%, diarrhea 5%, cardiotoxicity 5%. No patients died during IC or IC/RT. R0 resection was achieved in 15 patients (65%). Median survival was 14.5 months, and the actuarial 2-year survival rate was 35%. Conclusions Preoperative IC followed by IC/RT resulted in moderate response and resection rates with mild toxicity in patients with GC and EGJC.

Late-Onset Immune-Mediated Adverse Effects after Poly-L-Lactic Acid Injection in Non-HIV Patients: Clinical Findings and Long-Term Follow-Up

Abstract: Background: It has been thought that poly-L-lactic acid (PLLA) injections do not have inflammatory side effects. Recent evidence shows that local/regional/systemic delayed adverse effects may appear with its use. Objective: To evaluate the clinical complaints, treatment response and long-term follow-up of non-HIV patients with delayed immune-mediated adverse effects related to PLLA injections. Methods: Prospective, case series study of 10 patients with delayed adverse effects related to PLLA injections. The inclusion criterion was defined as the onset at least 6 months after PLLA use, with 1 or more of the following clinical signs: oedema, skin induration, swelling/tender nodules with or without discharge of pus or filler material. Several systemic manifestations were also included. Patients with immediate side effects were excluded. Patients underwent clinical management and long-term follow-up. Results: The average latency period to the onset of symptoms was 19.2 months (range: 6–60). Tender, inflammatory nodules and facial oedema were commonly seen. One case presented a systemic granulomatous disorder as a complication. After 50.2 months of average follow-up (range: 38–78), 5 patients are in remission, 4 have recurrent bouts and the last case has been lost to follow-up. Conclusion:Although infrequently, local and/or regional and/or systemic delayed and recurrent granulomatous reactions may complicate PLLA gel injections.

Final Overall Survival (OS) Results from the Randomised, Double-Blind, Placebo-Controlled, Phase III AVADO Study of Bevacizumab (BV) Plus Docetaxel (D) Compared with Placebo (PL) Plus D for the First-Line Treatment of Locally Recurrent (LR) or Metastatic Breast Cancer (mBC).

Abstract: Background: Anti-VEGF monoclonal antibody BV significantly improves efficacy in combination with standard therapies in multiple tumour types, with limited impact on toxicity. Three randomised phase III trials (E2100, AVADO and RIBBON-1) in mBC have demonstrated that BV + 1st-line chemotherapy (CTx) significantly improves progression-free survival (PFS) and overall response rates (ORR). We present mature OS data from AVADO.Methods: Patients (pts) with HER2-negative LR/mBC were randomised to D 100mg/m2 + PL, D + BV 7.5mg/kg or D + BV 15mg/kg. D was given q3w for ≤9 cycles. BV or PL was given q3w until disease progression/unacceptable toxicity. After progression, pts were offered BV with 2nd-line anticancer therapy in a post-study treatment phase. The primary endpoint was PFS; secondary endpoints included OS, time to treatment failure, ORR, duration of response and safety. An exploratory analysis conducted in pts receiving post-progression CTx compared OS in pts receiving 2nd-line BV with those who did not.Results: 736 pts were enrolled March 2006–April 2007. The primary analysis (data cut-off October 2007; median follow-up 10.2 months) showed significant improvements in PFS and ORR for both BV-containing arms compared with PL + D. Mature OS data (data cut-off April 2009; median follow-up 25 months) are shown (Table). There was no difference in median OS between the study arms (range 30–32 months). Recognising the limitations of the non-randomised comparison in exploratory analyses, results suggest that use of BV with 2nd-line therapy is a possible reason for lack of OS difference. Updated PFS and ORR were superior for the 15mg/kg BV arm compared with PL + D. Results for the 7.5mg/kg BV arm also indicated a, less pronounced, treatment benefit. BV had limited impact on the safety profile of docetaxel. Increased SAEs in the 15mg/kg BV arm may be due to more pts receiving 9 cycles of D than in the PL arm (51% vs 42%).Conclusions: There was no difference in OS between study arms. Exploratory analyses suggest that use of 2nd-line BV with CTx may influence OS. These mature data confirm the improvement in PFS and ORR with BV 15mg/kg combined with D compared with PL + D. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 41.