Citations

Purpose The characteristics and natural history of the paclitaxel–acute pain syndrome (P-APS) and paclitaxel's more chronic neuropathy have not been well delineated. Methods Patients receiving weekly paclitaxel (70 to 90 mg/m 2 ) completed daily questionnaires and weekly European Organisation for Research and Treatment of Cancer (EORTC) Chemotherapy-Induced Peripheral Neuropathy (CIPN) –20 instruments during the entire course of therapy. Results P-APS symptoms peaked 3 days after chemotherapy. Twenty percent of patients had pain scores of 5 to 10 of 10 with the first dose of paclitaxel. Sensory neuropathy symptoms were more prominent than were motor or autonomic neuropathy symptoms. Of the sensory neuropathy symptoms, numbness and tingling were more prominent than was shooting or burning pain. Patients with higher P-APS pain scores with the first dose of paclitaxel appeared to have more chronic neuropathy. Conclusion These data support that the P-APS is related to nerve pathology as opposed to being arthralgias and/or myalgias. Numbness and tingling are more prominent chronic neuropathic symptoms than is shooting or burning pain.

Purpose This phase III study compared the efficacy and safety of bevacizumab (BV) when combined with several standard chemotherapy regimens versus those regimens alone for first-line treatment of patients with human epidermal growth factor receptor 2–negative metastatic breast cancer. Patients and Methods Patients were randomly assigned in 2:1 ratio to chemotherapy plus BV or chemotherapy plus placebo. Before random assignment, investigators chose capecitabine (Cape; 2,000 mg/m 2 for 14 days), taxane (Tax) -based (nab-paclitaxel 260 mg/m 2 , docetaxel 75 or 100 mg/m 2 ), or anthracycline (Anthra) -based (doxorubicin or epirubicin combinations [doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide, fluorouracil/epirubicin/cyclophosphamide, or fluorouracil/doxorubicin/cyclophosphamide]) chemotherapy administered every 3 weeks. BV or placebo was administered at 15 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), 1-year survival rate, objective response rate, duration of objective response, and safety. Two independently powered cohorts defined by the choice of chemotherapy (Cape patients or pooled Tax/Anthra patients) were analyzed in parallel. Results RIBBON-1 (Regimens in Bevacizumab for Breast Oncology) enrolled 1,237 patients (Cape cohort, n = 615; Tax/Anthra cohort, n = 622). Median PFS was longer for each BV combination (Cape cohort: increased from 5.7 months to 8.6 months; hazard ratio [HR], 0.69; 95% CI, 0.56 to 0.84; log-rank P < .001; and Tax/Anthra cohort: increased from 8.0 months to 9.2 months; HR, 0.64; 95% CI, 0.52 to 0.80; log-rank P < .001). No statistically significant differences in OS between the placebo- and BV-containing arms were observed. Safety was consistent with results of prior BV trials. Conclusion The combination of BV with Cape, Tax, or Anthra improves clinical benefit in terms of increased PFS in first-line treatment of metastatic breast cancer, with a safety profile comparable to prior phase III studies.

Abstract We have demonstrated that crosstalk between the Hedgehog-GLI-GLI and EGFR signaling pathway exists and contribute to pancreatic tumorigenesis. This interaction can be abrogated by targeting both pathways simultaneously and results in a synergistic antitumor effect in vitro and in vivo in pancreatic tumor models. Based on these results we have undertaken a phase I trial of GDC-0449 (an orally administered Hedgehog pathway inhibitor) and erlotinib (EGFR tyrosine kinase inhibitor to: 1) determine the maximally tolerated dose (MTD) of GDC-0449 combined with erlotinib in unresectable solid tumors; 2) describe the adverse events associated with this treatment combination; 3) describe the responses of this treatment combination; and 4) to assess the effect of the erlotinib and GDC-0449 combination on selected biomarkers in circulating tumor cells (CTCs), tumor biopsies, and FDG-PET in a cohort of patients with metastatic pancreatic cancer patients treated at the MTD. During the dose escalation portion of the trial, eligible patients receive GDC-0449 150 mg p.o. daily and erlotinib 50, 75, 100, or 150 mg daily p.o. at dose levels 1, 2, 3, and 4 respectively. Eligibility criteria include: histologic proof of solid tumors that are unresectable, not amenable to any other standard therapies, or patient refused standard therapy,; ANC ≥&gt; 1500/μL; PLT ≥&gt; 100,000/ μL; Total bilirubin ≤&lt; upper limit of normal (ULN); AST ≤&lt; 3 x ULN; Creatinine ≤&lt; 1.5 x ULN; Hemoglobin ≥&gt; 9.0 g/dL; INR within normal limits (Cohort II [MTD Cohort] only); ECOG performance status (PS) 0, 1 or ≤ 2. For the MTD cohort, only patients with metastatic adenocarcinoma of the pancreas without prior systemic therapy for metastatic disease and tumor amenable to biopsies are eligible. Toxicity assessment is performed at each 28-day treatment cycles and response assessment every second treatment 28 day cycle. 12 patients have been entered-pancreas (3), colorectal (3), neuroendocrine (2), scc anus (2), gallbladder (1), thymoma (1). No dose-limiting toxicity (DLT) was reported at dose level 4. At the MTD, up to 20 patients with previously untreated metastatic pancreatic cancer will be entered to assess the biologic effect of GDC-0449+erlotinib. Pre- and post- treatment biopsies of metastases and FDG-PET will be performed. Weekly collection of CTCs will be undertaken and immunofluorescence microscopy of total & phosphoMAPK, EGFR, AKT, PATCHED1, GLI1, BCL-2, and quantitative PCR (Q-PCR) of PATCHED1, GLI1, and its target genes (BCL-2, BFL-1/A1, 4-1BB) will be performed. In addtion, total & phosphoMAPK, EGFR, and AKT, as well as PATCHED1, GLI1, BCL-2 by immunohistochemistry and Q-PCR of PATCHED1, GLI1, BCL-2, BFL-1/A1, 4-1BB will be analyzed in tumor biopsies. Supported by CA69912, CA136526 and CA102701. 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 1807.

Abstract DNA methylation abnormalities, either gain or loss of methylation in promoters or other regulatory regions, contribute to tumorigenesis by altering the activity of tumor suppressor or oncogenes. To identify the molecular alterations in prostate cancer, we have profiled gene methylation using Infinium Human Methylation27 bead chips in benign prostate tissue, primary prostate tumor tissue from patients who developed metastasis within 5 years of prostatectomy, and serum from patients who developed metastasis. Tissue DNA isolation and bisulfite conversion was done using ZR Genomic DNA kit and EZ methylation kit. Serum DNA isolation and bisulfite conversion was done using ZR serum DNA kit and EZ methylation kit. Methylation data was processed using the Beadstudio average normalization algorithm and differentially methylated genes identified using a two-group T-test p-value &lt; 0.05. To evaluate the impact of methylation on mRNA expression levels, we isolated RNA from LCM-derived epithelial cells of 124 patients using Picopure RNA isolation kit and measured expression using HG-U133+2 microarrays. The gene expression data was preprocessed using GCRMA background correction, FASTLO normalization, affinities-only PM correction, and median polish summarization, and differential gene expression was defined by a two-group T-test p-value &lt; 0.05, a log2 fold change &gt; 1, and a maximum average expression value &gt; log2 7. Comparison of the methylation and gene expression data identified 321 differentially expressed Affymetrix probesets which mapped to genes differentially methylated genes; 272 with differential methylation in the prostate cancer tissue and 97 with differential methylation in the prostate cancer serum. In general, we expected a complementary effect between gene methylation and expression, with hyper-methylation driving decreased expression, and hypo-methylation driving increased expression. This was seen in the prostate cancer tissue methylation data, where 228/272 (84%) probesets possessed this methylation-expression complementarity; 212/238 hyper-methylated genes and 16/34 hypo-methylated genes. The effect was not as strong in the prostate cancer serum methylation data, where 30/97 (31%) probesets displayed the methylation-expression complementarity; 19/79 hyper-methylated genes and 11/18 hypo-methylated genes. Overall, our results revealed a significant correlation of the DNA methylation with the down regulation in the mRNA expression levels of the genes, which could play potential roles in prostate cancer progression. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 4950.

Background— Prior studies demonstrate a direct relationship between treatment delays to primary percutaneous intervention and mortality in patients with ST-segment elevation myocardial infarction (STEMI). This analysis compared the relationship of symptom onset-to-balloon time and door-to-balloon time on mortality in patients with STEMI. Methods and Results— We analyzed different treatment delays (symptom onset-to-balloon time, door-to-balloon time) and mortality in 5745 STEMI patients. Baseline characteristics, flow grade, 90-day mortality, and clinical outcomes were compared in patients stratified by treatment delay. Multivariable logistic regression modeling was performed to assess the independent and relative effect of each treatment delay on 90-day mortality. Female sex, increased age, and worse thrombolysis in myocardial infarction flow grade were significantly associated with longer symptom onset-to-balloon times and door-to-balloon times. Longer symptom onset-to-balloon time was significantly associated with worse 90-day mortality (3.7%, 4.2%, and 6.5% for time delays <3 hours, 3 to 5 hours, and >5 hours, respectively, P <0.0001). Similarly, longer door-to-balloon times were significantly associated with worse 90-day mortality (3.2%, 4.0%, 4.6%, and 5.3% for delays <60 minutes, 60 to 90 minutes, 90 to 120 minutes, and ≥120 minutes respectively, P <0.0001). In a multivariate model of 90-day mortality, door-to-balloon time (χ 2 6.0, P <0.014), and symptom onset-to-hospital arrival (χ 2 9.8, P <0.007) remained independent determinants. Conclusions— Both symptom onset-to-balloon time and hospital door-to-balloon time are strongly associated with 90-day mortality following STEMI. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00091637.

Abstract Purpose: PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer. Experimental Design: We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and array CGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of ovarian cancer patients. Results: Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, RB, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration-and time-dependent manner, and enhanced the effects of chemotherapy. Rb-proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and was independently associated with poor progression-free survival (adjusted relative risk 1.49, 95% CI 1.00–2.24, P = 0.052). Conclusions: PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer. Clin Cancer Res; 17(6); 1591–602. ©2011 AACR.

A perception that living donor liver transplantation can be accomplished with an acceptable donor complication rate and recipient survival rate has led to the acceptance of living donor liver transplantation as a viable alternative to decreased deceased donor transplantation. Careful candidate evaluation and selection has been crucial to the success of this procedure. Advancements in the understanding of the lobar nature of the liver and of liver regeneration have advanced the surgical technique. Initial attempts at adult-to-adult donation utilized the left hepatic lobe, but now have evolved into use of the right hepatic lobe. Size matching is very important to successful graft function in the recipient. There is great concern regarding morbidity and mortality in donors. Biliary complications and infections continue to be among the most highly reported complications, although rates vary among centers and countries. Reports of single center complications have ranged from 9% to 67%. A survey of centers in the United States in 2003 reported complications of 10%. A series from our institution reported complications arising in 13 (33%) of 39 patients. A review focused on documenting donor deaths found 33 living liver donor deaths worldwide. The much publicized immediate postoperative mishap of 2002 that resulted in a donor’s death resulted in a drop in the utilization of living donor liver transplantation in the United States, from which this procedure has never fully recovered. The future development and expansion of living donor liver transplantation depends on open communication regarding donor complications and deaths. Close immediate postoperative monitoring and meticulous management will remain an essential aspect in limiting donor complications and deaths.