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Killer cell Ig-like receptors (KIRs) bind cognate HLA class I ligands with distinct affinities, affecting NK cell licensing and inhibition. We hypothesized that differences in KIR and HLA class I genotypes predictive of varying degrees of receptor-ligand binding affinities influence clinical outcomes in autologous hematopoietic cell transplantation (AHCT) for acute myeloid leukemia (AML). Using genomic DNA from a homogeneous cohort of 125 AML patients treated with AHCT, we performed KIR and HLA class I genotyping and found that patients with a compound KIR3DL1(+) and HLA-Bw4-80Thr(+), HLA-Bw4-80Ile(-) genotype, predictive of low-affinity interactions, had a low incidence of relapse, compared with patients with a KIR3DL1(+) and HLA-Bw4-80Ile(+) genotype, predictive of high-affinity interactions (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.06-0.78; p = 0.02). This effect was influenced by HLA-Bw4 copy number, such that relapse progressively increased with one copy of HLA-Bw4-80Ile (HR, 1.6; 95% CI, 0.84-3.1; p = 0.15) to two to three copies (HR, 3.0; 95% CI, 1.4-6.5; p = 0.005) and progressively decreased with one to two copies of HLA-Bw4-80Thr (p = 0.13). Among KIR3DL1(+) and HLA-Bw4-80Ile(+) patients, a predicted low-affinity KIR2DL2/3(+) and HLA-C1/C1 genotype was associated with lower relapse than a predicted high-affinity KIR2DL1(+) and HLA-C2/C2 genotype (HR, 0.25; 95% CI, 0.09-0.73; p = 0.01). Similarly, a KIR3DL1(+) and HLA-Bw4-80Thr(+), HLA-Bw4-80Ile(-) genotype, or lack of KIR3DL1(+) and HLA-Bw4-80Ile(+) genotype, rescued KIR2DL1(+) and HLA-C2/C2 patients from high relapse (p = 0.007). These findings support a role for NK cell graft-versus-leukemia activity modulated by NK cell receptor-ligand affinities in AHCT for AML., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Purpose: Recent developments in rare-cell technology have led to improved blood-based assays that allow for the reliable detection, enumeration, and more recently, genomic profiling of circulating tumor cells (CTC). We evaluated two different approaches for enumeration of CTCs in a prospective therapeutic study of patients with metastatic triple-negative breast cancer (TNBC)., Experimental Design: The CellSearch system, a commercially available and U.S. Food and Drug Administration (FDA)-cleared assay for CTC enumeration, and IE/FC, an alternative method using EPCAM-based immunomagnetic enrichment and flow cytometry that maintains cell viability, were used to enumerate CTCs in the blood of patients with metastatic TNBC. CTC numbers were assessed at baseline and 7 to 14 days after initiation of therapy with cetuximab ± carboplatin in a phase II multicenter clinical trial (TBCRC 001)., Results: CTC numbers from two methods were significantly correlated at baseline (r = 0.62) and at 7 to 14 days (r = 0.53). Baseline CTCs showed no association with time-to-progression (TTP), whereas CTCs at 7 to 14 days were significantly correlated with TTP (CellSearch P = 0.02; IE/FC P = 0.03). CTCs at both time points were significantly associated with overall survival (OS) [CellSearch: baseline (P = 0.0001) and 7 to 14 days (P < 0.0001); IE/FC: baseline (P = 0.0009) and 7 to 14 days (P = 0.0086)]., Conclusions: Our findings demonstrate that CTC enumeration by two different assays was highly concordant. In addition, results of both assays were significantly correlated with TTP and OS in patients with TNBC. The IE/FC method is also easily adapted to isolation of pure populations of CTCs for genomic profiling., (©2014 American Association for Cancer Research.)

Overactivation of the ErbB protein family, which is comprised of 4 receptor tyrosine kinase members (ErbB1/epidermal growth factor receptor [EGFR]/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4), can drive the development and progression of a wide variety of malignancies, including colorectal, head and neck, and certain non-small cell lung cancers (NSCLCs). As a result, agents that target a specific member of the ErbB family have been developed for the treatment of cancer. These agents include the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib; the EGFR-targeting monoclonal antibodies cetuximab and panitumumab; and the HER2-targeting monoclonal antibody trastuzumab. Lapatinib is a dual TKI that targets both EGFR and HER2. In addition, TKIs that inhibit multiple members of the ErbB family and also bind their targets irreversibly are under evaluation for the treatment of cancer. Three such compounds have progressed into clinical studies: the EGFR, HER2, and HER4 inhibitors afatinib, dacomitinib, and neratinib. Phase I studies of these agents have shown clinical activity in NSCLC, breast cancer, and other malignancies. Currently, afatinib is approved for EGFR mutation-positive NSCLC and is in development for squamous NSCLC, and dacomitinib is in phase III of clinical development for NSCLC, neratinib is in phase III of clinical development for the treatment of breast cancer, and afatinib is also in phase III development in head and neck cancer. Final results from clinical trials may lead to the potential approval of these agents in a variety of solid tumor malignancies.

Objectives: Our goal was to evaluate the ability of the hematopoietic cell transplantation comorbidity index (HCT-CI) to predict outcomes after allogeneic stem cell transplant (SCT) within the context of an older patient population, where multiple comorbidities are common., Materials and Methods: We performed a retrospective cohort study of SCT patients ≥50years of age at our institution, identifying 59 patients with complete HCT-CI data collected prospectively., Results: HCT-CI category distribution in our sample was disproportionate, with almost half of patients having scores ≥3. High HCT-CI score (≥3 vs <3) was associated with significantly inferior OS (median OS not reached for HCT-CI <3 vs 14months for HCT-CI ≥3; hazard ratio (HR) 2.2, p=0.02). HCT-CI score was a better predictor of OS than age, performance status or conditioning intensity. When adjusted for disease relapse risk, HCT-CI score conferred a worse prognosis in the low risk group (HR 1.43, p=0.03) but not in the intermediate/high risk group (HR 1.08, p=0.65). NRM was low in the total sample (6% at one year) and was not associated with HCT-CI score. Grade 3-4 non-hematologic adverse events within the first 100days after SCT were significantly more common in the higher HCT-CI groups (p=0.02)., Conclusions: In our older patient cohort with a high incidence of multiple comorbidities, HCT-CI score ≥3 was significantly associated with OS, particularly in the subset of patients with a low disease relapse risk., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The 5-year survival of pancreatic adenocarcinoma with surgery and adjuvant chemotherapy is below 25%. The original Gastrointestinal Tumor Study Group (GITSG) adjuvant study demonstrated a survival benefit attributed to weekly intravenous boluses of 5-fluorouracil (5-FU) for 2 years in addition to chemoradiation compared to surgery alone. In theory, the prolonged exposure to therapy could maintain pressure on dormant cancer cells that remain in G0 arrest and kill them as they infrequently enter the G1/S phase. We retrospectively evaluated outcomes in patients who were treated with adjuvant chemotherapy and maintenance capecitabine compared with those who received only adjuvant chemotherapy., Methods: Patients who had undergone surgical resection with curative intent and received adjuvant chemotherapy were analyzed. Those who subsequently received maintenance capecitabine therapy were compared to those who received adjuvant chemotherapy only. The primary end points were disease recurrence and all-cause mortality., Results: The median overall survival (OS) of patients receiving maintenance capecitabine was greater than 48.4 months (the exact estimate was not available, since the survival probability curve does not cross 0.5). It was 22.0 months (95% confidence interval [CI], 16.6-29.2) in patients who received adjuvant chemotherapy only (P < .001 by log-rank test). The median recurrence-free survival (RFS) was also longer in the maintenance capecitabine group: 54.3 (95% CI, 22.2-Inf) compared to 14.1 (95% CI, 11.6-16.7) months (P < .001, by log-rank test)., Conclusions: In this retrospective study, patients with resected pancreatic adenocarcinoma who received adjuvant chemotherapy had improved OS and RFS with additional maintenance therapy with capecitabine. These findings should be confirmed with a randomized, controlled trial.

Inhibition of tumor angiogenesis has emerged as an important therapeutic component in the management of metastatic colorectal cancer. Three anti-angiogenic agents are currently approved in this clinical setting: bevacizumab, ziv-aflibercept, and regorafenib. Bevacizumab, a monoclonal antibody that targets the angiogenesis-driving ligand vascular endothelial growth factor A (VEGF-A), is the only anti-angiogenic agent approved in first-line therapy for metastatic colorectal cancer, where it can be used in combination with intravenous 5-fluorouracil-containing chemotherapy regimens. In conjunction with second-line chemotherapies, bevacizumab also has anti-cancer activity, both for the management of metastatic colorectal cancer in patients who received it as a part of their first line therapy and for those who are naïve to it. Ziv-aflibercept also has demonstrated clinical activity in conjunction with the chemotherapeutic regimen FOLFIRI in the second line management of patients with metastatic colorectal cancer; it functions by binding VEGF-A to the vascular endothelial growth factor proteins VEGF-B and PIGF (placental growth factor). Regorafenib, which inhibits multiple tyrosine kinases, including the VEGF receptors, has proven clinical benefit in the management of patients with metastatic colorectal cancer refractory to all other therapies. For patients' whose cancers are refractory to all other therapies, there is also evidence for the use of bevacizumab with fluoropyrimidine monotherapy, but only in the bevacizumab-naïve patient subset. Presently, it is not clear if any one agent as more activity in a particular line of therapy than another, has greater efficacy when paired with a particular chemotherapy backbone, or if a particular patient subset is more likely to benefit from these agents. Given the present benefit and tolerance data, an anti-angiogenic agent should be considered in all lines of therapy in the management of metastatic colorectal cancer, with the evidence for the use of these agents in each specific line of therapy and in specific chemotherapeutic combinations driving agent selection.

Purpose: Dysregulation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is seen in 40% to 60% of patients with colorectal cancer. Everolimus, an oral inhibitor of mTOR, showed efficacy in patients with metastatic colorectal cancers in phase I studies., Experimental Design: In sequential phase II studies assessing two dosing schedules, patients with metastatic colorectal cancers refractory to bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens received everolimus 70 mg/wk (n = 99) or 10 mg/d (n = 100). Primary endpoints were disease control rate (DCR) and objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), and duration of response or stable disease (SD). Tumor tissue was collected from all patients for predefined exploratory biomarker analyses., Results: Seventy-one patients were included in the per-protocol set for each cohort. DCRs of 31.0% and 32.4% (all SD) were seen in the weekly and daily schedules, respectively. Median duration of SD was 3.9 months in each cohort. Median PFS and OS were 1.8 and 4.9 months and 1.8 and 5.9 months, respectively, for the weekly and daily schedules. Among patients receiving daily everolimus, those with a KRAS mutation experienced significantly shorter median OS (P = 0.008) and lower DCR (P = 0.035) compared with those with wild-type KRAS in exploratory biomarker analyses., Conclusions: Everolimus 70 mg/wk or 10 mg/d was well tolerated but did not confer meaningful efficacy in heavily pretreated patients with metastatic colorectal cancers. Future studies may consider evaluating everolimus in combination with other agents or in patients with dysregulation of the PI3K/Akt/mTOR pathway.

Context: Data on the risk of postthyroidectomy complications in elderly patients are sparse, unclear, and conflicting., Objective: We sought to use a population-based cohort to determine whether thyroid operations in the elderly are as safe as those done in younger patients., Design: This was a prospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program database from 2005 to 2008, with 30-d postoperative follow-up., Setting: The American College of Surgeons National Surgical Quality Improvement Program data set contains operative cases from a nationwide sampling of academic and community-based as well as high-volume and low-volume hospitals., Patients: All thyroidectomy and parathyroidectomy patients reported to the database during the study period were included in the analysis resulting in an experimental cohort of 7915 thyroidectomy cases and a control cohort of 3575 parathyroidectomy cases., Main Outcome Measures: We aggregated 83 complications into the following outcome measures: urinary tract infection, wound infection, systemic infection, cardiac complications, pulmonary complications, 30-d mortality, and total hospital length of stay., Results: Increased age is a risk factor for significant pulmonary, cardiac, and infectious complications after thyroidectomy. Elderly patients are twice as likely (odds ratio 2.1, 95% confidence interval 1.4-3.3), and the superelderly are 5 times as likely (odds ratio 4.9, 95% confidence interval 2.5-9.6) to have a complication compared with their young counterparts. Preexisting comorbidities are effect modifiers and increase the risk of complications even further., Conclusions: Elderly thyroidectomy patients are at increased risk for major systemic complications. A systematic approach to the care of elderly thyroidectomy patients is necessary to minimize their risk of serious postoperative complications.

Context: Parathyroid carcinoma is a rare but ominous cause of primary hyperparathyroidism. OBJECTIVES AND MAIN OUTCOME MEASURES: The objective of the study was to review the outcomes of parathyroid cancer patients and to evaluate the factors associated with mortality., Design, Setting, and Patients: This was a retrospective review performed on 37 patients with parathyroid cancer treated at a single university tertiary care center between 1966 and 2009., Results: The average age at cancer diagnosis was 53 yr (range 23-75 yr), and 23 patients (62%) were men. Eighteen patients (49%) recurred after their initial cancer operation. The average number of neck dissections done for cancer was three (range 1-11). After initial diagnosis, 22 patients (60%) eventually developed complications, including unilateral (n = 11) or bilateral (n = 3) vocal cord paralysis (38%). Eight patients (22%) had, at some point, an associated benign parathyroid adenoma. Median overall survival was 14.3 yr (range 10.5-25.7 yr) from the date of diagnosis. Factors associated with increased mortality included lymph node or distant metastases, number of recurrences, higher calcium level at recurrence, and a high number of calcium-lowering medications. Factors not associated with mortality included age, race, tumor size, time to first recurrence, and extent of initial operation. Initial operations done at our center had improved survival (P = 0.037) and decreased complication rates (P < 0.001) vs. those done elsewhere., Conclusion: Parathyroid cancer patients typically have a long survival, which often includes multiple reoperations for recurrence and thus a high rate of surgical complications. Patients in whom there is a high index of suspicion for parathyroid cancer should be referred to a dedicated endocrine surgery center for their initial operation.

Gastric cancer is the second leading cause of cancer death worldwide. The local surgical treatment of gastric cancer varies geographically. However, there has been a confluence of opinion regarding the optimal therapy of gastric cancer toward multimodality therapy. In the East, many clinicians pursue adjuvant chemotherapy after a D2 resection. However, in the West, clinicians use either perioperative chemotherapy or postoperative chemoradiation. It remains unclear at this time whether either perioperative approach is the optimal approach.

Background: A 3-gene (PCSK2, PLAB, CCND2) assay has been reported to have high accuracy for distinguishing benign from malignant thyroid tumors that are often indeterminate on fine-needle aspiration (FNA) biopsy. The aim of the current study was to determine the diagnostic accuracy of the 3-gene assay in thyroid tissue and in FNA biopsy for distinguishing benign from malignant thyroid neoplasms., Methods: The messenger ribonucleic acid (mRNA) expression level of 3 genes (PCSK2, PLAB, CCND2) was analyzed by real-time quantitative reverse transcriptase-polymerase chain reaction in 261 frozen thyroid tissue samples (138 benign and 123 malignant), and prospectively, in 144 clinical thyroid FNA samples. To determine the diagnostic accuracy of the 3-gene assay, the area under the curve (AUC) of the receiver operating characteristic curve for each gene individually and in combination was determined., Results: PCSK2 and CCND2 mRNA expression levels were found to be significantly different between benign and malignant thyroid tissue samples (P < .0001 and P = .0007, respectively), but PLAB mRNA expression level was not (P = .099). In the thyroid tissue samples, the AUC was 0.67 for PCSK2 and 0.62 for CCND2. In the thyroid FNA samples, PCSK2 and CCND2 were significantly differentially expressed between benign and malignant samples (P = .039 and P = .023, respectively). The AUC was 0.59 for PCSK2 and 0.61 for CCND2., Conclusions: Although PCSK2 and CCND2 were significantly differentially expressed between benign and malignant thyroid tumors both in tissue and in FNA samples, the diagnostic accuracy of the 3-gene assay was low. These findings demonstrate that it is essential for studies to validate the diagnostic accuracy and clinical utility of emerging candidate diagnostic thyroid cancer markers if they are to be translated into clinically useful markers for making patient care decisions., ((c) 2008 American Cancer Society.)

Objective: Cancerous neovascular changes in histologically normal-appearing breast tissue have been shown to increase risk for local recurrence after breast-conserving therapy. However, the imaging characteristics of this tissue have not been well studied. We hypothesized that signal enhancement ratios from dynamic contrast-enhanced breast MRI could be used to analyze the contrast kinetics of microvasculature in breast stroma beyond the tumor margin and that this information can be developed to improve local treatment options., Materials and Methods: Signal enhancement ratio analysis of nontumor breast stroma was performed on dynamic contrast-enhanced MRI scans of 42 patients who received neoadjuvant chemotherapy for invasive breast cancer performed before chemotherapy (scan 1) and after one cycle of chemotherapy (scan 2). Stromal signal enhancement ratio values were then correlated to several clinical parameters and to clinical outcome using univariate and multivariate analyses. Median follow-up for the group was 52.1 months., Results: On univariate analysis, factors that were significantly associated (p < 0.05) with disease-free survival included the mean stromal signal enhancement ratio at scan 2 (hazard ratio [HR] = 0.11, 95% CI = 0.013-0.88, p = 0.03), pretreatment tumor size (HR = 1.33, 95% CI = 1.07-1.66, p = 0.012), pretreatment tumor volume (HR = 1.04, 95% CI = 1.01-1.07, p = 0.006), and number of involved axillary lymph nodes (HR = 1.18, 95% CI = 1.05-1.32, p = 0.005). These factors were then analyzed in a multivariate Cox proportional hazards model. The only factor that was associated with disease-free survival was mean stromal signal enhancement ratio at scan 2 (HR = 0.11, 95% CI = 0.012-0.95, p < 0.045)., Conclusion: These findings indicate that breast stroma tissue outside the incident tumor can be quantified using signal enhancement ratio analysis on dynamic contrast-enhanced MRI. Stromal signal enhancement ratio is a potential indicator for response to treatment and for overall outcome in patients with breast cancer; however, these results should be validated in a prospective study.

VGV-1, a clinical-grade formulation of bovine thymus nuclear protein (TNP) has been demonstrated to possess anti-viral activity in HIV-1 patients in five clinical trials, one of which was placebo controlled double-blinded. However, to date molecular mechanisms remain to be identified. Using surface plasmon resonance we observed TNP components bind with high affinity to HIV-1 proteins involved in viral entry, gp41 and pg120, as well as the T cell HIV-1 receptor CD4. To identify protein components of TNP, gel electrophoresis was performed followed by tandem mass spectrometry (MS/MS). Searching of bovine protein databases revealed the presence of numerous histones. Further analysis of TNP by immunoaffinity chromatography using gp120 and CD4 molecules as targets followed by gel electrophoresis and MS/MS analysis confirmed these data, demonstrating that H1.1, H2B, H4, and H2A histones are the active component of TNP that bind to HIV envelop glycoprotein and its receptor. To conclusively demonstrate binding of histones to target proteins, we repeated the surface plasmon resonance experiments using commercially available bovine histones and demonstrated high-affinity interaction of histones with gp120, and CD4. The binding of histone proteins to CD4, as well as viral molecules has profound implications for basic understanding of immune functions as well as a possible mechanism of VGV-1 activity in AIDS patients.

Background: The extent to which academic general medicine providers screen Chinese-speaking patients for hepatitis B virus (HBV) is not known., Methods: Retrospective cohort study of Chinese-speaking patients' HBV screening status and survey of providers' HBV knowledge/screening., Results: Most patients (65%) received HBV screening. Being screened was independently associated with marital status and years in the clinic. Providers with Asian language abilities and greater knowledge of HBV risk factors/guidelines were more likely to screen., Conclusions: Chinese-speaking patients in this setting were underscreened for HBV. Providers underestimated the risks associated with Chinese ethnicity. Education is needed to improve risk assessment and guideline awareness.

There has been a revolution in the treatment of colorectal cancer over the last decade. Part of this revolution has been the discovery of agents that target particular aspects of cancer, namely vascular endothelial growth factor and epidermal growth factor receptor. Novel targeted agents have been evaluated in clinical trials and have demonstrated significant anticancer activity. Furthermore, a number of these compounds have been approved for clinical use. Data supporting the use of targeted agents in the treatment of colorectal cancer are reviewed, and the "future for potential novel agents and pathways are discussed.

Hypothesis: Preoperative clinical, biochemical, and imaging studies could be used to reliably select patients with single-gland primary hyperparathyroidism who could undergo minimally invasive parathyroidectomy and to determine whether additional perioperative testing is necessary., Design: Retrospective analysis., Setting: Tertiary referral center., Patients: A total of 238 patients who underwent neck surgical exploration and parathyroidectomy for primary hyperparathyroidism from January 7, 2002, to December 23, 2004., Main Outcome Measures: Demographic, clinical, biochemical, and imaging factors that predict single-gland vs multigland parathyroid disease, and biochemical cure., Results: Of the 238 patients, 75.2% had a single adenoma, 21.4% had asymmetric 4-gland hyperplasia, and 3.4% had double adenomas. A biochemical cure was achieved in 99.2% of the patients. Preoperative calcium and intact parathyroid hormone levels were significantly higher (P = .03 and .04, respectively) and ultrasound and sestamibi scan results were more likely to be positive (both P<.001) in single-gland primary hyperparathyroidism. A dichotomous scoring model based on preoperative total calcium level (>/=3 mmol/L [>/=12 mg/dL]), intact parathyroid hormone level (>/=2 times the upper limit of normal levels), positive ultrasound and sestamibi scan results for 1 enlarged gland, and concordant ultrasound and sestamibi scan findings reliably distinguished single-gland vs multigland cases (P<.001). The positive predictive value of this scoring model to correctly predict single-gland disease was 100% for a total score of 3 or higher., Conclusions: Preoperative biochemical and imaging study results reliably distinguished single-gland vs multigland parathyroid disease in primary hyperparathyroidism. Our findings suggest that patients with a score of 3 or higher can undergo a minimally invasive parathyroidectomy without the routine use of intraoperative parathyroid hormone or additional imaging studies, and those with a score of less than 3 should have additional testing to ensure that multigland disease is not overlooked.

In the past several years, the impact of the new biologic therapies on colorectal cancer has been dramatic. The focus of this article is to summarize some of the key advances of incorporating biologically targeted therapies into the routine management of patients with colorectal cancer. We will review important data presented at the 2005 American Society of Clinical Oncology annual meeting and discuss the incorporation of these data into the most optimal management of our patients, including how best to manage side effects and keep quality of life as high as possible.

Purpose: Our previous clinical experience with vaccinia and replication-defective avipox recombinant carcinoembryonic antigen (CEA) vaccines has demonstrated safety and clinical activity with a correlation between CEA-specific immune response and survival. Preclinical evidence demonstrated that the addition of the transgenes for three T-cell costimulatory molecules (B7-1, ICAM-1, LFA-3, designated TRICOM) results in a significant improvement in antigen-specific T-cell responses and antitumor activity. We describe here the first trial in humans of the CEA-TRICOM vaccines (also including an enhancer agonist epitope within the CEA gene)., Patients and Methods: Fifty-eight patients with advanced CEA-expressing cancers were accrued to eight cohorts that involved vaccinations with the following: replication-defective fowlpox recombinant (rF)-CEA(6D)-TRICOM; primary vaccination with recombinant vaccinia (rV)-CEA(6D)-TRICOM plus rF-CEA(6D)-TRICOM booster vaccinations; and rV-CEA(6D)-TRICOM and then rF-CEA(6D)-TRICOM, plus granulocyte-macrophage colony-stimulating factor (GM-CSF) with vaccines, or with divided doses of vaccine with GM-CSF. Vaccines were administered every 28 days for six doses and then once every 3 months. Reverting to treatments every 28 days was allowed if patients progressed on the 3-month schedule., Results: In this phase I study, no significant toxicity was observed. Twenty-three patients (40%) had stable disease for at least 4 months, with 14 of these patients having prolonged stable disease (> 6 months). Eleven patients had decreasing or stable serum CEA, and one patient had a pathologic complete response. Enhanced CEA-specific T-cell responses were observed in the majority of patients tested., Conclusion: We demonstrated that the CEA-TRICOM vaccines are safe and can generate significant CEA-specific immune responses, and they seem to have clinical benefit in some patients with advanced cancer.

Variations of fluorouracil (5-FU) therapy have formed the backbone of chemotherapy for advanced colorectal cancer for many years. With the advent of newer agents that often work best with or even require chemotherapy to optimize their activity, the issue of the optimal schedule and regimen of administration of 5-FU has taken on a renewed importance. The combination of irinotecan with 5-FU/leucovorin has consistently improved survival and response rates in comparison to 5-FU/leucovorin alone. However, the combination also increases the toxicity of the treatment, thus resulting in continuing attempts to improve on the toxicity profile of the combination, while retaining or improving upon the therapeutic outcomes. This article reviews the various combinations of irinotecan with 5-FU/leucovorin.

Oral retinoids can reduce basal cell carcinoma (BCC) incidence in genetically susceptible patients, and one topical retinoid, tazarotene, has been reported to cure some sporadic BCCs. Therefore, we have tested whether this agent would affect BCCs in Ptch1+/- mice in a controlled chemoprevention trial. We found that topical tazarotene dramatically inhibits the formation of BCCs induced with either UV or ionizing radiation. The ability of tazarotene to inhibit BCC formation in this mouse model provides encouragement for the use of tazarotene in skin cancer chemoprevention trials in humans.

Irinotecan (CPT-11, Camptosar) is one of the new generation of chemotherapeutic agents that has activity in advanced colorectal cancer. It has antitumor efficacy as a single agent, and also has been combined with fluorouracil (5-FU) and leucovorin (IFL) to treat these patients. Randomized studies have confirmed the superiority of IFL to 5-FU and leucovorin alone with regard to patient survival, time to progression, and tumor response rate. The optimal schedule for combining these agents remains uncertain, but in the United States, the schedule of IFL weekly for 4 consecutive weeks repeated every 6 weeks, according to the schedule reported by Saltz et al, has been widely used, although with some toxicity (especially myelosuppression and diarrhea). In an attempt to improve the tolerability of IFL, some have advocated modifying the schedule of IFL to weekly for 2 weeks, with repeated cycles every 21 days. Twenty-three patients with advanced colorectal cancer have been treated on this schedule at a single institution. Therapy was well tolerated, with 35% of patients experiencing grade 3/4 neutropenia, two of whom had episodes of febrile neutropenia, and 9% with grade 3/4 diarrhea. The median relative dose intensity of irinotecan administered in the first 18 patients treated with this regimen was 94%. These data support the hypothesis that modifying the schedule of administration of IFL improves the tolerability and ability to deliver the regimen, but must be confirmed by randomized prospective studies, which may also attempt to evaluate the role of bolus 5-FU in the treatment of advanced colorectal cancer.

Preclinical data suggest that the combination of inhibitors of topoisomerases I and II may be synergistic when administered together. The optimal sequence of such combinations is uncertain, but initial administration of a topoisomerase I inhibitor upregulates topoisomerase II. Several combinations of these inhibitors have been evaluated, but have not clearly demonstrated synergy. Thus, we have started a phase I study of the combination of irinotecan (CPT-11, Camptosar) and epirubicin (Ellence). Typical eligibility criteria for phase I studies were employed. Patients with a history of congestive heart failure, > 240 mg/m2 of prior doxorubicin, or > 10% weight loss in the prior 4 weeks were excluded. Irinotecan and epirubicin were administered on days 1 and 8, every 28 days. Initially, patients were treated with irinotecan at 100 mg/m2 and epirubicin at 40 mg/m2 (dose level 1). After substantial toxicity at this level, the doses to be evaluated were changed to irinotecan: 50-->75-->100 mg/m2, and epirubicin: 20-->25-->30 mg/m2. Dose-limiting toxicities were noted in 2/4 patients (2 neutropenic fever, 1 thrombocytopenia) on dose level 1; 0/3 on dose level 1A; 1/8 (neutropenia) on dose level 2A; and 1/3 (neutropenia) on dose level 3A. This is the first combination of irinotecan and epirubicin to be evaluated in humans. The toxicity, primarily myelosuppression, noted to date has exceeded the expected toxicity for the doses of the irinotecan and epirubicin alone, suggesting the possibility of a synergistic interaction of the agents on this schedule, at least in the bone marrow. Other toxicities were acceptable and non-dose-limiting. Accrual of patients continues, at level 3A (irinotecan at 75 mg/m2, epirubicin at 25 mg/m2).

Capecitabine is a synthetic oral fluoropyrimidine carbamate that is sequentially activated in a three-step process, which results in the preferential production of 5-fluorouracil in tumours, rather than in the normal surrounding tissue. Capecitabine is proven to be as effective as the combination of 5-fluorouracil and leucovorin administered on the Mayo clinic schedule in patients with metastatic colorectal cancer. It has also been proven to be effective in patients with metastatic breast cancer that has progressed despite prior anthracyclines and taxoids. More recently, it has also been shown to increase survival in combination with docetaxel in patients with metastatic breast cancer in comparison to docetaxel alone. This article reviews the pharmacology and clinical activity of capecitabine, as well as combinations of capecitabine with other chemotherapeutic agents and future directions of investigation with this convenient and widely active antitumour therapy.