Citations

Purpose To describe the prevalence, clinical characteristics, and pattern of use of complementary and alternative medicine (CAM) in patients enrolled onto phase I trials. Patients and Methods Questionnaires were administered to 108 patients with advanced malignancies enrolled onto phase I chemotherapy trials at the Mayo Clinic Comprehensive Cancer Center (Rochester, MN). CAM was classified into two modalities, pharmacologic and nonpharmacologic. Clinical and demographic data, including age, sex, and prior cancer treatment, were subsequently obtained from patient charts and examined for any correlation with CAM use, using χ2 analysis. Results One hundred two survey forms were returned. Among respondents, 88.2% (90 of 102) had used at least one CAM modality; 93.3% (84 of 90) and 53.3% (48 of 90) had used pharmacologic and nonpharmacologic CAM, respectively; and 46.7% (42 of 90) used both modalities. Vitamin and mineral preparations constituted 89.3% (75 of 84) of all pharmacologic CAM used. Intake was highest for vitamins E (48.8% [41 of 84]) and C (38.1% [32 of 84]), and 71.4% (60 of 84) of respondents took nonvitamin/mineral agents. Green tea (29.8% [25 of 84]), echinacea (13.1% [11 of 84]), and essiac (9.5% [8 of 84]) were the most popular. Prayer and spiritual practices were the most commonly used nonpharmacologic CAM, accounting for 52.1% (25 of 48). Chiropractors, the most frequently visited nontraditional medicine practitioners, were consulted by only 10% (9 of 90) of those who practiced CAM. Both CAM modalities were used more frequently by women (53.5% [23 of 43]) than men (40.4% [19 of 47]). Conclusion CAM use is common among patients in phase I trials and should be ascertained by investigators, because some of the agents used may interact with investigational agents and affect adverse effects and/or efficacy.

Purpose To determine whether weekly epoetin alfa could improve hemoglobin (HgB) levels, reduce RBC transfusions, and improve quality of life (QOL) in patients with advanced cancer and with anemia after receiving myelosuppressive chemotherapy. Patients and Methods This double-blind, placebo-controlled study randomly assigned patients to placebo or epoetin alfa (Ortho Biotech, Bridgewater, NJ) 40,000 U subcutaneous weekly for 16 weeks. QOL, HgB, and RBC transfusions were measured pretreatment and monthly. Results The study accrued 344 patients; 330 were assessable for efficacy and 305 were assessable for QOL. Placebo-treated patients had a mean increase in HgB of 0.9 g/dL (range, −3.8 to +5.3) compared with 2.8 g/dL (range, −2.2 to +7.5) for epoetin-treated patients (P < .0001). During the study, 31.7% of placebo-treated patients achieved a ≥ 2 g/dL HgB increase compared with 72.7% of epoetin-treated patients (P < .0001). The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6% and 25.3% (P = .005), respectively. The placebo group received 256 units of RBCs compared with 127 units in the epoetin group (P < .0001). The incidence of toxicity in the groups was similar. Changes in the average QOL scores from baseline to the end of the study were similar in the two groups (P = not significant). The HgB responders (irrespective of treatment arm) had a mean change in Functional Assessment of Cancer Therapy (FACT) fatigue score from a baseline of +5.1 compared with −2.1 for the nonresponders (P = .006). Conclusion Epoetin alfa significantly improved HgB and reduced transfusions in this patient population. These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia.

Purpose A pressing need exists for agents active against anthracycline- or taxane-refractory metastatic breast cancer (MBC), or both. Previous clinical trials suggested that irinotecan might have such activity. We conducted this multicenter phase II study to assess efficacy and tolerability of two irinotecan schedules. Patients and Methods MBC patients who experienced disease progression after one to three chemotherapy regimens, including at least one anthracycline- or taxane-based regimen, were randomly assigned to irinotecan in 6-week cycles comprising 100 mg/m2 weekly for 4 weeks, then a 2-week rest (weekly) or 240 mg/m2 every 3 weeks. Results The weekly arm had 52 assessable patients; the every-3-weeks arm had 51 assessable patients. In the weekly arm, the objective response (complete regression [CR] + partial regression [PR]) rate was 23% (one CR, 11 PR; 95% CI, 13% to 37%). Median response duration was 4.9 months (range, 1.9 to 15.9 months), and median overall survival was 9.7 months (95% CI, 8.0 to 14.2 months). In the every-3-weeks arm, the objective response rate was 14% (nine PR; 95% CI, 6% to 26%), median response duration was 4.2 months (range, 3.1 to 13.9 months), and median overall survival was 8.6 months (95% CI, 7.0 to 12.3 months). Treatment generally was well tolerated, especially in the weekly arm. Grade 3 to 4 adverse events with ≥ 10% incidence included neutropenia (29%) and diarrhea (17%) in the weekly arm and neutropenia (36%), vomiting (20%), dyspnea (18%), nausea (16%), and diarrhea (12%) in the every-3-weeks arm. Conclusion Irinotecan is active with good tolerability in refractory MBC. Irinotecan (especially weekly) warrants additional study as monotherapy and in combination regimens in this setting.

Purpose Molecular studies of colon cancer have provided insights into pathogenesis, yet it is unclear how important these markers are in predicting prognosis. This study investigated the prognostic significance of TUNEL, bcl-2, p53, proliferation marker Ki-67 and DNA mismatch repair (MMR) status in patients with Dukes' stage B2 and C colorectal adenocarcinomas. Patients and Methods Tumor tissue from 366 patients (75% Dukes' C, 25% Dukes' B2) from four randomized North Central Cancer Treatment Group phase III surgical adjuvant trials were used. Eighty-one percent of patients received adjuvant treatment, which was primarily fluorouracil (FU) based (90%). Tumor location was predominantly (87%) the colon. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Ki-67, p53, bcl-2, and MMR were assayed using immunohistochemistry. Stage, grade, MMR, Ki-67, and previously determined flow cytometry markers (ploidy and S phase) were explored for associations with each other and with overall survival (OS) and disease-free survival (DFS). Results Univariately, stage B2, low grade, diploid, Ki-67 more than 27%, normal p53, and FU-based adjuvant treatment were significantly associated with improved OS and DFS (P < .05). After adjusting for stage, grade, and ploidy in multivariate analysis, Ki-67 remained significantly related to both OS and DFS (P < .01). Active FU-based adjuvant treatment was significant only for OS in this multivariate model. Neither bcl-2 nor TUNEL were significant. Conclusion This retrospective study indicates that Ki-67 and ploidy may have stronger prognostic impact on OS and DFS than other parameters investigated after adjusting for stage and tumor grade. Prospective studies to elucidate the mechanism and prognostic significance of these findings are necessary.

AbstractThese cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at‐risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in this document is derived from extensivereview of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provid information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Key components include the intake (medical and family histories), psychosocial assessment (assessment of risk perception), cancer risk assessment (determination and communication of risk), molecular testing for hereditary cancer syndromes (regulations, informed consent, and counseling process), and follow‐up considerations. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of a client.

Focal adhesion kinase (FAK) is an intracellular kinase that localizes to focal adhesions. FAK is overexpressed in human tumours, and FAK regulates both cellular adhesion and anti-apoptotic survival signalling. Disruption of FAK function by overexpression of the FAK C-terminal domain [FAK-CD, analogous to the FRNK (FAK-related non-kinase) protein] leads to loss of adhesion and apoptosis in tumour cells. We have shown that overexpression of an activated form of the Src tyrosine kinase suppressed the loss of adhesion induced by dominant-negative; adenoviral FAK-CD and decreased the apoptotic response in BT474 and MCF-7 breast cancer cell lines. This adhesion-dependent apoptosis was increased by the Src-family kinase inhibitor PP2 {4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine}. We have also shown that expression of activated Src in breast cancer cells increased the expression of α2-integrin and that overexpression of α2-integrin suppressed FAK-CD-mediated loss of adhesion. Our results suggest a model in which Src regulates adhesion and survival through enhanced expression of the α2-integrin. This provides a mechanism through which Src promotes cellular adhesion and alters the adhesive function of FAK.

Mechanical unloading of the heart with a left ventricular assist device (LVAD) significantly decreases mortality in patients with heart failure. Moreover, it provides a human model to define the critical regulatory genes governing myocardial remodeling in response to significant reductions in wall stress. Statistical analysis of a gene expression library of 19 paired human heart samples harvested at the time of LVAD implant and again at explant revealed a set of 22 genes that were downregulated and 85 genes that were upregulated in response to mechanical unloading with a false discovery rate of less than 1%. The analysis revealed a high percentage of genes involved in the regulation of vascular networks including neuropilin-1 (a VEGF receptor), FGF9, Sprouty1, stromal-derived factor 1, and endomucin. Taken together these findings suggest that mechanical unloading alters the regulation of vascular organization and migration in the heart. In addition to vascular signaling networks, GATA-4 binding protein, a critical mediator of myocyte hypertrophy, was significantly downregulated following mechanical unloading. In summary, these findings may have important implications for defining the role of mechanical stretch and load on autocrine/paracrine signals directing vascular organization in the failing human heart and the role of GATA-4 in orchestrating reverse myocardial remodeling. This unbiased gene discovery approach in paired human heart samples has the potential to provide critical clues to the next generation of therapeutic treatments aimed at heart failure.