Self-reported sleep disturbance in patients with advanced cancer: Frequency, intensity, and factors associated with response to outpatient supportive care consultation--A preliminary report.

OBJECTIVES: Self-reported sleep disturbance (SD) is a distressing symptom in patients with advanced cancer. There are limited data on the treatment of SD and predictors to response of SD to outpatient supportive care clinic (OPC) consultation. The aims of our study was to determine the frequency, intensity, and correlates of SD as assessed with the Edmonton Symptom Assessment System (ESAS) sleep item at the time of initial consultation and identify the predictors of improvement in SD at follow-up. METHODS: We reviewed the records of consecutive patients with advanced cancer presenting to the OPC. ESAS scores were obtained at the initial and subsequent visits between January 2008 and February 2010. All patients underwent screening for SD (0-10 scale: 0 = best sleep, presence of SD defined as ≥ 3) and interdisciplinary assessment and treatment, including drug review, counseling, sleep hygiene review, and drug therapy. A response was defined as a 1-point improvement at the follow-up visit on the Edmonton Symptom Assessment Scale (ESAS) sleep item score. Baseline patient characteristics, medication use, and ESAS scores were analyzed to determine their association with response. RESULTS: The median age was 58 years, and 53% of patients were men. The most common cancer type was head and neck or lung (36%). Of the 442 patients, 330 had baseline SD (score ≥ 3/10, 75%). Median and mean (standard deviation) baseline SD scores were 5 and 5.1 (2.9). The multivariable regression model found the intensity of baseline ESAS sleep item scores to be associated with baseline sedative use, baseline ESAS pain scores, baseline ESAS fatigue scores, baseline ESAS feeling of well-being scores, and sedative use (R 2 = 0.22). Sleep disturbance response at first follow-up was seen in 196 of 330 patients (59%). Moderate to high SD score and anxiety at initial visit with odds ratios (OR) of 2.53 (p = 0.0007) and 1.59 (p = 0.048), respectively, were associated with a response. SIGNIFICANCE OF RESULTS: Both the frequency and severity of SD were high. Response to supportive care consultation was substantial. The severity of SD and anxiety at the initial visit predicted a response at first follow-up. Further research is needed.

Frequency, outcome, and predictors of success within 6 weeks of an opioid rotation among outpatients with cancer receiving strong opioids.

BACKGROUND: Opioid rotation is used to treat uncontrolled pain and/or opioid-related adverse effects. Our aim was to determine the frequency, indications, outcomes, and predictors of successful opioid rotation in outpatients with cancer. METHODS: Medical records of consecutive outpatients with cancer who received strong opioids and returned for follow-up visit within ≤6 weeks to our supportive care center from January to December 2008 were reviewed. Data on patient characteristics, symptoms, opioid use, indications for opioid rotation, outcomes, and morphine equivalent daily dose were collected. Successful opioid rotation was defined as a two-point or 30% reduction in the symptom score or the resolution of opioid-induced neurotoxicity and continuation of the new opioid at follow-up. RESULTS: Opioid rotation was performed in 120 of 385 patients (31%). The median patient age was 55 years. There were 6/120 patients with missing data. Of the 114 evaluable patients, 68 (60%) were men, 81 (71%) were white, 27 (24%) had gastrointestinal cancer, and 90 (80%) had advanced-stage disease. The median Eastern Cooperative Oncology Group score was 1 (interquartile range: 1-2) and the median time between opioid rotation and follow-up was 14 days (interquartile range: 7-21 days). The most common indications for opioid rotation were uncontrolled pain (95/114; 83%) and opioid-induced neurotoxicity (13/114; 12%). A total of 35 patients (31%) had partial opioid rotation. The median improvements in pain and symptom distress score were -2 (interquartile range: -4 to 0; p < .001) and -5 (interquartile range: -14 to 7; p = .004), respectively. The morphine equivalent daily dose did not change significantly after opioid rotation (p = .156). A total of 65% of patients (74/114) had successful opioid rotation. There were no clinically significant independent predictors for successful opioid rotation. CONCLUSION: Opioid rotation was conducted in 31% of outpatients with cancer, with a 65% success rate. The most frequent reason for opioid rotation was uncontrolled pain. There were no independent predictors for successful opioid rotation.

Case control study of women treated with chemotherapy for breast cancer during pregnancy as compared with nonpregnant patients with breast cancer.

BACKGROUND: The purpose of this analysis was to compare disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) between pregnant and nonpregnant patients with breast cancer. METHODS: From 1989 to 2009, 75 women were treated with chemotherapy during pregnancy. Each pregnant case was matched on age and cancer stage to two nonpregnant patients with breast cancer (controls). Fisher's exact test, the Kaplan-Meier method, and Cox proportional hazards regression models were used. RESULTS: Median follow-up time for patients who were alive at the end of follow-up (n = 159) was 4.20 years (range: 0.28-19.94 years). DFS at 5 years was 72% (95% confidence interval [CI]: 58.3%-82.1%) for pregnant patients and 57% (95% CI: 46.7%-65.8%) for controls (p = .0115). Five-year PFS was 70% (95% CI: 56.8%-80.3%) for pregnant patients and 59% (95% CI: 49.1%-67.5%) for controls (p = .0252). Five-year OS was 77% (95% CI: 63.9%-86.4%) for pregnant patients and 71% (95% CI: 61.1%-78.3%) for controls (p = .0461). Hazard ratio estimates favored improved survival for pregnant patients in univariate analyses and multivariate analyses, controlling for age, year of diagnosis, stage, and tumor grade. CONCLUSIONS: For patients who received chemotherapy during pregnancy, survival was comparable to-if not better than-that of nonpregnant women. Pregnant patients with breast cancer should receive appropriate local and systemic therapy for breast cancer.

Rasburicase in tumor lysis syndrome of the adult: a systematic review and meta-analysis.

BACKGROUND: The use of rasburicase has been evaluated extensively in children, but not in adults. We review the current literature to evaluate its effect on adults. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Adults receiving rasburicase for tumor lysis syndrome (TLS). SELECTION CRITERIA FOR STUDIES: Electronic databases, regulatory documents, and websites were searched up to August 7, 2012. Reference lists of published articles were examined for additional relevant references. Any controlled trial or observational studies (controlled before and after) were included. Studies considering children only or mixing data for children and adults were excluded. INTERVENTION: Rasburicase for TLS. OUTCOMES: The primary outcome was TLS development. Secondary outcomes included percentage of patients improving, total adverse events, acute kidney failure, deaths, and serum uric acid and creatinine levels. RESULTS: 21 studies (24 publications) reported data for 1,261 adult patients, 768 receiving rasburicase for either the treatment or prophylaxis of TLS; these comprised 4 controlled trials and 17 observational studies. No statistically significant differences in clinical TLS development were observed in the controlled trials between the rasburicase and control groups. For the observational studies, 7.4% of patients developed clinical TLS after rasburicase (95% CI, 1.7%-16.7%), 93.4% of patients achieved normalized serum uric acid levels after rasburicase treatment (95% CI, 91.7%-94.6%), 4.4% developed acute kidney injury (95% CI, 3.0%-6.0%), and 2.6% died (95% CI, 0.95%-5.0%). The mean reduction in serum uric acid levels ranged from 5.3-12.8 mg/dL, and for serum creatinine levels, from 0.10-2.1 mg/dL. LIMITATIONS: Controlled trials differed in outcomes reported; meta-analysis was not performed. CONCLUSIONS: Rasburicase is effective in reducing serum uric acid levels in adults with TLS but at a significant cost, and evidence currently is lacking in adults to report whether rasburicase use improves clinical outcomes compared with other alternatives. Until new evidence is available, use of rasburicase may be limited to adult patients with a high risk of TLS.

Mentoring in pediatric oncology: a report from the Children's Oncology Group Young Investigator Committee.

A formal Mentorship Program within the Children's Oncology Group (COG) was established to pair young investigators (mentees) with established COG members (mentors). Despite the American Academy of Pediatrics policy statement promoting mentorship programs, there are no publications describing and evaluating national mentorship programs in pediatric subspecialties. In this study, a series of internal program evaluations were performed using surveys of both mentors and mentees. Responses were deidentified and analyzed to determine the utility of the program by both participant satisfaction and self-reported academic productivity. Results indicated that mentees were generally satisfied with the program. Mentor-mentee pairs that met at least quarterly demonstrated greater academic productivity than pairings that met less frequently. This formal mentorship program appeared to have subjective and objective utility for the development of academic pediatric subspecialists.

Retrospective analysis of antitumor effects of zoledronic acid in breast cancer patients with bone-only metastases.

BACKGROUND: Bisphosphonates have been used successfully in the treatment of hypercalcemia and to reduce skeletal complications of bone metastasis, but have not been shown to prevent bone metastasis or to prolong survival time in metastatic breast cancer patients. The aim of this study was to determine whether the progression-free survival (PFS) and overall survival (OS) of patients with bone-only breast cancer metastasis differed based on whether patients received zoledronic acid, pamidronate, or no bisphosphonate upon diagnosis of their metastases. PATIENTS AND METHODS: We retrospectively identified 314 patients diagnosed with bone-only metastasis at the time of initial staging or who developed bone metastasis as the first recurrence site during follow-up from January 1, 1997 to December 31, 2008, at The MD Anderson Cancer Center. Univariate and multivariate Cox hazards models were used to assess the effects of each treatment on PFS and OS. RESULTS: Patients who had more than 1 bone metastasis and Eastern Cooperative Oncology Group (ECOG) performance status of 2 and 3 were more likely to receive zoledronic acid in this analysis. Compared with no bisphosphonate use, the use of zoledronic acid was not significantly associated with longer PFS (hazard ratio [HR] = 0.72, P = .058 in univariate analysis, and HR = 0.80, P = .235 in multivariate analysis) nor with longer OS (HR = 1.04, P = .863 in univariate analysis and HR = 1.34, P = .192 in multivariate analysis). CONCLUSION: Our study demonstrates that for patients with bone-only metastases, zoledronic acid did not prolong PFS or OS. In patients with bone-only metastasis, we could not demonstrate antitumor effects of zoledronic acid.

The relationship between body composition and response to neoadjuvant chemotherapy in women with operable breast cancer.

INTRODUCTION: Overweight women diagnosed with breast cancer have greater recurrence and mortality risks. Recent studies in advanced cancer showed that the combination of sarcopenia and an overweight or obese body mass index (BMI) is associated with poor clinical outcomes. OBJECTIVES: To compare pathological complete response (pCR) cases with controls and evaluate associations among a pCR, survival outcome, and sarcopenia as well as the combination of both sarcopenia and a BMI ≥25 kg/m(2). METHODS: Sixty-seven breast cancer patients with a pCR to neoadjuvant chemotherapy (NC) were matched with controls who did not have a pCR to NC. Patients were matched by age, Black's nuclear grading system, clinical cancer stage, and estrogen receptor and progesterone receptor status. Body composition was analyzed using computed tomography images taken prior to NC. RESULTS: BMI was associated with pCR. Among normal weight patients, the pCR rate was higher in sarcopenic patients and the progression-free survival (PFS) interval was significantly longer than in overweight or obese BMI patients. The death hazard was 2% higher for each unit higher skeletal muscle index and 0.6% higher for each unit higher visceral adipose tissue. CONCLUSIONS: Overweight patients treated with NC had a lower pCR rate and shorter PFS time. Among patients with a normal BMI, the pCR rate was better in sarcopenic patients. More research is required to evaluate the negative impact of sarcopenic obesity on prognosis and the contributors to better response rates in operable, normal weight breast cancer patients with sarcopenia.

Feasibility, reliability, and validity of the Pediatric Quality of Life Inventory ™ generic core scales, cancer module, and multidimensional fatigue scale in long-term adult survivors of pediatric cancer.

BACKGROUND: Most health-related quality of life assessments are designed for either children or adults and have not been evaluated for adolescent and young adult survivors of pediatric cancer. The objective of this study was to examine the feasibility, reliability, and validity of the Pediatric Quality of Life Inventory (PedsQL ™ Generic Core Scales, Cancer Module, and Multidimensional Fatigue Scale in adult survivors of pediatric cancer. METHODS: Adult survivors (n = 64; Mean age 35 year old; >2 years after treatment) completed the PedsQL™ Generic Core Scales, Cancer Module, and Multidimensional Fatigue Scale. Feasibility was examined with floor and ceiling effects; and internal consistency was determined by Cronbach's coefficient alpha calculations. Inter-factor correlations were also assessed. RESULTS: Significant ceiling effects were observed for the scales of social function, nausea, procedural anxiety, treatment anxiety, and communication. Internal consistency for all subscales was within the recommended ranges (α ≥ 0.70). Moderate to strong correlations between most Cancer Module and Generic Core Scales (r = 0.25 to r = 0.76) and between the Multidimensional Fatigue Scale and Generic Core Scales (r = 0.37 to r = 0.73). CONCLUSIONS: The PedsQL™ Generic Core Scales, Cancer Module, and Multidimensional Fatigue Scale appear to be feasible for an older population of pediatric cancer survivors; however, some of the Cancer Module Scales (nausea, procedural/treatment anxiety, and communication) were deemed not relevant for long-term survivors. More information is needed to determine whether the issues addressed by these modules are meaningful to long-term adult survivors of pediatric cancers.

Absolute lymphocyte counts refine minimal residual disease-based risk stratification in childhood acute lymphoblastic leukemia.

BACKGROUND: Several studies have demonstrated the prognostic utility of absolute lymphocyte count (ALC) during therapy for a range of malignancies, with low ALC associated with adverse outcome. Here we investigated whether ALC retained independent prognostic significance with respect to minimal residual disease (MRD) status in children with acute lymphoblastic leukemia (ALL). PROCEDURE: We reviewed 171 cases of pediatric ALL treated on the Children's Oncology Group P9900 series of treatment trials. Variables analyzed included ALC at several time points during Induction, age at diagnosis, cytogenetics, initial white blood cell count, and MRD status at Day 29 of Induction (MRD-29). RESULTS: We found high ALC at Induction Day 29 (ALC-29) to be an independent, clinically significant predictor of improved relapse-free and overall survival (OS). Patients with ALC-29 >1,500 cells/µl had a superior 6-year relapse-free survival (80 ± 4% vs. 62 ± 8%, P = 0.018) and overall survival (96 ± 2% vs. 74 ± 8%, P = 0.001). Moreover, ALC-29 identified distinct prognostic subgroups within cases stratified by MRD-29. In subjects with >0.01% MRD, ALC-29 > or <1,500 cells/µl had a significant 51% difference in 6-year OS (92 ± 7% vs. 41 ± 16%, P = 0.0001). CONCLUSIONS: ALC, a readily obtainable test, constitutes a significant and independent prognostic factor in childhood ALL that may refine current MRD-based risk stratification algorithms and provide key prognostic information in settings where MRD determination is not feasible.

Cervical spine radiographs in patients with rheumatoid arthritis undergoing anesthesia.

BACKGROUND: There is no consensus on the role of preoperative cervical spine radiographs to screen for instability in patients with rheumatoid arthritis (RA). OBJECTIVES: This study aimed to evaluate the preoperative use of cervical spine radiographs in patients with RA undergoing preoperative anesthesia assessment and to determine whether preoperative radiographic findings influenced anesthesia delivery techniques. METHODS: We reviewed all medical records of RA patients who underwent surgical procedures requiring general anesthesia with airway intubation or monitored anesthesia care without airway intubation. We examined cervical spine radiographs obtained up to 2 years before surgery and determined airway management techniques used during surgery. RESULTS: Overall, 215 patients with RA underwent 217 individual surgeries requiring anesthesia; of these, 176 (82%) underwent general anesthesia with airway management with direct laryngoscopy in 83%, fiber-optic intubation in 10%, and laryngeal mask in 7%. Ninety-two (52%) of the patients receiving airway management had radiographs available for cervical spine evaluation; of these, only 7 (8%) had complete radiographic examinations with which to evaluate possible atlantoaxial subluxation. Eighteen (20%) of the 92 patients receiving airway management had radiographic evidence of cervical spine abnormality. Multiple regression models were conducted to evaluate the association of patient demographics and airway management technique used and showed that the use of fiber-optic intubation or laryngeal mask was not influenced by radiographic results. A difficult oropharyngeal class/glottic visualization grade (3 or 4) as determined by the anesthesiologist was the only statistically significant predictor of fiber-optic intubation or laryngeal mask use. CONCLUSIONS: Cervical spine abnormalities were frequently noted in patients who underwent general surgery but did not influence the choice of airway management. Future prospective studies evaluating the utility of cervical spine radiographs in patients with RA and practice guidelines are needed to ensure appropriate and cost-effective perioperative cervical evaluation and management of patients with RA.

Treatment outcome and prognostic factors for patients with bone-only metastases of breast cancer: a single-institution retrospective analysis.

PURPOSE: Limited information is available about the optimal management and clinical outcome of bone-only metastases in breast cancer patients. The objective of this study was to define prognostic factors for patients with bone-only metastases. Our second objective was to compare progression-free survival (PFS) and overall survival (OS) between patients with hormone receptor (HR)(+) tumors and bone-only metastases who received combinatory therapy (chemotherapy followed by endocrine therapy, or endocrine therapy combined with molecular targeted therapy) and those treated with endocrine or chemotherapy alone. PATIENTS AND METHODS: We retrospectively identified 351 breast cancer patients diagnosed with bone-only metastasis in 1997-2008 at our institution. RESULTS: Patients with metastasis detected at the time of their primary breast cancer diagnosis (rather than at recurrence), a single metastasis, or asymptomatic bone disease had a longer PFS interval, and patients with a performance status of 0-1, a single metastasis, or asymptomatic bone disease had a longer OS time. Among patients with HR(+) human epidermal growth factor receptor (HER)-2(-) disease, combinatory therapy was associated with longer PFS and OS times than with endocrine therapy. In multivariate analyses, combinatory therapy was not associated with longer PFS or OS times than with endocrine therapy. Among patients with HER-2(+) disease, trastuzumab led to a longer PFS interval but no difference in the OS time. CONCLUSION: Our results indicate that, for HR(+) disease, a prospective trial of chemotherapy followed by endocrine therapy is warranted to determine whether it prolongs survival more than endocrine therapy alone in patients with bone-only metastases.

Preliminary report: vitamin D deficiency in advanced cancer patients with symptoms of fatigue or anorexia.

BACKGROUND: Vitamin D deficiency in noncancer patients is associated with symptoms of fatigue, muscle weakness, and depression. These symptoms are common among advanced cancer patients. We investigated the prevalence of low serum vitamin D levels in cancer patients with fatigue or poor appetite and their association with symptom burden and other correctable endocrine abnormalities. METHODS: This was a retrospective review of 100 consecutive cancer patients with appetite or fatigue scores of ≥4 of 10 referred to a supportive care clinic. We investigated serum levels of 25(OH) vitamin D, cortisol, thyroid-stimulating hormone, and bioavailable testosterone. Symptoms were measured by the Edmonton Symptom Assessment Scale. Serum 25(OH) vitamin D <20 ng/mL was considered deficient; ≥20 ng/mL and <30 ng/mL were considered insufficient. RESULTS: Patients were predominantly male (68%) and white (66%), with a median age of 60 years (range, 27-91 years). Gastrointestinal (30%) and lung (22%) cancers were predominant. Forty-seven patients (47%) were vitamin D deficient and 70 (70%) were insufficient. Thirteen of 70 patients (19%) with vitamin D insufficiency were on supplementation. Vitamin D deficiency was more common among nonwhites (82% versus 36%) and females. No significant association was found between vitamin D and symptoms. Hypogonadic males had a significantly lower mean 25(OH) vitamin D level than eugonadic males. CONCLUSIONS: Low vitamin D levels were highly prevalent among advanced cancer patients with cachexia or fatigue. Vitamin D deficiency was more frequent among nonwhite and female patients. Vitamin D levels were also significantly lower in male patients with hypogonadism.

Initial staging impact of fluorodeoxyglucose positron emission tomography/computed tomography in locally advanced breast cancer.

PURPOSE: Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) may reveal distant metastases more accurately than conventional imaging (CT, skeletal scintigraphy, chest radiography). We hypothesized that patients diagnosed with stage III noninflammatory breast cancer (non-IBC) and IBC by conventional imaging with PET/CT have a better prognosis than patients diagnosed without PET/CT. PATIENTS AND METHODS: We retrospectively identified 935 patients with stage III breast cancer in 2000-2009. We compared the relapse-free survival (RFS) and overall survival (OS) times of patients diagnosed by conventional imaging with those of patients diagnosed by conventional imaging plus PET/CT. Univariate and multivariate Cox proportional hazards regression models were used to assess associations between survival and PET/CT. RESULTS: RFS and OS times were not significantly different between patients imaged with PET/CT and those imaged without PET/CT. However, the RFS time in IBC patients was significantly different between patients imaged with PET/CT and those imaged without PET/CT on both univariate (hazard ratio [HR], 0.43; p = .014) and multivariate (HR, 0.33; p = .004) analysis. There was a trend for a longer OS duration in IBC patients imaged with PET/CT. CONCLUSION: Among IBC patients, adding PET/CT to staging based on conventional imaging might detect patients with metastases that were not detected by conventional imaging. The use of conventional imaging with PET/CT for staging in non-IBC patients is not justified on the basis of these retrospective data. The use of conventional imaging plus PET/CT in staging IBC needs to be studied prospectively to determine whether it will improve prognosis.

FDG-PET/CT compared with conventional imaging in the detection of distant metastases of primary breast cancer.

PURPOSE: Evidence from studies with small numbers of patients indicates that (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) accurately detects distant metastases in the staging of primary breast cancer. We compared the sensitivity and specificity of PET/CT and conventional imaging (CT, ultrasonography, radiography, and skeletal scintigraphy) for the detection of distant metastases in patients with primary breast cancer. PATIENTS AND METHODS: We performed a retrospective review that identified 225 patients with primary breast cancer seen from January 2000 to September 2009 for whom PET/CT data were available for review. Imaging findings were compared with findings on biopsy, subsequent imaging, or clinical follow-up. Sensitivity and specificity in the detection of distant metastases were calculated for PET/CT and conventional imaging. Fisher's exact tests were used to test the differences in sensitivity and specificity between PET/CT and conventional imaging. RESULTS: The mean patient age at diagnosis was 53.4 years (range, 23-84 years). The sensitivity and specificity in the detection of distant metastases were 97.4% and 91.2%, respectively, for PET/CT and 85.9% and 67.3%, respectively, for conventional imaging. The sensitivity and specificity of PET/CT were significantly higher than those of conventional imaging (p = .009 and p < .001, respectively). Eleven cases of distant metastases detected by PET/CT were clinically occult and not evident on conventional imaging. CONCLUSION: PET/CT has higher sensitivity and specificity than conventional imaging in the detection of distant metastases of breast cancer. A prospective study is needed to determine whether PET/CT could replace conventional imaging to detect distant metastases in patients with primary breast cancer.

The accuracy of probabilistic versus temporal clinician prediction of survival for patients with advanced cancer: a preliminary report.

Clinicians have limited accuracy in the prediction of patient survival. We assessed the accuracy of probabilistic clinician prediction of survival (CPS) and temporal CPS for advanced cancer patients admitted to our acute palliative care unit, and identified factors associated with CPS accuracy. Eight physicians and 20 nurses provided their estimation of survival on admission by (a) the temporal approach, "What is the approximate survival for this patient (in days)?" and (b) the probabilistic approach, "What is the approximate probability that this patient will be alive (0%-100%)?" for ≥24 hours, 48 hours, 1 week, 2 weeks, 1 month, 3 months, and 6 months. We also collected patient and clinician demographics. Among 151 patients, the median age was 58 years, 95 (63%) were female, and 138 (81%) had solid tumors. The median overall survival time was 12 days. The median temporal CPS was 14 days for physicians and 20 days for nurses. Physicians were more accurate than nurses. A higher accuracy of temporal physician CPS was associated with older patient age. Probabilistic CPS was significantly more accurate than temporal CPS for both physicians and nurses, although this analysis was limited by the different criteria for determining accuracy. With the probabilistic approach, nurses were significantly more accurate at predicting survival at 24 hours and 48 hours, whereas physicians were significantly more accurate at predicting survival at 6 months. The probabilistic approach was associated with high accuracy and has practical implications.

Androgen receptor levels and association with PIK3CA mutations and prognosis in breast cancer.

PURPOSE: To examine the androgen receptor (AR) levels in breast cancer and to assess the impact of AR expression on patient outcomes. EXPERIMENTAL DESIGN: Reverse-phase protein arrays were used to measure AR levels and a mass spectroscopy-based approach was used to detect PIK3CA mutations. Means and SDs were generated for AR levels. Linear regression models were used to determine if AR levels differed by tumor subtype and PIK3CA mutation status. Two-sample t tests were used to identify pair-wise differences. Survival probabilities were estimated with the use of the Kaplan-Meier product and log-rank test. RESULTS: The median age was 59 years (23-89 years). Significant differences in AR levels existed among different breast tumor subtypes (highest in estrogen receptor-positive and/or progesterone receptor-positive tumors) as well as by PIK3CA mutation status (P < 0.0001 for both). AR levels were significantly higher in breast tumors with kinase domain PIK3CA mutations versus tumors that are wild type or with PIK3CA helical mutations (P = 0.017 and P < 0.0001, respectively). In 347 patients, dichotomized AR level by the median was a significant prognostic factor of recurrence-free survival (P = 0.0002) and overall survival (P = 0.004). High AR levels were associated with a significantly improved recurrence-free survival in 207 patients with early-stage estrogen/progesterone receptor-positive tumors after adjuvant hormonal therapy. A trend (P = 0.07) was found toward higher AR expression in PIK3CA mutant versus PIK3CA wild-type triple-negative breast tumors. CONCLUSIONS: AR levels may represent a prognostic marker in breast cancers and may provide a valuable tool for selecting treatment. There was an association of PIK3CA mutation (kinase domain) with increased AR levels.

Cyclin E-associated kinase activity predicts response to platinum-based chemotherapy.

PURPOSE: The role of cyclin E as a predictive marker of response to chemotherapy remains unknown. We have previously shown that deregulation of cyclin E in an ovarian tumor cell line model enhances cyclin E-associated kinase activity and sensitizes tumor cells to cisplatinum. We hypothesized that cyclin E deregulation would predict for responsiveness to platinum-based regimens in ovarian cancer patients. EXPERIMENTAL DESIGN: Patients who met the following criteria were retrospectively identified from the institutional tumor bank records: (a) high-grade ovarian epithelial malignancy, (b) stage III/stage IV disease, (c) optimally debulked, (d) completed platinum-based therapy. Tumor samples were analyzed for cyclin E, p21, and p27 by Western blot analysis and assessed for cyclin E-associated kinase activity. RESULTS: Seventy-five patients, who met the study criteria, were identified. Cyclin E protein levels did not correlate with cyclin E-cdk2 kinase activity (Spearman's rho, 0.07; P = 0.58). Cyclin E-associated kinase activity was the only significant predictive marker for response to platinum-based therapy, with higher response rates seen in patients with higher levels of activity (P = 0.045). Cyclin E protein levels did not predict for platinum sensitivity (P = 0.20). In contrast, cyclin E protein levels, but not cyclin E-associated kinase activity, was a significant predictor for freedom from recurrence (P = 0.01 and P = 0.25, respectively). CONCLUSIONS: Cyclin E overexpression and cyclin E-associated kinase activity have distinct roles in predicting for response to chemotherapy and outcome in ovarian cancer patients. These results suggest a compartmentalization of cyclin E functions in the oncogenic process.

Serum lipids and glucose control: the SEARCH for Diabetes in Youth study.

OBJECTIVE: To assess the relationship of serum lipid concentrations with glucose control in youth with diabetes mellitus. DESIGN: Cross-sectional analyses of data from the SEARCH for Diabetes in Youth study. SETTING: Multicenter study of youth with diabetes onset at younger than 20 years. PATIENTS/ PARTICIPANTS: Nineteen hundred seventy-three SEARCH participants aged 10 years or older with hemoglobin A(1c) and fasting total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride measured at the SEARCH study examination. MAIN EXPOSURE: Hemoglobin A(1c). OUTCOME MEASURE: Lipid concentrations. RESULTS: There were significant trends of higher levels of TC, LDL-C, triglyceride, and non-HDL-C (but not HDL-C) with higher hemoglobin A(1c) concentrations for both diabetes types. The slopes of TC increase were 7.8 mg/dL (0.20 mmol/L) per unit increase in hemoglobin A(1c) for type 1 and 8.1 mg/dL (0.21 mmol/L) for type 2. Levels of TC, LDL-C, triglyceride, and non-HDL-C were all significantly higher (all P values <.001) in type 2 than in type 1 diabetes (mean differences in milligrams per deciliter [millimoles per liter], +13.6 [+0.35] for TC; +8.3 [+0.22] for LDL-C; +66.3 [+0.75] for triglyceride; +25.5 [+0.66] for non-HDL-C). Levels of HDL-C were lower in youth with type 2 diabetes (mean difference, -11.9 mg/dL [-0.31 mmol/L]). Among those with type 1 diabetes in poor glycemic control, 35%, 27%, and 12% had high concentrations of TC (>or=200 mg/dL [5.17 mmol/L]), LDL-C (>or=130 mg/dL [3.36 mmol/L]), and triglyceride (>or=200 mg/dL [2.26 mmol/L]), respectively. In youth with type 2 diabetes in poor glycemic control, percentages with high levels of TC, LDL-C, and triglycerides were 65%, 43%, and 40%, respectively. CONCLUSIONS: Glycemic control and lipid levels are independently associated in youth with both type 1 and type 2 diabetes.

Prevalence of cardiovascular disease risk factors in U.S. children and adolescents with diabetes: the SEARCH for diabetes in youth study.

OBJECTIVE: The purpose of this study was to determine the prevalence and correlates of selected cardiovascular disease (CVD) risk factors among youth aged <20 years with diabetes. RESEARCH DESIGN AND METHODS: The analysis included 1,083 girls and 1,013 boys examined as part of the SEARCH for Diabetes in Youth study, a multicenter, population-based study of youth 0-19 years of age with diabetes. Diabetes type was determined by a biochemical algorithm based on diabetes antibodies and fasting C-peptide level. CVD risk factors were defined as follows: HDL cholesterol <40 mg/dl; age- and sex-specific waist circumference >90th percentile; systolic or diastolic blood pressure >90th percentile for age, sex, and height or taking medication for high blood pressure; and triglycerides >110 mg/dl. RESULTS: The prevalence of having at least two CVD risk factors was 21%. The prevalence was 7% among children aged 3-9 years and 25% in youth aged 10-19 years (P < 0.0001), 23% among girls and 19% in boys (P = 0.04), 68% in American Indians, 37% in Asian/Pacific Islanders, 32% in African Americans, 35% in Hispanics, and 16% in non-Hispanic whites (P < 0.0001). At least two CVD risk factors were present in 92% of youth with type 2 and 14% of those with type 1A diabetes (P < 0.0001). In multivariate analyses, age, race/ethnicity, and diabetes type were independently associated with the odds of having at least two CVD risk factors (P < 0.0001). CONCLUSIONS: Many youth with diabetes have multiple CVD risk factors. Recommendations for weight, lipid, and blood pressure control in youth with diabetes need to be followed to prevent or delay the development of CVD as these youngsters mature.

The effects of hormone therapy on the markers of inflammation and endothelial function and plasma matrix metalloproteinase-9 level in postmenopausal women: the postmenopausal estrogen progestin intervention (PEPI) trial.

OBJECTIVE: The objective of this study was to determine whether oral conjugated equine estrogen (CEE) alone or with one of the three progestin regimens causes changes in biomarkers predictive of adverse cardiovascular events: C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule (ICAM) and matrix metalloproteinase-9 (MMP-9). METHODS AND RESULTS: The analysis included 271 postmenopausal women from the postmenopausal estrogen progestin intervention (PEPI) trial. Plasma levels of biomarkers were measured on frozen samples obtained at baseline, 1- and 3-year follow-up visits. Multivariable linear mixed effects models were used to estimate changes in CRP, IL-6, ICAM and MMP-9 levels from baseline to follow-up visits by treatment groups. Women assigned to CEE only or CEE plus a progestin had 121 and 150% 1-year increase in CRP levels, respectively. In contrast, these treatments caused no significant change in IL-6 levels. Women assigned to CEE with or without a progestin had a 6-8% decline in ICAM and a 26-33% decline in MMP-9. CONCLUSIONS: The linkage between CEE alone or with a progestin and increased cardiovascular events may be associated with a rise in CRP level, but not through the mechanisms of IL-6-mediated inflammation, endothelial dysfunction or increased MMP activity.