Comorbidity adjustment is an important component of health services research and clinical prognosis. When adjusting for comorbidities in statistical models, researchers can include comorbidities individually or through the use of summary measures such as the Charlson Comorbidity Index or Elixhauser score. We examined the conditions under which individual versus summary measures are most appropriate.
We provide an analytic proof of the utility of comorbidity summary measures when used in place of individual comorbidities. We compared the use of the Charlson and Elixhauser scores versus individual comorbidities in prognostic models using a SEER-Medicare data example. We examined the ability of summary comorbidity measures to adjust for confounding using simulations.
We devised a mathematical proof that found that the comorbidity summary measures are appropriate prognostic or adjustment mechanisms in survival analyses. Once one knows the comorbidity score, no other information about the comorbidity variables used to create the score is generally needed. Our data example and simulations largely confirmed this finding.
Summary comorbidity measures, such as the Charlson Comorbidity Index and Elixhauser scores, are commonly used for clinical prognosis and comorbidity adjustment. We have provided a theoretical justification that validates the use of such scores under many conditions. Our simulations generally confirm the utility of the summary comorbidity measures as substitutes for use of the individual comorbidity variables in health services research. One caveat is that a summary measure may only be as good as the variables used to create it.
Dissemination of genetic testing for disease susceptibility, one application of “personalized medicine”, holds the potential to empower patients and providers through informed risk reduction and prevention recommendations. Genetic testing has become a standard practice in cancer prevention for high-risk populations. Heightened consumer awareness of “cancer genes” and genes for other diseases (eg, cardiovascular and Alzheimer’s disease), as well as the burgeoning availability of increasingly complex genomic tests (ie, multi-gene, whole-exome and -genome sequencing), has escalated interest in and demand for genetic risk assessment and the specialists who provide it. Increasing demand is expected to surpass access to genetic specialists. Thus, there is urgent need to develop effective and efficient models of delivery of genetic information that comparably balance the risks and benefits to the current standard of in-person communication.
The aim of this pilot study was to develop and evaluate a theoretically grounded and rigorously developed protocol for telephone communication of BRCA1/2 (breast cancer) test results that might be generalizable to genetic testing for other hereditary cancer and noncancer syndromes.
Stakeholder data, health communication literature, and our theoretical model grounded in Self-Regulation Theory of Health Behavior were used to develop a telephone communication protocol for the communication of BRCA1/2 genetic test results. Framework analysis of selected audiotapes of disclosure sessions and stakeholders’ feedback were utilized to evaluate the efficacy and inform refinements to this protocol.
Stakeholder feedback (n=86) and audiotapes (38%, 33/86) of telephone disclosures revealed perceived disadvantages and challenges including environmental factors (eg, non-private environment), patient-related factors (eg, low health literacy), testing-related factors (eg, additional testing needed), and communication factors (eg, no visual cues). Resulting modifications to the communication protocol for BRCA1/2 test results included clarified patient instructions, scheduled appointments, refined visual aids, expanded disclosure checklist items, and enhanced provider training.
Analyses of stakeholders’ experiences and audiotapes of telephone disclosure of BRCA1/2 test results informed revisions to communication strategies and a protocol to enhance patient outcomes when utilizing telephone to disclose genetic test results.
genetic testing; test result disclosure; communication; telemedicine; cancer risk assessment; self-regulation theory of health behavior
Little is known about the effects of financial relationships between biomedical researchers and industry (financial conflicts of interest [FCOIs]) on research prominence. We examined the prevalence of FCOIs in oncology and associations between FCOIs and research prominence among abstracts presented at American Society of Clinical Oncology (ASCO) annual meetings.
We analyzed 20,718 abstracts presented at ASCO meetings in 2006 and 2008 to 2011. Measures included the following: financial relationships, peer review score (PRS), and meeting placement prominence (descending order of prominence: plenary session, clinical science symposium, oral presentation, poster discussion, general posters, and publish only).
Of 20,718 abstracts, 36% reported at least one author with an FCOI. The proportion of abstracts with any FCOI increased from 33% in 2006 to 38% in 2011 (P < .001). Abstracts with FCOIs had significantly higher meeting prominence compared with publish only and general poster abstracts. The odds ratios compared with general posters were 7.3 for plenary session, 2.2 for clinical science symposium, 1.9 for oral presentation, and 1.7 for poster discussion (P < .001). Abstracts with FCOIs had significantly better PRSs compared with those without FCOIs. For all abstracts, PRS was 2.76 (95% CI, 2.75 to 2.77) with FCOIs compared with 3.01 (95% CI, 3.001 to 3.02) without FCOIs (P < .001). Omitting publish-only abstracts, PRS was 2.62 (95% CI, 2.61 to 2.63) with FCOIs compared with 2.73 without FCOIs (95% CI, 2.71 to 2.73).
Abstracts with FCOIs had more prominent meeting placement and better PRSs. FCOIs were reported more frequently by year, suggesting an increasing influence of industry on cancer research, greater disclosure, or both.
Psychosocial functioning is associated with vascular endothelial growth factor (VEGF) in various patient populations. This study examined whether psychosocial functioning in patients with head and neck squamous cell carcinoma (HNSCC) is associated with tumor VEGF expression, a protein that stimulates angiogenesis and is associated with poor prognosis.
Forty-two newly diagnosed patients completed assessments of psychosocial functioning (i.e. depressive symptoms, perceived stress, anxiety, social support) prior to surgery. Tumor samples were obtained for VEGF analysis and HPV-typing.
Poorer psychosocial functioning was associated with greater VEGF expression controlling for disease stage (OR=4.55, 95% CI = 1.72, 12.0, p < 0.01). When examined by HPV-status, the association between psychosocial functioning and VEGF remained significant among HPV-negative patients (OR=5.50, 95% CI = 1.68, 17.3, p < 0.01), but not among HPV-positive patients.
These findings inform our understanding of the biobehavioral pathways that may contribute to poor outcomes in non-HPV-associated HNSCCs.
depressive symptoms; perceived stress; anxiety; social support; human papillomavirus
upper tract urothelial carcinoma; SEER; nephron-sparing surgery
Inhibitors of the DNA damage checkpoint kinase, Chk1, are highly effective as chemo- and radio-sensitizers in preclinical studies but are not well-tolerated by patients. We exploited the promiscuous nature of kinase inhibitors to screen 9 clinically relevant kinase inhibitors for their ability to sensitize pancreatic cancer cells to a sub-lethal concentration of gemcitabine. Bosutinib, dovitinib, and BEZ-235 were identified as sensitizers that abrogated the DNA damage checkpoint. We further characterized bosutinib, an FDA-approved Src/Abl inhibitor approved for chronic myelogenous leukemia. Unbeknownst to us, we used an isomer (Bos-I) that was unknowingly synthesized and sold to the research community as “authentic” bosutinib. In vitro and cell-based assays showed that both the authentic bosutinib and Bos-I inhibited DNA damage checkpoint kinases Chk1 and Wee1, with Bos-I showing greater potency. Imaging data showed that Bos-I forced cells to override gemcitabine-induced DNA damage checkpoint arrest and destabilized stalled replication forks. These inhibitors enhanced sensitivity to the DNA damaging agents’ gemcitabine, cisplatin, and doxorubicin in pancreatic cancer cell lines. The in vivo efficacy of Bos-I was validated using cells derived directly from a pancreatic cancer patient’s tumor. Notably, the xenograft studies showed that the combination of gemcitabine and Bos-I was significantly more effective in suppressing tumor growth than either agent alone. Finally, we show that the gatekeeper residue in Wee1 dictates its sensitivity to the 2 compounds. Our strategy to screen clinically relevant kinase inhibitors for off-target effects on cell cycle checkpoints is a promising approach to re-purpose drugs as chemosensitizers.
Checkpoint override; DNA damage; Kinase inhibitors; Mitosis; drug repurposing
During adolescence the breasts undergo rapid growth and development under the influence of sex hormones. Although the hormonal etiology of breast cancer is hypothesized, it remains unknown whether adolescent sex hormones are associated with adult breast density, which is a strong risk factor for breast cancer.
Percentage of dense breast volume (%DBV) was measured in 2006 by magnetic resonance imaging in 177 women aged 25–29 years who had participated in the Dietary Intervention Study in Children from 1988 to 1997. They had sex hormones and sex hormone-binding globulin (SHBG) measured in serum collected on one to five occasions between 8 and 17 years of age. Multivariable linear mixed-effect regression models were used to evaluate the associations of adolescent sex hormones and SHBG with %DBV.
Dehydroepiandrosterone sulfate (DHEAS) and SHBG measured in premenarche serum samples were significantly positively associated with %DBV (all Ptrend ≤0.03) but not when measured in postmenarche samples (all Ptrend ≥0.42). The multivariable geometric mean of %DBV across quartiles of premenarcheal DHEAS and SHBG increased from 16.7 to 22.1 % and from 14.1 to 24.3 %, respectively. Estrogens, progesterone, androstenedione, and testosterone in pre- or postmenarche serum samples were not associated with %DBV (all Ptrend ≥0.16).
Our results suggest that higher premenarcheal DHEAS and SHBG levels are associated with higher %DBV in young women. Whether this association translates into an increased risk of breast cancer later in life is currently unknown.
Clinical trials registration
ClinicalTrials.gov Identifier, NCT00458588 April 9, 2007; NCT00000459 October 27, 1999
Randomized trials have demonstrated that escalated-dose external-beam radiotherapy (EDRT) is better than standard-dose radiotherapy (SDRT) for patients with prostate cancer and that adding androgen-deprivation therapy (ADT) to SDRT is better than SDRT alone; however, no trials have compared EDRT versus SDRT plus ADT or EDRT versus EDRT plus ADT. The authors designed a model to estimate the results of various doses of radiotherapy (RT) combined with various durations of ADT.
From 1989 to 2007, 3215 men consecutively received definitive EDRT with or without ADT. In total, 2012 patients had complete records available for creating the nomogram. The duration of ADT varied for patients who received no RT (n = 1562), ≤6 months of RT (n = 145), from >6 months to <24 months of RT (n = 140), and ≥24 months of RT (n = 165) with a median follow-up of 65.7 months, 66.2 months, 60.1 months, and 63 months, respectively. The model included the following covariates: palpation T-category, biopsy Gleason score, the percentage of tumor cells with a Gleason pattern of 4 or 5, the percentage of tumor tissue, initial pretreatment prostate-specific antigen (PSA) level, ADT duration, and RT dose. Two nomograms, for outcomes with and without ADT, were created from a single competing-risks model. Biochemical failure was defined as a rise in serum PSA of 2 ng/mL over the post-treatment PSA nadir.
According to the results from analyzing representative intermediate-risk to high-risk patient parameters, the gains from increasing the RT dose from 70 Gray (Gy) to 80 Gy were far less than the gains from adding ≥3 months of ADT.
The nomograms provided unique patient-specific estimates of the effects of various doses and durations of RT and ADT. The results indicated that adding ADT to treatment for intermediate-risk and high-risk prostate cancer is far more beneficial than a modest RT dose escalation.
nomogram; prostate cancer; radiation treatment; androgen-deprivation therapy
One problem with assessing effects of smoking cessation interventions on withdrawal symptoms is that symptoms are affected by whether participants abstain from smoking during trials. Those who enter a randomized trial but do not change smoking behavior might not experience withdrawal related symptoms.
We present a tutorial of how one can use a principal stratification sensitivity analysis to account for abstinence in the estimation of smoking cessation intervention effects. The paper is intended to introduce researchers to principal stratification and describe how they might implement the methods.
We provide a hypothetical example that demonstrates why estimating effects within observed abstention groups is problematic. We demonstrate how estimation of effects within groups defined by potential abstention that an individual would have in either arm of a study can provide meaningful inferences. We describe a sensitivity analysis method to estimate such effects, and use it to investigate effects of a combined behavioral and nicotine replacement therapy intervention on withdrawal symptoms in a female prisoner population.
Overall, the intervention was found to reduce withdrawal symptoms but the effect was not statistically significant in the group that was observed to abstain. More importantly, the intervention was found to be highly effective in the group that would abstain regardless of intervention assignment. The effectiveness of the intervention in other potential abstinence strata depends on the sensitivity analysis assumptions.
We make assumptions to narrow the range of our sensitivity parameter estimates. While appropriate in this situation, such assumptions might not be plausible in all situations.
A principal stratification sensitivity analysis provides a meaningful method of accounting for abstinence effects in the evaluation of smoking cessation interventions on withdrawal symptoms. Smoking researchers have previously recommended analyses in subgroups defined by observed abstention status in the evaluation of smoking cessation interventions. We believe that principal stratification analyses should replace such analyses as the preferred means of accounting for post-randomization abstinence effects in the evaluation of smoking cessation programs.
We conducted a systematic review and pooled analysis of small renal masses under active surveillance to identify progression risk and characteristics associated with metastases.
Materials and Methods
A MEDLINE search was performed to identify all clinical series reporting surveillance of localized renal masses. For studies reporting individual level data, clinical and radiographic characteristics of tumors without progression were compared to those progressing to metastases.
18 series (880 patients, 936 masses) met screening criteria from which 18 patients progressing to metastasis were identified (mean 40.2 months). Six studies (259 patients, 284 masses) provided individual level data for pooled analysis. With a mean follow up of 33.5±22.6 months, mean initial tumor diameter was 2.3±1.3 cm and mean linear growth rate was 0.31±0.38 cm/year. 65 masses (23%) exhibited zero net growth under surveillance; of which none progressed to metastasis. Pooled analysis revealed increased age (75.1±9.1 vs. 66.6±12.3 years, p=0.03), initial tumor diameter (4.1±2.1 vs. 2.3±1.3 cm, p<0.0001), initial estimated tumor volume (66.3±100.0 vs. 15.1±60.3 cm3, p<0.0001), linear growth rate (0.8±0.65 vs. 0.3±0.4 cm/yr, p=0.0001), and volumetric growth rate (27.1±24.9 vs. 6.2±27.5 cm3/yr, p<0.0001) in the progression cohort.
A substantial proportion of small renal masses remain radiographically static following an initial period of active surveillance. Progression to metastases occurs in a small percentage of patients and is generally a late event. These results indicate that in patients with competing health risks, radiographic surveillance may be an acceptable initial approach with delayed intervention reserved for those exhibiting significant linear or volumetric growth.
ACOSOG Z0011 spares axillary dissection (AD) in breast conservation surgery (BCS) patients with T1/T2 tumors and 1–2 positive nodes. Current patterns of care and the impact of Z0011 on AD versus additional surgery rates for Medicare patients undergoing BCS are unknown. SEER data linked to Medicare claims for 1999–2005 were reviewed for women with invasive non-metastatic breast cancer who underwent nodal staging on the same day as BCS. There were 3,280 women with T1/T2 tumors and positive nodes who underwent same-day nodal staging; 2,532 (77.2 %) of these women had 1–2 positive nodes. Assuming 25.7 % have extracapsular extension, 651 women would require AD. However, 1,881 women, or 57.4 % of those with T1/T2 tumors and positive nodes, would be spared AD. Meanwhile, among the 748 women having ≥3 positive nodes, 579 underwent same-day AD, but under Z0011, would now wait for permanent section. A total of 160 of these women underwent re-excision or completion mastectomy at a later date anyway, when delayed AD could be performed. The remaining 419 women with ≥3 positive nodes would require an additional surgery date for the sole purpose of completion AD. The Z0011 paradigm would consequently necessitate an additional surgery date for 1,070 (651 + 419) women, or 32.6 % of those with T1/T2 tumors and positive nodes. The Z0011 paradigm appears to increase the number of Medicare patients undergoing BCS who require an additional surgery date but decrease the number requiring AD to a greater extent. Future changes in the use of AD or axillary irradiation may yet modify that impact substantially.
Clinical trials; ACOSOG Z0011; Lymph node metastases; Sentinel lymphadenectomy; Sentinel node biopsy; Axillary lymphadenectomy; Axillary lymph node dissection; Patterns of care; Surveillance, epidemiology and end results; Medicare; Medicare claims
Polycystic liver disease (PLD) occurs in 75–90% of patients affected by autosomal dominant polycystic kidney disease (ADPKD), which affects 1∶400–1,000 adults and arises from inherited mutations in the PKD1 or PKD2 genes. PLD can lead to bile duct obstructions, infected or bleeding cysts, and hepatomegaly, which can diminish quality of life. At present, no effective, approved therapy exists for ADPKD or PLD. We recently showed that inhibition of the molecular chaperone heat shock protein 90 (HSP90) with a small molecule inhibitor, STA-2842, induced the degradation of multiple HSP90-dependent client proteins that contribute to ADPKD pathogenesis and slowed the progression of renal cystogenesis in mice with conditional deletion of Pkd1. Here, we analyzed the effects of STA-2842 on liver size and cystic burden in Pkd-/- mice with established PLD. Using magnetic resonance imaging over time, we demonstrate that ten weeks of STA-2842 treatment significantly reduced both liver mass and cystic index suggesting selective elimination of cystic tissue. Pre-treatment cystic epithelia contain abundant HSP90; the degree of reduction in cysts was accompanied by inhibition of proliferation-associated signaling proteins EGFR and others, and induced cleavage of caspase 8 and PARP1, and correlated with degree of HSP90 inhibition and with inactivation of ERK1/2. Our results suggest that HSP90 inhibition is worth further evaluation as a therapeutic approach for patients with PLD.
Breast density is strongly related to breast cancer risk, but determinants of breast density in young women remain largely unknown.
Associations of reproductive and menstrual characteristics with breast density measured by magnetic resonance imaging were evaluated in a cross-sectional study of 176 healthy women, 25–29 years old, using linear mixed effects models.
Parity was significantly inversely associated with breast density. In multivariable adjusted models that included non-reproductive variables, mean percent dense breast volume (%DBV) decreased from 20.5 % in nulliparous women to 16.0 % in parous women, while mean absolute dense breast volume (ADBV) decreased from 85.3 to 62.5 cm3. Breast density also was significantly inversely associated with the age women started using hormonal contraceptives, whereas it was significantly positively associated with duration of hormonal contraceptive use. In adjusted models, mean %DBV decreased from 21.7 % in women who started using hormones at 12–17 years of age to 14.7 % in those who started using hormones at 22–28 years of age, while mean ADBV decreased from 86.2 to 53.7 cm3. The age at which women started using hormonal contraceptives and duration of hormone use were inversely correlated, and mean %DBV increased from 15.8 % in women who used hormones for not more than 2.0 years to 22.0 % in women who used hormones for more than 8 years, while mean ADBV increased from 61.9 to 90.4 cm3 over this interval.
Breast density in young women is inversely associated with parity and the age women started using hormonal contraceptives but positively associated with duration of hormone use.
Breast density; Parity; Breast feeding; Hormonal contraceptives; Menarche; Menstrual cycle
With an increasing demand for genetic services, effective and efficient delivery models for genetic testing are needed.
In this prospective single-arm communication study, participants received clinical BRCA1/2 results by telephone with a genetic counselor and completed surveys at baseline, after telephone disclosure (TD) and after in-person clinical follow-up.
Sixty percent of women agreed to participate; 73% of decliners preferred in-person communication. Anxiety decreased from baseline to post-TD (p = 0.03) and satisfaction increased (p < 0.01). Knowledge did not change significantly from baseline to post-TD, but was higher post-clinical follow-up (p = 0.04). Cancer patients had greater declines in state anxiety and African-American participants reported less increase in satisfaction. 28% of participants did not return for in-person clinical follow-up, particularly those with less formal education, and higher post-disclosure anxiety and depression (p < 0.01).
Telephone disclosure of BRCA1/2 test results may not be associated with negative cognitive and affective responses among willing patients, although some subgroups may experience less favorable responses. Some patients do not return for in-person clinical follow-up and longitudinal outcomes are unknown.
Further evaluation of longitudinal outcomes of telephone disclosure and differences among subgroups can inform how to best incorporate telephone communication into delivery of genetic services.
Genetic testing; Cancer susceptibility; Cancer risk assessment; Communication
This study reports a randomized clinical trial evaluating the efficacy of an intervention to prepare individuals to communicate BRCA1/BRCA2 results to family members.
Women aged 18 years and older, who had genetic testing, and who had adult first-degree relatives (FDRs), were randomly assigned to a communication skills-building intervention or a wellness control session. Primary outcomes were the percentage of probands sharing test results, and the level of distress associated with sharing. The ability of the Theory of Planned Behavior variables to predict the outcomes was explored.
Four hundred twenty-two women were enrolled in the study, 219 (intervention) and 203 (control). Data from 137 in the intervention group and 112 in the control group were analyzed. Two hundred forty-nine probands shared test results with 838 relatives (80.1%). There were no significant differences between study groups in the primary outcomes. Combining data from both arms revealed that perceived control and specific social influence were associated with sharing. Probands were more likely to share genetic test results with their children, female relatives and relatives who they perceived had a favorable opinion about learning the results.
The communication skills intervention did not impact sharing of test results. The proband’s perception of her relative’s opinion of genetic testing and her sense of control in relaying this information influenced sharing. Communication of test results is selective, with male relatives and parents less likely to be informed.
Prevalent psychosocial factors play a role in the communication of genetic test results within families.
Genetic testing; BRCA1/2; family communication; theory of planned behavior; social pressure
Cost concerns are common among patients with cancer who have health insurance. Health care providers may alleviate concerns by discussing cost-related concerns with all patients, not only those of lower socioeconomic status or those without insurance.
Health care providers are accustomed to identifying populations for whom cost-related concerns may be a significant barrier, such as the poor, but few empiric data have been collected to substantiate such assumptions, particularly among insured patients.
Patients with cancer from academic and community hospitals completed a questionnaire that included closed-ended items concerning demographic variables, optimism, numeracy, and concerns about present and future medical costs. In addition, they answered open-ended questions regarding cost concerns and medical expenses.
Nearly all (99%) participants were insured. In response to the closed-ended questions, 30.3% of patients reported concern about paying for their cancer treatment, 22.3% reported that their family had made sacrifices to pay for their care, and 8.3% stated that their insurance adequately covered their current health care costs, and 17.3% reported concerns about coverage for their costs in the future. On open-ended questions, 35.3% reported additional expenses, and 47.5% reported concerns about health care costs. None of the assessed patient characteristics proved to be a robust predictor across all cost-related concerns. There was a strong association between the identification of concerns or expenses on the open-ended questions and concerns on closed-ended questions.
Cost concerns are common among patients with cancer who have health insurance. Health care providers may alleviate concerns by discussing cost-related concerns with all patients, not only those of lower socioeconomic status or those without insurance. A closed-ended screening question may help to initiate these conversations. This may identify potential resources, lower distress, and enable patients to make optimal treatment decisions.
When making treatment decisions, cancer patients must make trade-offs among efficacy, toxicity and cost. However little is known about what patient characteristics may influence these trade-offs.
400 cancer patients reviewed two of three stylized curative and non-curative scenarios that asked them to choose between two treatments of varying levels of efficacy, toxicity and cost. Each scenario which included nine choice sets. Demographics, cost concerns, numeracy and optimism were assessed. Within each scenario, we used latent class methods to distinguish groups with discrete preferences. We then used regressions with group membership probabilities as covariates to identify associations.
Median age was 61 years (range 27-90). 25% were enrolled at a community hospital. and 99% were insured. Three latent classes were identified that demonstrated 1) Preference for survival or aversion to 2) high cost or 3) toxicity. Across all scenarios, patients with higher income were more likely to be in the class that favored survival. Lower income patients were more likely to be in the class that was averse to high cost (p<.05). Similar associations were found between education, employment status, numeracy, cost concerns and latent class.
Even in these stylized scenarios, socioeconomic status (SES) predicted treatment choice. Higher income patients may be more likely to focus on survival while those of lower SES may be more likely to avoid expensive treatment, regardless of survival or toxicity. This raises the possibility that insurance plans with greater cost-sharing may have the unintended consequence of increasing disparities in cancer care.
Overexpression of the NEDD9/HEF1/Cas-L scaffolding protein is frequent, and drives invasion and metastasis in breast, head and neck, colorectal, melanoma, lung, and other types of cancer. We have examined the consequences of genetic ablation of Nedd9 in the MMTV-HER2/ERBB2/neu mouse mammary tumor model. Unexpectedly, we found that only a limited effect on metastasis in MMTV-neu;Nedd9−/− mice compared to MMTV-neu;Nedd9+/+ mice, but instead a dramatic reduction in tumor incidence (18% versus 80%), and a significantly increased latency until tumor appearance. Orthotopic reinjection and tail vein injection of cells arising from tumors, coupled with in vivo analysis, indicated tumors arising in MMTV-neu;Nedd9−/− mice had undergone mutational selection that overcame the initial requirement for Nedd9. To better understand the defects in early tumor growth, we compared mammary progenitor cell pools from MMTV-neu;Nedd9−/− versus MMTV-neu;Nedd9+/+ mice. The MMTV-neu;Nedd9−/− genotype selectively reduced both the number and colony-forming potential of mammary luminal epithelial progenitor cells, while not affecting basal epithelial progenitors. MMTV-neu;Nedd9−/−mammospheres had striking defects in morphology and cell polarity. All of these defects were seen predominantly in the context of the HER2/neu oncogene, and were not associated with randomization of the plane of mitotic division, but rather with depressed expression the cell attachment protein FAK, accompanied by increased sensitivity to small molecule inhibitors of FAK and SRC. Surprisingly, in spite of these significant differences, only minimal changes were observed in the gene expression profile of Nedd9−/− mice, indicating critical Nedd9-dependent differences in cell growth properties were mediated via post-transcriptional regulation of cell signaling. Coupled with emerging data indicating a role for NEDD9 in progenitor cell populations during the morphogenesis of other tissues, these results indicate a functional requirement for NEDD9 in the growth of mammary cancer progenitor cells.
breast cancer; HER2; mammary precursor cells; drug resistance
To investigate possible predictors of tanning dependence including demographic variables, exposure and protective behaviors, and other health-related behaviors.
This study consisted of an online survey of 400 students and other volunteers from a university community.
Twenty-seven percent of the sample was classified as tanning dependent. Tanning dependence was predicted by ethnicity and skin type, indoor and outdoor tanning and burning, and lower skin protective behaviors, as well as smoking and body mass index.
Young adults are at risk for tanning dependence, which can be predicted by specific demographic and behavioral variables.
tanning; skin cancer prevention; addiction
Symptom distress remains a significant health problem among older adults with cancer following surgery. Understanding factors influencing older adults’ symptom distress may lead to early identification and interventions, decreasing morbidity and improving outcomes.
We conducted this study to identify factors associated with symptom distress following surgery among 326 community-residing patients ages 65 and older diagnosed with thoracic, digestive, gynecologic, and genitourinary cancers.
Secondary analysis using combined subsets of data from five nurse-directed intervention clinical trials targeting patients post-surgery at academic cancer centers in northwest and northeastern United States. Symptom distress was assessed by the Symptom Distress Scale at baseline, 3, and 6 months.
A multivariable analysis, using Generalized Estimating Equations, showed symptom distress was significantly less at 3 and 6 months (3 months: p<0.001, 6 months: p=0.002) than at baseline while controlling for demographic, biologic, psychological, treatment, and function covariates. Thoracic cancer, comorbidities, worse mental health, and decreased function were, on average, associated with increased symptom distress (all p<0.05). Participants ages 75 and older reported increased symptom distress over time compared with those ages 65 to 69 (p<0.05).
Age, type of cancer, comorbidities, mental health, and function may influence older adults’ symptom distress following cancer surgery.
Implications for Practice
Older adults generally experience decreasing symptom distress after thoracic, abdominal, or pelvic cancer surgery. Symptom management over time for those with thoracic cancer, comorbidities, worse mental health, decreased function, and ages 75 and older may prevent morbidity and improve outcomes of older adults following surgery.
Cancer; Surgery; Older; Symptom Distress
To evaluate prostate cancer diagnosis rates and survival outcomes in patients receiving unrelated (non-prostate) urologic care as compared to patients receiving non-urologic care.
Materials and Methods
We conducted a population based study using the Surveillance Epidemiology and End Results (SEER) database to identify men who underwent surgical treatment of RCC (18,188) and CRC (45,093) from 1992 to 2008. Using SEER*stat software to estimate standardized incidence ratios (SIRs), we investigated rates of prostate cancer diagnosis in RCC and CRC patients. Adjusting for patient age, race, and year of diagnosis on multivariate analysis, Cox and Fine & Gray proportional hazards regressions were used to evaluate overall and disease specific survival endpoints.
Expected incidence of prostate cancer was higher in both RCC and CRC patients (SIR=1.36[1.27–1.46] vs. 1.06[1.02–1.11]). Adjusted prostate cancer SIRs were 30% higher (p<0.001) in patients with RCC. Overall (HR=1.13, p<0.001) and primary cancer (sHR=1.17, p<0.001) adjusted mortalities were higher in patients with RCC with no significant difference in prostate cancer-specific mortality (sHR=0.827, p=0.391).
Rates of prostate cancer diagnosis were higher in patients with RCC (a cohort with unrelated urologic cancer care) vs. CRC. Despite higher overall mortality in RCC patients, prostate cancer specific survival was similar in both groups. Opportunities may exist to better target prostate cancer screening in patients who receive non-prostate related urologic care. Furthermore, urologists should not feel obligated to perform PSA-screening for all patients receiving non-prostate related urologic care.
prostate carcinoma; screening; prostate specific antigen; urologic care; overdiagnosis
The present study examined associations between psychological reactivity and hormonal responses to a standardized laboratory stressor (the Trier Social Stress Test [TSST]) in postmenopausal women.
Forty postmenopausal women ages 50–74 completed anxiety and mood assessments prior to and following the TSST. Blood samples were drawn across multiple time points for assessment of cortisol, adrenocorticotropic hormone (ACTH), and DHEA.
As expected, significant increases in anxiety and negative affect and decreases in positive affect were observed from pre- to post-TSST; however, the magnitude of change in anxiety and mood varied considerably across individuals. Analyses indicated that greater increases in anxiety and negative affect from pre- to post-TSST were associated with higher levels of cortisol, ACTH, and DHEA, controlling for race, age, body mass index, and smoking status. Changes in positive affect were not associated with cortisol, ACTH, or DHEA.
These findings suggest that enhanced reactivity to stress is associated with higher hormone levels among postmenopausal women, which could have potential implications for health.
Trier Social Stress Test; anxiety; negative affect; cortisol; DHEA; ACTH
Accumulating data suggest that depression is associated with risk factors for cardiovascular disease, but few studies have investigated potential behavioral mediators of such associations, particularly among women. In this study of healthy young adult women (n = 225), we examined associations among depressive symptoms, health behaviors, and serum lipid levels. Depressive symptoms were assessed with the 20-item Center for Epidemiologic Studies – Depression (CES-D) scale, and a fasting blood sample was obtained for serum lipid levels, including total cholesterol, high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C). Diet was measured using 24-hour recalls, and other health behaviors (physical activity, smoking) were assessed via self-report questionnaire. Results indicated a modest negative association between depressive symptoms and LDL-C levels. Higher levels of depressive symptoms were also associated with lower total and insoluble dietary fiber intake, both of which were associated with HDL-C and LDL-C. Mediational analyses indicated a significant indirect effect of depressive symptoms on LDL-C via total and insoluble dietary fiber in unadjusted analyses, but not in adjusted analyses. The present findings suggest that depressive symptoms are inversely associated with serum LDL-C levels in young adult women, but that these associations are not likely mediated by adverse lifestyle behaviors.
Depression; cholesterol; health behaviors; diet
Cancer patients and their oncologists often report differing perceptions of consultation discussions and discordant expectations regarding treatment outcomes. CONNECT™, a computer-based communication aid, was developed to improve communication between patients and oncologists.
CONNECT includes assessment of patient values, goals, and communication preferences; patient communication skills training; and a pre-consult physician summary report. CONNECT was tested in a three-arm, prospective, randomized clinical trial. Prior to the initial medical oncology consultation, adult patients with advanced cancer were randomized to (a) control; (b) CONNECT with physician summary, or (c) CONNECT without physician summary. Outcomes were assessed with post-consultation surveys.
Of 743 patients randomized, 629 completed post-consultation surveys. Patients in the intervention arms (versus control) felt that the CONNECT program made treatment decisions easier to reach (p=0.003) and helped them to be more satisfied with these decisions (p<0.001). In addition, patients in the intervention arms reported higher levels of satisfaction with physician communication format (p=0.026) and discussion regarding support services (p=0.029) and quality of life concerns (p=0.042). The physician summary did not impact outcomes. Patients with higher levels of education and poorer physical functioning experienced greater benefit from CONNECT.
This prospective randomized clinical trial demonstrates that computer-based communication skills training can positively affect patient satisfaction with communication and decision making. Measureable patient characteristics may be used to identify subgroups most likely to benefit from an intervention such as CONNECT.
Cancer communication; health communication; physician-patient communication; decision making; computer assisted; cancer
Circulating tumor cells (CTC) represent a new outcome-associated biomarker independently from known prognostic factors in metastatic breast cancer (MBC). The objective here was to develop and validate nomograms that combined baseline CTC counts and the other prognostic factors to assess the outcome of individual patients starting first-line treatment for MBC.
We used a training set of 236 MBC patients starting a first-line treatment from the MD Anderson Cancer Center to establish nomograms that calculated the predicted probability of survival at different time points: 1, 2, and 5 years for overall survival (OS) and 6 months and 1 and 2 years for progression-free survival (PFS). The covariates computed in the model were: age, disease subtype, visceral metastases, performance status, and CTC counts by CellSearch. Nomograms were independently validated with 210 MBC patients from the Institut Curie who underwent first-line chemotherapy. The discriminatory ability and accuracy of the models were assessed using Harrell’s c-statistic and calibration plots at different time points in both training and validation datasets.
Median follow-up was of 23 and 29 months in the MD Anderson and Institut Curie cohorts, respectively. Nomograms demonstrated good C-statistics: 0.74 for OS and 0.65 for PFS and discriminated OS prediction at 1, 2, and 5 years, and PFS prediction at 6 months and 1 and 2 years.
Nomograms, which relied on CTC counts as a continuous covariate, easily facilitated the use of a web-based tool for estimating survival, supporting treatment-decisions and clinical trial stratification in first-line MBC.
circulating tumor cells; first-line; metastatic breast cancer; nomogram; survival