Patient-reported causes of distress predict disparities in time to evaluation and time to treatment after breast cancer diagnosis.

BACKGROUND: We examined whether the National Comprehensive Cancer Network distress thermometer (DT), a patient-reported outcome measure, could be used to identify levels and causes of distress associated with racial/ethnic disparities in time to care among patients with breast cancer. METHODS: We identified women aged ≥18 years with stage 0-IV breast cancer who were diagnosed in a single health system between January 2014 and July 2016. The baseline visit was defined as the first postdiagnosis, pretreatment clinical evaluation. Zero-inflated negative binomial (ZINB) regression (modeling non-zero DT scores and DT scores = 0) and logistic regression (modeling DT score ≥ 4, threshold for social services referral) were used to examine associations between baseline score (0 = none to 10 = extreme) and types of stressors (emotional, familial, practical, physical, spiritual) after adjustment for race/ethnicity and other characteristics. Linear regression with log transformation was used to identify predictors of time to evaluation and time to treatment. RESULTS: A total of 1029 women were included (median baseline DT score = 4). Emotional, physical, and practical stressors were associated with distress in both the ZINB and logistic models (all P < .05). Black patients (n = 258) were more likely to report no distress than Whites (n = 675; ZINB zero model odds ratio, 2.72; 95% CI, 1.68-4.40; P < .001) despite reporting a similar number of stressors (P = .07). Higher DT scores were associated with shorter time to evaluation and time to treatment while being Black and having physical or practical stressors were associated with delays in both (all P < .05). CONCLUSIONS: Patient-reported stressors predicted delays in time to care, but patient-reported levels of distress did not, with Black patients having delayed time to care despite reporting low levels of distress. We describe anticipatory, culturally responsive strategies for using patient-reported outcomes to address observed disparities.

Using Latent Class Modeling to Jointly Characterize Economic Stress and Multipollutant Exposure.

BACKGROUND: Work is needed to better understand how joint exposure to environmental and economic factors influence cancer. We hypothesize that environmental exposures vary with socioeconomic status (SES) and urban/rural locations, and areas with minority populations coincide with high economic disadvantage and pollution. METHODS: To model joint exposure to pollution and SES, we develop a latent class mixture model (LCMM) with three latent variables (SES Advantage, SES Disadvantage, and Air Pollution) and compare the LCMM fit with K-means clustering. We ran an ANOVA to test for high exposure levels in non-Hispanic black populations. The analysis is at the census tract level for the state of North Carolina. RESULTS: The LCMM was a better and more nuanced fit to the data than K-means clustering. Our LCMM had two sublevels (low, high) within each latent class. The worst levels of exposure (high SES disadvantage, low SES advantage, high pollution) are found in 22% of census tracts, while the best levels (low SES disadvantage, high SES advantage, low pollution) are found in 5.7%. Overall, 34.1% of the census tracts exhibit high disadvantage, 66.3% have low advantage, and 59.2% have high mixtures of toxic pollutants. Areas with higher SES disadvantage had significantly higher non-Hispanic black population density (NHBPD; P < 0.001), and NHBPD was higher in areas with higher pollution (P < 0.001). CONCLUSIONS: Joint exposure to air toxins and SES varies with rural/urban location and coincides with minority populations. IMPACT: Our model can be extended to provide a holistic modeling framework for estimating disparities in cancer survival.See all articles in this CEBP Focus section, "Environmental Carcinogenesis: Pathways to Prevention."

How Many Lymph Nodes Are Enough? Assessing the Adequacy of Lymph Node Yield for Papillary Thyroid Cancer.

PURPOSE: Patients who undergo surgery for papillary thyroid cancer with only a limited lymph node examination are thought to be at risk for potentially harboring occult disease. However, this risk has not been objectively quantified and may have implications for subsequent management and surveillance. METHODS: Data from the National Cancer Database (1998 to 2012) were used to characterize the distribution of nodal positivity of adult patients diagnosed with localized ≥ 1-cm papillary thyroid cancer who underwent thyroidectomy with one or more lymph nodes (LNs) examined. A ß-binomial distribution was used to estimate the probability of occult nodal disease as a function of total number of LNs examined and pathologic tumor stage. RESULTS: A total of 78,724 patients met study criteria; 38,653 patients had node-positive disease. The probability of falsely identifying a patient as node negative was estimated to be 53% for patients with a single node examined and decreased to less than 10% when more than six LNs were examined. To rule out occult nodal disease with 90% confidence, six, nine, and 18 nodes would need to be examined for patients with T1b, T2, and T3 disease, respectively. Sensitivity analyses limited to patients likely undergoing prophylactic central neck dissection resulted in three, four, and eight nodes needed to provide comparable adequacy of LN evaluation. CONCLUSION: To our knowledge, our study provides the first empirically based estimates of occult nodal disease risk in patients after surgery for papillary thyroid cancer as a function of primary tumor stage and number of LNs examined. Our estimates provide an objective guideline for evaluating adequacy of LN yield for surgeons and pathologists in the treatment of papillary thyroid cancer, and especially intermediate-risk disease, for which use of adjuvant radioactive iodine and surveillance intensity are not currently standardized.

A phase I study of the combination of sorafenib with temozolomide and radiation therapy for the treatment of primary and recurrent high-grade gliomas.

PURPOSE: Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. METHODS AND MATERIALS: This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m(2)) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). RESULTS: Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. CONCLUSIONS: Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.

Harmonization of regulatory approaches for evaluating therapeutic equivalence and interchangeability of multisource drug products: workshop summary report.

Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products.

A uroguanylin-GUCY2C endocrine axis regulates feeding in mice.

Intestinal enteroendocrine cells are critical to central regulation of caloric consumption, since they activate hypothalamic circuits that decrease appetite and thereby restrict meal size by secreting hormones in response to nutrients in the gut. Although guanylyl cyclase and downstream cGMP are essential regulators of centrally regulated feeding behavior in invertebrates, the role of this primordial signaling mechanism in mammalian appetite regulation has eluded definition. In intestinal epithelial cells, guanylyl cyclase 2C (GUCY2C) is a transmembrane receptor that makes cGMP in response to the paracrine hormones guanylin and uroguanylin, which regulate epithelial cell dynamics along the crypt-villus axis. Here, we show that silencing of GUCY2C in mice disrupts satiation, resulting in hyperphagia and subsequent obesity and metabolic syndrome. This defined an appetite-regulating uroguanylin-GUCY2C endocrine axis, which we confirmed by showing that nutrient intake induces intestinal prouroguanylin secretion into the circulation. The prohormone signal is selectively decoded in the hypothalamus by proteolytic liberation of uroguanylin, inducing GUCY2C signaling and consequent activation of downstream anorexigenic pathways. Thus, evolutionary diversification of primitive guanylyl cyclase signaling pathways allows GUCY2C to coordinate endocrine regulation of central food acquisition pathways with paracrine control of intestinal homeostasis. Moreover, the uroguanylin-GUCY2C endocrine axis may provide a therapeutic target to control appetite, obesity, and metabolic syndrome.

Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast cancer predicts poor clinical outcome and increased risk of antiestrogen therapy failure.

PURPOSE: To investigate nuclear localized and tyrosine phosphorylated Stat5 (Nuc-pYStat5) as a marker of prognosis in node-negative breast cancer and as a predictor of response to antiestrogen therapy. PATIENTS AND METHODS: Levels of Nuc-pYStat5 were analyzed in five archival cohorts of breast cancer by traditional diaminobenzidine-chromogen immunostaining and pathologist scoring of whole tissue sections or by immunofluorescence and automated quantitative analysis (AQUA) of tissue microarrays. RESULTS: Nuc-pYStat5 was an independent prognostic marker as measured by cancer-specific survival (CSS) in patients with node-negative breast cancer who did not receive systemic adjuvant therapy, when adjusted for common pathology parameters in multivariate analyses both by standard chromogen detection with pathologist scoring of whole tissue sections (cohort I; n = 233) and quantitative immunofluorescence of a tissue microarray (cohort II; n = 291). Two distinct monoclonal antibodies gave concordant results. A progression array (cohort III; n = 180) revealed frequent loss of Nuc-pYStat5 in invasive carcinoma compared to normal breast epithelia or ductal carcinoma in situ, and general loss of Nuc-pYStat5 in lymph node metastases. In cohort IV (n = 221), loss of Nuc-pYStat5 was associated with increased risk of antiestrogen therapy failure as measured by univariate CSS and time to recurrence (TTR). More sensitive AQUA quantification of Nuc-pYStat5 in antiestrogen-treated patients (cohort V; n = 97) identified by multivariate analysis patients with low Nuc-pYStat5 at elevated risk for therapy failure (CSS hazard ratio [HR], 21.55; 95% CI, 5.61 to 82.77; P < .001; TTR HR, 7.30; 95% CI, 2.34 to 22.78; P = .001). CONCLUSION Nuc-pYStat5 is an independent prognostic marker in node-negative breast cancer. If confirmed in prospective studies, Nuc-pYStat5 may become a useful predictive marker of response to adjuvant hormone therapy.

Opportunities for near-infrared thermal ablation of colorectal metastases by guanylyl cyclase C-targeted gold nanoshells.

Colorectal cancer is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. While surgery remains the mainstay of therapy, approximately 50% of patients who undergo resection develop parenchymal metastatic disease. Unfortunately, current therapeutic regimens offer little improvement to the survival of patients with parenchymal metastases in the liver and lung. In that context, there is a significant unrealized opportunity at the intersection of engineering and biology for the development of novel targeted therapeutic approaches to colorectal cancer metastases. This opportunity exploits the discovery that an intestinal receptor, guanylyl cyclase C, which mediates diarrhea induced by bacterial heat-stable enterotoxins (STs), is over-expressed by metastatic colorectal tumors only. Moreover, it leverages recent advances in the fabrication of metal nanoshells with defined thicknesses absorb near-infrared (NIR) light, resulting in resonance and transfer of thermal energies of more than 40 degrees C. Thus, the conjugation of ST to gold nanoshells, which can undergo resonance excitation by NIR light and emit heat, represents a previously unrecognized approach for the targeted therapy of parenchymal colorectal cancer metastases, specifically to the liver and lung. This article discusses the potential of ST-targeted nanoshells for NIR thermal ablation of metastatic colorectal tumors and highlights the significant challenges and solutions linked to the translation of this emerging technology to patient care.

Effectiveness of complete diagnostic examination in clinical practice settings.

BACKGROUND: Thorough follow-up of a positive fecal occult blood test (FOBT) result, or a complete diagnostic evaluation (CDE), is recommended as routine care on the basis of findings from colorectal cancer (CRC) screening trials. CDE involves either colonoscopy or the combination of flexible sigmoidoscopy and double contrast barium enema X-ray. However, little evidence outside clinical screening trial settings has been reported in the literature to support CDE performance. The focus of this study was to determine the impact of CDE in primary care practice settings. METHODS: We determined diagnostic outcomes for 461 adult patients with a positive FOBT result in 318 primary care practices in southeastern Pennsylvania and southern New Jersey. Sociodemographic data were collected and CDE status was ascertained for these patients. Polytomous logistic models were used to identify whether having CDE was associated with subsequently being diagnosed with lower gastrointestinal "neoplastic disease" or "other gastrointestinal disease" as compared to "normal findings. RESULTS: Patients who underwent CDE were significantly more likely to have a reported diagnosis of colorectal neoplasia than normal findings (adjusted odds ratio = 3.65, 95% confidence interval = 1.58-8.39, p = 0.02). CDE performance did not result in the differential diagnosis of other gastrointestinal disease. CONCLUSIONS: Patients with a positive screening FOBT who underwent CDE were more likely to be diagnosed with colorectal neoplasia than with less serious conditions or have normal findings. Results support the use of CDE in CRC screening.

Impact of a physician-oriented intervention on follow-up in colorectal cancer screening.

BACKGROUND: Complete diagnostic evaluation or CDE (i.e., colonoscopy or combined flexible sigmoidoscopy plus barium enema X-ray) is often not performed for persons with an abnormal screening fecal occult blood test (FOBT+) result. METHOD: This study evaluated the impact of a reminder-feedback and educational outreach intervention on primary care practice CDE recommendation and performance rates. Four hundred seventy primary care physicians (PCPs) in 318 practices participated in the study. Patients were mailed an FOBT kit annually as part of a screening program. Practices were randomly assigned to a Control Group (N = 198) or an Intervention Group (N = 120). During an 18-month pre-randomization period and a 9-month post-randomization period, 2992 screening FOBT+ patients were identified. Intervention practices received the screening program and the intervention. Control practices received only the screening program. Study outcomes were baseline-adjusted CDE recommendation and performance rates. RESULTS: At baseline, about two-thirds of FOBT+ patients received a CDE recommendation, and about half had a CDE performed. At endpoint, CDE recommendation and performance rates were both significantly higher for the Intervention as compared to the Control practices (OR = 2.28; 95% CI: 1.37, 3.78, and OR = 1.63; 95% CI: 1.06, 2.50, respectively). CONCLUSIONS: The reminder-feedback plus educational outreach intervention significantly increased CDE recommendation and performance.

Physician and patient factors associated with ordering a colon evaluation after a positive fecal occult blood test.

OBJECTIVE: Successful colorectal cancer screening relies in part on physicians ordering a complete diagnostic evaluation of the colon (CDE) with colonoscopy or barium enema plus sigmoidoscopy after a positive screening fecal occult blood test (FOBT). DESIGN: We surveyed primary care physicians about colorectal cancer screening practices, beliefs, and intentions. At least 1 physician responded in 318 of 413 (77%) primary care practices that were affiliated with a managed care organization offering a mailed FOBT program for patients aged >/=50 years. Of these 318 practices, 212 (67%) had 602 FOBT+ patients from August through November 1998. We studied 184 (87%) of these 212 practices with 490 FOBT+ patients after excluding those judged ineligible for a CDE or without demographic data. Three months after notification of the FOBT+ result, physicians were asked on audit forms if they had ordered CDEs for study patients. Patient- and physician-predictors of ordering CDEs were identified using logistic regression. MEASUREMENTS AND MAIN RESULTS: A CDE was ordered for only 69.5% of 490 FOBT+ patients. After adjustment, women were less likely to have had CDE initiated than men (adjusted odds, 0.66; confidence interval, 0.44 to 0.97). Physician survey responses indicating intermediate or high intention to evaluate a FOBT+ patient with a CDE were associated with nearly 2-fold greater adjusted odds of actually initiating a CDE in this circumstance versus physicians with a low intention. CONCLUSIONS: Primary care physicians often fail to order CDE for FOBT+ patients. A CDE was less likely to be ordered for women and was influenced by physician's beliefs about CDEs.