SWAN pathway-network identification of common aneuploidy-based oncogenic drivers.

Haploinsufficiency drives Darwinian evolution. Siblings, while alike in many aspects, differ due to monoallelic differences inherited from each parent. In cancer, solid tumors exhibit aneuploid genetics resulting in hundreds to thousands of monoallelic gene-level copy-number alterations (CNAs) in each tumor. Aneuploidy patterns are heterogeneous, posing a challenge to identify drivers in this high-noise genetic environment. Here, we developed Shifted Weighted Annotation Network (SWAN) analysis to assess biology impacted by cumulative monoallelic changes. SWAN enables an integrated pathway-network analysis of CNAs, RNA expression, and mutations via a simple web platform. SWAN is optimized to best prioritize known and novel tumor suppressors and oncogenes, thereby identifying drivers and potential druggable vulnerabilities within cancer CNAs. Protein homeostasis, phospholipid dephosphorylation, and ion transport pathways are commonly suppressed. An atlas of CNA pathways altered in each cancer type is released. These CNA network shifts highlight new, attractive targets to exploit in solid tumors.

Relating Physiologic Swallowing Impairment, Functional Swallowing Ability, and Swallow-Specific Quality of Life.

Many studies include functional swallowing ability and quality of life information to indicate a response to a specific swallowing intervention or to describe the natural history of dysphagia across diseases and conditions. Study results are difficult to interpret because the association between these factors and actual swallowing impairment is not understood. We set out to test the associations between components of physiologic swallowing impairment, functional swallowing ability, and swallow-specific quality of life using standardized and validated measurement tools: Modified Barium Swallow Impairment Profile (MBSImP), Functional Oral Intake Scale (FOIS), Eating Assessment Tool (EAT-10), and Dysphagia Handicap Index (DHI). We specifically aimed to understand which factors may contribute to the overall relationships between these measurement tools when analyzed using total scores and item-level scores. This study included a heterogeneous cohort of 273 outpatients who underwent a modified barium swallow study (MBSS). We found significant correlations between MBSImP total scores and FOIS scores and DHI total scores, but not between MBSImP total scores and EAT-10 total scores. Significant correlations were also found between MBSImP item-level component scores and FOIS scores, EAT-10 total scores, and DHI total scores. Detailed item-level analyses revealed the MBSImP components of bolus transport/lingual motion, oral residue, and tongue base retraction were correlated with EAT-10 item-level scores and DHI item-level scores. The clinically modest associations between physiologic swallowing impairment, functional swallowing ability, and swallow-specific quality of life reveal different factors that uniquely contribute to patients' overall dysphagic profile, emphasizing the clinical impact of a comprehensive swallowing assessment.

A randomized, open-label, phase 2, multicenter trial of gemcitabine with pazopanib or gemcitabine with docetaxel in patients with advanced soft-tissue sarcoma.

BACKGROUND: Therapeutic options for patients with advanced soft-tissue sarcoma (STS) are limited. The goal of the current phase 2 study was to examine the clinical activity and safety of the combination of gemcitabine plus pazopanib, a multityrosine kinase inhibitor with activity in STS. METHODS: The current randomized, phase 2 trial enrolled patients with advanced nonadipocytic STS who had received prior anthracycline-based therapy. Patients were assigned 1:1 to receive gemcitabine at a dose of 1000 mg/m2 on days 1 and 8 with pazopanib at a dose of 800 mg daily (G+P) or gemcitabine at a dose of 900 mg/m2 on days 1 and 8 and docetaxel at a dose of 100 mg/m2 on day 8 (G+T) every 3 weeks. Crossover was allowed at the time of disease progression. The study used a noncomparative statistical design based on the precision of 95% confidence intervals for reporting the primary endpoints of median progression-free survival (PFS) and rate of grade ≥3 adverse events (AEs) for these 2 regimens based on the intent-to-treat patient population (AEs were graded using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events). RESULTS: A total of 90 patients were enrolled: 45 patients on each treatment arm. The median PFS was 4.1 months for each arm (P = .3, log-rank test). The best overall response of stable disease or better (complete response + partial response + stable disease) was the same for both treatment arms (64% for both the G+T and G+P arms). The rate of related grade ≥3 AEs was 82% for the G+T arm and 78% for the G+P arm. Related grade ≥3 AEs occurring in ≥10% of patients in the G+T and G+P arms were anemia (36% and 20%, respectively), fatigue (29% and 13%, respectively), thrombocytopenia (53% and 49%, respectively), neutropenia (20% and 49%, respectively), lymphopenia (13% and 11%, respectively), and hypertension (2% and 20%, respectively). CONCLUSIONS: The data from the current study have demonstrated the safety and efficacy of G+P as an alternative to G+T for patients with nonadipocytic STS.

Immunological effects of nivolumab immunotherapy in patients with oral cavity squamous cell carcinoma.

BACKGROUND: Although checkpoint blockades have become widely used, the immunological impact in cancer patients, especially those with oral cavity squamous cell carcinoma (OCSCC), has not been well studied. METHODS: The present study assessed the immunological impact of anti-PD-1 (nivolumab) treatment in 10 patients with OCSCC. This involved phenotypic analyses of peripheral blood T-cell subpopulations and their expression of immune mediators prior to and following nivolumab treatment. The focus was on immunological effects of treatment without regard to possible clinical responses. RESULTS: Nivolumab caused a decline in the frequency of blood CD4+ cells but did not affect their expression of IFN-γ. However, nivolumab increased the proportion of CD4+ cells expressing the Treg-supporting factor Foxp3. Nivolumab treatment caused an increase in the proportion of CD8+ cells. While their expression of granzyme B increased, it did not attain significance. Analyses of CD8+ cell subpopulations showed nivolumab caused an increase in levels of unconventional CD8dimCD3+ T-cells. It also caused an increase in expression of granzyme B by these unconventional T-cells as well as by the conventional CD8hiCD3+ cells. The CD8hiCD3+ subpopulation also had a near-significant increase in IFN-γ expression. Treatment with nivolumab had no effect on the levels of the NK containing CD8dimCD3- subpopulation of cells or their expression of IFN-γ or granzyme B. CONCLUSIONS: These results show nivolumab causes opposing effects on CD4+ and CD8+ cell populations, with CD4+ cell levels declining but increasing the proportion of Treg cells, and unconventional CD8+ T-cell levels increasing with increased expression of immune mediators by CD8+ T-cell subpopulations.

Advanced glycation end products are elevated in estrogen receptor-positive breast cancer patients, alter response to therapy, and can be targeted by lifestyle intervention.

PURPOSE: Lifestyle factors associated with personal behavior can alter tumor-associated biological pathways and thereby increase cancer risk, growth, and disease recurrence. Advanced glycation end products (AGEs) are reactive metabolites produced endogenously as a by-product of normal metabolism. A Western lifestyle also promotes AGE accumulation in the body which is associated with disease phenotypes through modification of the genome, protein crosslinking/dysfunction, and aberrant cell signaling. Given the links between lifestyle, AGEs, and disease, we examined the association between dietary-AGEs and breast cancer. METHODS: We evaluated AGE levels in bio-specimens from estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer patients, examined their role in therapy resistance, and assessed the ability of lifestyle intervention to reduce circulating AGE levels in ER+ breast cancer survivors. RESULTS: An association between ER status and AGE levels was observed in tumor and serum samples. AGE treatment of ER+ breast cancer cells altered ERα phosphorylation and promoted resistance to tamoxifen therapy. In a proof of concept study, physical activity and dietary intervention was shown to be viable options for reducing circulating AGE levels in breast cancer survivors. CONCLUSIONS: There is a potential prognostic and therapeutic role for lifestyle derived AGEs in breast cancer. Given the potential benefits of lifestyle intervention on incidence and mortality, opportunities exist for the development of community health and nutritional programs aimed at reducing AGE exposure in order to improve breast cancer prevention and treatment outcomes.

Eukaryotic initiation factor 4E-binding protein as an oncogene in breast cancer.

BACKGROUND: Eukaryotic Initiation Factor 4E-Binding Protein (EIF4EBP1, 4EBP1) is overexpressed in many human cancers including breast cancer, yet the role of 4EBP1 in breast cancer remains understudied. Despite the known role of 4EBP1 as a negative regulator of cap-dependent protein translation, 4EBP1 is predicted to be an essential driving oncogene in many cancer cell lines in vitro, and can act as a driver of cancer cell proliferation. EIF4EBP1 is located within the 8p11-p12 genomic locus, which is frequently amplified in breast cancer and is known to predict poor prognosis and resistance to endocrine therapy. METHODS: Here we evaluated the effect of 4EBP1 targeting using shRNA knock-down of expression of 4EBP1, as well as response to the mTORC targeted drug everolimus in cell lines representing different breast cancer subtypes, including breast cancer cells with the 8p11-p12 amplicon, to better define a context and mechanism for oncogenic 4EBP1. RESULTS: Using a genome-scale shRNA screen on the SUM panel of breast cancer cell lines, we found 4EBP1 to be a strong hit in the 8p11 amplified SUM-44 cells, which have amplification and overexpression of 4EBP1. We then found that knock-down of 4EBP1 resulted in dramatic reductions in cell proliferation in 8p11 amplified breast cancer cells as well as in other luminal breast cancer cell lines, but had little or no effect on the proliferation of immortalized but non-tumorigenic human mammary epithelial cells. Kaplan-Meier analysis of EIF4EBP1 expression in breast cancer patients demonstrated that overexpression of this gene was associated with reduced relapse free patient survival across all breast tumor subtypes. CONCLUSIONS: These results are consistent with an oncogenic role of 4EBP1 in luminal breast cancer and suggests a role for this protein in cell proliferation distinct from its more well-known role as a regulator of cap-dependent translation.

Causal attributions and their impact on psychosocial functioning in head and neck cancer patient-caregiver dyads: a preliminary, longitudinal study.

PURPOSE: This longitudinal study explores causal attributions in newly diagnosed head/neck cancer (HNC) patients and their caregivers. METHODS: Perceptions of causal attributions and associated level of responsibility regarding each patient's HNC diagnosis at baseline (n = 72 dyads) were described and then tested as predictors of depressive symptoms, cancer worry, and perceived support 6 months later. RESULTS: When causes were reported, tobacco and alcohol use topped the list of both patients and caregivers. Three-quarters of dyads agreed about perceptions of the patients' responsibility in causing their HNC. Some dyad-level patterns of causal attribution were associated with patients' and caregivers' cancer worry (p < 0.05) and caregivers' perceived support (p < 0.05) in unadjusted models. CONCLUSIONS: This preliminary study indicates that causal attributions warrant further exploration in HNC patient-caregiver dyads specifically, as well as studies of quality of life in patient-caregiver dyads more broadly considered.

Syringotropic Mycosis Fungoides: A Variant of Folliculotropic Mycosis Fungoides or a Distinct Entity?

Syringotropic mycosis fungoides (MF) is classified under folliculotropic MF. Although there is significant overlap between the 2, this study demonstrates that folliculotropism is frequently present in syringotropic MF, and when not present, the specimen did not include a follicle to examine. In addition, few of the pathology reports mentioned folliculotropism or syringotropism, although this is an important prognostic feature.

Comparison of psychosocial factors over time among HPV+ oropharyngeal cancer and tobacco-related oral cavity cancer patients.

INTRODUCTION: The role of human papilloma virus (HPV) in the pathogenesis of oropharyngeal squamous cell carcinoma (OPSCC) is well documented, as is the excellent prognosis of patients with HPV-associated disease; in contrast, oral cavity squamous cell carcinoma (OCSCC) is associated with tobacco and alcohol use and has a worse prognosis. While causative factors, staging, and treatment guidelines differ between these cancer subsets, few studies have compared psychosocial factors in these groups. OBJECTIVE: To explore differences in psychosocial factors between HPV+ OPSCC patients versus OCSCC smokers. METHODS: A prospective cohort study at a single multidisciplinary, tertiary care HNC center was completed with recruitment from 2010 to 2013 using self-administered questionnaires before treatment and at 12 months. Patients were included with a diagnosis of HPV+ OPSCC or OCSCC with a smoking history. 38 (21 HPV+ OPSCC/17 OCSCC) met criteria. The main outcomes included self-efficacy, symptom severity, cancer worry, and depression. RESULTS: A total of 38 (21 HPV+ OPSCC/17 OCSCC) patients (mean age: 57 [32-76], 73.7% male, 78.9% Caucasian, 71% stage IV) met inclusion criteria. OPSCC patients tended to be of male sex, Caucasian race, and single. Furthermore, OPSCC patients were more likely than OCSCC patients to have private insurance, be employed, and use alcohol and tobacco less frequently. Regarding psychosocial factors, HPV+ OPSCC patients reported lower symptom severity (2.7 versus 3.3), depression (12.0 versus 14.0) and cancer worry (2.8 versus 3.2) at baseline compared to OCSCC patients. Depression decreased significantly over time in OPSCC patients (12.0 to 9.9; effect size: -3.2 (95% CI: -5.9 to -0.4)). Although not statistically significant, cancer worry decreased in both groups (2.8 to 2.4 and 3.2 to 2.7, respectively, effect sizes: -0.3 (95% CI: -0.7-0.08) and -0.6 (95% CI: -1.2-0.05), respectively). No statistically significant differences in patterns of change over time were noted between groups. CONCLUSIONS AND RELEVANCE: This pilot study highlighted a pattern of reduced quality of life parameters in OCSCC patients at baseline with similar improvements over time compared to the OPSCC cohort. Although different in cancer etiology and treatment plans, HPV+ OPSCC and tobacco-related OCSCC patients both require multidisciplinary cancer care plans that address psychosocial concerns. LEVEL OF EVIDENCE: 2B.

Systematic Review of Mammography Screening Educational Interventions for Hispanic Women in the United States.

In the United States (U.S.), Hispanics experience breast cancer disparities. Breast cancer is the leading cause of cancer-related death among Hispanic women, and Hispanic women receive mammography screening at lower rates than some other ethnic groups. This low rate of screening mammography is associated with increased risk for possible late-stage diagnosis and lower survival rates. Educational interventions could play a role in increasing screening mammography rates among Hispanic women. This systematic review synthesized the current literature on educational interventions to increase mammography screening among Hispanic women. The review included studies published between May 2003 and September 2017 with experimental and quasi-experimental interventions to increase mammography screening among Hispanics in the U.S. Five studies out of an initial 269 studies met inclusion criteria for the review. All studies employed an interpersonal intervention strategy with community health workers, or promotoras, to deliver the mammography screening intervention. For each study, odds ratios (OR) were calculated to estimate intervention effectiveness based on similar follow-up time periods. The study ORs resulted in a narrow range between 1.02 and 2.18, indicating a low to moderate intervention effect for these types of interpersonal cancer education interventions. The summary OR for the random effects model was 1.67 (CI 1.24-2.26). Hispanics exhibit lower levels of adherence to screening mammography than non-Hispanic whites. Interpersonal cancer education interventions such as the use of promotoras may help to mediate the impact of barriers to receiving a mammogram such as low health literacy, deficits in knowledge about the benefits of screening, and low awareness of the availability of screening services.

Factors Influencing Adherence to Recommended Colorectal Cancer Surveillance: Experiences and Behaviors of Colorectal Cancer Survivors.

The number of colorectal cancer (CRC) survivors in the USA is increasing and factors associated with CRC surveillance require attention. This study examined the role of personal, provider, and practice-level factors on CRC survivor care surveillance experiences and outcomes. A telephone survey, informed by the Chronic Care Model, was conducted over a 1-year period with 150 CRC survivors identified via the South Carolina Central Cancer Registry. Participants were ages ≥ 21 years and diagnosed with stages I-III CRC within 1.5 years of study enrollment. Data were analyzed using descriptive statistics and logistic regression. Adherence was defined as receipt of surveillance colonoscopy at 13 months post-CRC surgery, as recommended by evidence-based guidelines. The majority of participants were male (55%) and white (86%), with a median age of 65 years (range 25-89). Almost half (43%) had attained a high school degree or less. Cancer stage was fairly evenly distributed, and 58% had received treatment by surgery alone (provider-level factor). Few participants (56%) received a survivorship care plan (practice-level factor), and adherence to surveillance colonoscopy was lowest (36%) among participants with more than one comorbidity (personal-level factor). Logistic regression models showed that the only significant effect of personal, provider, or practice-level factors on CRC surveillance adherence was related to type of health insurance coverage (private/HMO vs. other; p = 0.04). This is one of the first studies to evaluate CRC surveillance in a socioeconomically diverse sample. The only associations found among the examined factors and adherence were related to type of health insurance coverage. Participants with private/HMO health insurance were significantly more likely than participants with "other" health insurance coverage types (i.e., none, Medicare without supplement, Medicare with supplement) to be adherent to the 13-month colonoscopy. Therefore, future education strategies and patient navigation interventions could focus on identifying and overcoming multi-level barriers to CRC surveillance services.

Physical and emotional well-being and support in newly diagnosed head and neck cancer patient-caregiver dyads.

The purpose of this study was to examine the physical and emotional well-being and social support in newly diagnosed head and neck cancer (HNC) patients and caregivers and identify sociodemographic, clinical, and behavioral risk factors associated with compromised well-being in patients and caregivers. Newly diagnosed HNC patients and their primary caregivers (N = 72 dyads) completed questionnaires before treatment assessing physical and mental well-being, depression, cancer worry, and open-ended support questions. Patients reported worse physical well-being than caregivers (p < 0.05) but similar levels of mental well-being. Caregivers reported providing emotional and instrumental support most frequently with an emphasis on nutrition and assistance with speech, appearance, and addictions. Both patients and their caregivers reported suboptimal mental well-being and depression. Smoking was associated with compromised well-being in patients, caregivers, and dyads. Compromised well-being in patients and their caregivers was more likely when patients were younger, had worse symptoms, and smoked/consumed alcohol (p < 0.05). While patients face more physical strain than caregivers, both equally confront emotional challenges. Results highlight risk factors for compromised well-being in both patients and their caregivers that should be assessed at diagnosis to guide identification of needed dyadic-focused supportive care resources.

Limited Role of Sinus CT in the Management of Febrile Pediatric HSCT Recipients.

Management guidelines have questioned the role of sinus computed tomography (CT). We reviewed 55 febrile episodes with sinus CT during 1 year after admission for hematopoietic stem cell transplant to determine predictive factors for positive sinus CT and the impact on management. Positive sinus CT findings were seen in 42% of febrile episodes. No characteristics were identified as predictors of a positive sinus CT. No other infectious source was identified in 17% of positive sinus CT episodes, with no pharmacotherapy modifications based solely on a positive sinus CT. Sinus CT should be examined in multicenter groups to develop practice guidelines.

Impact of group motivational interviewing on enhancing treatment engagement for homeless Veterans with nicotine dependence and other substance use disorders: A pilot investigation.

BACKGROUND: Prior studies have shown that Group Motivational Interviewing (GMI) for dually diagnosed patients holds promise for increasing treatment engagement. OBJECTIVES: The current study evaluated the impact of a novel GMI protocol that included tobacco-specific components (referred to as "Tobacco GMI or T-GMI") targeting enhanced engagement in smoking cessation treatment. METHODS: Thirty-seven primary alcohol and nicotine-dependent cigarette smoking homeless Veterans with co-morbid psychiatric conditions were recruited to receive four GMI sessions over 4 consecutive days. The first 16 participants received standard GMI, aimed at enhancing engagement in substance abuse treatment and for reducing substance use, while the remaining 21 participants received a modified "tobacco-specific" GMI protocol (T-GMI) that included additional content specific to cessation of tobacco use and enhancing smoking cessation treatment, in addition to the standard substance abuse content of GMI. RESULTS: Participants in T-GMI were more likely to attend tobacco cessation programming (p = .05), as well as to attend combined tobacco cessation programming with prescribed nicotine replacement therapy (p = .03), compared to those in standard GMI. Differences between treatment conditions with respect to alcohol and illicit drug use outcomes were not significant, although overall substance use declined over time in both groups. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Results suggest that inclusion of tobacco-specific components in the context of GMI for substance abuse may enhance treatment engagement for tobacco cessation behaviors among dually diagnosed nicotine dependent homeless patients, a highly vulnerable population for which interventional resources targeting engagement in smoking cessation treatment has historically been lacking. (Am J Addict 2016;25:533-541).

A closer look at unmet needs at the end of primary treatment for breast cancer: a longitudinal pilot study.

This study describes the nature of unmet needs (UN) as women with breast cancer transition from "patient" to "survivor." Data are from a longitudinal study of 90 women with stage I-III breast cancer. Data were collected 2-3 weeks before, and 10 weeks after, completion of radiation. A modified Cancer Survivors' Unmet Needs (CaSUN) instrument measured UN. Most participants reported ≥1 unmet need at baseline (80.00%) and follow-up (69.31%), with UN across physical, healthcare, information, psychosocial, and survivorship domains. Total number of UN declined over time, t(87) = 3.00, p < .01. UN likely to persist from baseline to follow-up involved cancer recurrence concerns, stress management, household responsibilities, and others not acknowledging/understanding cancer. Younger women (p = .01) and those with more severe (p < .01), life-interfering (p = .01) symptoms had greater burden of UN. This study highlights the dynamics of UN in the weeks before and after primary treatment. Future studies should identify long-term consequences of persistent UN.

Physician perspectives on colorectal cancer surveillance care in a changing environment.

The purpose of this formative qualitatively driven mixed-methods study was to refine a measurement tool for use in interventions to improve colorectal cancer (CRC) surveillance care. We employed key informant interviews to explore the attitudes, practices, and preferences of four physician specialties. A national survey, literature review, and expert consultation also informed survey development. Cognitive pretesting obtained participant feedback to improve the survey's face and content validity and reliability. Results showed that additional domains were needed to reflect contemporary interdisciplinary trends in survivorship care, evolving practice changes and current health policy. Observed dissonance in specialists' perspectives poses challenges for the development of interventions and psychometrically sound measurement. Implications for future research include need for a flexible care model with enhanced communication and role definitions among clinical specialists, improvements in surveillance at multilevels (patients, providers, and systems), and measurement tools that focus on multispecialty involvement and the changing practice and policy environment.

A Formative Study of Colon Cancer Surveillance Care: Implications for Survivor-Centered Interventions.

Colon cancer is one of the most commonly diagnosed cancers in the United States, and an increasing number of survivors has underscored the need for improved colon cancer surveillance care quality. Post-treatment surveillance includes follow-up care visits and tests as well as psychosocial support and lifestyle counseling. This formative study explored the individual, interpersonal, and organizational-level factors related to adherence to surveillance care guidelines to identify modifiable factors for potential educational intervention strategies. A convenience sample of 22 survivors (12 women and 10 men) from two cancer centers were recruited to participate in focus groups or key informant telephone interviews to explore their experiences with care after completing treatment and complete a brief survey. Content analysis was used to identify themes. Results confirmed that survivors navigated a complex surveillance care schedule and described a strong trust in their health care providers that guided their follow-up care experiences. Participants defined the terms "survivorship" and "follow-up" in a variety of different ways. Individual-level themes critical to survivors' experiences included having a positive attitude, relying on one's faith, and coping with fears. Interpersonal-level themes centered around interactions and communication with family and health care providers in follow-up care. While organizational-level factors were highlighted infrequently, participants rated office reminder systems and communication among their multiple providers as valuable. Educational interventions capitalizing on survivors' connections with their physicians and focusing on preparing survivors for what to expect in the next phase of their cancer experience, could be beneficial at the end of treatment to activate survivors for the transition to the post-treatment period.

Quantifying Oropharyngeal Swallowing Impairment in Response to Bolus Viscosity.

PURPOSE: The purpose of this study was to test the feasibility for quantifying changes in oropharyngeal swallowing impairment in response to alteration in bolus viscosity using a reliable and valid method of observational measurement-the Modified Barium Swallow Impairment Profile (MBSImP). METHOD: This retrospective analysis included a heterogeneous cohort of 119 patients with suspected dysphagia that underwent a videofluoroscopic swallowing study as part of clinical care. Using consensus scoring, two expert clinicians assigned MBSImP scores to components related to oropharyngeal swallowing function between two bolus viscosities (thin liquid and pudding): epiglottic movement, laryngeal elevation, anterior hyoid excursion, tongue base retraction, pharyngeal stripping wave, and pharyngoesophageal segment opening (PESO). Comparisons between the two bolus viscosities were investigated for each component. RESULTS: Higher (worse) scores were observed in the thin-liquid trial compared with the pudding trial for the following MBSImP components: anterior hyoid excursion (p = .03), epiglottic movement (p < .001), pharyngeal stripping wave (p < .001), and PESO (p = .002). Lower (better) scores were observed in the liquid trial compared with the pudding trial for one component-tongue base retraction (Component 15) only (p < .001). CONCLUSION: These findings provide further evidence for positive influences of viscosity on the swallow mechanism, including influences of sensory feedback on the sensorimotor swallow program.

A phase I study of docetaxel plus synthetic lycopene in metastatic prostate cancer patients.

PURPOSE: Our preclinical studies showed that lycopene enhanced the anti-prostate cancer efficacy of docetaxel in animal models. A phase I trial (NCT0149519) was conducted to identify an optimum dose of synthetic lycopene in combination with docetaxel (and androgen blockade [androgen deprivation therapy, ADT]), and to evaluate its effect on the safety and pharmacokinetics of docetaxel in men with metastatic prostate cancer. METHODS: Subjects were treated with 21-day cycles of 75 mg/m2 docetaxel (and ADT), plus lycopene at 30, 90 or 150 mg/day. A Bayesian model averaging continual reassessment method was used to guide dose escalation. Pharmacokinetics of docetaxel and multiple correlative studies were carried out. RESULTS: Twenty-four participants were enrolled, 18 in a dose escalation cohort to define the maximum tolerated dose (MTD), and six in a pharmacokinetic cohort. Docetaxel/ADT plus 150 mg/day synthetic lycopene resulted in dose-limiting toxicity (pulmonary embolus) in one out of 12 participants with an estimated probability of .106 and thus was chosen as the MTD. Lycopene increased the AUCinf and Cmax of plasma docetaxel by 9.5% and 15.1%, respectively. Correlative studies showed dose-related changes in circulating endothelial cells and vascular endothelial growth factor A, and reduction in insulin-like growth factor 1R phosphorylation, associated with lycopene therapy. CONCLUSIONS: The combination of docetaxel/ADT and synthetic lycopene has low toxicity and favourable pharmacokinetics. The effects of lycopene on biomarkers provide additional support for the toxicity-dependent MTD definition. HIGHLIGHTS: The maximum tolerated dose was identified as 150 mg/day of lycopene in combination with docetaxel/ADT for the treatment of metastatic prostate cancer patients. Small increases in plasma exposure to docetaxel were observed with lycopene co-administration. Mechanistically significant effects were seen on angiogenesis and insulin-like growth factor 1 signalling by lycopene co-administration with docetaxel/ADT.

Risk and outcome of non-Hodgkin lymphoma among classical Hodgkin lymphoma survivors.

BACKGROUND: Survivors of classical Hodgkin lymphoma (cHL) are at an increased risk of developing secondary non-Hodgkin lymphomas (sNHLs). To the authors' knowledge, the outcome of patients with sNHL compared with their de novo counterparts (dnNHL) is unknown. METHODS: Data from 26,826 cases of HL from the Surveillance, Epidemiology, and End Results (SEER) program that were diagnosed between 1992 and 2009 were used to obtain the risk of further development of different subtypes of sNHL. The survival of patients with sNHL was compared with that of matched patients with dnNHL. RESULTS: The estimated cumulative incidence of sNHL was 2.50% (95% confidence interval [95% CI], 2.10-2.89) at 15 years from the diagnosis of cHL. The standardized incidence ratio was 10.5 (95% CI, 8.9-12.4) for aggressive B-cell NHL, 4.0 (95% CI, 3.1-5.1) for indolent B-cell NHL, and 14.6 (95% CI, 10.3-20.1) for T-cell NHL. Patients with indolent B-cell sNHL had a worse overall survival compared with their dnNHL counterparts (hazards ratio [HR] of death, 2.7; 95% CI, 1.3-5.7). Survival was not significantly different between patients with sNHL and those with dnNHL with regard to aggressive B-cell NHL (HR, 1.3; 95% CI, 0.6-2.7) or T-cell NHL (HR, 0.8; 95% CI, 0.3-1.8). CONCLUSIONS: The risk of developing sNHL after cHL is substantial. Although patients with indolent B-cell sNHL have inferior survival, patients with aggressive B-cell sNHL and T-cell sNHL have survival comparable to that of their de novo counterparts.