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.

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.

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 pilot randomized controlled trial to evaluate a survivorship care planning intervention for head and neck cancer survivor-caregiver dyads.

PURPOSE: Head and neck cancer (HNC) survivors and caregivers face significant challenges after treatment. This study's objective was to evaluate the effects of a dyadic survivorship care planning (SCP) intervention on survivor and caregiver outcomes. METHODS: This randomized controlled trial enrolled HNC survivors and caregivers within 18 months post-treatment, randomized dyads to SCP (one-session with written SCP and follow-up telephone call) or usual care and administered baseline and 6-month surveys. Multivariable linear regression examined intervention effects on depression and unmet needs in dyads and burden on caregiverss and a set of secondary outcomes. Rating scales and open-ended questions assessed acceptability. RESULTS: We randomized 89 survivor-caregiver dyads (42 usual care, 47 SCP dyads). Fidelity to SCP was high for most survivorship domains except discussing care barriers (13%). The most commonly discussed referrals included nutrition (83%) and behavioral medicine (38%), but referral uptake was low. The SCP intervention did not improve depression or unmet needs among dyads or burden among caregivers at 6 months relative to usual care (p's > .05). Nurses and dyads rated SCP favorably with > 80% positive ratings for session length and care plan content. Qualitative findings highlighted that SCP helped consolidate complex clinical information and strengthened survivor-caregiver-clinician relationships. CONCLUSIONS: An HNC SCP intervention was acceptable but ineffective in improving dyads' outcomes. IMPLICATIONS FOR CANCER SURVIVORS: Post-treatment SCP in HNC dyads was ineffective in improving outcomes in survivors and caregivers as delivered in this study. More research is needed to understand how to capitalize on the acceptability of the SCP approach and enhance its effectiveness to support dyads.

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.

Neoadjuvant presurgical PD-1 inhibition in oral cavity squamous cell carcinoma.

Oral cavity squamous cell carcinoma (OCSCC) is a prevalent surgically treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer. However, whether antitumor responses could be fostered by neoadjuvant presurgical immunotherapy remains unclear. Using a Simon's two-stage design, we present results of a single-arm phase-II trial where 12 patients with stage II-IVA OCSCC received 3 to 4 biweekly doses of 3 mg/kg nivolumab followed by definitive surgical resection with curative intent. Presurgical nivolumab therapy in this cohort shows an overall response rate of 33% (n = 4 patients; 95% CI: 12%-53%). With a median follow up of 2.23 years, 10 out of 12 treated patients remain alive. Neoadjuvant nivolumab is safe, well-tolerated, and is not associated with delays in definitive surgical treatment in this study. This work demonstrates feasibility and safety for incorporation of nivolumab in the neoadjuvant setting for OCSCC (ClinicalTrials.gov: NCT03021993).

A single strain of Bacteroides fragilis protects gut integrity and reduces GVHD.

Graft-versus-host disease (GVHD) is a pathological process caused by an exaggerated donor lymphocyte response to host antigens after allogeneic hematopoietic cell transplantation (allo-HCT). Donor T cells undergo extensive clonal expansion and differentiation, which culminate in damage to recipient target organs. Damage to the gastrointestinal tract is a main contributor to morbidity and mortality. The loss of diversity among intestinal bacteria caused by pretransplant conditioning regimens leads to an outgrowth of opportunistic pathogens and exacerbated GVHD after allo-HCT. Using murine models of allo-HCT, we found that an increase of Bacteroides in the intestinal microbiota of the recipients was associated with reduced GVHD in mice given fecal microbial transplantation. Administration of Bacteroides fragilis through oral gavage increased gut microbiota diversity and beneficial commensal bacteria and significantly ameliorated acute and chronic GVHD development. Preservation of gut integrity following B. fragilis exposure was likely attributed to increased short chain fatty acids, IL-22, and regulatory T cells, which in turn improved gut tight junction integrity and reduced inflammatory cytokine production of pathogenic T cells. The current study provides a proof of concept that a single strain of commensal bacteria can be a safe and effective means to protect gut integrity and ameliorate GVHD after allo-HCT.

Respiratory-swallow coordination and swallowing impairment in head and neck cancer.

BACKGROUND: The aim of the study was to determine the link between frequency of optimal respiratory-swallow coordination, swallowing impairment, and airway invasion in head and neck cancer (HNC) patients. METHOD: A cross-sectional study of a heterogeneous group of HNC patients (49), precancer (N = 30) or postcancer treatment (N = 29), participated in a single Modified Barium Swallow Study (MBSS) with synchronized respiratory data. RESULTS: Spearman correlation coefficients revealed significant negative correlations between optimal respiratory-swallow phase pattern and objective measures of swallowing impairment: penetration-aspiration scale max, pharyngeal total, and oral total scores with Spearman correlation coefficients of -0.53 (z .001), -0.50 (P < .001), and -0.43 (P = .002), respectively. Optimal respiratory-swallow pattern was significantly decreased (P = .03) in patients after cancer treatment compared with another patient group before cancer treatment. CONCLUSION: These findings indicate that as the percentage of optimal respiratory-swallow phase patterns increase, swallowing impairment decreases in the HNC patient population.

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.

Neuropilin-2b facilitates resistance to tyrosine kinase inhibitors in non-small cell lung cancer.

OBJECTIVE: Innate and acquired resistance is the principle factor limiting the efficacy of tyrosine kinase inhibitors in lung cancer. We have observed a dramatic upregulation of the cell surface co-receptor neuropilin-2b in lung cancers clinically treated with tyrosine kinase inhibitors correlating with acquired resistance. We hypothesize that neuropilin-2b plays a functional role in acquired tyrosine kinase inhibitor resistance. METHODS: Non-small cell lung cancer proliferation and survival were determined during chronic tyrosine kinase inhibitor exposure in the presence or absence of neuropilin-2b knock-down. Interactions of neuropilin-2a and neuropilin-2b isoforms with PTEN and GSK3ß were assessed by immunoprecipitation. Neuropilin-2a and neuropilin-2b mutants deleted for their cytoplasmic domains were used to identify regions responsible for neuropilin-2b-GSK3ß interaction. Because GSK3ß is known to phosphorylate and degrade PTEN, phospho-PTEN and total PTEN levels were assessed after transfection of neuropilin-2a and neuropilin-2b wild-type and mutant constructs. RESULTS: Non-small cell lung cancer cells chronically treated with gefitinib or osimertinib developed drug resistance and exhibited logarithmic growth in the presence of endothelial growth factor receptor tyrosine kinase inhibitors. However, neuropilin-2b knockdown cells remained sensitive to gefitinib. Likewise, neuropilin-2b knockdown suppressed and neuropilin-2a knockdown enhanced cellular migration. Acquired drug resistance and cell migration correlated with neuropilin-2b-dependent AKT activation with the intermediate step of GSK3ß-dependent PTEN degradation. A specific binding site for GSK3ß on the cytoplasmic domain of neuropilin-2b was identified with truncated protein constructs and computer modeling. CONCLUSIONS: Neuropilin-2b facilitates non-small cell lung cancer resistance to tyrosine kinase inhibitors, and this biological effect relates to AKT activation. Neuropilin-2b GSK3ß interactions appear to be essential for PTEN degradation and AKT activation in lung cancer cells. Disruption of the neuropilin-2b GSK3ß interaction may represent a novel treatment strategy to preserve sensitivity to tyrosine kinase inhibitors in non-small cell lung cancer.

Identification of human CD4+ T cell populations with distinct antitumor activity.

How naturally arising human CD4+ T helper subsets affect cancer immunotherapy is unclear. We reported that human CD4+CD26high T cells elicit potent immunity against solid tumors. As CD26high T cells are often categorized as TH17 cells for their IL-17 production and high CD26 expression, we posited these populations would have similar molecular properties. Here, we reveal that CD26high T cells are epigenetically and transcriptionally distinct from TH17 cells. Of clinical importance, CD26high and TH17 cells engineered with a chimeric antigen receptor (CAR) regressed large human tumors to a greater extent than enriched TH1 or TH2 cells. Only human CD26high T cells mediated curative responses, even when redirected with a suboptimal CAR and without aid by CD8+ CAR T cells. CD26high T cells cosecreted effector cytokines, produced cytotoxic molecules, and persisted long term. Collectively, our work underscores the promise of CD4+ T cell populations to improve durability of solid tumor therapies.

Classification of Physiologic Swallowing Impairment Severity: A Latent Class Analysis of Modified Barium Swallow Impairment Profile Scores.

Purpose Our objectives were to (a) identify oral and pharyngeal physiologic swallowing impairment severity classes based on latent class analyses (LCAs) of the Modified Barium Swallow Impairment Profile (MBSImP) swallow task scores and (b) quantify the probability of severity class membership given composite MBSImP oral total (OT) and pharyngeal total (PT) scores. Method MBSImP scores were collected from a patient database of 319 consecutive modified barium swallow studies. Because of missing swallow task scores, LCA was performed using 25 multiply imputed data sets. Results LCA revealed a three-class structure for both oral and pharyngeal models. We identified OT and PT score intervals to assign subjects to oral and pharyngeal impairment latent severity classes, respectively, with high probability (probability of class membership ≥ 0.9 given OT or PT scores within specified ranges) and high confidence (95% credible interval [CI] widths ≤ 0.24 for all total scores within specified ranges). OT scores ranging from 0 to 10 and from 14 to 18 yielded assignments in Oral Latent Classes 1 and 2, respectively, while OT = 22 was assigned to Oral Latent Class 3. PT scores ranging from 0 to 13 and from 18 to 24 yielded assignments in Pharyngeal Latent Classes 1 and 2, respectively, while PT = 26 was assigned to Pharyngeal Latent Class 3. Conclusions LCA of MBSImP task-level data revealed significant underlying oral and pharyngeal ordinal class structures representing increasingly severe gradations of physiologic swallow impairment. Clinically meaningful OT and PT score ranges were derived facilitating latent class assignment. Supplemental Material https://doi.org/10.23641/asha.12315677.

Development and implementation of the SUM breast cancer cell line functional genomics knowledge base.

Several years ago, the SUM panel of human breast cancer cell lines was developed, and these cell lines have been distributed to hundreds of labs worldwide. Our lab and others have developed extensive omics data sets from these cells. More recently, we performed genome-scale shRNA essentiality screens on the entire SUM line panel, as well as on MCF10A cells, MCF-7 cells, and MCF-7LTED cells. These gene essentiality data sets allowed us to perform orthogonal analyses that functionalize the otherwise descriptive genomic data obtained from traditional genomics platforms. To make these omics data sets available to users of the SUM lines, and to allow users to mine these data sets, we developed the SUM Breast Cancer Cell Line Knowledge Base. This knowledge base provides information on the derivation of each cell line, provides protocols for the proper maintenance of the cells, and provides a series of data mining tools that allow rapid identification of the oncogene signatures for each line, the enrichment of KEGG pathways with screen hit and gene expression data, an analysis of protein and phospho-protein expression for the cell lines, as well as a gene search tool and a functional-druggable signature tool. Recently, we expanded our database to include genomic data for an additional 27 commonly used breast cancer cell lines. Thus, the SLKBase provides users with deep insights into the biology of human breast cancer cell lines that can be used to develop strategies for the reverse engineering of individual breast cancer cell lines.

IL6 Fuels Durable Memory for Th17 Cell-Mediated Responses to Tumors.

The accessibility of adoptive T-cell transfer therapies (ACT) is hindered by the cost and time required for product development. Here we describe a streamlined ACT protocol using Th17 cells expanded only 4 days ex vivo. While shortening expansion compromised cell yield, this method licensed Th17 cells to eradicate large tumors to a greater extent than cells expanded longer term. Day 4 Th17 cells engrafted, induced release of multiple cytokines including IL6, IL17, MCP-1, and GM-CSF in the tumor-bearing host, and persisted as memory cells. IL6 was a critical component for efficacy of these therapies via its promotion of long-term immunity and resistance to tumor relapse. Mechanistically, IL6 diminished engraftment of FoxP3+ donor T cells, corresponding with robust tumor infiltration by donor effector over regulatory cells for the Day 4 Th17 cell product relative to cell products expanded longer durations ex vivo. Collectively, this work describes a method to rapidly generate therapeutic T-cell products for ACT and implicates IL6 in promoting durable immunity of Th17 cells against large, established solid tumors. SIGNIFICANCE: An abbreviated, 4-day ex vivo expansion method licenses Th17 cells to confer long-lived immunity against solid malignancies via induction of systemic IL6 in the host.See related commentary by Fiering and Ho, p. 3795.

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.

Aging Effects on Eating Assessment Tool-10 (EAT-10) Total Scores in Healthy, Community-Dwelling Adults.

The purpose of this study was to examine how aging and sex impacted scores on the Eating Assessment Tool-10 in a large sample of healthy, non-dysphagic adults. Differences in Eating Assessment Tool-10 total normal (< 3) and abnormal (≥ 3) scores were examined across four age categories (21-39 years, 40-59 years, 60-79 years, 80 years and older) and between sexes. The mean (± SD) Eating Assessment Tool-10 total score for this healthy cohort of 167 individuals was 0.6 (± 1.6), with the majority of participants (75%) earning a score of zero. No significant differences were found in Eating Assessment Tool-10 total scores across age categories (p = .53) or between sexes (p = .79). Post-hoc analyses further explored relationships between Eating Assessment Tool-10 total scores and swallow performance measures as observed during videofluoroscopy. All participants (n = 15) scoring 3 and greater on the Eating Assessment Tool-10 passed an aspiration screen (i.e., 3-ounce water swallow challenge). Nine participants scoring less than 3 and failing the aspiration screen were not observed to have airway invasion as measured by the Penetration-Aspiration Scale during videofluoroscopy. A significant relationship was not observed between Eating Assessment Tool-10 total scores and highest Penetration-Aspiration Scale score. Eating Assessment Tool-10 total scores reported in the current study for patients with gastroesophageal reflux disease were significantly lower (p < .001) than total scores reported in the Eating Assessment Tool-10 validation study by Belafsky et al. (2008). In summary, aging or sex effects did not appear to impact self-report of dysphagia-related symptoms as measured by the Eating Assessment Tool-10. The Eating Assessment Tool-10, therefore, may not demonstrate the sensitivity needed to capture sub-clinical changes of the aging swallowing mechanism.

L'objectif de cette étude était d'examiner l'impact du vieillissement et du sexe sur les scores du Eating Assessment Tool-10, et ce, auprès d'un grand échantillon d'adultes en santé qui n'ont pas de dysphagie. Les scores totaux normaux (< 3) et anormaux (≥ 3) obtenus à l'Eating Assessment Tool-10 ont été examinés au sein de quatre catégories d'âge (21­39 ans, 40­59 ans, 60­79 ans, 80 ans et plus), ainsi qu'en fonction du sexe. La moyenne (± ÉT) des scores totaux était de 0,6 (± 1,6) pour cette cohorte de 167 individus en santé et une majorité d'entre eux (75%) ont obtenu un score de zéro. Aucune différence significative n'a été trouvée entre les catégories d'âge (p = 0,53) ou en fonction du sexe (p = 0,79). Des analyses post-hoc ont exploré plus en détail la relation entre les scores totaux du Eating Assessment Tool-10 et des mesures de performance de la déglutition recueillies lors d'une vidéofluoroscopie. Aucune aspiration n'a été dépistée (à l'aide d'une épreuve demandant d'avaler 3 onces d'eau) chez les 15 participants ayant obtenu un score égal ou plus grand que 3 à l'Eating Assessment Tool-10. Des aspirations ont été dépistées (à l'aide d'une épreuve demandant d'avaler 3 onces d'eau) chez neuf des participants ayant obtenu un score inférieur à 3 à l'Eating Assessment Tool-10. Néanmoins, aucun matériel n'est entré dans leurs voies respiratoires, si l'on se fie aux résultats obtenus avec la Penetration-Aspiration Scale lors de la vidéofluoroscopie. Aucune relation significative n'a été observée entre les scores totaux obtenus à l'Eating Assessment Tool-10 et les scores plus élevés obtenus à la Penetration-Aspiration Scale. Les scores totaux obtenus à l'Eating Assessment Tool-10 par les patients de la présente étude ayant du reflux gastro-oesophagien étaient significativement inférieurs (p < 0,001) à ceux obtenus dans l'étude de validation de Belafsky et al. (2008). En résumé, l'âge et le sexe ne semblent pas influencer les symptômes de dysphagie rapportés par les patients et mesurés par l'Eating Assessment Tool-10. Par conséquent, l'Eating Assessment Tool-10 ne semble pas avoir la sensibilité nécessaire pour identifier les changements subcliniques se produisant en cours de vieillissement au niveau du mécanisme de la déglutition.

HUNK phosphorylates EGFR to regulate breast cancer metastasis.

Epidermal growth factor receptor (EGFR) is commonly over-expressed in metastatic breast cancer yet metastatic breast cancer is generally resistant to anti-EGFR therapies, and the mechanism for resistance to EGFR inhibitors in this setting is not fully understood. Hormonally up-regulated neu-associated kinase (HUNK) kinase is up-regulated in aggressive breast cancers and is thought to play a role in breast cancer metastasis. However, no studies have been conducted to examine a relationship between EGFR and HUNK in breast cancer metastasis. We performed a kinase substrate screen and identified that EGFR is phosphorylated by HUNK. Our studies show that HUNK phosphorylates EGFR at T654, enhancing receptor stability and downstream signaling. We found that increased phosphorylation of T654 EGFR correlates with increased epithelial to mesenchymal, migration and invasion, and metastasis. In addition, we found that HUNK expression correlates with overall survival and distant metastasis free survival. This study shows that HUNK directly phosphorylates EGFR at T654 to promote metastasis and is the first study to show that the phosphorylation of this site in EGFR regulates metastasis.

Polo-like kinase 1 (Plk1) inhibition synergizes with taxanes in triple negative breast cancer.

Within triple negative breast cancer, several molecular subtypes have been identified, underlying the heterogeneity of such an aggressive disease. The basal-like subtype is characterized by mutations in the TP53 gene, and is associated with a low pathologic complete response rate following neoadjuvant chemotherapy. In a genome-scale short hairpin RNA (shRNA) screen of breast cancer cells, polo-like kinase 1 (Plk1) was a frequent and strong hit in the basal breast cancer cell lines indicating its importance for growth and survival of these breast cancer cells. Plk1 regulates progression of cells through the G2-M phase of the cell cycle. We assessed the activity of two ATP-competitive Plk1 inhibitors, GSK461364 and onvansertib, alone and with a taxane in a set of triple negative breast cancer cell lines and in vivo. GSK461364 showed synergism with docetaxel in SUM149 (Combination Index 0.70) and SUM159 (CI, 0.62). GSK461364 in combination with docetaxel decreased the clonogenic potential (interaction test for SUM149 and SUM159, p<0.001 and p = 0.01, respectively) and the tumorsphere formation of SUM149 and SUM159 (interaction test, p = 0.01 and p< 0.001). In the SUM159 xenograft model, onvansertib plus paclitaxel significantly decreased tumor volume compared to single agent paclitaxel (p<0.0001). Inhibition of Plk1 in combination with taxanes shows promising results in a subset of triple negative breast cancer intrinsically resistant to chemotherapy. Onvansertib showed significant tumor volume shrinkage when combined with paclitaxel in vivo and should be considered in clinical trials for the treatment of triple negative cancers.

Hematology and Depression Levels: Examining Correlated Factors Among Hospitalized Patients.

BACKGROUND: Depression in patients with cancer negatively influences physical symptoms, treatment success, coping, and quality of life (QOL), and is associated with increased mortality. OBJECTIVES: This study investigated the prevalence of depression and explored fatigue, QOL, and pain that is associated with depression in patients on first admission to a hematologic oncology unit. METHODS: This descriptive study measured depression, QOL, and fatigue with the Patient Health Questionnaire-9, the Functional Assessment of Cancer Therapy (FACT)-General, and the FACT-Anemia scale, respectively. Pain levels were examined with a numeric rating scale. FINDINGS: 58 patients participated; 17 reported moderate to severe depression, which highly correlated with fatigue, QOL, and pain. Among all factors, multivariate analysis showed that fatigue, particularly the physical domain of fatigue, has the strongest reverse correlation with depression.