Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer.

Two major populations of myeloid-derived suppressor cells (MDSCs), monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) regulate immune responses in cancer and other pathologic conditions. Under physiologic conditions, Ly6C(hi)Ly6G(-) inflammatory monocytes, which are the normal counterpart of M-MDSCs, differentiate into macrophages and dendritic cells. PMN-MDSCs are the predominant group of MDSCs that accumulates in cancer. Here we show that a large proportion of M-MDSCs in tumor-bearing mice acquired phenotypic, morphological and functional features of PMN-MDSCs. Acquisition of this phenotype, but not the functional attributes of PMN-MDSCs, was mediated by transcriptional silencing of the retinoblastoma gene through epigenetic modifications mediated by histone deacetylase 2 (HDAC-2). These data demonstrate a new regulatory mechanism of myeloid cells in cancer.

CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation.

Recruitment of monocytic myeloid-derived suppressor cells (MDSCs) and differentiation of tumor-associated macrophages (TAMs) are the major factors contributing to tumor progression and metastasis. We demonstrated that differentiation of TAMs in tumor site from monocytic precursors was controlled by downregulation of the activity of the transcription factor STAT3. Decreased STAT3 activity was caused by hypoxia and affected all myeloid cells but was not observed in tumor cells. Upregulation of CD45 tyrosine phosphatase activity in MDSCs exposed to hypoxia in tumor site was responsible for downregulation of STAT3. This effect was mediated by the disruption of CD45 protein dimerization regulated by sialic acid. Thus, STAT3 has a unique function in the tumor environment in controlling the differentiation of MDSC into TAM, and its regulatory pathway could be a potential target for therapy.

Preventing smoking relapse in patients with cancer: A randomized controlled trial.

BACKGROUND: Abstaining from smoking after a cancer diagnosis is critical to mitigating the risk of multiple adverse health outcomes. Although many patients with cancer attempt to quit smoking, the majority relapse. The current randomized controlled trial evaluated the efficacy of adapting an evidence-based smoking relapse prevention (SRP) intervention for patients with cancer. METHODS: The trial enrolled 412 patients newly diagnosed with cancer who had recently quit smoking. Participants were randomized to usual care (UC) or SRP. Participants in the UC group received the institution's standard of care for treating tobacco use. Participants in the SRP group in addition received a targeted educational DVD plus a validated self-help intervention for preventing smoking relapse. The primary outcome was smoking abstinence at 2 months, 6 months, and 12 months. RESULTS: Abstinence rates for participants in the SRP and UC groups were 75% versus 71% at 2 months and 69% versus 64% at 6 months (Ps > .20). At 12 months, abstinence rates among survivors were 68% for those in the SRP group and 63% for those in the UC group (P = .38). Post hoc analyses revealed that across 2 months and 6 months, patients who were married/partnered were more likely to be abstinent after SRP than UC (P = .03). CONCLUSIONS: A smoking relapse prevention intervention did not reduce relapse rates overall, but did appear to have benefited those participants who had the social support of a partner. Future work is needed to extend this effect to the larger population of patients.

Development of a Targeted Smoking Relapse-Prevention Intervention for Cancer Patients.

We describe the series of iterative steps used to develop a smoking relapse-prevention intervention customized to the needs of cancer patients. Informed by relevant literature and a series of preliminary studies, an educational tool (DVD) was developed to target the unique smoking relapse risk factors among cancer patients. Learner verification interviews were conducted with 10 cancer patients who recently quit smoking to elicit feedback and inform the development of the DVD. The DVD was then refined using iterative processes and feedback from the learner verification interviews. Major changes focused on visual appeal, and the inclusion of additional testimonials and graphics to increase comprehension of key points and further emphasize the message that the patient is in control of their ability to maintain their smoking abstinence. Together, these steps resulted in the creation of a DVD titled Surviving Smokefree®, which represents the first smoking relapse-prevention intervention for cancer patients. If found effective, the Surviving Smokefree® DVD is an easily disseminable and low-cost portable intervention which can assist cancer patients in maintaining smoking abstinence.

Determining optimal follow-up in the management of human papillomavirus-positive oropharyngeal cancer.

BACKGROUND: Determining the optimal follow-up for patients can help maximize the use of health care resources. This is particularly true in a growing epidemic such as human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV+OPSCC). The objective of the current study was to evaluate time to disease recurrence or late toxicity in this cohort of patients to optimize patient management. METHODS: An institutional database identified 232 patients with biopsy-proven, nonmetastatic HPV+OPSCC who were treated with radiotherapy. A retrospective review was conducted in patients who were followed every 3 months for the first year, every 4 months in year 2, and every 6 months in years 3 to 5. Late toxicity (grade ≥ 3; toxicity was scored based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 4]), locoregional control, distant control, and overall survival were assessed. RESULTS: The median follow-up was 33 months. Based on Radiation Therapy Oncology Group (RTOG) 0129 study risk groupings, patients were either considered to be at low (162 patients; 70%) or intermediate (70 patients; 30%) risk. Concurrent systemic therapy was used in 85% of patients (196 patients). The 3-year locoregional control, distant control, and overall survival rates were 94%, 91%, and 91%, respectively. Late toxicity occurred in 9% of patients (21 patients). Overall, 64% of toxicity and failure events occurred within the first 6 months of follow-up, with a < 2% event incidence noted at each subsequent follow-up. Only 4 patients experienced their first event after 2 years. CONCLUSIONS: HPV+OPSCC has a low risk of disease recurrence and late toxicity after treatment; approximately two-thirds of events occur within the first 6 months of follow-up. These data suggest that it may be reasonable to reduce follow-up in patients with HPV+OPSCC to every 3 months for the first 6 months, every 6 months for the first 2 years, and annually thereafter.

A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment.

BACKGROUND: Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1-VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1-FGFR4), platelet-derived growth factor receptor α (PDGFRα), ret proto-oncogene (RET), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine-refractory, differentiated thyroid cancer (RR-DTC). METHODS: Fifty-eight patients with RR-DTC who had disease progression during the previous 12 months received lenvatinib 24 mg once daily in 28-day cycles until disease progression, unmanageable toxicity, withdrawal, or death. Previous VEGFR-targeted therapy was permitted. The primary endpoint was the objective response rate (ORR) based on independent imaging review. Secondary endpoints included progression-free survival (PFS) and safety. Serum levels of 51 circulating cytokines and angiogenic factors also were assessed. RESULTS: After ≥14 months of follow-up, patients had an ORR of 50% (95% confidence interval [CI], 37%-63%) with only partial responses reported. The median time to response was 3.6 months, the median response duration was 12.7 months, and the median PFS was 12.6 months (95% CI, 9.9-16.1 months). The ORR for patients who had received previous VEGF therapy (n = 17) was 59% (95% CI, 33%-82%). Lower baseline levels of angiopoietin-2 were suggestive of tumor response and longer PFS. Grade 3 and 4 treatment-emergent adverse events, regardless of their relation to treatment, occurred in 72% of patients and most frequently included weight loss (12%), hypertension (10%), proteinuria (10%), and diarrhea (10%). CONCLUSIONS: In patients with and without prior exposure to VEGF therapy, the encouraging response rates, median time to response, and PFS for lenvatinib have prompted further investigation in a phase 3 trial. Cancer 2015;121:2749-2756. © 2015 American Cancer Society.

Anaplastic Thyroid Carcinoma, Version 2.2015.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma focuses on anaplastic carcinoma because substantial changes were made to the systemic therapy recommendations for the 2015 update. Dosages and frequency of administration are now provided, docetaxel/doxorubicin regimens were added, and single-agent cisplatin was deleted because it is not recommended for patients with advanced or metastatic anaplastic thyroid cancer.

Predictors of smoking relapse in patients with thoracic cancer or head and neck cancer.

BACKGROUND: Cancer patients who continue smoking are at increased risk for adverse outcomes including reduced treatment efficacy and poorer survival rates. Many patients spontaneously quit smoking after diagnosis; however, relapse is understudied. The goal of this study was to evaluate smoking-related, affective, cognitive, and physical variables as predictors of smoking after surgical treatment among patients with lung cancer and head and neck cancer. METHODS: A longitudinal study was conducted with 154 patients (57% male) who recently quit smoking. Predictor variables were measured at baseline (ie, time of surgery); smoking behavior was assessed at 2, 4, 6, and 12 months after surgery. Analyses of 7-day point prevalence were performed using a Generalized Estimating Equations approach. RESULTS: Relapse rates varied significantly depending on presurgery smoking status. At 12 months after surgery, 60% of patients who smoked during the week prior to surgery had resumed smoking versus only 13% who were abstinent prior to surgery. Smoking rates among both groups were relatively stable across the 4 follow-ups. For patients smoking before surgery (N = 101), predictors of smoking relapse included lower quitting self-efficacy, higher depression proneness, and greater fears about cancer recurrence. For patients abstinent before surgery (N = 53), higher perceived difficulty quitting and lower cancer-related risk perceptions predicted smoking relapse. CONCLUSIONS: Efforts to encourage early cessation at diagnosis, and increased smoking relapse-prevention efforts in the acute period following surgery, may promote long-term abstinence. Several modifiable variables are identified to target in future smoking relapse-prevention interventions for cancer patients.

Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSC) are a major component of the immune suppressive network described in cancer and many other pathological conditions. Recent studies have demonstrated that one of the major mechanisms of MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). However, the mechanism of this phenomenon remained unknown. In this study, we observed a substantial up-regulation of ROS by MDSC in all of seven different tumor models and in patients with head and neck cancer. The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). MDSC from tumor-bearing mice had significantly higher expression of NOX2 subunits, primarily p47(phox) and gp91(phox), compared with immature myeloid cells from tumor-free mice. Expression of NOX2 subunits in MDSC was controlled by the STAT3 transcription factor. In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. These findings expand our fundamental understanding of the biology of MDSC and may also open new opportunities for therapeutic regulation of these cells in cancer.

Adjuvant radiotherapy versus concurrent chemoradiotherapy for the management of high-risk salivary gland carcinomas.

BACKGROUND: Given the aggressive behavior of advanced salivary malignancies, the purpose of the current study was to explore the utility of adjuvant chemoradiotherapy (CRT) in this population. METHODS: A retrospective study of salivary carcinomas treated from 1998 to 2013 with postoperative CRT (37 patients) or radiotherapy (RT; 103 patients) was completed. RESULTS: The decision to utilize adjuvant CRT versus RT was influenced by tumor grade and histology, cervical lymph node status, surgical margins, and perineural invasion. In both treatment cohorts, high locoregional control rates were obtained (79% for CRT vs 91% for RT; p = .031). Multivariate Cox regression analysis did not identify a difference in 3-year progression-free survival (PFS) with the use of CRT versus RT (hazard ratio [HR] = 0.783; 95% confidence interval [CI] = 0.396-1.549; p = .482). CONCLUSION: Until prospective evidence is available, such as from Radiation Therapy Oncology Group 1008, the standard use of CRT for advanced salivary malignancies cannot be recommended. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016.

Institutional prevalence of malignancy of indeterminate thyroid cytology is necessary but insufficient to accurately interpret molecular marker tests.

OBJECTIVE: Several molecular marker tests are available to refine the diagnosis of thyroid nodules. Knowing the true prevalence of malignancy (PoM) within each cytological category is considered necessary to select the most appropriate test and to interpret results accurately. We describe our institutional PoM among cytological categories and report our experience with molecular markers. DESIGN: Single-center retrospective study. METHODS: We calculated the institutional PoM for each category of the Bethesda system (Bethesda) on all thyroid nodules with cytological evaluation from October 2008 to May 2014. We estimated the predictive values for Afirma, miRInform, and ThyroSeq v2, based on published sensitivity and specificity. Finally, we assessed our own experience with miRInform. RESULTS: The PoMs for Bethesda III and IV categories were 21 and 28%, respectively. ThyroSeq v2 achieves the highest theoretical negative and positive predictive values (NPV and PPV) in Bethesda III (98 and 75%) and Bethesda IV categories (96 and 83%). At our institution, miRInform detected a mutation in 16% of 109 indeterminate nodules tested, all in Bethesda IV specimens. Histology was available in 56 (51%) nodules. The observed sensitivity and specificity in Bethesda IV specimens were 63 and 86%, yielding an NPV and a PPV of 75 and 77%, respectively. CONCLUSIONS: For our current Bethesda III and IV PoM, the actual performance of miRInform was worse than expected. Theoretically ThyroSeq v2 should have the best performance, but it could be affected in the same way as miRInform, given the similarities between the tests. Assessing the institutional performance of each test is necessary along with PoM individualization.

Outcomes of mucosal melanoma of the head and neck.

INTRODUCTION: Mucosal melanoma of the head and neck is a rare disease with limited data available on outcomes; therefore, we reviewed our institutional experience. METHODS: An institutional database was queried and 38 patients with head and neck mucosal melanoma were identified. Charts were abstracted and local control (LC), progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS: Most patients had T4 disease (86%), although nodes were positive in 11%. En bloc or endoscopic resection was performed on 93%. Adjuvant or definitive radiotherapy to a median dose of 60 Gy was utilized in 90%. Chemotherapy was given in 21%, and 16% received interferon. Three-year LC, PFS and OS were 90%, 48% and 59%, respectively. Median OS was 4.6 years. Site of first failure was distant in 52% of cases. CONCLUSION: With aggressive therapy median OS was 4.6 years in this cohort. Distant recurrence remains the primary mode of failure. It may be reasonable to include mucosal melanoma patients in trials of systemic agents along with high-risk cutaneous melanomas.

Smoking relapse-prevention intervention for cancer patients: Study design and baseline data from the surviving SmokeFree randomized controlled trial.

Continued smoking after a cancer diagnosis contributes to several negative health outcomes. Although many cancer patients attempt to quit smoking, high smoking relapse rates have been observed. This highlights the need for a targeted, evidence-based smoking-relapse prevention intervention. The design, method, and baseline characteristics of a randomized controlled trial assessing the efficacy of a self-help smoking-relapse prevention intervention are presented. Cancer patients who had recently quit smoking were randomized to one of two conditions. The Usual Care (UC) group received the institution's standard of care. The smoking relapse-prevention intervention (SRP) group received standard of care, plus 8 relapse-prevention booklets mailed over a 3month period, and a targeted educational DVD developed specifically for cancer patients. Four hundred and fourteen participants were enrolled and completed a baseline survey. Primary outcomes will be self-reported smoking status at 6 and 12-months after baseline. Biochemical verification of smoking status was completed for a subsample. If found to be efficacious, this low-cost intervention could be easily disseminated with significant potential for reducing the risk of negative cancer outcomes associated with continued smoking.

The Effects of Preoperative Embolization on Carotid Body Paraganglioma Surgery: A Systematic Review and Meta-analysis.

OBJECTIVE: There is no definitive consensus on the impact of preoperative embolization on carotid body paraganglioma management. The purpose of this study was to assess the effects of preoperative embolization on carotid body paraganglioma excision. DATA SOURCES: A systematic search was conducted without limits, and it included studies published on or before July 2013 from PubMed, CINAHL, Web of Knowledge, and the Cochrane Library. Relevant synonyms for the search terms "paraganglioma,""carotid body tumor," and "embolization" were applied. REVIEW METHODS: Studies evaluating patients undergoing surgical intervention with embolization for carotid body tumors were included. Two reviewers independently assessed the titles and abstracts for inclusion and extracted the data. The guidelines set forth by the Cochrane Collaboration were followed in the process of data extraction. Data were pooled with a fixed effects model, and standardized mean difference (SMD) and 95% confidence intervals (95% CIs) are reported. RESULTS: A total of 22 studies (15 nonrandomized studies with a comparator, 7 single-arm studies) were included, enrolling 578 patients with 607 tumors. Patients undergoing preoperative embolization had significantly less estimated blood loss compared with those of surgical excision only (12 studies; 295 tumors; SMD: -0.52; 95% CI: -0.77, -0.28). Patients undergoing preoperative embolization had less operative time compared with that of surgical excision only (6 studies; 174 tumors; SMD: -0.46; 95% CI: -0.77, -0.14). CONCLUSION: Surgical excision with preoperative embolization appears to decrease estimated blood loss and operative time when compared with that without preoperative embolization for carotid body paragangliomas.

Management of invasive well-differentiated thyroid cancer: an American Head and Neck Society consensus statement. AHNS consensus statement.

BACKGROUND: Invasive differentiated thyroid cancer (DTC) is relatively frequent, yet there is a paucity of specific guidelines devoted to its management. The Endocrine Committee of the American Head and Neck Society (AHNS) convened a panel to provide clinical consensus statements based on review of the literature, synthesized with the expert opinion of the group. METHODS: An expert panel, selected from membership of the AHNS, constructed the manuscript and recommendations for management of DTC with invasion of recurrent laryngeal nerve, trachea, esophagus, larynx, and major vessels based on current best evidence. A Modified Delphi survey was then constructed by another expert panelist utilizing 9 anchor points, 1 = strongly disagree to 9 = strongly agree. Results of the survey were utilized to determine which statements achieved consensus, near-consensus, or non-consensus. RESULTS: After endorsement by the AHNS Endocrine Committee and Quality of Care Committee, it received final approval from the AHNS Council.

ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis.

Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF-related apoptosis-induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor-bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs.

Intensity-modulated radiation therapy as primary treatment for oropharyngeal squamous cell carcinoma.

BACKGROUND: Over the past decade, intensity-modulated radiation therapy (IMRT) has gained widespread use in the treatment of head and neck cancer. METHODS: All patients with squamous cell carcinoma of the oropharynx treated with primary IMRT with or without chemotherapy over a 5-year period were reviewed. Outcomes and morbidity were analyzed and compared with previously published data. RESULTS: In all, 170 patients were included in the analysis. The 3-year local control, locoregional control, disease-free survival, and overall survival rates were 92%, 91%, 80%, and 87%, respectively. Feeding tubes were present in 55% of patients during treatment, but remained in only 1% 2 years following treatment. CONCLUSIONS: This study confirms that IMRT yields excellent treatment outcomes for oropharyngeal carcinoma. Although acute toxicity remains a problem, late toxicity rates are low and long-term feeding tube dependence is rare compared with conventional radiation therapy.

HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment.

Myeloid-derived suppressor cells (MDSCs) are a major component of the immune-suppressive network described in cancer and many other pathological conditions. We demonstrate that although MDSCs from peripheral lymphoid organs and the tumor site share similar phenotype and morphology, these cells display profound functional differences. MDSC from peripheral lymphoid organs suppressed antigen-specific CD8(+) T cells but failed to inhibit nonspecific T cell function. In sharp contrast, tumor MDSC suppressed both antigen-specific and nonspecific T cell activity. The tumor microenvironment caused rapid and dramatic up-regulation of arginase I and inducible nitric oxide synthase in MDSC, which was accompanied by down-regulation of nicotinamide adenine dinucleotide phosphate-oxidase and reactive oxygen species in these cells. In contrast to MDSC from the spleen, MDSC from the tumor site rapidly differentiated into macrophages. Exposure of spleen MDSC to hypoxia resulted in the conversion of these cells to nonspecific suppressors and their preferential differentiation to macrophages. Hypoxia-inducible factor (HIF) 1α was found to be primarily responsible for the observed effects of the tumor microenvironment on MDSC differentiation and function. Thus, hypoxia via HIF-1α dramatically alters the function of MDSC in the tumor microenvironment and redirects their differentiation toward tumor-associated macrophages, hence providing a mechanistic link between different myeloid suppressive cells in the tumor microenvironment.

Lipid accumulation and dendritic cell dysfunction in cancer.

Dendritic cells (DCs), a type of professional antigen-presenting cells, are responsible for initiation and maintenance of immune responses. Here we report that a substantial proportion of DCs in tumor-bearing mice and people with cancer have high amounts of triglycerides as compared with DCs from tumor-free mice and healthy individuals. In our studies, lipid accumulation in DCs was caused by increased uptake of extracellular lipids due to upregulation of scavenger receptor A. DCs with high lipid content were not able to effectively stimulate allogeneic T cells or present tumor-associated antigens. DCs with high and normal lipid levels did not differ in expression of major histocompatibility complex and co-stimulatory molecules. However, lipid-laden DCs had a reduced capacity to process antigens. Pharmacological normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of cancer vaccines. These findings suggest that immune responses in cancer can be improved by manipulating the lipid levels in DCs.

Patient-provider communication and perspectives on smoking cessation and relapse in the oncology setting.

OBJECTIVE: To fill a gap in research by examining cancer patient-provider communication regarding tobacco use and patients' perspectives regarding their experiences with smoking cessation and relapse. METHODS: In-depth interviews were conducted with 20 lung and head and neck cancer patients and 11 health care providers. RESULTS: Qualitative analyses revealed that cancer patients express high levels of motivation to quit smoking; however, patients do not ask providers for assistance with quitting and maintaining abstinence and relapsed patients are reluctant to disclose smoking behavior due to stigma and guilt. Health care providers vary in the advice and type of assistance they supply, and their awareness and sensitivity to relapsed patients' feelings. Whereas providers emphasized long-term risks of continued smoking in their interactions with patients and recommendations for intervention content, patients expressed a preference for a balance between risks and benefits. CONCLUSION: Findings underscore the need for increased awareness, emphasis, and communication about the immediate risks of continued smoking and the benefits of continued abstinence specifically for cancer patients. PRACTICE IMPLICATIONS: Our findings demonstrate the potential to affect cancer outcomes by improved training in conducting smoking cessation and relapse-prevention interventions. Additional training could be given to health care providers to increase adherence to clinical practice guidelines (5 A's), to learn ways to enhance patients' motivation to maintain abstinence, and to deliver smoking messages in a non-threatening manner.