Laryngeal Preservation Strategies in Locally Advanced Laryngeal and Hypopharyngeal Cancers.

For long, the treatment of locoregionally advanced laryngeal and hypopharyngeal squamous cell cancers (SCC) consisted of either total laryngectomy (TL) or definitive radiotherapy (RT). The development of induction cisplatin plus 5-fluorouracil (PF) and the correlation between chemosensitivity and radiosensitivity in previously untreated patients opened a new era of treatment aiming at laryngeal preservation (LP). The fundamental concept was to employ induction PF in order to select patients for subsequent treatment with either TL or RT according to tumor response to PF. The first two trials (VALGSG for laryngeal SCC and EORTC 24891 for hypopharyngeal SCC) concluded that such an approach could preserve nearly 60% of larynx without deleterious impact on survival. The EORTC 24954 trial compared 4 cycles of induction PF followed by RT in good responders vs. alternating PF-RT in laryngeal and hypopharyngeal SCC. There was no significant difference in 5-year overall survival with a functional larynx between the two arms (31 vs. 35%). The GORTEC 2000-01 trial compared induction PF to induction PF plus docetaxel (TPF) both followed by RT in good responders in larynx and hypopharynx SCC. The 5-year LP was significantly higher in the TPF arm (60 vs. 39%) but without a difference in survival. The RTOG 91-11 trial compared induction PF followed by RT in good responders vs. concurrent chemoradiotherapy (chemo-RT) vs. RT alone in laryngeal SCC. There was no significant difference in 5-year laryngectomy-free survival between the patients treated with induction chemotherapy (44%) vs. those treated with chemo-RT (47%), both being superior to RT alone (34%). At 5 years, LP was superior with chemo-RT: 84 vs. 71% with induction PF. Two phase II trials explored the role of cetuximab (E) in LP in laryngeal and hypopharyngeal SCC. The TREMPLIN trial compared RT+E or chemo-RT (RT + P) after TPF. The DeLOS-II trial compared TPE followed by RT+E vs. TP followed by RT. However, these trials failed to indicate an advantage for the incorporation of E in the treatment paradigm. To date, two approaches for LP have been validated: induction TPF followed by RT for laryngeal and hypopharyngeal SCC and concurrent chemo-RT for laryngeal SCC. An ongoing trial (SALTORL) is comparing these two approaches, induction TPF and chemo-RT, in laryngeal/ hypopharyngeal SCC

Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck.

The major development of the past decade in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy (CT), followed by maintenance cetuximab (the EXTREME regimen). This regimen is supported by a phase 3 randomized trial and subsequent observational studies, and it confers well-documented survival benefits, with median survival ranging between approximately 10 and 14 months, overall response rates between 36 and 44%, and disease control rates of over 80%. Furthermore, as indicated by patient-reported outcome measures, the addition of cetuximab to platinum-based CT leads to a significant reduction in pain and problems with social eating and speech. Conversely, until very recently, there has been a lack of evidence-based second-line treatment options, and the therapies that have been available have shown low response rates and poor survival outcomes. Presently, a promising new treatment option in R/M SCCHN has emerged: immune checkpoint inhibitors (ICIs), which have demonstrated favorable results in second-line clinical trials. Nivolumab and pembrolizumab are the first two ICIs that were approved by the US Food and Drug Administration. We note that the trials that showed benefit with ICIs included not only patients who previously received ≥1 platinum-based regimens for R/M SCCHN but also patients who experienced recurrence within 6 months after combined modality therapy with a platinum agent for locally advanced disease. In this review, we outline the available clinical and observational evidence for the EXTREME regimen and the initial results from clinical trials for ICIs in patients with R/M SCCHN. We propose that these treatment options can be integrated into a new continuum of care paradigm, with first-line EXTREME regimen followed by second-line ICIs. A number of ongoing clinical trials are comparing regimens with ICIs, alone and in combination with other ICIs or CT, with the EXTREME regimen for first-line treatment of R/M SCCHN. As we eagerly await the results of these trials, the EXTREME regimen remains the standard of care for the first-line treatment of R/M SCCHN

Whole transcriptome analysis of human erythropoietic cells during ontogenesis suggests a role of VEGFA gene as modulator of fetal hemoglobin and pharmacogenomic biomarker of treatment response to hydroxyurea in β-type hemoglobinopathy patients

Background: Human erythropoiesis is characterized by distinct gene expression profiles at various developmental stages. Previous studies suggest that fetal-to-adult hemoglobin switch is regulated by a complex mechanism, in which many key players still remain unknown. Here, we report our findings from whole transcriptome analysis of erythroid cells, isolated from erythroid tissues at various developmental stages in an effort to identify distinct molecular signatures of each erythroid tissue.Results: From our in-depth data analysis, pathway analysis, and text mining, we opted to focus on the VEGFA gene, given its gene expression characteristics. Selected VEGFA genomic variants, identified through linkage disequilibrium analysis, were explored further for their association with elevated fetal hemoglobin levels in β-type hemoglobinopathy patients. Our downstream analysis of non-transfusion-dependent β-thalassemia patients, β-thalassemia major patients, compound heterozygous sickle cell disease/β-thalassemia patients receiving hydroxyurea as fetal hemoglobin augmentation treatment, and non-thalassemic individuals indicated that VEGFA genomic variants were associated with disease severity in β-thalassemia patients and hydroxyurea treatment efficacy in SCD/β-thalassemia compound heterozygous patients.Conclusions: Our findings suggest that VEGFA may act as a modifier gene of human globin gene expression and, at the same time, serve as a genomic biomarker in β-type hemoglobinopathy disease severity and hydroxyurea treatment efficacy

Diagnostic modalities for distant metastasis in head and neck squamous cell carcinoma: Are we changing life expectancy?

Objectives/Hypothesis: To determine if the various imaging modalities for distant metastasis (DM) diagnosis alters life expectancy in head and neck squamous cell carcinoma (HNSCC). Study Design: Retrospective. Methods: One hundred seventy patients (mean age, 59.1 years; male:female, 135:35) with HNSCC who developed DM were reviewed. The main outcome measures were the method of DM diagnosis and time from DM diagnosis to death while controlling for clinical parameters (age, gender, tobacco status, primary tumor site, initial TNM classification, number and site of DM, administration of palliative chemotherapy). Results: Tumor subsites were: 40 oral cavity, 75 oropharynx, 36 larynx, 10 hypopharynx, one nasopharynx, and eight unknown primary. Of the patients, 16.5% (28/170) had distant metastasis at presentation; the remaining 142 patients were diagnosed with DM at a median of 324 days from diagnosis. Although patients diagnosed with DM by positron‐emission tomography (PET) scan were more likely to have multiple DM sites ( P = .0001), there were no differences in life expectancy in patients who were diagnosed with or without PET scan (median, 185 vs. 165 days, P = .833). There were no differences in life expectancy based on age, gender, site of primary tumor, or number/site of DM. The use of palliative chemotherapy resulted in a significantly longer life expectancy (median, 285 vs. 70 days; P = .001). Conclusions: Although a PET scan is more likely to diagnose multiple DM sites, there was no difference in life expectancy based on imaging modality. Patients who are symptomatic from their distant metastasis have a worse life expectancy, and palliative chemotherapy was able to increase life expectancy, even in patients who were symptomatic from the distant metastasis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92128/1/23264_ftp.pd

Novel neoadjuvant immunotherapy regimen safety and survival in head and neck squamous cell cancer

Background Cellular immune suppression is observed in head and neck squamous cell cancer (HNSCC) and contributes to poor prognosis. Restoration of immune homeostasis may require primary cell‐derived cytokines at physiologic doses. An immunotherapy regimen containing a biologic, with multiple‐active cytokine components, and administered with cytoxan, zinc, and indomethacin was developed to modulate cellular immunity. Methods Study methods were designed to determine the safety and efficacy of a 21‐day neoadjuvant immunotherapy regimen in a phase 2 trial that enrolled 27 therapy‐naïve patients with stage II to IVa HNSCC. Methods included safety, clinical and radiologic tumor response, disease‐free survival (DFS), overall survival (OS), and tumor lymphocytic infiltrate (LI) data collection. Results Acute toxicity was minimal. Patients completed neoadjuvant treatment without surgical delay. By independent radiographic review, 83% had stable disease during treatment. OS was 92%, 73%, and 69% at 12, 24, and 36 months, respectively. Histologic analysis suggested correlation between survival and tumor LI. Conclusion Immunotherapy regimen was tolerated. Survival results are encouraging. © 2011 Wiley Periodicals, Inc. Head Neck, 2011Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/88112/1/21660_ftp.pd

National discourses, fragments of otherness, and the denial of gaze: Representational minimization and simplification of the Other in pro-migrant media texts

This paper investigates the social representation of migrants in western/European discourses. Our main claim is that the video texts under study, although explicitly pro-migrant, do not affirm the realities of migrants, but rather seem to draw more on national and western-oriented discourses, thus providing a calculated projection of visibility to migrants. That is, the video texts overrepresent a “tolerable”, “simplified” migrant who is socioculturally and linguistically familiar with the European/western audience. This familiar and thus tolerable migrant seems to be in contrast with some distant, vague and threatening “intolerable” Others, who remain largely minimized, delegitimized, and denied a gaze in advance. The racist background of this process is deconstructed on the basis of two theoretical premises: a) that the stereotypical representation of the “Other as threat” often continues to underpin pro-migrant discourses when they are articulated in terms of tolerance; and b) that such discursive scaffolding is more implicit, pushed to the margins of the representations that sustain these discourses and involves a more or less fragmented representation of otherness. The language and the degree of explicitness and marginality of such representations will be explored in our data through a discursive analysis based on the categories of highlighting and minimization respectively, which will be conceptualized drawing upon van Leeuwen’s (2008) framework

Raman spectroscopy can discriminate between normal, dysplastic and cancerous oral mucosa: a tissue-engineering approach.

Head and neck cancer (HNC) is the sixth most common malignancy worldwide. Squamous cell carcinoma, the primary cause of HNC, evolves from normal epithelium through dysplasia before invading the connective tissue to form a carcinoma. However, less than 18% of suspicious oral lesions progress to cancer, with diagnosis currently relying on histopathological evaluation, which is invasive and time consuming. A non-invasive, real-time, point-of-care method could overcome these problems and facilitate regular screening. Raman spectroscopy is a non-invasive optical technique with the ability to extract molecular level information to help determine the functional groups present in a tissue and the molecular conformations of tissue constituents. In the present study, Raman spectroscopy was assessed for its ability to discriminate between normal, dysplastic and HNC. Tissue engineered models of normal, dysplastic and HNC were constructed using normal oral keratinocytes, dysplastic and HNC cell lines, and their biochemical content predicted by interpretation of spectral characteristics. Spectral differences were evident in both the fingerprint (600/cm to 1800/cm) and high wave-number compartments (2800/cm to 3400/cm). Visible differences were seen in peaks relating to lipid content (2881/cm), protein structure (amide I, amide III), several amino acids and nucleic acids (600/cm to 1003/cm). Multivariate data analysis algorithms successfully identified subtypes of dysplasia and cancer, suggesting that Raman spectroscopy not only has the potential to differentiate between normal, pre-malignant and cancerous tissue models but could also be sensitive enough to detect subtypes of dysplasia or cancer on the basis of their subcellular differences. Copyright © 2016 John Wiley & Sons, Ltd