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

Immune Dysregulation in Myelodysplastic Syndromes: Pathogenetic-Pathophysiologic Aspects and Clinical Consequences

Myelodysplastic syndromes are clonal hematopoietic stem cell disorders, in which the immune system plays a substantial pathogenetic role. Patients manifest frequent infections, mainly attributed to neutropenia, but sometimes opportunistic pathogens are isolated in non-neutropenic patients. They also exhibit autoimmune diseases or syndromes with a background of immune activation and various “abnormalities” of T-lymphocytes, B-lymphocytes, and NK cells. The most typical profile includes reduced total T lymphocytes (mainly CD4+ helper T-cells, resulting in decrease or inversion of the CD4/CD8 cell ratio) and impaired NK cell function. Many TH1 direction cytokines, and particularly sIL-2R, IL-6, and TNF-α are usually found increased in the serum and bone marrow, which have been strongly associated with advanced disease, anemia, and other disease-related features. Clonal origin of lymphocytes has been confirmed only in few cases. Mixed lymphocyte cultures and genomic assays have shown severely impaired immunoregulatory abnormalities, probably induced by the hematopoietic cells. In a minority of patients, immune activation is capable to prevent or delay clonal expansion, but these patients have more profound hematopoietic impairment. Immunosuppressive treatment may not only relieve the autoimmune manifestations but also improve hematopoiesis. However, this kind of treatment is not well tolerated, is associated with severe infections, and in some cases may enhance AML evolution

Growth-Promoting Interaction of IGF-II with the Insulin Receptor during Mouse Embryonic Development

AbstractGenetic analyses of dwarfing phenotypes resulting from targeted mutagenesis of the genes encoding the insulin-like growth factors (IGF-I and IGF-II) and their cognate type 1 IGF receptor (IGF1R) have demonstrated that this signaling system is a major determinant of mouse embryonic growth. Of the two IGF ligands, IGF-I interacts exclusively with IGF1R, whereas IGF-II recognizes an additional receptor (XR), because the growth retardation of embryos lacking both IGR1R and IGF-II (30% of normal birthweight) is more severe than that manifested in either class of singleIgf1rorIgf2null mutants (45 and 60% of normal, respectively). To determine whether XR is the insulin receptor (IR), we examined embryos nullizygous for bothIgf1randInsr.While the growth of embryos lacking solely IR is affected very mildly and only at the end of gestation, concomitant absence of IGF1R results in a severe growth-deficiency phenotype (30% of normal size at birth) that is first detected at Embryonic Day 13.5 and is also characterized by transient edema, curly tail, generalized organ hypoplasia, including the muscles, developmental delays in ossification, and thin epidermis. TheIgf1r/Insrdouble nullizygotes are phenotypically indistinguishable from double mutants lacking IGF1R and IGF-II and from other double and triple mutants in which all of the IGF ligand/receptor interactions have been eliminated. Therefore, these results provide genetic evidence that the growth-promoting function of IGF-II during mouse embryogenesis is mediated in part by signaling through the insulin receptor

From the illegal migrant-criminal to the illegal migrant-invader: Critical analysis of the semantic change of the Greek term λαθρομετανάστης 'illegal migrant'

Following a critical discourse analysis (CDA) approach, the present study reports on the analysis of 49 texts from the Hellenic Parliament Proceedings, where the term λαθρομετανάστης “illegal migrant” is used. The texts under scrutiny date back to 2015 (i. e., the year the migration crisis reached its peak) and reveal the recontextualized use of this term, which is identified with the hegemonic national-racist discourse of the 1990s perceiving migrants as criminals. Since the 1990s, the term has been stigmatized by political correctness as racist and inaccurate. We consider political correctness as a type of corrective practice, since it detects naturalized language uses reproducing stereotypes and power relationships. We will examine how the re-emergence of the older, racist use of the term in question as a reaction against the guidelines of political correctness is anew connected with national-xenophobic discourse and, in particular, with framing migrants as invaders and a national threat. Overall, tracing the semantic trajectory of the term λαθρομετανάστης “illegal migrant” allows us to explore how language use at the micro-level is dialectically connected with discourses at the macro-level

No fruits without color: Cross-modal priming and EEG reveal different roles for different features across semantic categories

Category-specific impairments witnessed in patients with semantic deficits have broadly dissociated into natural and artificial kinds. However, how the category of food (more specifically, fruits and vegetables) fits into this distinction has been difficult to interpret, given a pattern of deficit that has inconsistently mapped onto either kind, despite its intuitive membership to the natural domain. The present study explores the effects of a manipulation of a visual sensory (i.e., color) or functional (i.e., orientation) feature on the consequential semantic processing of fruits and vegetables (and tools, by comparison), first at the behavioral and then at the neural level. The categorization of natural (i.e., fruits/vegetables) and artificial (i.e., utensils) entities was investigated via cross-modal priming. Reaction time analysis indicated a reduction in priming for color-modified natural entities and orientationmodified artificial entities. Standard event-related potentials (ERP) analysis was performed, in addition to linear classification. For natural entities, a N400 effect at central channel sites was observed for the color-modified condition compared relative to normal and orientation conditions, with this difference confirmed by classification analysis. Conversely, there was no significant difference between conditions for the artificial category in either analysis. These findings provide strong evidence that color is an integral property to the categorization of fruits/vegetables, thus substantiating the claim that feature-based processing guides as a function of semantic category

The FoodCast research image database (FRIDa)

In recent years we have witnessed an increasing interest in food processing and eating behaviors. This is probably due to several reasons. The biological relevance of food choices, the complexity of the food-rich environment in which we presently live (making food-intake regulation difficult), and the increasing health care cost due to illness associated with food (food hazards, food contamination, and aberrant food-intake). Despite the importance of the issues and the relevance of this research, comprehensive and validated databases of stimuli are rather limited, outdated, or not available for non-commercial purposes to independent researchers who aim at developing their own research program. The FoodCast Research Image Database (FRIDa) we present here includes 877 images belonging to eight different categories: natural-food (e.g., strawberry), transformed-food (e.g., french fries), rotten-food (e.g., moldy banana), natural-non-food items (e.g., pinecone), artificial food-related objects (e.g., teacup), artificial objects (e.g., guitar), animals (e.g., camel), and scenes (e.g., airport). FRIDa has been validated on a sample of healthy participants (N = 73) on standard variables (e.g., valence, familiarity, etc.) as well as on other variables specifically related to food items (e.g., perceived calorie content); it also includes data on the visual features of the stimuli (e.g., brightness, high frequency power, etc.). FRIDa is a well-controlled, flexible, validated, and freely available (http://foodcast.sissa.it/neuroscience/) tool for researchers in a wide range of academic fields and industry. \ua9 2013 Foroni, Pergola, Argiris and Rumiati