Lluís Nisa

Pharyngolaryngeal Involvement by Varicella-Zoster Virus

INTRODUCTION Involvement of cranial nerves V, VII, and VIII by varicella-zoster virus (VZV) is widely reported in the literature, whereas involvement of cranial nerves IX and X is rarer and therefore poorly characterized. MATERIAL AND METHODS We performed a systematic review of the literature through MEDLINE (up to January 2012). We selected cases reporting pharyngolaryngeal involvement by VZV and extracted clinical features, complementary studies, treatments, and outcome. We added three cases to the existing literature. RESULTS Of the 65 screened articles, 38 were included reporting 54 cases. The main clinical features were odynodysphagia and dysphonia reflecting underlying hemipharyngolaryngeal palsy. Vesicles were seen in 66% of the patients. Besides the involvement of cranial nerves IX and X, concomitant involvement of other cranial nerves was seen in 48% of the cases. The most concerned nerves were cranial nerves VII and VIII. Virological tests (63%) and imaging (28%) were performed, with the latter being systematically normal. Seventy-two percent of patients were treated with antiviral agents and/or corticosteroids. Twenty-six percent of patients made a full recovery while the remaining had some persistent deficits. We did not find statistically significant differences in outcomes according to age or treatments received. CONCLUSIONS Pharyngolaryngeal involvement by VZV is rare and seldom restricted to the ninth and tenth cranial nerves. It occurs mostly within the context of cranial polyneuropathy. Regardless of the treatment, full recovery is rare and long-term sequelae persist in many cases, especially with speech and swallowing impairment. Close monitoring and follow-up are therefore essential.

Orbital involvement in Pott's puffy tumor: a systematic review of published cases.

Background Potts puffy tumor (PPT) is a frontal subperiosteal abscess associated with underlying frontal bone osteomyelitis. It represents a well-known source of sinogenic intracranial infection, but the orbital complications related to this entity are rarely reported. The goal of this study was to characterize the orbital involvement in PPT. Methods We performed a systematic review through a Medline search (1950–2010). The authors reviewed all cases of PPT, selecting those explicitly describing orbital complications associated with PPT. Results We screened 139 articles, of which 93 reported cases of PPT. Of these, 35 articles described a total of 42 cases presenting simultaneous orbital complications. Eyelid and/or periorbital edema was the most common finding in patients with orbital involvement, and preseptal cellulitis is by far the most prevalent orbital complication in PPT. Postseptal involvement (orbital cellulitis, subperiosteal abscess of the orbit, and orbital abscess) is much rarer. Although treatment of the classic PPT is surgical, only a minority of patients with orbital infection required orbital drainage. Most reported patients made a full recovery, without permanent sequelae. Conclusion Orbital infections are possible in patients with PPT. In contrast to surgical treatment of the frontal subperiosteal abscess, the orbital complications can be treated conservatively most of the time. Early diagnosis and aggressive therapy of the underling PPT are essential to avoid severe local or systemic complications.

Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer.

Head and neck cancer constitutes the 6th most common malignancy worldwide and affects the crucial anatomical structures and physiological functions of the upper aerodigestive tract. Classical therapeutic strategies such as surgery and radiotherapy carry substantial toxicity and functional impairment. Moreover, the loco-regional control rates as well as overall survival still need to be improved in subgroups of patients. The scatter-factor/hepatocyte growth factor receptor tyrosine kinase MET is an established effector in the promotion, maintenance and progression of malignant transformation in a wide range of human malignancies, and has been gaining considerable interest in head and neck cancer over the last 15 years. Aberrant MET activation due to overexpression, mutations, tumor-stroma paracrine loops, and cooperative/redundant signaling has been shown to play prominent roles in epithelial-to-mesenchymal transition, angiogenesis, and responses to anti-cancer therapeutic modalities. Accumulating preclinical and translational evidence highly supports the increasing interest of MET as a biomarker for lymph node and distant metastases, as well as a potential marker of stratification for responses to ionizing radiation. The relevance of MET as a therapeutic molecular target in head and neck cancer described in preclinical studies remains largely under-evaluated in clinical trials, and therefore inconclusive. Also in the context of anti-cancer targeted therapy, a large body of preclinical data suggests a central role for MET in treatment resistance towards multiple therapeutic modalities in malignancies of the head and neck region. These findings, as well as the potential use of combination therapies including MET inhibitors in these tumors, need to be further explored.

KRAS and HRAS mutations confer resistance to MET targeting in preclinical models of MET‐expressing tumor cells

The MET receptor tyrosine kinase is often deregulated in human cancers and several MET inhibitors are evaluated in clinical trials. Similarly to EGFR, MET signals through the RAS‐RAF‐ERK/MAPK pathway which plays key roles in cell proliferation and survival. Mutations of genes encoding for RAS proteins, particularly in KRAS, are commonly found in various tumors and are associated with constitutive activation of the MAPK pathway. It was shown for EGFR, that KRAS mutations render upstream EGFR inhibition ineffective in EGFR‐positive colorectal cancers. Currently, there are no clinical studies evaluating MET inhibition impairment due to RAS mutations. To test the impact of RAS mutations on MET targeting, we generated tumor cells responsive to the MET inhibitor EMD1214063 that express KRAS G12V, G12D, G13D and HRAS G12V variants. We demonstrate that these MAPK‐activating RAS mutations differentially interfere with MET‐mediated biological effects of MET inhibition. We report increased residual ERK1/2 phosphorylation indicating that the downstream pathway remains active in presence of MET inhibition. Consequently, RAS variants counteracted MET inhibition‐induced morphological changes as well as anti‐proliferative and anchorage‐independent growth effects. The effect of RAS mutants was reversed when MET inhibition was combined with MEK inhibitors AZD6244 and UO126. In an in vivo mouse xenograft model, MET‐driven tumors harboring mutated RAS displayed resistance to MET inhibition. Taken together, our results demonstrate for the first time in details the role of KRAS and HRAS mutations in resistance to MET inhibition and suggest targeting both MET and MEK as an effective strategy when both oncogenic drivers are expressed.

Clinicobiological progression and prognosis of oral squamous cell carcinoma in relation to the tumor invasive front: impact on prognosis.

Abstract Conclusion: There are several factors that influence the final outcome when treating oral squamous cell carcinoma (OSCC). Invasive front phenomena and more importantly their clinicopathological translation can have a direct impact on survival, and subsequently on the decision for an adjuvant treatment. Objectives: In recent years, the concept of tumor–host interaction has been the subject of substantial efforts in cancer research. Tumoral behavior may be better understood when studying the changes occurring at the tumor–host interface. This study evaluated the influence of several clinicopathological features on the outcome of OSCCs. Methods: The clinical records and pathology specimens of 54 patients with OSCC treated by primary resection were reviewed retrospectively. The pathologic features reviewed were: invasive front grading (IFG), stromal reaction, lymphovascular invasion (LVI), perineural invasion (PNI), margin status, and depth of invasion. Results: High IFGs had a significant relationship with pT status and pN status. High IFGs were strongly correlated with nodal metastases (odds ratio (OR) = 4.77; confidence interaval (CI) = 1.37–16.64). Concerning survival, IFG had a strong impact on disease-free survival in patients treated unimodally, as did the depth of invasion in the same group. Lymphovascular involvement was found to have a negative impact on overall survival in patients treated multimodally.

Paralyzed neonatal larynx in adduction. Case series, systematic review and analysis

OBJECTIVE Bilateral vocal cord abductor paralysis (BVCAbP) is considered a rare cause of stridor in the newborn. The goal of this work is to present a case series and to review systematically the literature on bilateral vocal cord abductor paralysis in the newborn to better characterize the current knowledge on this entity. METHODS We performed a systematic literature review with Medline (1950-2011). The authors screened all cases of BVCAbP reported and selected those affecting newborns. RESULTS Out of the 129 articles screened, 16 were included. A total of 69 cases could be retrieved and analyzed. Associated co-morbidities were found in 54% of the patients, most notably malformative conditions (intracranial or other), or a positive perinatal history (trauma/asphyxia, prematurity). Tracheostomy placement was required in 59% of children, and of these 44% were successfully decannulated. In terms of functional outcome full recovery or improvement were seen in 61% of patients. Major underlying co-morbidities affected negatively the functional outcome (p=.004), but not the need for tracheostomy (p=.604) or the decannulation success rate (p=.063). CONCLUSION BVCAbP in the newborn is a serious cause of airway obstruction. It can be seen either in a context of multisystem anomalies or as an isolated finding. Newborns with major co-morbidities affecting their normal development are more likely to have poor functional outcomes and to remain tracheostomy-dependant.

Prolonged remission of juvenile-onset respiratory papillomatosis: A post-expositional role of the tetravalent anti-HPV vaccine?

Juvenile-onset recurrent respiratory papillomatosis (JORRP) is an HPV-related neoplasm affecting primarily the larynx. JORRP often requires repeated surgical debridement, which yield variable but generally moderate remission periods. We report the case of a 6-year-old boy with severe course JORRP since the age of 2, requiring tracheostomy, that underwent prolonged remission and was decannulated some months after administration of the HPV vaccine. The post-exposure use for the anti-HPV vaccine in JORRP is a topic of capital interest but still poorly characterized. Some published cases suggest a potential post-exposure role of the vaccine in JORRP, but prospective multicentric trials are still needed.

Profiling invasiveness in head and neck cancer: recent contributions of genomic and transcriptomic approaches.

High-throughput molecular profiling approaches have emerged as precious research tools in the field of head and neck translational oncology. Such approaches have identified and/or confirmed the role of several genes or pathways in the acquisition/maintenance of an invasive phenotype and the execution of cellular programs related to cell invasion. Recently published new-generation sequencing studies in head and neck squamous cell carcinoma (HNSCC) have unveiled prominent roles in carcinogenesis and cell invasion of mutations involving NOTCH1 and PI3K-patwhay components. Gene-expression profiling studies combined with systems biology approaches have allowed identifying and gaining further mechanistic understanding into pathways commonly enriched in invasive HNSCC. These pathways include antigen-presenting and leucocyte adhesion molecules, as well as genes involved in cell-extracellular matrix interactions. Here we review the major insights into invasiveness in head and neck cancer provided by high-throughput molecular profiling approaches.

Up-front neck dissection followed by definitive (chemo)-radiotherapy in head and neck squamous cell carcinoma: Rationale, complications, toxicity rates, and oncological outcomes – A systematic review

BACKGROUND AND PURPOSE Lymph node metastases of head and neck cancer are considered one of the most negative prognostic factors. While outcomes and feasibility of chemo-radiotherapy ((C)RT) with or without adjuvant planned neck dissection (ND) in organ-preservation treatment strategy have been addressed, the role of ND before (C)RT, called up-front neck dissection (UFND), is not clearly established. This review provides a critical appraisal of UFND. MATERIAL AND METHODS Articles were identified with a systematic approach. Outcomes included post-UFND delay of (C)RT, surgical complications, radiation toxicity and oncologic outcome. RESULTS Fifteen studies met inclusion criteria, totaling 607 patients undergoing UFND. Part of the data suggest advantages toward less surgical complications compared with salvage ND, decreased serious acute radiation toxicity and better oncological outcomes when compared with (C)RT alone. The overall heterogeneity of the analyzed data does not allow a meta-analysis that provides high-quality evidence in favor or against UFND. CONCLUSIONS Due to lack of well-designed randomized trials, it is difficult to assess the role of UFND in organ-preserving (C)RT setting of head and neck cancer.

Depletion of FOXM1 via MET targeting underlies establishment of a DNA damage-induced senescence program in gastric cancer

Purpose: Deregulated signaling via the MET receptor tyrosine kinase is abundant in gastric tumors, with up to 80% of cases displaying aberrant MET expression. A growing body of evidence suggests MET as a potential target for tumor radiosensitization. Experimental Design: Cellular proliferation and DNA damage-induced senescence were studied in a panel of MET-overexpressing human gastric cancer cell lines as well as in xenograft models after MET inhibition and/or ionizing radiation. Pathways activation and protein expression were assessed by immunoblotting and immunohistochemistry. Tumor tissue microarrays (91 gastric cancer patients) were generated and copy number alteration (178 patients) and gene expression (373 patients) data available at The Cancer Genome Atlas were analyzed to assess the coalterations of MET and FOXM1. Results: MET targeting administered before ionizing radiation instigates DNA damage–induced senescence (∼80%, P < 0.001) rather than cell death. MET inhibition–associated senescence is linked to the blockade of MAPK pathway, correlates with downregulation of FOXM1, and can be abrogated (11.8% vs. 95.3%, P < 0.001) by ectopic expression of FOXM1 in the corresponding gastric tumor cells. Cells with ectopic FOXM1 expression demonstrate considerable (∼20%, P < 0.001) growth advantage despite MET targeting, suggesting a novel clinically relevant resistance mechanism to MET inhibition as the copresence of both MET and FOXM1 protein (33%) and mRNA (30%) overexpression as well as gene amplification (24,7%) are common in patients with gastric cancer. Conclusions: FOXM1, a negative regulator of senescence, has been identified as a key downstream effector and potential clinical biomarker that mediates MET signaling following infliction of DNA damage in gastric tumors. Clin Cancer Res; 22(21); 5322–36. ©2016 AACR.