Open airway surgery for post-COVID laryngotracheal stenosis.

INTRODUCTION: This study reports our experience with open reconstructive surgery in patients with laryngotracheal stenosis (LTS) following prolonged intubation and/or tracheostomy in the context of COVID-19. METHODS: All patients underwent a preoperative endoscopic airway assessment. Posterior glottic lesions were graded according to the Bogdasarian classification, subglottic-tracheal lesions according to the Cotton-Myers classification and postoperative complications reported by the Clavien-Dindo classification. We report postoperative outcomes and functional results in this patient subset. RESULTS: We include 14 patients diagnosed to have post COVID LTS, one female and 13 males. This group was compared with a control group, diagnosed with LTS following prolonged intubation. In the COVID group, mean age of patients at the time of the airway surgery was 52.1 ± 16.8 years (range: 13.7-76.3). More than half the patients were multi-morbid with hypertension and obesity being the most common conditions. Eleven patients had multi-site stenoses. Open surgical interventions performed were tracheal resection and anastomosis, laryngotracheal reconstruction and extended cricotracheal resection, and postoperative complications were seen in 12 (85.6%) patients. 70% patients with pre-existing tracheostomy were decannulated. Oral swallowing was not tolerated in one-fifth of the patients and a significant number of them have poor voice quality. CONCLUSION: Post-COVID pandemic, airway surgeons are seeing an increased number of patients with complex LTS, and we report significant postoperative complications in this patient subset. Decannulation rates, voice and swallowing results are poor in patients with glottic involvement as compared to isolated tracheal stenosis.

Laryngeal myxedema as a cause of reversible subglottic stenosis in a newborn.

Myxedema is a manifestation of severe hypothyroidism, and when affecting the larynx it constitutes a rare cause of upper airway obstruction. We present a case of laryngeal myxedema in a newborn causing subglottic stenosis. The atypical aspect of the stenosis along with a thyroid goiter and a positive screening for neonatal hypothyroidism allowed the diagnosis of laryngeal myxedema. Thyroid hormone replacement and non-invasive ventilation led to quick resolution while avoiding invasive approaches. Laryngeal myxedema is possibly underdiagnosed. Physician awareness is essential to avoid pitfalls in such children with reversible airway obstruction.

Airway management in patients with lingual thyroid: a case report and review of the literature.

PURPOSE: To review the management of patients with lingual thyroid (LT) causing upper airway obstruction and to suggest a diagnostic and therapeutic workflow. METHODS: A PubMed review of published cases from January 1980 up to December 2020 of LT causing upper airway obstruction. We selected cases of confirmed LTs that presented with non-state-dependent airway obstruction. An illustrative case report is presented. RESULTS: Twenty-one articles fulfilling the inclusion criteria were found, reporting 24 cases (7 neonatal, 2 pediatric and 15 adults). The main presenting symptoms was dyspnea with increased work of breathing, followed by dysphagia and stridor most commonly in neonates. At least one imaging modality was performed in all patients. Thyroid function was altered in half the patients and normal in the other half. The LT was the only thyroid tissue in all cases except 2. Altogether, 5/24 patients required tracheostomies and two-thirds of the patients underwent surgical resection of the LT (mostly transoral). Also 2/3 of the patients received thyroid replacement therapy. After a median follow-up of 17 months, airway symptoms had fully resolved for all patients but one. CONCLUSION: While rare, ectopic LTs should be considered in the differential diagnosis of stridor, dyspnea and airway obstruction. In neonates, concomitant presence of hypothyroidism on neonatal screening and airway obstruction should prompt the search for a LT. Early identification and thyroid replacement therapy seem to significantly relieve symptoms of upper airway obstruction, but severe obstruction and concomitant airway lesions may require more definitive management approaches.

Association of Multiprofessional Preoperative Assessment and Information for Patients With Head and Neck Cancer With Postoperative Outcomes.

IMPORTANCE: Multidisciplinary perioperative assessment for patients undergoing complex oncologic head and neck cancer (HNC) surgery is widely implemented. However, to our knowledge, the association of multiprofessional preoperative assessment, information, and briefing with postoperative outcomes has not been evaluated. OBJECTIVE: To compare postoperative complications, length of hospital stay (LOS), readmissions, mortality, and costs per case among patients undergoing complex oncologic HNC surgery before and after the implementation of a comprehensive preoperative multiprofessional assessment and information day (MUPAID). DESIGN, SETTING, AND PARTICIPANTS: This retrospective, single-center case-control study was conducted at a tertiary referral head and neck anticancer center/university cancer institute and compared patients with HNC who were undergoing complex oncological surgeries between January 2012 and July 2018 before (control group) and after (intervention group) implementation of the institutional MUPAID. Data analysis was conducted between 2019 and 2020. The intervention group comprised patients who participated in the MUPAID beginning in February 2015. These patients were assessed by a multiprofessional team and provided with structured and comprehensive information on the surgical procedure and its functional, social, financial, and psychological effects, as well as the postoperative care, rehabilitation, and follow-up period. Patients in the control group had also undergone complex oncologic HNC surgery and were selected through surgical procedure codes. MAIN OUTCOMES AND MEASURES: The end points were postoperative rate and severity of complications, LOS, readmissions, mortality, and costs per case. RESULTS: The study included 161 patients, 81 in the intervention (25 women [30.9%]) and 80 in the control group (18 women [22.5%]). The groups showed no relevant differences in sociodemographic, disease, and procedural characteristics. The intervention cohort presented with fewer major local and systemic complications (Clavien-Dindo score, III-V: 34.6% vs 52.5%; difference proportion, -0.179; 95% CI, -0.33 to -0.03), shorter median LOS (12 days [IQR, 10-16 days] vs 16 days [IQR, 11-20] days; effect size, 0.482; 95% CI Cohen d, 0.152-0.812) and decreased median charge per case ($50 848 [IQR, $42 510-$63 479] vs $69 602 [IQR, $45 631-$96 280]; effect size, 0.534; 95% CI Cohen d, 0.22-0.85). CONCLUSIONS AND RELEVANCE: The results of this case-control study suggest that MUPAID for patients who are undergoing complex oncologic HNC surgery is associated with shortened LOS and costs per case as well as decreased complications severity. These results are promising on a patient level in the potential to minimize individual treatment burden, as well as on an institutional and health care system level in the potential significant optimization of surgical outcomes and financial aspects.

Patterns of airway obstruction of non-acquired origin in children with and without major congenital anomalies.

Major congenital anomalies are known to play a role in the management and prognosis of airway obstruction. Most studies assess acquired forms of airway obstruction. Data on congenital or otherwise non-acquired forms of airway obstruction is sparse. In this retrospective, single-institution cohort study, we sought to evaluate and compare the patterns of airway obstruction in children with and without major congenital anomalies, and to assess the impact of management and outcome, irrespective of aetiology. Fifty-five patients were included, 23 with and 32 without underlying major congenital anomalies. Multilevel airway obstruction (usually affecting the nasopharynx, oropharynx, and the trachea) was more common in children with congenital anomalies (91% vs. 41%, p < .001). Consequently, these children required more frequent and earlier surgical management, especially tracheostomy and adenotonsillar surgery.Conclusions: Major congenital anomalies are associated with multilevel airway obstruction and poor functional prognosis. A simple clinical definition considering impact of major congenital anomalies on development and growth may help guide management plans following endoscopic evaluation of the entire airway and flanked by multidisciplinary discussions. What is Known: • Children with major comorbidities display increased disease severity and more prevalent multilevel airway obstruction • Previous studies include both children with acquired and non-acquired forms of airway obstruction; therefore, the actual impact major comorbidities in children with non-acquired causes of airway obstruction remain unclear. What is New: • A total of 42% children in this study population had major comorbidities with and impact on growth and/or psychomotor development, with a higher prevalence of multilevel airway obstruction and worse rates of functional improvement/recovery. • Children with major comorbidities require tracheostomy more often and earlier than those without major comorbidities, and remain tracheostomy-dependent for a longer time.

Lymph Node Yield and Ratio in Selective and Modified Radical Neck Dissection in Head and Neck Cancer-Impact on Oncological Outcome.

Background: Lymph node metastases are associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). Neck dissection (ND) is often performed prior to or after (chemo)radiation (CRT) and is an integral part of HNSCC treatment strategies. The impact of CRT delivered prior to ND on lymph node yield (LNY) and lymph node ratio (LNR) has not been comprehensively investigated. Material and methods: A retrospective cohort study was conducted from January 2014 to 30 June 2019 at the University Hospital of Bern, Switzerland. We included 252 patients with primary HNSCC who underwent NDs either before or after CRT. LNY and LNR were compared in patients undergoing ND prior to or after CRT. A total of 137 and 115 patients underwent modified radical ND (levels I to V) and selective ND, respectively. The impact of several features on survival and disease control was assessed. Results: Of the included patients, 170 were male and 82 were females. There were 141 primaries from the oral cavity, 55 from the oropharynx, and 28 from the larynx. ND specimens showed a pN0 stage in 105 patients and pN+ in 147. LNY, but LNR was not significantly higher in patients undergoing upfront ND than in those after CRT (median: 38 vs. 22, p < 0.0001). Cox hazard ratio regression showed that an LNR ≥ 6.5% correlated with poor overall (HR 2.42, CI 1.12-4.89, p = 0.014) and disease-free survival (HR 3.416, CI 1.54-754, p = 0.003) in MRND. Conclusion: ND after CRT leads to significantly reduced LNY. An LNR ≥6.5% is an independent risk factor for decreased overall, disease-free, and distant metastasis-free survival for MRND.

Diagnostic use of fine-needle aspiration cytology and core-needle biopsy in head and neck sarcomas.

The diagnostic role of fine-needle aspiration cytology (FNAC) and core-needle biopsy (CNB) has not been comprehensively assessed in head and neck sarcomas. A systematic review of published cases (1990-2020) was conducted. Diagnostic performance of both FNAC/CNB to determine tumor dignity and histopathological diagnosis was calculated. One hundred and sixty-eight cases were included for which FNAC (n = 156), CNB (n = 8), or both (n = 4) were used. Predominant histologies were skeletal muscle, chondrogenic and vascular sarcomas. FNAC correctly assessed dignity in 76.3% and histology in 45% of cases. Dignity was significantly better for vascular tumors, metastatic and recurrent specimens, and worse for chondrogenic sarcomas. CNB showed a 92% accuracy to identify dignity and 83% for histopathology. FNAC and CNB are useful methods for the diagnosis of head and neck sarcomas, particularly well-suited in the context of recurrent or metastatic disease. The role of CNB remains largely unexplored for this indication.

Primary neoplasms of the parapharyngeal space: diagnostic and therapeutic pearls and pitfalls.

PURPOSE: Parapharyngeal space neoplasms (PSNs) are rare tumors of the head and neck region. In this study, we report our institutional experience with PSNs over a 27-years period. METHODS: Patients treated between 1992 and 2018 were identified through our tumor board database. Data concerning demographics, clinical presentation, disease features, treatment, complications and follow-up were obtained retrospectively. RESULTS: In total, 48 patients were identified. Most patients had benign tumors (67.5%), with pleomorphic adenoma and schwannoma being the most frequent entities. Malignant tumors represented the remaining 32.5% of neoplasms. Concerning tissue of origin, 67.5% of neoplasms originated from salivary glands and 17.5% were neurogenic. The vast majority of PSNs required open surgical approaches (77%). The most frequent reversible and irreversible complications included paralysis of facial, vagal, and hypoglossal nerves (transient 62.5%, permanent 31.3%). Tumor recurrences occurred in 16.7% of our patients. CONCLUSION: Neoplasms of the parapharyngeal space (PPS) are rare. In our series, consistent with the literature, most patients had benign tumors. Fine-needle aspiration cytology (FNAC) and/or transoral biopsy in selected cases combined with radiographic imaging are helpful to plan the optimal approach (open/transoral) and extent of primary surgery. Close follow-up in malignant neoplasms is crucial to assess recurrence early. We present one of the largest recent studies on PPS tumors treated in a center. Given the low incidence of these tumors, our results contribute to the existing sparse evidence regarding the management and outcome of such tumors.

Multimodal Imaging With Positron Emission Tomography/Computed Tomography and Magnetic Resonance Imaging to Detect Extracapsular Extension in Head and Neck Cancer.

OBJECTIVES/HYPOTHESIS: To assess the ability of specific positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) features to detect extracapsular extension (ECE) in head and neck squamous cell carcinoma (HNSCC) patients. STUDY DESIGN: Retrospective study in a tertiary certified university cancer institute. METHODS: We performed a review of patients with advanced HNSCC at Bern University Hospital between 2014 and 2018. Patients with pretherapeutic PET/CT and/or MRI who underwent neck dissection were included, with 212 patients fulfilling inclusion criteria. Blinded evaluation of specific PET/CT and MRI features with respect to presence of ECE was performed. Histopathological examination of neck dissection specimens was used as the gold standard to determine ECE status. RESULTS: Out of the 212 included patients, 184 had PET/CT, 186 MRI, and 158 both modalities. Overall clinical stage IV (odds ratio [OR]: 2.26, 95% confidence interval [CI]: 2.25-11.74), ill-defined margins in both PET/CT and MRI (OR: 3.48, 95% CI: 1.21-9.98 and OR: 2.14, 95% CI: 0.94-4.89, respectively), and a maximum standardized uptake value ≥ 10 (OR: 5.44, 95% CI: 1.21-9.98) were all significant independent predictors of ECE. When combined, these four features led to a cumulative score able to predict ECE status with an accuracy of 91.43%. CONCLUSIONS: The current findings indicate specific features in PET/CT and MRI are potential predictors of ECE status and may help in pretherapeutic stratification in HNSCC. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E163-E169, 2021.

Relevance of Intraparotid Metastases in Head and Neck Skin Squamous Cell Carcinoma.

OBJECTIVES: Parotid lymph node metastases are common in head and neck cutaneous squamous cell carcinoma (cSCCHN). Here we evaluate the diagnostic, prognostic, and therapeutic implications of intraglandular lymph node (IGLN) metastases in cSCCHN. STUDY DESIGN: Retrospective study in a tertiary referral university cancer institute. METHODS: We included patients with cSCCHN who underwent parotidectomy and neck dissection (ND), with or without synchronous resection of the skin primary, between January 1999 and January 2018. The characteristics of cSCCHN with or without IGLN involvement were compared. RESULTS: Altogether, 68 patients were included. Of the 29 (42.6%) patients classified as cN0, eight were upstaged pN+ and had concomitant IGLN involvement. Of 21 patients with pN0 disease, IGLN metastases were absent in only three cases, resulting in a specificity and sensitivity of parotid metastases to diagnose occult nodal neck metastases of 14.29% and 100%, respectively. The positive and negative predictive values were 14.29% and 100%, respectively. Univariate analyses only displayed a significantly higher rate of moderately and poorly differentiated primaries in patients with IGLN metastases (P = .015). Only advanced T-stages were significantly associated with neck recurrences. CONCLUSION: IGLN status in advanced cSCCHN is potentially predictive for occul nodal neck metastases. Our results suggest that ND in patients with histopathologically negative IGLNs and clinically negative neck lymph nodes may not be necessary given the high negative predictive value of IGLN status in this group of patients. Therefore, accurate diagnostic evaluation of IGLN involvement is mandatory. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:788-793, 2021.

Targeting the MET Receptor Tyrosine Kinase as a Strategy for Radiosensitization in Locoregionally Advanced Head and Neck Squamous Cell Carcinoma.

Radiotherapy (RT) along with surgery is the mainstay of treatment in head and neck squamous cell carcinoma (HNSCC). Radioresistance represents a major source of treatment failure, underlining the urgent necessity to explore and implement effective radiosensitization strategies. The MET receptor widely participates in the acquisition and maintenance of an aggressive phenotype in HNSCC and modulates the DNA damage response following ionizing radiation (IR). Here, we assessed MET expression and mutation status in primary and metastatic lesions within a cohort of patients with advanced HNSCC. Moreover, we investigated the radiosensitization potential of the MET inhibitor tepotinib in a panel of cell lines, in vitro and in vivo, as well as in ex vivo patient-derived organotypic tissue cultures (OTC). MET was highly expressed in 62.4% of primary tumors and in 53.6% of lymph node metastases (LNM), and in 6 of 9 evaluated cell lines. MET expression in primaries and LNMs was significantly associated with decreased disease control in univariate survival analyses. Tepotinib abrogated MET phosphorylation and to distinct extent MET downstream signaling. Pretreatment with tepotinib resulted in variable radiosensitization, enhanced DNA damage, cell death, and G2-M-phase arrest. Combination of tepotinib with IR led to significant radiosensitization in one of two tested in vivo models. OTCs revealed differential patterns of response toward tepotinib, irradiation, and combination of both modalities. The molecular basis of tepotinib-mediated radiosensitization was studied by a CyTOF-based single-cell mass cytometry approach, which uncovered that MET inhibition modulated PI3K activity in cells radiosensitized by tepotinib but not in the resistant ones.

Comprehensive Genomic Profiling of Patient-matched Head and Neck Cancer Cells: A Preclinical Pipeline for Metastatic and Recurrent Disease.

Metastases and tumor recurrence have a major prognostic impact in head and neck squamous cell carcinoma (HNSCC); however, cellular models that comprehensively characterize metastatic and recurrent HNSCC are lacking. To this end, we obtained genomic, transcriptomic, and copy number profiles of the UM-SCC cell line panel, encompassing patient-matched metastatic and recurrent cells. UM-SCC cells recapitulate the most prevalent genomic alterations described in HNSCC, featuring common TP53, PI3K, NOTCH, and Hippo pathway mutations. This analysis identified a novel F977Y kinase domain PIK3CA mutation exclusively present in a recurrent cell line (UM-SCC14B), potentially conferring resistance to PI3K inhibitors. Small proline-rich protein 2A (SPRR2A), a protein involved in epithelial homeostasis and invasion, was one of the most consistently downregulated transcripts in metastatic and recurrent UM-SCC cells. Assessment of SPRR2A protein expression in a clinical cohort of patients with HNSCC confirmed common SPRR2A downregulation in primary tumors (61.9% of cases) and lymph node metastases (31.3%), but not in normal tissue. High expression of SPRR2A in lymph node metastases was, along with nonoropharyngeal location of the primary tumor, an independent prognostic factor for regional disease recurrence after surgery and radiotherapy (HR 2.81; 95% CI, 1.16-6.79; P = 0.02). These results suggest that SPRR2A plays a dual role in invasion and therapeutic resistance in HNSCC, respectively through its downregulation and overexpression. IMPLICATIONS: The current study reveals translationally relevant mechanisms underlying metastasis and recurrence in HNSCC and represents an adjuvant tool for preclinical research in this disease setting. Underlining its discovery potential this approach identified a PIK3CA-resistant mutation as well as SPRR2A as possible theragnostic markers.

Identification of a MET-eIF4G1 translational regulation axis that controls HIF-1α levels under hypoxia.

Poor oxygenation is a common hallmark of solid cancers that strongly associates with aggressive tumor progression and treatment resistance. While a hypoxia-inducible factor 1α (HIF-1α)-associated transcriptional overexpression of the hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) MET has been previously documented, any regulation of the HIF-1α system through MET downstream signaling in hypoxic tumors has not been yet described. By using MET-driven in vitro as well as ex vivo tumor organotypic fresh tissue models we report that MET targeting results in depletion of HIF-1α and its various downstream targets. Mechanistically, we provide evidence that MET regulates HIF-1α levels through a protein translation mechanism that relies on phosphorylation modulation of the eukaryotic initiation factor 4G1 (eIF4G1) on serine 1232 (Ser-1232). Targeted phosphoproteomics data demonstrate a significant drop in eIF4G1 Ser-1232 phosphorylation following MET targeting, which is linked to an increased affinity between eIF4G1 and eIF4E. Since phosphorylation of eIF4G1 on Ser-1232 is largely mediated through mitogen-activated protein kinase (MAPK), we show that expression of a constitutively active K-RAS variant is sufficient to abrogate the inhibitory effect of MET targeting on the HIF-1α pathway with subsequent resistance of tumor cells to MET targeting under hypoxic conditions. Analysis of The Cancer Genome Atlas data demonstrates frequent co-expression of MET, HIF-1α and eIF4G1 in various solid tumors and its impact on disease-free survival of non-small cell lung cancer patients. Clinical relevance of the MET-eIF4G1-HIF-1α pathway is further supported by a co-occurrence of their expression in common tumor regions of individual lung cancer patients.

Early experience with high-flow nasal oxygen therapy (HFNOT) in pediatric endoscopic airway surgery.

OBJECTIVE: Reporting our institutional experience with high-flow nasal oxygen therapy (HFNOT), a recently-introduced technique, for endoscopic airway approaches. METHODS: Prospective collection of data of children (<16 years) undergoing endoscopic between January 2016 and August 2017 at a tertiary referral university hospital. RESULTS: HFNOT was used in 6 children who underwent 14 procedures for different forms and causes of upper airway obstruction of various origins. No intraoperative complications; related to oxygenation were observed, and the surgical procedures could be carried out as; initially planned. CONCLUSIONS: We found that HFNOT is an effective and safe technique with a variety of potential applications in the field of endoscopic pediatric airway surgery.

Recurrent parotid gland carcinoma: how effective is salvage surgery?

OBJECTIVE: Recurrent parotid gland carcinomas (PGCs) are poorly characterized and studies focusing on this topic are rare due to their low incidence. The goal of this study is to analyze the therapeutic strategies, prognostic factors, and oncological outcomes of a series of patients with recurrent PGCs. PATIENTS AND METHODS: Retrospective chart review (1997-2012) of patients with recurrent PGCs was initially treated with curative intent. RESULTS: We identified 20 patients with recurrent PGCs. Eleven patients presented isolated local, regional, or distant metastases, while the rest had recurrences in multiple sites. Recurrent tumors tended to present more advanced T-stage (p = 0.01) and overall stage (p < 0.001), but not N-stage (p = 0.74) when compared to the initial tumors. Half the patients (50%) had distant metastases at the moment of recurrence diagnosis, and another three developed them after attempted salvage surgery. Only 8/20 patients with isolated local or regional recurrences were surgically salvaged with extended revision parotidectomy and neck dissection, respectively. The remaining 12 patients were managed on palliative basis. Overall survival (31.70 months vs. 20.73 months) and progression-free survival (28.70 months vs. 13.61 months) were not significantly different in patients managed surgically vs. palliatively. CONCLUSION: Recurrent PGCs are aggressive neoplasms with a high rate of distant metastases. Surgical salvage can be considered in patients with limited local and/or regional recurrences. The alternative to surgical salvage is palliative management with different chemotherapeutic regimens. Survival does not differ between the two strategies in the present series.

Refashioned lamb tissue as an animal model for training complex techniques of laryngotracheal stenosis surgery.

Open reconstructive upper airway surgery for laryngotracheal stenosis (LTS), whether for subglottic or tracheal stenosis, constitutes a group of complex approaches. LTS requiring open reconstruction is overall rare and primarily performed at tertiary centres. This poses an obvious challenge for the acquisition and maintenance of surgical skills for this group of complex approaches. In this context, animal models provide a unique opportunity for open reconstructive airway surgery training. Such models ought to take into consideration ethical aspects, be easily available and easy to maintain, and have similar macroscopic anatomical features to the human laryngotracheal frame. Here, we provide a brief surgical guide for the use of refashioned lamb tissue as a training model for surgery of adult and pediatric reconstructive airway surgery. The techniques of laryngotracheal reconstruction, partial cricotracheal resection, tracheal resection with end-to-end anastomosis, and slide tracheoplasty are presented. Proper training in open LTS surgery is challenging, time consuming and its complexity further lengthens the learning curve. The lamb larynx and trachea model is an effective model for practising various airway reclaiming surgeries.

PIK3CA hotspot mutations differentially impact responses to MET targeting in MET-driven and non-driven preclinical cancer models.

BACKGROUND: The MET receptor tyrosine kinase represents a promising target in cancer. PIK3CA activating mutations are common in several tumor types and can potentially confer resistance to anti-receptor tyrosine kinase therapy. METHODS: MET and/or PI3K pathway inhibition was assessed in NIH3T3 cells harboring MET-activating point mutation with or without ectopic expression of PIK3CAE545K and PIK3CAH1047R, as well as in MET-expressing head and neck cancer cells with endogenous PIK3CA mutations. Endpoints included PI3K pathway activation, cell proliferation, colony-forming ability, cell death, wound-healing, and an in vivo model. RESULTS: PIK3CAE545K and PIK3CAH1047R confer resistance to MET inhibition in MET-driven models. PIK3CAH1047R was more potent than PIK3CAE545K at inducing resistance in PI3K pathway activation, cell proliferation, colony-forming ability, induction of cell death and wound-healing upon MET inhibition. Resistance to MET inhibition could be synergistically overcome by co-targeting PI3K. Furthermore, combined MET/PI3K inhibition led to enhanced anti-tumor activity in vivo in tumors harboring PIK3CAH1047R. In head and neck cancer cells the combination of MET/PI3K inhibitors led to more-than-additive effects. CONCLUSIONS: PIK3CA mutations can lead to resistance to MET inhibition, supporting future clinical evaluation of combinations of PI3K and MET inhibitors in common scenarios of malignant neoplasms featuring aberrant MET expression and PIK3CA mutations.

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.

Pectoralis major myofascial interposition flap prevents postoperative pharyngocutaneous fistula in salvage total laryngectomy.

Pharyngocutaneous fistula (PCF) is the most cumbersome complication after salvage total laryngectomy (STL) in patients who have been previously irradiated for laryngeal or hypopharyngeal cancer. To assess the fistula rate, risk factors and effects of primary closure with and without pectoralis major myofascial interposition flap (PMMIF) on fistula formation, we conducted a retrospective review. We identified 48 patients from 2004 to 2013 who underwent STL after failure of primary curative (chemo)radiotherapy in laryngeal or hypopharyngeal cancer. Details of risk factors for PCF formation, other postoperative complications and general outcome data were analyzed. Ten (20.8 %) out of 48 patients underwent STL with PMMIF closure. Patient and tumor features were not different between the groups with or without PMMIF closure. PCF rates were 0 and 42.1 % in patients with and without PMMIF, respectively (p = 0.002). Other operative complications were similar. We identified prior neck irradiation to be a risk factor for fistula formation (p = 0.04). Patients without PCF had a statistically significant reduction of average hospital stay (20 vs. 56 days; p = 0.001). Analysis of fistula management revealed 50 % of PCF to be closed secondarily by a pectoralis major myocutaneous flap. Over one-third of fistulae persisted despite attempted surgical closure in some cases. PMMIF is useful to prevent PCF in STL following (chemo)radiotherapy. Neck irradiation during primary treatment is a risk factor for PCF formation.

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.