Personalized neck irradiation guided by sentinel lymph node biopsy in patients with squamous cell carcinoma of the oropharynx, larynx or hypopharynx with a clinically negative neck:(Chemo)radiotherapy to the PRIMary tumor only. Protocol of the PRIMO study

Background: Elective neck irradiation (ENI) is performed in head and neck cancer patients treated with definitive (chemo)radiotherapy. The aim is to eradicate nodal metastases that are not detectable by pretreatment imaging techniques. It is conceivable that personalized neck irradiation can be performed guided by the results of sentinel lymph node biopsy (SLNB). It is expected that ENI can be omitted to one or both sides of the neck in 9 out of 10 patients, resulting in less radiation side effects with better quality of life. Methods/design: This is a multicenter randomized controlled trial aiming to compare safety and efficacy of treatment with SLNB guided neck irradiation versus standard bilateral ENI in 242 patients with cN0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx for whom bilateral ENI is indicated. Patients randomized to the experimental-arm will undergo SLNB. Based on the histopathologic status of the SLNs, patients will receive no ENI (if all SLNs are negative), unilateral neck irradiation only (if a SLN is positive at one side of the neck) or bilateral neck irradiation (if SLNs are positive at both sides of the neck). Patients randomized to the control arm will not undergo SLNB but will receive standard bilateral ENI. The primary safety endpoint is the number of patients with recurrence in regional lymph nodes within 2 years after treatment. The primary efficacy endpoint is patient reported xerostomia-related quality of life at 6 months after treatment. Discussion: If this trial demonstrates that the experimental treatment is non-inferior to the standard treatment in terms of regional recurrence and is superior in terms of xerostomia-related quality of life, this will become the new standard of care.</p

Tumor microenvironment in head and neck squamous cell carcinomas: predictive value and clinical relevance of hypoxic markers. A review.

BACKGROUND: Hypoxia and tumor cell proliferation are important factors determining the treatment response of squamous cell carcinomas of the head and neck. Successful approaches have been developed to counteract these resistance mechanisms although usually at the cost of increased short- and long-term side effects. To provide the best attainable quality of life for individual patients and the head and neck cancer patient population as a whole, it is of increasing importance that tools be developed that allow a better selection of patients for these intensified treatments. METHODS: A literature review was performed with special focus on the predictive value and clinical relevance of endogenous hypoxia-related markers. RESULTS: New methods for qualitative and quantitative assessment of functional microenvironmental parameters such as hypoxia, proliferation, and vasculature have identified several candidate markers for future use in predictive assays. Hypoxia-related markers include hypoxia inducible factor (HIF)-1alpha, carbonic anhydrase IX, glucose transporters, erythropoietin receptor, osteopontin, and others. Although several of these markers and combinations of markers are associated with treatment outcome, their clinical value as predictive factors remains to be established. CONCLUSIONS: A number of markers and marker profiles have emerged that may have potential as a predictive assay. Validation of these candidate assays requires testing in prospective trials comparing standard treatment against experimental treatments targeting the related microregional constituent

Clinical aspects and treatment of primary tracheal malignancies.

Contains fulltext : 87450.pdf (publisher's version ) (Closed access)CONCLUSIONS: Selecting patients that are candidates for surgical treatment is important in the work-up of patients with tracheal cancer. Toward this goal, centralization of care concerning tracheal tumors is advised. Centralization may increase long-term survival and decrease operative morbidity and mortality even further. OBJECTIVE: Primary tracheal tumors pose a diagnostic and therapeutic challenge for the physician when confronted with this mostly malignant tumor. Diagnosis is often delayed for months or years due to its aspecific and asthma-mimicking symptoms. Knowledge from retrospective series is limited and few clinicians have gained experience with this tumor. The available literature on the diagnosis and management of this group of tumors is reviewed to summarize the available knowledge about these uncommon tumors. New diagnostic, staging, and treatment guidelines are proposed. METHODS: PubMed was searched for English publications from 1960. The available literature was reviewed and summarized. RESULTS: Surgical resection and primary reconstruction is the best curative treatment modality available at present. In centers of experience, more than half of all patients with tracheal cancer may be candidates for surgical resection, although in population-based studies this treatment is applied in only 10-25% of patients.1 juli 201

Vascular architecture and microenvironmental parameters in human squamous cell carcinoma xenografts: effects of carbogen and nictorinamide.

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Hypoxia in larynx carcinomas assessed by pimonidazole binding and the value of CA-IX and vascularity as surrogate markers of hypoxia.

Contains fulltext : 80424.pdf (publisher's version ) (Closed access)Tumour hypoxia as driving force in tumour progression and treatment resistance has been well established. Assessment of oxygenation status of tumours may provide important prognostic information and improve selection of patients for treatment. In this study, a large homogenous group of 103 laryngeal carcinomas has been investigated in the presence of hypoxia by pimonidazole binding and the usefulness of Carbonic anhydrase IX (CA-IX) and vascular parameters as surrogate markers of hypoxia. These parameters are further related to clinical and biological characteristics. One hundred and three patients with T2-T4 larynx carcinoma were included. They were given the hypoxia marker pimonidazole intravenously (i.v.) 2h prior to taking a biopsy. Expression of all the parameters was examined by immunohistochemistry, excluding large necrotic areas. Among tumours a large variation in pimonidazole positivity (hypoxic fraction based on pimonidazole, HFpimo) (range 0-19%) and CA-IX expression (hypoxic fraction based on CA-IX staining, HFCA-IX) (range 0-34%) was observed. In 67% of the tumours, hypoxia involved 1% of the viable tumour area. HFpimo and HFCA-IX correlated significantly albeit weak (p=0.04). Both parameters showed weak inverse correlations with the relative vascular area (RVA) (p=0.01). HFpimo was further associated with histopathological grade, with poorly differentiated tumours being more hypoxic. The fraction of the tumour area positive for both pimonidazole and CA-IX correlated significantly with N stage. From these results, it was concluded that CA-IX and RVA have only limited value for measuring hypoxia and are not as robust as pimonidazole, probably due to the influence of other factors in the microenvironment. A combination of staining patterns of exogenous and endogenous markers might give important additive information about tumour biology and behaviour

Expression of EGFR under tumor hypoxia: identification of a subpopulation of tumor cells responsible for aggressiveness and treatment resistance

Item does not contain fulltextPURPOSE: Overexpression of epidermal growth factor receptor (EGFR) and tumor hypoxia have been shown to correlate with worse outcome in several types of cancer including head-and-neck squamous cell carcinoma. Little is known about the combination and possible interactions between the two phenomena. METHODS AND MATERIALS: In this study, 45 cases of histologically confirmed squamous cell carcinomas of the head and neck were analyzed. All patients received intravenous infusions of the exogenous hypoxia marker pimonidazole prior to biopsy. Presence of EGFR, pimonidazole binding, and colocalization between EGFR and tumor hypoxia were examined using immunohistochemistry. RESULTS: Of all biopsies examined, respectively, 91% and 60% demonstrated EGFR- and pimonidazole-positive areas. A weak but significant association was found between the hypoxic fractions of pimonidazole (HFpimo) and EGFR fractions (F-EGFR) and between F-EGFR and relative vascular area. Various degrees of colocalization between hypoxia and EGFR were found, increasing with distance from the vasculature. A high fraction of EGFR was correlated with better disease-free and metastasis-free survival, whereas a high degree of colocalization correlated with poor outcome. CONCLUSIONS: Colocalization of hypoxia and EGFR was demonstrated in head-and-neck squamous cell carcinomas, predominantly at longer distances from vessels. A large amount of colocalization was associated with poor outcome, which points to a survival advantage of hypoxic cells that are also able to express EGFR. This subpopulation of tumor cells might be indicative of tumor aggressiveness and be partly responsible for treatment resistance

Distributed coding and algorithm optimization for large-scale networked systems

In this thesis design and optimization of several distributed algorithms in large-scale networked systems is studied. The studied algorithms operate on networks of autonomous agents in general including the sensor networks and the ad hoc networks. The main focus here is on distributed algorithms operating on large-scale networks. This is due to their robustness to node failure and ability to extend according to the size and topology of the system. Regarding the optimization of the studied algorithms, it is aimed to increase their convergence rate to their equilibrium state considering the constraints of the system including the available bandwidth, memory and power for each agent. The first topic addresses the optimization of two algorithms; namely the distributed random gossip algorithm and the distributed average consensus algorithm. The underlying graph of the network is exploited to provide an analytical solution to the semidefinite programming formulation of the problems. In the second topic, two distributed algorithms are proposed for increasing data persistency in wireless sensor networks based on LT and Raptor codes. In the proposed algorithms, the sensed data is disseminated using random walks with the non-uniform stationary distribution. A new distributed method is proposed for assigning the transition probabilities of the random walks. The third topic studies distributed coding of LT codes in Y networks where multiple sources communicate with the same destination through a common relay node. The Adaptive Distributed LT coding algorithm is proposed that combines the LT codes with the network coding technique. The fourth topic addresses optimization of the LT codes for short message lengths. Unlike previous formulations, the provided novel semidefinite programming formulation has finite number of constraints while it is free of approximation

18F-FLT PET does not discriminate between reactive and metastatic lymph nodes in primary head and neck cancer patients.

Contains fulltext : 52879.pdf (publisher's version ) (Closed access)Repopulation of clonogenic tumor cells is inversely correlated with radiation treatment outcome in head and neck squamous cell carcinomas. A functional imaging tool to assess the proliferative activity of tumors could improve patient selection for treatment modifications and could be used for evaluation of early treatment response. The PET tracer 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) can image tumor cell proliferation before and during radiotherapy, and it may provide biologic tumor information useful in radiotherapy planning. In the present study, the value of (18)F-FLT PET in determining the lymph node status in squamous cell carcinoma of the head and neck was assessed, with pathology as the gold standard. METHODS: Ten patients with newly diagnosed stage II-IV squamous cell carcinoma of the head and neck underwent (18)F-FLT PET before surgical tumor resection with lymph node dissection. Emission (18)F-FLT PET and CT images of the head and neck were recorded and fused, and standardized uptake values (SUVs) were calculated. From all 18 (18)F-FLT PET-positive lymph node levels and from 8 (18)F-FLT PET-negative controls, paraffin-embedded lymph node sections were stained and analyzed for the endogenous proliferation marker Ki-67 and for the preoperatively administered proliferation marker iododeoxyuridine. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated for (18)F-FLT PET. RESULTS: Primary tumor sites were oral cavity (n=7), larynx (n=2), and maxillary sinus (n=1). Nine of the 10 patients examined had (18)F-FLT PET-positive lymph nodes (SUV(mean): median, 1.2; range, 0.8-2.9), but only 3 of these patients had histologically proven metastases. All metastatic lymph nodes showed Ki-67 and iododeoxyuridine staining in tumor cells. In the remaining 7 patients, there was abundant Ki-67 and iododeoxyuridine staining of B-lymphocytes in germinal centers in PET-positive lymph nodes, explaining the high rate of false-positive findings. The sensitivity, specificity, positive predictive value, and negative predictive value of (18)F-FLT PET were 100%, 16.7%, 37.5%, and 100%, respectively. CONCLUSION: In head and neck cancer patients, (18)F-FLT PET showed uptake in metastatic as well as in nonmetastatic reactive lymph nodes, the latter due to reactive B-lymphocyte proliferation. Because of the low specificity, (18)F-FLT PET is not suitable for assessment of pretreatment lymph node status. This observation may also negatively influence the utility of (18)F-FLT PET for early treatment response evaluation of small metastatic nodes

Patterns of proliferation related to vasculature in human head-and-neck before and after transplantation in nude mice.

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Assessing radiation-induced carotid vasculopathy using ultrasound after unilateral irradiation: a cross-sectional study

Background: Increased head and neck cancer (HNC) survival requires attention to long-term treatment sequelae. Irradiated HNC survivors have a higher ischemic stroke risk. However, the pathophysiology of radiation-induced vasculopathy is unclear. Arterial stiffness could be a biomarker. This study examined alterations in intima-media thickness (IMT) and stiffness-related parameters, shear wave (SWV) and pulse wave velocity (PWV), in irradiated compared to control carotids in unilateral irradiated patients. Methods: Twenty-six patients, median 40.5 years, 5–15 years after unilateral irradiation for head and neck neoplasms underwent a bilateral carotid ultrasound using an Aixplorer system with SL18-5 and SL10-2 probes. IMT, SWV, and PWV were assessed in the proximal, mid, and distal common (CCA) and internal carotid artery (ICA). Plaques were characterized with magnetic resonance imaging. Measurements were compared between irradiated and control sides, and radiation dose effects were explored. Results: CCA-IMT was higher in irradiated than control carotids (0.54 [0.50–0.61] vs. 0.50 [0.44–0.54] mm, p = 0.001). For stiffness, only anterior mid-CCA and posterior ICA SWV were significantly higher in the irradiated side. A radiation dose–effect was only (weakly) apparent for PWV (R2: end-systolic = 0.067, begin-systolic = 0.155). Ultrasound measurements had good–excellent intra- and interobserver reproducibility. Plaques had similar characteristics but were more diffuse in the irradiated side. Conclusions: Increased CCA-IMT and SWV in some segments were seen in irradiated carotids. These alterations, even in young patients, mark the need for surveillance of radiation-induced vasculopathy. Trial registration: clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT04257968)