Management of head and neck cancer of unknown primary: A phase IV study by DAHANCA.

Background: Diagnostic and therapeutic management of patients with head and neck squamous cell carcinoma of unknown primary (HNSCCUP) remains a challenge. The aim of the present phase IV study was to assess adherence to the current Danish guidelines and evaluate the treatment outcome in HNSCCUP patients.

Materials And Methods: Prospectively collected data in the DAHANCA database from patients treated between 2014 and 2020 was evaluated.

Epidemiology and treatment outcome of nasopharyngeal carcinoma in a low-incidence population - a DAHANCA analysis in Denmark 2000-2018.

Introduction: Nasopharyngeal carcinoma (NPC) is a rare disease and most studies have therefore been conducted in endemic areas. The aim of this study was to describe epidemiology and treatment outcomes of NPC in a population-based, non-endemic setting.

Material And Methods: Patients with NPC diagnosed in Denmark from 2000 to 2018 were identified in the Danish Head and Neck Cancer Study Group (DAHANCA) database.

High-dose loco-regional pattern of failure after primary radiotherapy in p16 positive and negative head and neck squamous cell carcinoma - A DAHANCA 19 study.

Introduction: Patients with failure after primary radiotherapy (RT) for head and neck squamous cell carcinoma (HNSCC) have a poor prognosis. This study investigates pattern of failure after primary curatively intended IMRT in a randomized controlled trial in relation to HPV/p16 status.

Material And Methods: Patients with HNSCC of the oral cavity, oropharynx (OPSCC), hypopharynx or larynx were treated with primary curative IMRT (+/-cisplatin) and concomitant nimorazole between 2007 and 12.

Mesenchymal Stem/Stromal Cell Therapy for Radiation-Induced Xerostomia in Previous Head and Neck Cancer Patients: A Phase II Randomized, Placebo-Controlled Trial.

Purpose: No effective treatment exists for radiation-induced xerostomia. The objective of this study was to compare the effect of adipose-derived mesenchymal stem/stromal cell (ASC) injection, relative to placebo, on salivary gland function in patients with radiation-induced xerostomia.

Patient And Methods: In this single-centre, double-blind, placebo-controlled trial, patients with hyposalivation were randomised to receive ultrasound-guided injections of allogeneic ASCs or placebo into the submandibular glands.

Tumor volume and cancer stem cell expression as prognostic markers for high-dose loco-regional failure in head and neck squamous cell carcinoma - A DAHANCA 19 study.

Background And Purpose: Reliable and accessible biomarkers for patients with Head and Neck Squamous Cell Carcinoma (HNSCC) are warranted for biologically driven radiotherapy (RT). This study aimed to investigate the prognostic value of putative cancer stem cell (CSC) markers, hypoxia, and tumor volume using loco-regional high-dose failure (HDF) as endpoint.

Materials And Methods: Tumor tissue was retrieved from patients treated with primary chemo-(C-)RT and nimorazole for HNSCC in the Danish Head and Neck Cancer Study Group (DAHANCA) 19 study.

Split-filter dual energy computed tomography radiotherapy: From calibration to image guidance.

Background And Purpose: Dual-energy computed tomography (DECT) is an emerging technology in radiotherapy (RT). Here, we investigate split-filter DECT throughout the RT treatment chain as compared to single-energy CT (SECT).

Materials And Methods: DECT scans were acquired with a tin-gold split-filter at 140 kV resulting in a low- and high-energy CT reconstruction (recon).

Considerations for study design in the DAHANCA 35 trial of protons versus photons for head and neck cancer.

Proton radiotherapy offers a dosimetric advantage compared to photon therapy in sparing normal tissue, but the clinical evidence for toxicity reductions in the treatment of head and neck cancer is limited. The Danish Head and Neck Cancer Group (DAHANCA) has initiated the DAHANCA 35 randomised trial to clarify the value of proton therapy (NCT04607694). The DAHANCA 35 trial is performed in an enriched population of patients selected by an anticipated benefit of proton therapy to reduce the risk of late dysphagia or xerostomia based on normal tissue complication probability (NTCP) modelling.

HPV testing versus p16 immunohistochemistry in oropharyngeal squamous cell carcinoma: results from the DAHANCA 19 study.

Introduction: The prognosis after primary (chemo-)radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC) is affected by Human Papillomavirus (HPV) status, with a better prognosis in HPV-positive OPSCC. HPV-status is routinely assessed by p16 immunohistochemistry (IHC), but additional HPV DNA testing is debated. Also, there are numerous HPV genotypes, which prognostic role may need clarification.

Consistency in contouring of organs at risk by artificial intelligence vs oncologists in head and neck cancer patients.

Background: In the Danish Head and Neck Cancer Group (DAHANCA) 35 trial, patients are selected for proton treatment based on simulated reductions of Normal Tissue Complication Probability (NTCP) for proton compared to photon treatment at the referring departments. After inclusion in the trial, immobilization, scanning, contouring and planning are repeated at the national proton centre. The new contours could result in reduced expected NTCP gain of the proton plan, resulting in a loss of validity in the selection process.

Effectiveness and safety of mesenchymal stem/stromal cell for radiation-induced hyposalivation and xerostomia in previous head and neck cancer patients (MESRIX-III): a study protocol for a single-centre, double-blinded, randomised, placebo-controlled, phase II study.

Background: A predominant side effect of radiotherapy for head and neck cancer is salivary gland hypofunction and xerostomia leading to debilitating oral disorders and impaired quality of life (QoL). Intraglandular mesenchymal stem cell therapy has shown promising results as a treatment for xerostomia.

Methods: This is a randomised, double-blinded, placebo-controlled, parallel-group, prospective, single-centre trial investigating the safety, tolerability, and effectiveness of allogeneic stem cells as a treatment for radiation-induced hyposalivation and xerostomia for previous head and neck cancer patients.

Co-registration of radiotherapy planning and recurrence scans with different imaging modalities in head and neck cancer.

MRI (magnetic resonance imaging) scans are frequently used in follow-up after radiotherapy for head and neck cancer. With the overall aim of enabling MRI-based pattern of failure analysis, this study evaluated the accuracy of recurrence MRI (rMRI) deformable co-registration with planning CT (computed tomography)-scans (pCT). Uncertainty of anatomical changes between pCT and rMRI was assessed by similarity metric analyses of co-registered image structures from 19 patients.

Early non-cancer mortality risk prediction after curative-intent radiotherapy or chemoradiotherapy for head and neck squamous cell carcinoma.

Background: In patients with head and neck squamous cell carcinoma (HNSCC), curative-intent radiotherapy (RT) and chemoradiotherapy (CRT) are associated with substantial acute morbidity and 5-10% of patients die within 180 days of treatment initiation. Most of these early deaths occur without HNSCC recurrence or progression and may therefore be preventable to some extent. We developed a prediction tool to estimate the risk of non-HNSCC mortality occurring within the first 180 days followingRT/CRT initiation.

NTCP model validation method for DAHANCA patient selection of protons versus photons in head and neck cancer radiotherapy.

Prediction models using logistic regression may perform poorly in external patient cohorts. However, there is a need to standardize and validate models for clinical use. The purpose of this project was to describe a method for validation of external NTCP models used for patient selection in the randomized trial of protons versus photons in head and neck cancer radiotherapy, DAHANCA 35.

Associations between skin rash, treatment outcome, and single nucleotide polymorphisms in head and neck cancer patients receiving the EGFR-inhibitor zalutumumab: results from the DAHANCA 19 trial.

Purpose: To study the associations between development of moderate to severe skin rash, clinical outcome, and single nucleotide polymorphisms (SNPs) in candidate genes in head and neck cancer patients from the DAHANCA 19 trial receiving the EGFR-inhibitor zalutumumab concurrently with radiation treatment.

Material And Methods: 310 patients were included from the zalutumumab-arm of the DAHANCA 19 study. Nine SNPs in the candidate genes EGFR, EGF, AREG, FCGR2A, FCGR3A, and CCND1 were successfully determined in 294 patients.

Dosimetric and geometric evaluation of the use of deformable image registration in adaptive intensity-modulated radiotherapy for head-and-neck cancer.

The aim of this study was to carry out geometric and dosimetric evaluation of the usefulness of a deformable image registration algorithm utilized for adaptive head-and-neck intensity-modulated radiotherapy. Data consisted of seven patients, each with a planning CT (pCT), a rescanning CT (ReCT) and a cone beam CT (CBCT). The CBCT was acquired on the same day (± 1 d) as the ReCT (i.

Cancer of the external auditory canal and middle ear in Denmark from 1992 to 2001.

Background: In the context of the Danish Head and Neck Cancer Group, nationwide material from 1992-2001 was analyzed to study the extent and nature of the disease, evaluate treatment, compare staging systems, and examine prognosis and survival.

Methods: Review of 68 consecutive cases: 47 squamous cell carcinoma, 10 basal cell carcinoma, and 11 other histologies. Moody (modified Pittsburgh) stages were T1 (26), T2 (9), T3 (8), T4 (23), Tx (2).

Influence of chemosensitizers on resistance mechanisms in daunorubicin-resistant Ehrlich ascites tumour cells.

Aim: To determine whether treatment with chemosensitizers influences the development of the drug-resistant phenotype.

Methods: Three sublines were developed from the sensitive Ehrlich ascites tumour cell line (EHR2) and six sublines from the EHR2/DNR cell line positive for P-glycoprotein (PGP) by treatment with daunorubicin (DNR), a combination of DNR and verapamil (VER), or a combination of DNR and cyclosporin A (CsA). A clonogenic assay was used to determine resistance, the expression of PGP, the multidrug resistance associated protein ( Mrp1) and topoisomerase IIalpha and beta were measured by Western blotting, and reverse transcriptase-polymerase chain reaction was used for determination of mdr1a and b, and Mrp1 mRNA.

Expression of P-glycoprotein and multidrug resistance associated protein in Ehrlich ascites tumor cells after fractionated irradiation.

Purpose: To characterize irradiated murine tumor cells with respect to drug resistance, drug kinetics, and ATPase activity, and to evaluate the possible role of P-glycoprotein (PGP) and murine multidrug resistance associated protein (Mrp1) in the drug-resistant phenotype of these cells.

Methods And Materials: Sensitive Ehrlich ascites tumor cells (EHR2) were in vitro exposed to fractionated irradiation (60 Gy). Western blot analysis was performed for determination of PGP and Mrp1, reverse transcriptase-polymerase chain reaction (RT-PCR) for determination of mdr1a + b mRNA, and semiquantitative RT-PCR for Mrp1 mRNA.

Characterisation of non-P-glycoprotein multidrug-resistant Ehrlich ascites tumour cells selected for resistance to mitoxantrone.

An Ehrlich ascites tumour cell line (EHR2) was selected in vivo for resistance to mitoxantrone (MITOX). The resistant cell line (EHR2/MITOX) was 6123-, 33-, and 30-fold-resistant to mitoxantrone, daunorubicin, and etoposide, respectively, but retained sensitivity to vincristine. The resistant cells showed moderate sensitisation to mitoxantrone on treatment with verapamil or cyclosporin A.

Characterisation of multidrug-resistant Ehrlich ascites tumour cells selected in vivo for resistance to etoposide.

An Ehrlich ascites tumour cell line (EHR2) was selected for resistance to etoposide (VP16) by in vivo exposure to this agent. The resulting cell line (EHR2/VP16) was 114.3-, 5.

P-glycoprotein expression in Ehrlich ascites tumour cells after in vitro and in vivo selection with daunorubicin.

Fluctuation analysis experiments were performed to assess whether selection or induction determines expression of P-glycoprotein and resistance in the murine Ehrlich ascites tumour cell line (EHR2) after exposure to daunorubicin. Thirteen expanded populations of EHR2 cells were exposed to daunorubicin 7.5 x 10(-9) M or 10(-8) M for 2 weeks.

Cellular resistance to anthracyclines.

The antracyclines induce multiple intracellular effects; however, inhibition of the nuclear enzyme topoisomerase II (TOPO II) is the main mechanism of action. Resistance to anthracyclines in tumor cells is multifactorial. The main mechanisms are: (1) the classic multidrug resistance (MDR) phenotype, which is due to the presence of P-glycoprotein (PGP) in plasma membrane, that is, a "pump" that can extrude a wide range of anticancer drugs.

Influx of daunorubicin in multidrug resistant Ehrlich ascites tumour cells: correlation to expression of P-glycoprotein and efflux. Influence of verapamil.

Classic multidrug resistance is characterized by a decrease in the intracellular concentration of drugs in resistant cells as compared to sensitive cells. This is correlated with the presence of P-glycoprotein in the membrane. P-glycoprotein is responsible for an active efflux of drug.

Kinetics of daunorubicin transport in Ehrlich ascites tumor cells with different expression of P-glycoprotein.

The classical multidrug resistance (MDR) phenotype is characterized by a decrease in the intracellular drug concentration in resistant cells as compared to sensitive cells. P-glycoprotein (P-gp) is thought to be responsible for an active efflux of lipophilic drugs. Four Ehrlich ascites tumor cell lines selected in vivo for resistance to daunorubicin (DNR) and their sensitive counterpart were investigated.