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Significant tumour progression was observed during waiting time for treatment of head and neck cancer. To reduce waiting times, a Danish national policy of fast track accelerated clinical pathways was introduced in 2007. This study describes changes in waiting time and the potential influence of fast track by comparing waiting times in 2010 to 2002 and 1992.Charts of all new patients diagnosed with squamous cell carcinoma of the oral cavity, pharynx and larynx at the five Danish head and neck oncology centres from January to April 2010 (n=253) were reviewed and compared to similar data from 2002 (n=211) and 1992 (n=168).The median time to diagnosis was 13 days (2010) versus 17 days (2002; p0.001) and 20 days (1992; p0.001). Median days from diagnosis to treatment start were 25 (2010) versus 47 (2002; p0.001) and 31 (1992; p0.001). Total pre-treatment time was median 41 days in 2010 versus 69 days (2002) (p0.001) and 50 days (1992; p0.001). Significantly more diagnostic imaging was done in 2010 compared to 2002 and 1992. When compared to current fast track standards the adherence to diagnosis improved slightly from 47% (1992) to 51% (2002) and 64% (2010); waiting time for radiotherapy was within standards for 7%, 1% and 22% of cases, respectively; waiting time for surgery was within standards for 17%, 22% and 48%, respectively.The study showed a significant reduction in delay of diagnosis and treatment of head and neck cancer in 2010, but still less than half of all patients start treatment within the current standards.

To describe outcome and prognostic factors in a national Danish series of patients treated for salivary gland carcinoma. From three Danish nation-wide registries and supplementary patient records, 871 patients diagnosed with primary major or minor salivary gland carcinoma in the period from 1990 to 2005 were identified. A total of 796 (91%) histological specimens were revised according to the WHO 2005 classification. The median follow-up time was 78 months. Three hundred and thirty-four patients (38%) experienced recurrence. Crude survival, disease-specific survival and recurrence-free survival after 5 and 10 years were 66%, 76%, 64% and 51%, 69%, 58%, respectively. In multivariate analysis age, latency, stage, microscopic margins, vascular invasion and histological grade were all independent prognostic factors with regards to crude and disease-specific survival. Stage, microscopic margins, vascular invasion and histological grade were independent prognostic factors for recurrence-free survival. Age over 61 years, latency under 8 months, stage 3+4 disease, involved or close microscopic margins, vascular invasion and high histological grade are all independent prognostic factors with a negative impact on survival in salivary gland carcinoma patients. This knowledge can be helpful in guiding clinicians in daily work and choice of treatment across the large variety of salivary gland carcinoma subtypes.

To describe the incidence, site and histology (WHO 2005) of salivary gland carcinomas in Denmark. Nine hundred and eighty-three patients diagnosed from 1990 to 2005 were identified from three nation-wide registries. The associated clinical data were retrospectively retrieved from patient medical records. Histological revision was performed in 886 cases (90%). Based on histological revision, 31 patients (3%) were excluded from the study leaving 952 for epidemiological analysis. The mean crude incidence in Denmark was 1.1/100,000/year. The male vs. female ratio was 0.97 and the median age was 62 years. The parotid gland was the most common site (52.5%) followed by the minor salivary glands of the oral cavity (26.3%). The most frequent histological subtypes were adenoid cystic carcinoma (25.2%), mucoepidermoid carcinoma (16.9%), adenocarcinoma NOS (12.2%) and acinic cell carcinoma (10.2%). The revision process changed the histological diagnosis in 121 out of 886 cases (14%). The incidence of salivary gland carcinoma in Denmark is higher than previously reported. More than half of salivary gland carcinomas are located in the parotid gland with adenoid cystic carcinoma being the most frequent subtype. Histological classification of salivary gland carcinomas is difficult and evaluation by dedicated pathology specialists might be essential for optimal diagnosis and treatment.

A 63-years-old male suffered from palpitations, syncope and near syncope for 43 years. He had diagnosed paroxystic atrial fibrillation and was treated with betablocade, calcium antagonists, and flecanide with potentially severe complications. Blood tests, electrocardiography, echocardiography and myocardial scintigraphy were all normal. The patient was admitted for drug cessation, and at admittance sinus caroticus massage was performed. The patient developed an 11 second pause in heart rhythm and was diagnosed with sinus caroticus syndrome. After pacemaker implantation, he was free of symptoms.

In Denmark, a general impression of prolonged pretreatment delay for patients with head and neck cancer led to a nationwide study of time spans from symptom debut over first health care contact to start of treatment. Charts of consecutive new patients with squamous cell carcinoma of the pharynx and larynx, seen at the five Danish oncology centers in January/April 1992 and 2002, respectively, were reviewed. Of the 288 patients identified, definitive treatment was radiotherapy in 264 cases, surgery in one case. Twenty-three patients had neither surgery nor radiotherapy. Total time from first health care contact to start of definitive treatment was significantly longer in 2002 than in 1992 (median 70 versus 50 days, p B /0.001). There was no significantly difference in time used for diagnosis. Time for treatment preparation and planning was 46 days in 2002 versus 31 days in 1992 (pB /0.001). Significantly more diagnostic procedures (CT, MR, US, PET) were done in 2002. In conclusion, this nationwide study showed that waiting time before start of radiotherapy was significantly longer in 2002 compared to 1992. An increasing number of imaging procedures including CT-based dose planning was observed. The prolongation was mainly related to shortage of radiotherapy capacity. The three weeks extra pretreatment delay could theoretically lead to a 10% lower tumor control probability in 2002 compared to 1992. The clinical workup for patients with head and neck cancer is often complex. Since the options for primary treatment include surgery, radiation therapy, chemotherapy or a combination of these, multidisciplinary care over long periods of time is often required. The expression ‘continuum of care’ has been introduced to describe this ‘coordinated activities in health care linked together to achieve the best possible result for the patient’ [1]. A prolonged delay prior to treatment start may cause decrease in the local control rate as well as survival due to tumor growth [2/5]. Radiobiological studies indicate that a 4-week delay of start of

Checkpoint kinase 2 (Chk2) is a tumour suppressor and signal transducer in genome integrity checkpoints that coordinate cell-cycle progression with DNA repair or cell death in response to DNA damage. Defects of Chk2 occur in subsets of diverse sporadic malignancies and predispose to several types of hereditary carcinomas. However, the status of Chk2 in tumours of the urinary bladder remains unknown. Here, we report that among 58 advanced (grade T2-T4) human bladder carcinomas, immunohistochemical analysis revealed tumour-specific reduction or lack of Chk2 protein in 6 (10.3%) cases. Genetic analysis of the latter subset showed that a Chk2-negative carcinoma #668 harboured a truncating mutation 1100delC, in one Chk2 allele and loss of the corresponding second allele. The 1100delC mutation was also found in the germ line of this patient. Sequencing of TP53 in tumour #668 identified two missense mutations. Furthermore, the vast majority of the tumours showed 'unscheduled' activatory phosphorylation on Thr68 of Chk2 in the absence of any DNA-damaging treatment. Our results indicate that the otherwise dormant DNA damage signal transducer Chk2 is aberrantly and constitutively activated in invasive urinary bladder carcinomas, and that such likely proapoptotic checkpoint signalling can be disabled by inactivation of Chk2 and/or p53 tumour suppressors in subsets of these tumours.

Background: Bladder cancer is characterized by genomic instability. In this study, we investigated whether genomewide screening using single-nucleotide polymorphism (SNP) arrays could detect allelic imbalance (loss or gain of at least one allele) in bladder cancers. Methods: For microarray analysis, DNA was isolated from microdissected bladder tumors and leukocytes from 11 patients. The stage T1 tumor (connective tissue invasive) and the subsequent stage T2–4 tumor (muscle invasive) were available from eight of these patients, and only the first muscle-invasive stage T2–4 tumor was available from three of the 11 patients. The microarray contained 1494 biallelic polymorphic sequences. For microsatellite analyses, DNA was isolated from tumors and leukocytes of nine patients with primary T2–4 tumors and 13 patients with Ta (noninvasive) tumors. All statistical tests were two-sided. Results: We assigned a genotype to 1204 loci, 343 of which were heterozygous. Allelic imbalance was detected in known areas of imbalance on chromosomes 6, 8, 9, 11, and 17, and a new area of imbalance was detected on the p arm of chromosome 6. Microsatellite analysis of nine other T2–4 tumors and 13 Ta tumors showed that allelic imbalance was more frequent in T2–4 tumors than in Ta tumors (P

Purpose. The cell cycle is known to be deregulated in cancer. We therefore analyzed the expression of the cell cycle related proteins p21, p27, p16, Rb, and L-myc by immunohistochemical staining of bladder tumors. Methods. The tissue material consisted of bladder tumors from three groups of patients; group 1, 23 patients with recurrent stage Ta (non-invasive) tumors; group 2, 22 patients presenting at their first admission with T2–4 (muscle invasive) tumors; group 3, 24 patients who experienced disease progression from Ta or T1 (invasive in connective tissue) to a higher stage. By immunohistochemical staining the protein expression was compared to allelic deletions of the corresponding genes. The allelic deletions were detected by PCR-based microsatellite analyses. Results. We detected a significant reduction in the expression levels of the cell cycle related proteins p21waf1 (P=0.002), p27kip1 (P=0.03), Rb (P=0.00002), and L-myc (P=0.00000007) in muscle invasive tumors compared to noninvasive tumors. Tumors presenting as muscle invasive at first diagnosis had significantly lower levels of p16/CDKN2A (P=0.01) when compared to muscle invasive tumors that followed Ta or T1 precursor lesions. We found no general correlation between allelic deletion of a gene and its immunohistochemical protein expression, indicating that the remaining allele may be capable of encoding a normal or even increased protein level. Conclusions. Our results support the hypothesis that bladder tumors with invasion at first diagnosis differ from those in which invasion follow superficial tumors. This difference is reflected as a different level in cell cycle related protein expression. The data also indicate that allelic deletions of cell cycle related genes do not correlate with an altered level of protein expression.

In a previous study we found allelic imbalances of Rb and L-myc associated with disease stage and disease course in bladder cancer. The primary aim of the present study was to determine whether the changes found in tumors were reflected in urine sediments. Secondly we wanted to test if Rb and L-myc were frequently lost in urine sediments from patients with carcinoma in situ and no bladder tumor at present. Based on this we examined allelic deletions of the Rb and L-myc genes in tumor and urine from 55 patients with bladder tumors or carcinoma in situ. Deletions were examined on extracted DNA from tumors and urine sediments by the use of microsatellite markers located as close to the genes as possible. Fifty-five patients and 10 controls were included. We found no strict correlation between allelic deletions in bladder tumors and urine sediments from the same patient. Allelic deletions in urine sediments were at least as common in patients with carcinoma in situ and no bladder tumor (32%) as in patients with bladder tumors (20%). It was possible to identify allelic deletions in urine sediment from 1 patient with cystitis and no history of malignant bladder disease (6%). In conclusion we found no strict correlation between allelic deletions in bladder tumors and urine sediments. Allelic deletions in urine sediments seem to be at least as common in patients with carcinoma in situ as in patients with bladder tumors.

Evaluation of the EGFR-Inhibitor Zalutumumab Given With Primary Curative (Chemo)radiation Therapy to Patients With Squamous Cell Carcinoma of the Head and Neck: Results of the DAHANCA 19 Randomized Phase 3 Trial Definitive Management of Head-and-Neck Squamous Cell Carcinoma J.G. Eriksen, C. Maare, J. Johansen, H. Primdahl, J.F. Evensen, C.A. Kristensen, L.J. Andersen, and J. Overgaard,; Odense University Hospital, Odense, Denmark, Herlev Hospital, Herlev, Denmark, Aarhus University Hospital, Aarhus C, Denmark, Oslo University Hospital, Oslo, Norway, Copenhagen University Hospital, Copenhagen, Denmark, Aalborg University Hospital, Aalborg, Denmark

Purpose/Objective: Tumour HPV-status has major impact on radiotherapy (RT) outcome in oropharyngeal carcinoma (OPC). Likewise smoking history is known to have prognostic implications on its own. The aim of this study was to investigate the impact of HPVstatus and smoking in patients (pts) with advanced OPC treated with accelerated RT and the hypoxic cell radiosensitizer Nimorazole, but no chemotherapy. Materials and Methods: 181 pts with stage III-IV OPC and known smoking history were identified in the DAHANCA database. All pts were treated between 1992-2005 with curatively intended primary RT delivered as moderately accelerated fractionation (66-68Gy in 33-34 fx, 6fx/week) and concomitant Nimorazole. Pre-treatment tumour blocks were evaluated by immunohistochemistry for HPV-associated p16-expression (pos/neg) and smoking history was analysed as number of cumulative packyears (> or 10pckyrs (N=70) were 77%, 81% and 63% at 5 years, respectively. Essentially all pts with p16neg tumours (N=78) had a smoking history of >10pckyrs, and outcome in this group of pts was significantly worse than that of patients with p16pos tumours, regardless of packyears. See Figure 1.