Diagnostic Value of Preoperative uPAR-PET/CT in Regional Lymph Node Staging of Oral and Oropharyngeal Squamous Cell Carcinoma: A Prospective Phase II Trial.

The detection of lymph node metastases is a major challenge in oral and oropharyngeal squamous cell carcinoma (OSCC and OPSCC). 68Ga-NOTA-AE105 is a novel positron emission tomography (PET) radioligand with high affinity to urokinase-type plasminogen activator receptor (uPAR), a receptor expressed on the surfaces of tumor cells. The aim of this study was to investigate the diagnostic value of uPAR-PET/CT (computerized tomography) in detecting regional metastatic disease in patients with OSCC and OPSCC compared to the current imaging work-up. In this phase II trial, patients with OSCC and OPSCC referred for surgical treatment were prospectively enrolled. Before surgery, 68Ga-NOTA-AE105 uPAR-PET/CT was conducted, and SUVmax values were obtained from the primary tumor and the suspected lymph nodes. Histology results from lymph nodes were used as the standard of truth of metastatic disease. The diagnostic values of 68Ga-uPAR-PET/CT were compared to conventional routine preoperative imaging results (CT and/or MRI). The uPAR expression in resected primary tumors and metastases was determined by immunohistochemistry and quantified digitally (H-score). A total of 61 patients underwent uPAR-PET/CT. Of the 25 patients with histologically verified lymph node metastases, uPAR-PET/CT correctly identified regional metastatic disease in 14 patients, with a median lymph node metastasis size of 14 mm (range 3-27 mm). A significant correlation was found between SUVmax and the product of the H-score and tumor depth (r = 0.67; p = 0.003). The sensitivity and specificity of uPAR-PET/CT in detecting regional metastatic disease were 56% and 100%, respectively. When added to CT/MRI, uPAR-PET was able to upstage 2/11 (18%) of patients with occult metastases and increase the sensitivity to 64%. The sensitivity and specificity of 68Ga-NOTA-AE105 uPAR-PET/CT were equivalent to those of CT/MRI. The significant correlation between SUVmax and uPAR expression verified the target specificity of 68Ga-NOTA-AE105. Despite the target specificity, the sensitivity of imaging is too low for nodal staging and it cannot replace neck dissection.

Potential of uPAR, αvß6 Integrin, and Tissue Factor as Targets for Molecular Imaging of Oral Squamous Cell Carcinoma: Evaluation of Nine Targets in Primary Tumors and Metastases by Immunohistochemistry.

No clinically approved tumor-specific imaging agents for head and neck cancer are currently available. The identification of biomarkers with a high and homogenous expression in tumor tissue and minimal expression in normal tissue is essential for the development of new molecular imaging targets in head and neck cancer. We investigated the expression of nine imaging targets in both primary tumor and matched metastatic tissue of 41 patients with oral squamous cell carcinoma (OSCC) to assess their potential as targets for molecular imaging. The intensity, proportion, and homogeneity in the tumor and the reaction in neighboring non-cancerous tissue was scored. The intensity and proportion were multiplied to obtain a total immunohistochemical (IHC) score ranging from 0-12. The mean intensity in the tumor tissue and normal epithelium were compared. The expression rate was high for the urokinase-type plasminogen activator receptor (uPAR) (97%), integrin αvß6 (97%), and tissue factor (86%) with a median total immunostaining score (interquartile range) for primary tumors of 6 (6-9), 12 (12-12), and 6 (2.5-7.5), respectively. For the uPAR and tissue factor, the mean staining intensity score was significantly higher in tumors compared to normal epithelium. The uPAR, integrin αvß6, and tissue factor are promising imaging targets for OSCC primary tumors, lymph node metastases, and recurrences.

Differences in gene expression despite identical histomorphology in sinonasal intestinal-type adenocarcinoma and metastases from colorectal adenocarcinoma.

Sinonasal intestinal-type adenocarcinoma (sITAC) is histomorphologically indistinguishable from colorectal adenocarcinoma (CRC) leading to diagnostic challenges. Metastases from CRCs to the sinonasal tract have been reported. The aim of the study was to identify a biomarker making it possible to distinguish between sITAC and metastases of colorectal origin. Formalin-fixated paraffin-embedded (FFPE) tissue from 20 consecutive patients with sITAC treated at Rigshospitalet, Denmark from 2005 to 2017, 20 patients with CRC, and second patients with both sinonasal and colorectal carcinomas were included, and RNA-sequencing was performed on all samples. Moreover, a series of 26 samples from metastasizing CRC were included (in-house data). 3139 differentially expressed genes were identified, of these several were deemed as possible biomarkers, including CSDE1, for which immunohistochemical staining was performed. sITAC and CRC differ in genomic expression. CSDE1, previously found upregulated in CRC, was significantly differentially expressed. Using immunohistochemical staining, no sITACs displayed strong and diffuse staining for CSDE1, which represents a potential marker to use in distinguishing sITAC from a metastasis of colorectal origin. This knowledge could improve the diagnostic process and hopefully the outcome in patients with this rare tumor.

Improved surgical resection of metastatic pancreatic cancer using uPAR targeted in vivo fluorescent guidance: comparison with traditional white light surgery.

Pancreatic cancer remains one of the deadliest cancers. The five-year survival rates have been reported as 3%. Radical surgical tumor resection is critical for improved outcome and the low survival rate for pancreatic cancer is due to lack of other effective treatments and here optical guided surgery could be a solution for better surgical outcome. In the present study, we targeted the urokinase plasminogen activator receptor (uPAR) with a peptide conjugated with the fluophore ICG (ICG-Glu-Glu-AE105) for optical imaging. In the first part of the study we aimed to validate ICG-Glu-Glu-AE105 for resection of the primary tumor and metastases in an orthotopic human xenograft pancreatic cancer model. In the second part of the study we aimed to investigate if fluorescent-guided imaging could locate additional metastases following conventional removal of metastasis under normal white light surgery. Our study showed that ICG-Glu-Glu-AE105 was an excellent probe for intraoperative optical imaging with a mean tumor-to-background ratio (TBR) for the primary tumor of 3.5 and a TBR for the metastases of 3.4. Further, a benefit using intraoperative fluorescent guidance yielded identification of an additional 14% metastases compared to using normal white light surgery. In 4 of 8 mice there were identified additional metastases with uPAR optical imaging compared to white light. In conclusion, the uPAR-targeted optical probe ICG-Glu-Glu-AE105 enables intraoperative optical cancer imaging, including robotic surgery, and may be a benefit during intended radical resection of disseminated pancreas cancer by finding more metastasis than with traditional white light surgery.

Incidence and survival of hypopharyngeal cancer: a Danish Nation-Wide Study from 1980 to 2014.

Objectives: To evaluate changes in incidence and survival of patients diagnosed with hypopharyngeal cancer (HPC) in Denmark in the period 1980-2014.Methods: All patients registered with HPC in the Danish Cancer Registry (DCR) in the period 1980-2014 were included. Age-adjusted incidence rates (AAIRs), average annual percentage change in incidence, and overall survival were calculated.Results: Two thousand and nine patients were included (79.7% men). The overall AAIR increased significantly from 0.3 per 100,000 to 1.1 per 100,000 during the study period, corresponding to an increase of 4.1% per year. The most frequent histology was squamous cell carcinoma (SCC) comprising 90.3%. The overall five-year survival increased with 13.5 percentage points from 13.4% in the period 1980-1985 to 26.9% in the period 2010-2014. Women demonstrated better survival compared to men with a hazard ratio of 0.83, and patients with SCC had better survival compared to the remaining histology groups.Conclusions: This nation-wide study, covering nearly four decades, showed a significant increase in incidence and survival of HPC in Denmark.

Incidence and survival of laryngeal cancer in Denmark: a nation-wide study from 1980 to 2014.

Background: The purpose of this registry study was to evaluate trends in incidence and survival of laryngeal cancer in the Danish population from 1980 to 2014. Methods: This study includes all patients with laryngeal cancer registered in the Danish Cancer Registry (DCR) in the period 1980-2014. The age-adjusted incidence rate (AAIR) per 100,000 and average annual percent change (AAPC) were calculated. We evaluated the relative survival at five years in relation to gender, anatomical location, year at diagnosis, and histological type. Further, an age-period-cohort (APC) model of incidence was constructed. Results: A total of 8748 patients (82% males) were included. The median age at diagnosis was 60 years, range 18-101 years. The AAIR decreased from 3.6 per 100,000 in 1980 to 2.3 per 100,000 in 2014 with an AAPC of -0.8% (p < .008). Considering the anatomic location, we found that glottic cancer had a significantly better survival at five years compared to the other locations. We observed no significant difference in survival for supraglottic, subglottic and larynx unspecified cancer during the observation period. During the period 1980-2014, we found no improvement in five year relative survival. Conclusions: This nation-wide study reports a significant decrease in the incidence of laryngeal cancer. Glottic cancer had a significantly better survival at five years compared to other locations.

[Progressive loss of vision as the only symptom of sinonasal cancer].

In this case report, an 81-year-old former carpenter presented with unilateral deteriorating vision. Due to gradual worsening and involvement of the other eye, he was seen by an ophthalmologist and underwent both CT and MRI, which gave rise to suspicion of a sinonasal cancer. Nasal endoscopy revealed a tumour in the ethmoid bilaterally, and a biopsy showed intestinal type adenocarcinoma. This type of cancer is rare, but strongly associated with occupational exposure to wood dust. Symptoms are usually vague, and the diagnosis is made with some delay, which is reflected in a poor prognosis.

[Diagnostics and treatment of sinonasal cancer].

Sinonasal cancer is rare, and the symptoms are often vague leading to a delay in diagnosis which affects the prognosis. This cancer type is most common in elderly men, and it consists of many different histological types, mainly carcinomas. The risk factors remain elusive, except for an association between intestinal type adenocarcinoma and exposure to wood dust. Human papillomavirus may play a role in squamous cell carcinomas. The treatment of choice is surgery, often combined with radiotherapy. Most surgeries are endoscopic (image-guided) to secure complete resection in a complex anatomic region.

Trends in thyroid cancer: Retrospective analysis of incidence and survival in Denmark 1980-2014.

BACKGROUND: Thyroid cancer incidence has been reported to be increasing since the 1970 s. The aim of this study was to investigate the change in incidence and survival from 1980 to 2014 in Denmark. METHODS: We identified patients registered with thyroid cancer in the period 1980-2014. We evaluated the age-adjusted incidence rate (AAIR) and the average annual percentage change (AAPC), constructed age-period-cohort models (APCs), and evaluated relative survival (RS). RESULTS: We included 5139 patients. The AAIR was 1.6 cases per 100,000 in 1980 and 4.5 cases in 2014 with an AAPC of 3.4%. The AAIR for papillary carcinomas (n = 2864) quintupled in the study period, and accounts for most of the observed increase in incidence with an AAPC of 4.9%. Follicular carcinomas (n = 920) nearly tripled in AAIR and had the second greatest increase in AAPC. Papillary carcinomas had the best prognosis with 1-year and 5-year RSs of 95% and 91%, followed by the follicular carcinomas with 1-year and 5-year RSs of 90% and 80%, respectively. Anaplastic carcinomas (n = 320) had the worst prognosis with 1-year and 5-year RSs of 18% and 12%. We found a significant age effect in the APC model for the incidence of thyroid cancer but no significant cohort or period effects. CONCLUSION: The incidence of thyroid cancer is rising. This is primarily attributable to an increase in papillary carcinomas. The relative survival has improved significantly in Denmark since 1980. The cause of the increasing incidence remains to be established, but enhanced diagnostic scrutiny and increased iodine intake may be influential.

Incidence and survival in sinonasal carcinoma: a Danish population-based, nationwide study from 1980 to 2014.

BACKGROUND: Sinonasal cancers are rare and comprise <1% of all malignancies. This study describes incidence and survival in sinonasal carcinomas in Denmark from 1980 to 2014. METHODS: All patients registered in the Danish Cancer Registry in the period were included. Age-adjusted incidence rate, average annual percentage change, and relative survival were calculated. Age-period-cohort models were constructed. RESULTS: 1,720 patients with sinonasal carcinoma (median age 67 years, 63% males) were identified. There was no significant change in age-adjusted incidence; 0.70 in 1980 to 0.43 per 100,000 in 2014 (p > .05). Relative 5- and 10-year survival were 52% and 40% for men, 58% and 42% for women. An increase in 5-year survival from 1980 to 2014 from 46% to 65% (p < .05) was found. Nasal carcinomas had a significantly better relative survival compared to sinus carcinoma, as did squamous cell carcinomas when compared to neuroendocrine malignancies. CONCLUSION: In Denmark between 1980 and 2014, the incidence of sinonasal carcinomas has been stable and the relative survival has increased significantly.

Increasing incidence and survival of head and neck cancers in Denmark: a nation-wide study from 1980 to 2014.

BACKGROUND: The purpose of the study was to determine trends in age-adjusted incidence rates (AAIR) and survival probability in head and neck cancers (HNCs) in the Danish population from 1980 to 2014. MATERIAL AND METHODS: All patients registered with HNC in the nationwide Danish Cancer Registry from 1980 to 2014 were included. We evaluated the AAIR per 100,000 and the average annual percent change (AAPC). The relative survival probability at 5 years was calculated in relation to gender, anatomical location and histology, and we constructed age-period-cohort models of incidence. RESULTS: About 34,606 patients were included (64.7% men). The AAIR increased from 9.1 per 100,000 in 1980 to 17.4 per 100,000 in 2014 with an AAPC of 2.1%. The greatest incidence increase was observed in oropharyngeal cancer (AAPC: 5.4%) followed by hypopharyngeal cancer (AAPC: 4.2%). Adenocarcinomas had the highest AAPC (5.0%) followed by squamous cell carcinomas (AAPC: 2.0%). The AAPC was significantly higher in women (2.4%) compared with men (1.6%). For all HNC patients, the relative survival at 5 years rose significantly from 49.0% in 1980-1984 to 62.4% in 2010-2014. Women had a significantly higher survival than men with a relative survival of 61.7% compared to 50.0% in men. Laryngeal cancer had the best survival probability of cancers in the upper aerodigestive tract with hypopharyngeal cancer having the poorest survival. CONCLUSION: This nation-wide study showed a significant rise in incidence of HNC for men and women along with a significant increase in relative survival. Oropharyngeal cancer had the highest increase in incidence followed by hypopharyngeal cancer which showed the poorest survival of HNCs.

An Applied Anatomical Study of the Ethmoidal Arteries: Computed Tomographic and Direct Measurements in Human Cadavers.

Computed tomography (CT) images have been used in very few studies on distances to the ethmoidal arteries in the orbit. Most other studies have included direct measurements on cadavers and frequently quote the 24-12-6 mm rule to describe distances from the anterior lacrimal crest to the anterior and posterior ethmoidal foramina (AEF and PEF), optic canal (OC), respectively. However, the large interindividual variation of distances renders absolute values less applicable in a clinical setting. Preoperative measurements on CT images may provide more precise distances than absolute rules and thus lead to safer orbital surgery. The authors hypothesize that the distances to the ethmoidal arteries and the length of the medial wall are positively correlated and that measurements of the distances from the posterior lacrimal crest (PLC) on CT images are feasible with a low intra- and interobserver variability.Fifty intact orbits from 25 Caucasian cadavers were exenterated and examined. In additional, high-resolution CT scans of 48 orbits from 24 other Caucasian nonexenterated cadavers were examined. Distances were measured from 4 different anterior landmarks to the AEF and PEF and the OC.Distances from the most anterior landmarks to the arteries were positively correlated with the length of the medial wall. Measurements of the distances from the PLC to the ethmoidal arteries on CT images were feasible with a low intra- and interobserver variability. In conclusion, iatrogenic damage to the ethmoidal arteries in the orbit may be best avoided by using CT measurements in presurgical planning.

Incidence and survival of oropharyngeal cancer in Denmark: a nation-wide, population-based study from 1980 to 2014.

BACKGROUND: Oropharyngeal carcinomas (OPCs) constitute a significant and increasing proportion of head and neck carcinomas and are an important global cause of morbidity and mortality. The purpose of this study was to determine trends in incidence and survival in OPC in the Danish population from 1980 to 2014. METHODS: This study included all patients registered in the nationwide Danish Cancer Registry over the period 1980-2014. The age-adjusted incidence rates (AAIR) per 100,000, annual percentage change (APC) and average annual percent change (AAPC) were evaluated. Five-year relative survival (RS) was calculated with Cox regression analyses in relation to gender, anatomical location and histology. RESULTS: A total of 6555 patients (69% male) were included, with a median age at diagnosis of 60 years. The AAIR of patients with OPC increased from 0.815 per 100,000 in 1980 to 4.51 per 100,000 in 2014 with an AAPC of 5.3. The 5-year RS increased significantly from 33.1% over the period 1980-1984 to 58.5% (25.4% points) over the period 2010-2014. With no significant difference stratified for gender. Tumors located at the palatine tonsils (n = 3333) and salivary gland OPC (n = 90) had significantly better survival compared with other sub-locations and histology subtypes. In the APC model the birth cohort effect rate ratio increased until 1925 and then decreased until 1935 from which point it increased in the last cohorts. CONCLUSIONS: In this population-based study, we observed a significant increase in the incidence of OPCs and in the RS for OPC. We also identified a profound birth cohort effect on the incidence.

Increasing incidence and survival in oral cancer: a nationwide Danish study from 1980 to 2014.

BACKGROUND: Oral carcinomas (OCs) make up a significant proportion of head and neck carcinomas (HNCs) and are an important cause of morbidity and mortality globally. The purpose of this population-based study was to determine trends in incidence and survival in OC in the Danish population from 1980 to 2014. MATERIAL AND METHODS: This study covered all patients registered in the nationwide Danish cancer registry (DCR) in the period 1980-2014. Age-adjusted incidence rate (AAIR) per 100,000 and annual percentage change (APC) were evaluated. Also, 5-year overall survival (OS) was calculated with Cox regression analysis in relation to location, gender, age, and calendar year at diagnosis. RESULTS: Altogether, 8299 patients with oral cancer were identified, 5062 (61%) of whom were males and 3237 (39%) were females. The median age at diagnosis was 63 years. The AAIR of patients with OC increased from 1.9 per 100,000 in 1980 to 3.5 per 100,000 in 2014, and we observed a significant increase in 5-year OS of 12% points (a relative increase of 38%) from the period 1980-1984 to 2005-2009. Women were found to have a better prognosis than men. CONCLUSIONS: We found an unexpected increase in the age-standardized incidence of OC during the last 30 years in Denmark, and also an improvement in survival. The 5-year OS was significantly better in recent years even when we adjusted the analysis for relevant covariates.

Ten-Year Follow-up on Tumor Growth and Hearing in Patients Observed With an Intracanalicular Vestibular Schwannoma.

BACKGROUND: Reports on the natural history of tumor growth and hearing in patients with a vestibular schwannoma (VS) are almost exclusively short-term data. Long-term data are needed for comparison with results of surgery and radiotherapy. OBJECTIVE: To report the long-term occurrence of tumor growth and hearing loss in 156 patients diagnosed with an intracanalicular VS and managed conservatively. METHODS: In this longitudinal cohort study, diagnostic and follow-up magnetic resonance imaging and audiometry were compared. RESULTS: After a follow-up of 9.5 years, tumor growth had occurred in 37% and growth into the cerebellopontine angle had occurred in 23% of patients. Conservative treatment failed in 15%. The pure tone average had increased from 51- to 72-dB hearing level, and the speech discrimination score (SDS) had decreased from 60% to 34%. The number of patients with good hearing (SDS > 70%) was reduced from 52% to 22%, and the number of patients with American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) class A hearing was reduced from 19% to 3%. Hearing was preserved better in patients with 100% SDS at diagnosis than in patients with even a small loss of SDS. Serviceable hearing was preserved in 34% according to AAO-HNS (class A-B) and in 58% according to the word recognition score (class I-II). Rate of hearing loss was higher in patients with growing tumors. CONCLUSION: Tumor growth occurred in only a minority of patients diagnosed with an intracanalicular VS during 10 years of observation. The risk of hearing loss is small in patients with normal discrimination at diagnosis. Serviceable hearing is preserved spontaneously in 34% according to AAO-HNS and in 58% according to the word recognition score.

Isolated facial vein thrombophlebitis: a variant of lemierre syndrome.

Lemierre syndrome is a rare complication of acute tonsillitis. It is caused by the anaerobic bacterium Fusobacterium necrophorum and is characterized by bacteremia and septic thrombosis of the internal jugular vein. Dissemination of septic emboli may occur. The diagnosis can be difficult since different organs can be involved. We discuss a case of Lemierre syndrome in a 35-year-old woman with isolated thrombophlebitis of the facial vein and fusobacteria growth in blood culture. This case emphasizes the need for awareness of the condition.