Feasibility and early clinical impact of precision medicine for late-stage cancer patients in a regional public academic hospital.

AIM: Our goal was to describe a precision medicine program in a regional academic hospital, characterize features of included patients and present early data on clinical impact. MATERIALS AND METHODS: We prospectively included 163 eligible patients with late-stage cancer of any diagnosis from June 2020 to May 2022 in the Proseq Cancer trial. Molecular profiling of new or fresh frozen tumor biopsies was done by WES and RNAseq with parallel sequencing of non-tumoral DNA as individual reference. Cases were presented at a National Molecular Tumor Board (NMTB) for discussion of targeted treatment. Subsequently, patients were followed for at least 7 months. RESULTS: 80% (N = 131) of patients had a successful analysis done, disclosing at least one pathogenic or likely pathogenic variant in 96%. A strongly or potentially druggable variant was found in 19% and 73% of patients, respectively. A germline variant was identified in 2.5%. Median time from trial inclusion to NMTB decision was one month. One third (N = 44) of patients who underwent molecularly profiling were matched with a targeted treatment, however, only 16% were either treated (N = 16) or are waiting for treatment (N = 5), deteriorating performance status being the primary cause of failure. A history of cancer among 1st degree relatives, and a diagnosis of lung or prostate cancer correlated with greater chance of targeted treatment being available. The response rate of targeted treatments was 40%, the clinical benefit rate 53%, and the median time on treatment was 3.8 months. 23% of patients presented at NMTB were recommended clinical trial participation, not dependent on biomarkers. CONCLUSIONS: Precision medicine in end-stage cancer patients is feasible in a regional academic hospital but should continue within the frame of clinical protocols as few patients benefit. Close collaboration with comprehensive cancer centers ensures expert evaluations and equality in access to early clinical trials and modern treatment.

Regional and socio-economic variation in survival after glioblastoma in Denmark, 2013-2018.

INTRODUCTION: Glioblastoma is the most frequent primary brain tumour in adults. In Denmark, the treatment of glioblastoma is centralised to four neurosurgical and oncological departments located in four of the five Danish administrative regions. The aim of this study was to examine the regional and socioeconomic variation in survival after a diagnosis of glioblastoma in Denmark. METHODS: We included 1,731 patients with histologically confirmed glioblastoma from 2013 to 2018 registered in the Danish Neuro-oncology Registry. The data sources were the Danish National Registries. The exposure was region of residence at diagnosis and household income in the year before diagnosis. Follow-up was initiated at diagnosis and concluded at death or end-of-follow-up on 15 July 2019. Cox regression was used to examine overall mortality by exposure. RESULTS: With adjustment for age, sex, year of diagnosis and comorbidity, mortality rates of glioblastoma patients varied significantly between regions and were lowest in the Region of Southern Denmark and highest in the Capital Region (hazard ratio = 0.79; 95% confidence interval: 0.68-0.91, compared with the Capital Region). Further adjustment for surgical resection attenuated the regional differences in mortality. Income was not a predictor of survival. CONCLUSIONS: We found significant regional variation in survival after a diagnosis of glioblastoma. Differences in treatment patterns between regions may explain part of this mortality variation. Household income and education level did not explain the regional differences. FUNDING: none. TRIAL REGISTRATION: not relevant.

Treatment and survival of glioblastoma patients in Denmark: The Danish Neuro-Oncology Registry 2009-2014.

BACKGROUND: As many glioblastoma patients are in a poor condition they are unable to undergo the full treatment documented in clinical trials. We aimed to examine the survival and its relationship to clinical characteristics and treatment in a nationwide population of glioblastoma patients in Denmark. METHODS: We included prospectively recorded clinical data from 1364 adult patients with histologically verified glioblastoma from the Danish Neuro-Oncology Registry, 2009-2014. RESULTS: The age standardized incidence rate was 6.3/100,000 person-years for males and 3.9 for females and the median age was 66 years. The median overall survival was 11.2 months. There was an independently significant prognostic effect of age, performance status, cognitive symptoms, tumor diameter, multifocality, crossing midline, and contrast enhancement. For partial and total resection compared to biopsy only, the adjusted risk of dying was reduced by 43% (HR [CI] 0.57 [0.48-0.68]) and 51% (0.49 [0.40-0.60]), respectively. For patients receiving a partial and full radiochemotherapy regimen compared to no postsurgical treatment, the risk reduction was 56% (HR [CI] 0.44 [0.37-0.53]) and 70% (0.30 [0.25-0.35]), respectively. The full radiochemotherapy regimen was only allocated to 50% of the patients, 29% among the oldest (70+ years) and 60% among the younger (18-69 years). CONCLUSIONS: Glioblastoma patients had a poor overall survival but with several specific independent prognostic factors. Extensive cancer treatment was associated with an increasing survival in all age groups, but only half of the patients were sufficiently fit for a full regimen of postoperative combined radiochemotherapy.

Epidemiology of glioma: clinical characteristics, symptoms, and predictors of glioma patients grade I-IV in the the Danish Neuro-Oncology Registry.

In this national population-based study of glioma, we present epidemiologic data on incidence, demographics, survival, clinical characteristics and symptoms, and evaluate the association of specific indicators with the grade of glioma. We included 1930 patients registered in the Danish Neuro-Oncology Registry (DNOR) from 2009 to 2014. DNOR is a large-scale national population-based database including all adult glioma patients in Denmark. The age-adjusted annual incidence of histologic verified glioma was 7.3 cases pr. 100,000 person-years. High-grade gliomas were present in 85% and low-grade glioma in 15%. The overall male:female ratio was 3:2 and the mean age at onset was 60 years. Data for WHO grade I, II, III and IV glioma showed several important differences regarding age and sex distribution and symptomatology at presentation. The mean age increased with the grade of glioma and males predominated in all grades. Focal deficits were the most frequent presenting symptom, but among patients with glioma, grade II epileptic seizures were the most frequent symptom. Headache was a rare mono-symptomatic onset symptom. At presentation, higher age, focal deficits and cognitive change for <3 months duration, and headache <1 month were significant independent indicators of high-grade gliomas. Younger age and epileptic seizures for more than 3 months were indicative for low-grade gliomas. Survival rates for glioma grade I-IV showed decreasing survival with increasing grade. Glioma grade I-IV showed high diversity regarding several demographic and clinical characteristics emphasizing the importance of individually tailored disease treatments and support.

The Danish Neuro-Oncology Registry: establishment, completeness and validity.

BACKGROUND: The Danish Neuro-Oncology Registry (DNOR) is a nationwide clinical cancer database that has prospectively registered data on patients with gliomas since January 2009. The purpose of this study was to describe the establishment of the DNOR and further to evaluate the database completeness of patient registration and validity of data. METHODS: The completeness of the number of patients registered in the database was evaluated in the study period from January 2009 through December 2014 by comparing cases reported to the DNOR with the Danish National Patient Registry and the Danish Pathology Registry. The data validity of important clinical variables was evaluated by a random sample of 100 patients from the DNOR using the medical records as reference. RESULTS: A total of 2241 patients were registered in the DNOR by December 2014 with an overall patient completeness of 92 %, which increased during the study period (from 78 % in 2009 to 96 % in 2014). Medical records were available for all patients in the validity analyses. Most variables showed a high agreement proportion (56-100 %), with a fair to good chance-corrected agreement (k = 0.43-1.0). CONCLUSIONS: The completeness of patient registration was very high (92 %) and the validity of the most important patient data was good. The DNOR is a newly established national database, which is a reliable source for future scientific studies and clinical quality assessments among patients with gliomas.

Cripto-1 expression in glioblastoma multiforme.

Human glioblastoma multiforme (GBM) is an aggressive cancer with a very poor prognosis. Cripto-1 (CR-1) has a key regulatory role in embryogenesis, while in adult tissue re-expression of CR-1 has been correlated to malignant progression in solid cancers of non-neuronal origin. As CR-1 expression has yet to be described in cerebral cancer and CR-1 is regulated by signaling pathways dysregulated in GBM, we aimed to investigate CR-1 in the context of expression in GBM. The study was performed using enzyme-linked immunosorbent assay (ELISA), Western blotting, polymerase chain reaction (PCR) and immunohistochemistry to analyze the blood and tissue from 28 GBM and 4 low-grade glioma patients. Within the patient cohort, we found high CR-1 protein levels in blood plasma to significantly correlate with a shorter overall survival. We identified CR-1 in different areas of GBM tissue, including perivascular tumor cells, and in endothelial cells. Collectively, our data suggest that CR-1 could be a prognostic biomarker for GBM with the potential of being a therapeutic target.

[Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant gliomas--a new treatment modality]. / 5-aminolevulinsyre-fluorescens-vejledt resektion af maligne gliomer er en ny behandlingsmodalitet.

5-aminolevulinic acid (ALA) is a precursor of haemoglobin which leads to the synthesis of porphyrins in malignant gliomas which then appears with red fluorescence under blue light. In the literature we see that there is class Ib evidence that 5-ALA guided surgery significantly increases the radicalism of surgery and gives rise to a marked improvement in 6-month progression-free survival and that there is now class II evidence confirming the value of maximal cytoreductive surgery. Furthermore, existing class II evidence indicates that there is a synergistic effect between aggressive cytoreductive surgery and radiochemotherapy.

Fluorescence-guided resection of gliomas.

INTRODUCTION: Malignant gliomas remain associated with a poor prognosis despite both surgical treatment and radiochemotherapy.Previous studies have shown that complete resection of contrast-enhancing tumours is achieved in less than 20-30% of patients. 5-aminolevulinic acid (5-ALA) is a pro-drug that leads to accumulation of fluorescent protoporphyrins in malignant gliomas. The fluorescence can be visualized intraoperatively by use of a modified microscope. The Department of Neurosurgery at Aalborg Hospital has recently adopted this new technique as the first centre in Denmark. Our preliminary results are presented as a retrospective case series. MATERIAL AND METHODS: All patients who had undergone 5-ALA fluorescence-guided surgery due to suspected malignant glioma were included. Patients received a standard preoperative dose of Gliolan. All patients had a postoperative cerebral magnetic resonance imaging scan done within 72 hours to determine their postoperative resection status. RESULTS: To date, 13 patients have undergone fluorescence-guided surgery. Total resection was achieved in 54-70% of the patients depending on the inclusion criteria. Total or near total resection was achieved in 92% of patients. CONCLUSION: The small numbers in our case series do not allow for direct comparison to be made, but show that our results on postoperative resection status fall within the range reported in other studies on the efficacy of 5-ALA. The literature offers mounting evidence in support of the role of aggressive cytoreductive surgery in patients with malignant gliomas. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Opioid-insensitive hypoalgesia to mechanical stimuli at sites ipsilateral and contralateral to experimental muscle pain in human volunteers.

Musculoskeletal pains are often characterised by referred pain and hyperalgesia. The aim of the present study was to examine the sensitivity to pressure and pinprick at sites ipsi- and contralateral to capsaicin-induced pain in the tibialis anterior (TA) muscle. Visual analogue scale (VAS) scores of the sensation to sub- and supra-pain threshold stimuli by pressure and pinprick were recorded before, during and after experimental muscle pain. It was found that pressure stimulation (120% of baseline pain threshold) delivered over the ipsilateral deep peroneal nerve between the 1st and 2nd metatarsal bones showed a significant increase in VAS scores during muscle pain. The referred pain did not overlap this hyperalgesic site. Ipsilateral test sites at the TA muscle, great toe and between the 3rd and 4th metatarsal bones did not show any changes in response to pressure stimulation during pain. In contrast, test sites at the ipsilateral ankle showed hypoalgesia to pressure during muscle pain. In the contralateral leg hypoalgesia to pressure was found at all sites during pain. The decreased sensitivity to pressure was confirmed with both sub- and supra-pressure pain-threshold stimuli. VAS scores to pinprick were either decreased or unchanged during pain compared to before pain. Naloxone administrated in a placebo-controlled manner had no effect on hypoalgesia to pressure or pinprick during muscle pain. Thus, the generalised decreased sensitivity may reflect activation of non-opioid endogenous pain inhibitory systems. The lack of change in sensitivity at some sites could indicate a competitive balance between excitatory and inhibitory mechanisms. The deep peroneal nerve specifically innervates both the TA muscle and the only site of hyperalgesia indicating spatial summation of afferent activity from these structures.