A randomised trial of [18F]PSMA-1007-PET/CT versus NaF-PET/CT for staging primary prostate cancer: A trial protocol.

Background: Prostate-specific membrane antigen (PSMA)-positron emission tomography/contrast-enhanced computed tomography (PET/CT) is a sensitive imaging modality for prostate cancer (PCa). Due to lack of knowledge of the patient benefit, PSMA-PET/CT is not yet recommended in the European guidelines for staging and treatment planning of patients with newly diagnosed PCa. We will investigate the potential difference in progression-free survival (PFS) and quality of life (QoL) of using PSMA-PET/CT versus sodium fluoride (NaF)-PET/CT for staging and treatment planning in patients with newly diagnosed PCa. Study Design: This is a prospective randomised controlled multicentre trial carried out at three centres in the Region of Southern Denmark. Endpoints: The primary endpoint is PFS. Secondary endpoints are residual disease, stage migration, impact on treatment strategies, stage distribution, QoL and diagnostic accuracy measures. Patients and Methods: Patients eligible for the study have newly diagnosed unfavourable intermediate- or high-risk PCa. A total of 448 patients will be randomised 1:1 into two groups: (A) a control group staged with Na[18F]F-PET/CT and (B) an intervention group staged with [18F]PSMA-1007-PET/CT. A subgroup in the intervention group will have a supplementary blinded Na[18F]F-PET/CT performed for the purpose of performing accuracy analyses. QoL will be assessed at baseline and with regular intervals (3-12 months) during the study period. Treatment decisions are achieved at multidisciplinary team conferences based on the results of the respective scans and according to current Danish guidelines. Trial Registration: The Regional Committees on Health Research Ethics for Southern Denmark (S-20190161) and the Danish Medicines Agency (EudraCT Number 2021-000123-12) approved the study, and it has been registered on clinicaltrials.gov (Record 2020110469).

Characteristics of Patients in SPCG-15-A Randomized Trial Comparing Radical Prostatectomy with Primary Radiotherapy plus Androgen Deprivation Therapy in Men with Locally Advanced Prostate Cancer.

Background: There is no high-grade evidence for surgery as primary treatment for locally advanced prostate cancer. The SPCG-15 study is the first randomized trial comparing surgical treatment with radiotherapy. Objective: To describe the baseline characteristics of the first 600 randomized men in the SPCG-15 study. The study will compare mortality and functional outcomes. Design setting and participants: This study is a Scandinavian prospective, open, multicenter phase III randomized clinical trial aiming to randomize 1200 men. Intervention: Radical prostatectomy with or without consecutive radiotherapy (experimental) and radiotherapy with neoadjuvant androgen deprivation therapy (standard of care). Outcome measurements and statistical analysis: Cause-specific survival, metastasis-free survival, overall survival, and patient-reported bowel function, sexual health, and lower urinary tract symptoms were measured. Results and limitations: The distribution of characteristics was similar in the two study arms. The median age was 67 yr (range 45-75 yr). Among the operated men, 36% had pT3a stage of disease and 39% had pT3b stage. International Society of Urological Pathology grades 2, 3, 4, and 5 were prevalent in 21%, 35%, 7%, and 27%, respectively. Half of the men (51%) in the surgery arm had no positive lymph nodes. The main limitation is the pragmatic design comparing the best available practice at each study site leading to heterogeneity of treatment regimens within the study arms. Conclusions: We have proved that randomization between surgery and radiotherapy for locally advanced prostate cancer is feasible. The characteristics of the study population demonstrate a high prevalence of advanced disease, well-balanced comparison groups, and a demography mirroring the Scandinavian population of men with prostate cancer at large. Patient summary: This study, which has recruited >600 men, compares radiotherapy with surgery for prostate cancer, and an analysis at the time of randomization indicates that the study will be informative and generalizable to most men with locally advanced but not metastasized prostate cancer.

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.

A phase I/II study of acute and late physician assessed and patient-reported morbidity following whole pelvic radiation in high-risk prostate cancer patients.

BACKGROUND: The aim of this study was to assess acute and late morbidity measured by the physician and patient-reported outcomes (PROs) in high-risk prostate cancer (PC) patients receiving whole pelvic intensity-modulated radiotherapy (IMRT) in the setting of a national clinical trial. MATERIAL AND METHODS: A total of 88 patients with adenocarcinoma of the prostate and high-risk parameters were enrolled from 2011 to 2013. All patients received 78 Gy in 39 fractions of IMRT delivering simultaneous 78 Gy to the prostate and 56 Gy to the seminal vesicles and lymph nodes. Physician-reported morbidity was assessed by CTCAE v.4.0. PROs were registered for gastro-intestinal (GI) by the RT-ARD score, genito-urinary (GU) by DAN-PSS, sexual and hormonal by EPIC-26, and quality of life (QoL) by EORTC QLQ-C30. RESULTS: Median follow-up (FU) time was 4.6 years. No persistent late CTCAE grade 3+ morbidity was observed. Prevalence of CTCAE grade 2+ GI morbidities varied from 0 to 6% at baseline throughout FU time, except for diarrhea, which was reported in 19% of the patients post-RT. PROs revealed increased GI morbidity (≥1 monthly episode) for "rectal urgency", "use of pads", "incomplete evacuation", "mucus in stool" and "bowel function impact on QoL" all remained significantly different (p < .05) at 60 months compared to baseline. CTCAE grade 2+ GU and sexual morbidity were unchanged. GU PROs on obstructive and irritative GU items (≥daily episode) increased during RT and normalized at 24 months. No clinically significant differences were found in sexual, hormonal, and QoL scores compared to baseline. CONCLUSIONS: Whole pelvic RT resulted in a mild to the moderate burden of late GI morbidities demonstrated by a relatively high prevalence of PROs. Whereas, physician-assessed morbidity revealed a low prevalence of late GI morbidity scores. This emphasizes the importance of using both PROs and physician-reported scoring scales when reporting late morbidity in clinical trials.

Prediagnosis epilepsy and survival in patients with glioma: a nationwide population-based cohort study from 2009 to 2018.

OBJECTIVE: Considering that epilepsy is common, and knowledge is lacking on its role especially for the prognosis of high-grade gliomas, the objective of this study was to investigate the association between epilepsy prior to glioma diagnosis and survival among glioma patients. METHODS: In a nationwide population-based cohort study, we included 3763 adult glioma patients diagnosed between 2009 and 2018 according to the Danish Neuro-Oncology Registry. Information on epilepsy was redeemed through Danish Neuro-Oncology Registry, National Patient Registry, and National Prescription Registry. Cox proportional hazard models with 95% confidence intervals (CIs) were applied to examine hazard ratios (HRs) for the association between epilepsy (< 1 year prior to glioma including epilepsy at onset; 1-10 years prior to glioma; no prior epilepsy) and risk of death, and whether it differed according to tumor grade and size, performance status, and treatment modalities. RESULTS: A 32% decreased risk of death in patients with epilepsy within 1 year prior to glioma compared to no prior epilepsy was found (HR = 0.68; CI 0.63-0.75). A favorable prognosis was seen for epilepsy in all glioma grades: II (HR = 0.55; CI 0.39-0.77), III (HR = 0.59; CI 0.48-0.73), and IV (HR = 0.85; CI 0.77-0.94). CONCLUSIONS: Patients with epilepsy within 1 year prior to glioma diagnosis had significant survival benefits compared to patients with no prior epilepsy. This association was significant for both low-grade gliomas (grade II) and high-grade gliomas (grade III and IV). Survival benefits in glioma patients with epilepsy at onset are possibly primarily attributable to tumor-specific histopathology, molecular biomarkers, and early diagnosis.

Online adaptive radiotherapy potentially reduces toxicity for high-risk prostate cancer treatment.

BACKGROUND AND PURPOSE: With daily, MR-guided online adapted radiotherapy (MRgART) it may be possible to reduce the PTV in pelvic RT. This study investigated the potential reduction in normal tissue complication probability (NTCP) of MRgART compared to standard radiotherapy for high-risk prostate cancer. MATERIALS AND METHODS: Twenty patients treated with 78 Gy to the prostate and 56 Gy to elective pelvic lymph nodes were included. VMAT plans were generated with standard clinical PTV margins. Additionally to the planning MR, patients had three MRI scans during treatment to simulate an MRgART. A reference plan with PTV margins determined for MRgART was created per patient and adapted to each of the following MRs. Adapted plans were warped to the planning MR for dose accumulation. The standard plan was rigidly registered to each adaptation MR before it was warped to the planning MR for dose accumulation. Dosimetric impact was compared by DVH analysis and potential clinical effects were assessed by NTCP modeling. RESULTS: MRgART yielded statistically significant lower doses for the bladder wall, rectum and peritoneal cavity, compared to the standard RT, which translated into reduced median risks of urine incontinence (ΔNTCP 2.8%), urine voiding pain (ΔNTCP 2.8%) and acute gastrointestinal toxicity (ΔNTCP 17.4%). Mean population accumulated doses were as good or better for all investigated OAR when planned for MRgART as standard RT. CONCLUSION: Online adapted radiotherapy may reduce the dose to organs at risk in high-risk prostate cancer patients, due to reduced PTV margins. This potentially translates to significant reductions in the risks of acute and late adverse effects.

The Epigenetic Regulator Jumonji Domain-Containing Protein 6 (JMJD6) Is Highly Expressed but Not Prognostic in IDH-Wildtype Glioblastoma Patients.

Patients with IDH-wildtype glioblastoma (GBM) generally have a poor prognosis. However, there is an increasing need of novel robust biomarkers in the daily clinico-pathological setting to identify and support treatment in patients who become long-time survivors. Jumonji domain-containing protein 6 (JMJD6) is involved in epigenetic regulation of demethylation of histones and has been associated with GBM aggressiveness. We investigated the expression and prognostic potential of JMJD6 tumor fraction score in 184 IDH-wildtype GBMs. Whole-slides were double-stained with an antibody against JMJD6 and an exclusion-cocktail consisting of 4 antibodies (CD31, SMA, CD45, and Iba-1), enabling evaluation of tumor cells only. Stainings were quantified with a combined software- and scoring-based approach. For comparison, IDH-mutated WHO grade II, III and IV astrocytic gliomas were also stained, and the JMJD6 tumor fraction score increased with increasing WHO grade, although not significantly. In multivariate analysis including age, gender, performance status and post-surgical treatment high JMJD6 tumor fraction score was associated with longer overall survival in IDH-wildtype GBMs (p = 0.03), but the effect disappeared when MGMT promoter status was included (p = 0.34). We conclude that JMJD6 is highly expressed in IDH-wildtype GBM but it has no independent prognostic value.

Prognostic role of Ki-67 in glioblastomas excluding contribution from non-neoplastic cells.

Survival of glioblastoma patients varies and prognostic markers are important in the clinical setting. With digital pathology and improved immunohistochemical multiplexing becoming a part of daily diagnostics, we investigated the prognostic value of the Ki-67 labelling index (LI) in glioblastomas more precisely than previously by excluding proliferation in non-tumor cells from the analysis. We investigated the Ki-67 LI in a well-annotated population-based glioblastoma patient cohort (178 IDH-wildtype, 3 IDH-mutated). Ki-67 was identified in full tumor sections with automated digital image analysis and the contribution from non-tumor cells was excluded using quantitative double-immunohistochemistry. For comparison of the Ki-67 LI between WHO grades (II-IV), 9 IDH-mutated diffuse astrocytomas and 9 IDH-mutated anaplastic astrocytomas were stained. Median Ki-67 LI increased with increasing WHO grade (median 2.7%, 6.4% and 27.5%). There was no difference in median Ki-67 LI between IDH-mutated and IDH-wildtype glioblastomas (p = 0.9) and Ki-67 LI was not associated with survival in glioblastomas in neither univariate (p = 0.9) nor multivariate analysis including MGMT promoter methylation status and excluding IDH-mutated glioblastomas (p = 0.2). Ki-67 may be of value in the differential diagnostic setting, but it must not be over-interpreted in the clinico-pathological context.

Evolution of the gross tumour volume extent during radiotherapy for glioblastomas.

BACKGROUND AND PURPOSE: Tumour growth during radiotherapy may lead to geographical misses of the target volume. This study investigates the evolution of the tumour extent and evaluates the need for plan adaptation to ensure dose coverage of the target in glioblastoma patients. MATERIALS AND METHODS: The prospective study included 29 patients referred for 59.4 Gy in 33 fractions. Magnetic resonance imaging (MRI) was performed at the time of treatment planning, at fraction 10, 20, 30, and three weeks after the end of radiotherapy. The gross tumour volume (GTV) was defined as the T1w contrast-enhanced region plus the surgical cavity on each MRI set. The relative GTV volume and the maximum distance (Dmax) of the extent of the actual GTV outside the original GTV were measured. Based on the location of the actual GTV during radiotherapy and the original planned dose, a prospective clinical decision was made whether to adapt the treatment. RESULTS: Dose coverage of the GTV during radiotherapy was not compromised, and none of the radiotherapy plans was adapted. The median Dmax (range) was 5.7 (2.0-18.9) mm, 8.0 (2.0-27.4) mm, 8.0 (1.9-27.3) mm, and 8.9 (1.9-34.4) mm at fraction 10, 20, 30, and follow-up. The relative GTV volume and Dmax observed at fraction 10 were correlated with the values observed at follow-up (R = 0.74, p < 0.001 and R = 0.79, p < 0.001, respectively). CONCLUSION: Large variations in the GTV extent were observed, and changes often occurred early in the treatment. Plan adaptation for geographical misses was not performed in our cohort due to sufficient CTV margins.

Long-term follow-up 3 years after a randomized rehabilitation study among radiated prostate cancer survivors.

PURPOSE: In the Rehabilitation of Prostate Cancer (RePCa) study, the intervention reduced early adverse effects in prostate cancer 6 months after radiotherapy. This 3-year follow-up study assesses late adverse effects, evaluates rehabilitative long-term effects and identifies patients who benefit the most. DESIGN: RePCa was a randomized clinical trial with multidisciplinary rehabilitation (n = 79) or usual care (n = 82). The intervention during the first 6 months consisted of consultations by nurses and physiotherapists focusing on psychosocial support and physical activity, respectively. Here we report the 3-year follow-up. Data consisted of disease-specific quality of life (EPIC-26), general quality of life (SF-12) and pelvic floor strength measured by electromyography. RESULTS: One hundred forty-three patients (92%) responded. The primary outcome urinary irritative sum-score was no longer significantly different between groups. In patients with moderate-severe urinary problems at baseline, we observed a significant long-term effect on the urinary irritative sum-score in favour of the intervention (+ 13.4 points P = .014). More patients had moderate-severe bowel problems in the control group (n = 10; 14%) compared to the intervention group (n = 2; 3%) (P = .016). Pelvic floor strength deteriorated significantly in both groups. CONCLUSION: The short-term rehabilitation was beneficial but of limited benefit in the long term for all patients. A significant and clinically relevant effect was found in irradiated prostate cancer patients with moderate-severe urinary problems at baseline. In both groups, pelvic floor strength was weakened during follow-up. IMPACT FOR CANCER SURVIVORS: Prior research showed patients benefit from early rehabilitation. Identification of patients with moderate-severe urinary problems followed by a focused rehabilitation during the first 6 months after radiotherapy results in long-term improvement. Radiated patients have to be aware of their pelvic floor strength. IMPLICATIONS FOR CANCER SURVIVORS: Patients can be informed that they benefit from early rehabilitation, and they cannot expect larger changes in adverse effects within the first years, but they have to be aware of their pelvic floor strength. Future rehabilitation studies could be applied mainly to patients with assessed rehabilitation needs after radiotherapy and intensified with long-term follow-up.

Final Analysis of the Ipilimumab Versus Placebo Following Radiotherapy Phase III Trial in Postdocetaxel Metastatic Castration-resistant Prostate Cancer Identifies an Excess of Long-term Survivors.

BACKGROUND: The phase 3 trial CA184-043 evaluated radiotherapy to bone metastases followed by Ipilimumab or placebo in men with metastatic castrate-resistant prostate cancer (mCRPC) who had received docetaxel previously. In a prior analysis, the trial's primary endpoint (overall survival [OS]) was not improved significantly. OBJECTIVE: To report the final analysis of OS. DESIGN, SETTING, AND PARTICIPANTS: A total of 799 patients were randomized to receive a single dose of radiotherapy to one or more bone metastases followed by either Ipilimumab (n = 399) or placebo (n = 400). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS was analyzed in the intention-to-treat population. Prespecified and exploratory subset analyses based on Kaplan-Meier/Cox methodology were performed. RESULTS AND LIMITATIONS: During an additional follow-up of approximately 2.4 yr since the primary analysis, 721/799 patients have died. Survival analysis showed crossing of the curves at 7-8 mo, followed by persistent separation of the curves beyond that point, favoring the ipilimumab arm. Given the lack of proportional hazards, a piecewise hazard model showed that the hazard ratio (HR) changed over time: the HR was 1.49 (95% confidence interval 1.12, 1.99) for 0-5 mo, 0.66 (0.51, 0.86) for 5-12 mo, and 0.66 (0.52, 0.84) beyond 12 mo. OS rates were higher in the ipilimumab versus placebo arms at 2 yr (25.2% vs 16.6%), 3 yr (15.3% vs 7.9%), 4 yr (10.1% vs 3.3%), and 5 yr (7.9% vs. 2.7%). Disease progression was the most frequent cause of death in both arms. In seven patients (1.8%) in the ipilimumab arm and one (0.3%) in the placebo arm, the primary cause of death was reported as study drug toxicity. No long-term safety signals were identified. CONCLUSIONS: In this preplanned long-term analysis, OS favored ipilimumab plus radiotherapy versus placebo plus radiotherapy for patients with postdocetaxel mCRPC. OS rates at 3, 4, and 5 yr were approximately two to three times higher in the ipilimumab arm. PATIENT SUMMARY: After longer follow-up, survival favored the group of men who received ipilimumab, with overall survival rates being two to three times higher at 3 yr and beyond.

Posttreatment Effect of MGMT Methylation Level on Glioblastoma Survival.

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) removes temozolomide-induced alkylation, thereby preventing DNA damage and cytotoxicity. We investigated the prognostic effect of different MGMT methylation levels on overall and progression-free survival in 327 patients with primary glioblastoma undergoing standard treatment. We obtained MGMT methylation level in 4 CpG sites using pyrosequencing. The association between MGMT methylation level and survival was investigated using Cox proportional hazards model and an extension to detect time-varying effects. We found an association between MGMT methylation level and overall survival (OS) from around 9 months after the diagnosis, with no association between MGMT methylation level and OS before that. For patients surviving at least 9 months even small increases in MGMT methylation level are significantly beneficial (HR = 0.97, 95% CI [0.96, 0.98]). The predictive ability of MGMT methylation level on OS from 9 months after diagnosis has a Harrel's C of 66%. We conclude that the MGMT methylation level is strongly associated with survival only for patients surviving beyond 9 months with considerable effects for levels much lower than previously reported. Prognostic evaluation of cut-points of MGMT methylation levels and of CpG island site selection should take the time-varying effect on overall survival into account.

Evaluation of the proliferation marker Ki-67 in gliomas: Interobserver variability and digital quantification.

BACKGROUND: The Ki-67 Labelling Index (LI) is used as an ancillary tool in glioma diagnostics. Interobserver variability has been reported and no precise guidelines are available. Nor is it known whether novel digital approaches would be an advantage. Our aim was to evaluate the inter- and intraobserver variability of the Ki-67 LI between two pathologists and between pathologists and digital quantification both in whole tumour slides and in hot spots using narrow but diagnostically relevant intervals. METHODS: In samples of 235 low and high grade gliomas, two pathologists (A and B) estimated the Ki-67 LI (5-10% intervals) for whole tumour slides and for hot spots. In 20 of the cases intraobserver variability was evaluated. For digital quantification (C) slides were scanned with subsequent systematic random sampling of viable tumour areas. A software classifier trained to identify positive and negative nuclei calculated the Ki-67 LI. The interobserver agreements were evaluated using kappa (κ) statistics. RESULTS: The observed proportions of agreement and κ values for Ki-67 LI for whole tumour slides were: A/B: 46% (κ = 0.32); A/C: 37% (κ = 0.26); B/C: 37% (κ = 0.26). For hot spots equivalent values were: A/B: 14% (κ = 0.04); A/C: 18% (κ = 0.09); B/C: 31% (κ = 0.21). CONCLUSIONS: Interobserver variability was pronounced between pathologists and for pathologists versus digital quantification when attempting to estimate a precise value of the Ki-67 LI. Ki-67 LI should therefore be used with caution and should not be over interpreted in the grading of gliomas. Digital quantification of Ki-67 LI in gliomas was feasible, but intra- and interlaboratory robustness need to be determined.

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.

Transferrin receptor-1 and ferritin heavy and light chains in astrocytic brain tumors: Expression and prognostic value.

Astrocytic brain tumors are the most frequent primary brain tumors. Treatment with radio- and chemotherapy has increased survival making prognostic biomarkers increasingly important. The aim of the present study was to investigate the expression and prognostic value of transferrin receptor-1 (TfR1) as well as ferritin heavy (FTH) and light (FTL) chain in astrocytic brain tumors. A cohort of 111 astrocytic brain tumors (grade II-IV) was stained immunohistochemically with antibodies against TfR1, FTH, and FTL and scored semi-quantitatively. Double-immunofluorescence stainings were established to determine the phenotype of cells expressing these markers. We found that TfR1, FTH, and FTL were expressed by tumor cells in all grades. TfR1 increased with grade (p<0.001), but was not associated with prognosis in the individual grades. FTH and FTL were expressed by tumor cells and cells with microglial/macrophage morphology. Neither FTH nor FTL increased with malignancy grade, but low FTH expression by both tumor cells (p = 0.03) and microglia/macrophages (p = 0.01) correlated with shorter survival in patients anaplastic astrocytoma. FTL-positive microglia/macrophages were frequent in glioblastomas, and high FTL levels correlated with shorter survival in the whole cohort (p = 0.01) and in patients with anaplastic astrocytoma (p = 0.02). Double-immunofluorescence showed that TfR1, FTH, and FTL were co-expressed to a limited extent with the stem cell-related marker CD133. FTH and FTL were also co-expressed by IBA-1-positive microglia/macrophages. In conclusion, TfR1 was highly expressed in glioblastomas and associated with shorter survival in the whole cohort, but not in the individual malignancy grades. Low levels of FTH-positive tumor cells and microglia/macrophages were associated with poor survival in anaplastic astrocytomas, while high amounts of FTL-positive microglia/macrophages had a negative prognostic value. The results suggest that regulation of the iron metabolism in astrocytic brain tumors is complex involving both autocrine and paracrine signaling.

Cabazitaxel Versus Docetaxel As First-Line Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer: A Randomized Phase III Trial-FIRSTANA.

Purpose In patients with metastatic castration-resistant prostate cancer (mCRPC), overall survival (OS) is significantly improved with cabazitaxel versus mitoxantrone after prior docetaxel treatment. FIRSTANA ( ClinicalTrials.gov identifier: NCT01308567) assessed whether cabazitaxel 20 mg/m2 (C20) or 25 mg/m2 (C25) is superior to docetaxel 75 mg/m2 (D75) in terms of OS in patients with chemotherapy-naïve mCRPC. Patients and Methods Patients with mCRPC and Eastern Cooperative Oncology Group performance status of 0 to 2 were randomly assigned 1:1:1 to receive C20, C25, or D75 intravenously every 3 weeks plus daily prednisone. The primary end point was OS. Secondary end points included safety; progression-free survival (PFS); tumor, prostate-specific antigen, and pain response; pharmacokinetics; and health-related quality of life. Results Between May 2011 and April 2013, 1,168 patients were randomly assigned. Baseline characteristics were similar across cohorts. Median OS was 24.5 months with C20, 25.2 months with C25, and 24.3 months with D75. Hazard ratio for C20 versus D75 was 1.01 (95% CI, 0.85 to 1.20; P = .997), and hazard ratio for C25 versus D75 was 0.97 (95% CI, 0.82 to 1.16; P = .757). Median PFS was 4.4 months with C20, 5.1 months with C25, and 5.3 months with D75, with no significant differences between treatment arms. Radiographic tumor responses were numerically higher for C25 (41.6%) versus D75 (30.9%; nominal P = .037, without multiplicity test adjustment). Rates of grade 3 or 4 treatment-emergent adverse events were 41.2%, 60.1%, and 46.0% for C20, C25, and D75, respectively. Febrile neutropenia, diarrhea, and hematuria were more frequent with C25; peripheral neuropathy, peripheral edema, alopecia, and nail disorders were more frequent with D75. Conclusion C20 and C25 did not demonstrate superiority for OS versus D75 in patients with chemotherapy-naïve mCRPC. Tumor response was numerically higher with C25 versus D75; pain PFS was numerically improved with D75 versus C25. Cabazitaxel and docetaxel demonstrated different toxicity profiles, with overall less toxicity with C20.

Late urinary morbidity and quality of life after radical prostatectomy and salvage radiotherapy for prostate cancer.

OBJECTIVE: There is a paucity of knowledge of long-term urinary morbidity in patients treated for prostate cancer (PCa) with radical prostatectomy (RP) and salvage radiotherapy (SRT). Improved long-term survival calls for heightened awareness of late effects from radiotherapy after RP. The purpose of this study was to assess late urinary morbidity and its potential impact on quality of life (QoL) in patients treated with RP plus SRT compared with patients treated with RP alone. MATERIALS AND METHODS: Long-term morbidity and QoL were evaluated using a cross-sectional design with validated questionnaires in urinary morbidity [Danish Prostatic Symptom Score (DAN-PSS)] and QoL [European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)]. Included were a total of 227 patients treated with SRT and 192 treated with RP in the periods 2006-2010 and 2005-2007, respectively. RESULTS: Weak stream, straining, frequency and nocturia were significantly more prevalent in patients treated with RP + SRT than in patients treated with RP alone. Patients treated with RP + SRT generally suffered from more severe urinary symptoms. The QoL scores of the two treatment groups were not statistically significantly different, but a high level of urinary morbidity was significantly related to decreased QoL (p = 0.000). CONCLUSIONS: Patients treated with SRT have a higher rate of urinary morbidity than do patients treated with RP alone. Severe urinary morbidity was significantly related to decreased QoL, but did not differ between the two treatment groups.

Expression and prognostic value of JAM-A in gliomas.

Gliomas are among the most lethal cancers, being highly resistant to both chemo- and radiotherapy. The expression of junctional adhesion molecule-A (JAM-A) was recently identified on the surface of stem cell-like brain tumor-initiating cells and suggested to function as a unique glioblastoma niche adhesion factor influencing the tumorigenic potential of brain tumor-initiating cells. We have recently identified high JAM-A expression to be associated with poor outcome in glioblastomas, and our aim was to further investigate the expression of JAM-A in gliomas focusing especially on the prognostic value in WHO grade II and III gliomas. JAM-A protein expression was evaluated by immunohistochemistry and advanced quantitative image analysis with continuous estimates of staining intensity. The JAM-A antibody stained tumor cell membranes and cytoplasm to various extent in different glioma subtypes, and the intensity was higher in glioblastomas than low-grade gliomas. We could not detect an association with overall survival in patients with grade II and III tumors. Double-immunofluorescence stainings in glioblastomas revealed co-expression of JAM-A with CD133, SOX2, nestin, and GFAP in tumor cells as well as some co-expression with the microglial/macrophage marker IBA-1. In conclusion, JAM-A expression was higher in glioblastomas compared to low-grade gliomas and co-localized with recognized stem cell markers suggesting an association of JAM-A with glioma aggressiveness. No significant association between JAM-A expression and overall survival was found in grade II and III gliomas. Further research is needed to determine the function and clinical impact of JAM-A in gliomas.

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial.

INTRODUCTION: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ. PATIENTS AND METHODS: Patients, after surgery for GBM or AA, age ≤60 years and performance status (PS) 0-2, were randomized to either 2-3 cycles of TMZ, 200 mg/m2 days 1-5 every 28 days, followed by RT 60 Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75 mg/m2 was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety. RESULTS: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24-60) and 89 (62%) were male. PS was 0-1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p = .76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p = .022). For patients with GBM, no difference in survival was observed (p = .10). MGMT and IDH status affected outcome. CONCLUSIONS: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.