Therese Seierstad

Objectives: To explore if MRI can monitor treatment and predict outcome in patients with human epidermal growth factor 2 (HER2)-negative breast cancer receiving neoadjuvant chemotherapy (NACT) with or without bevacizumab. Methods: Multiparametric MRI was performed at baseline and after 12 and 25 weeks of NACT. MRI assessment included tumour size, apparent diffusion coefficient (ADC) from diffusion-weighted imaging (DWI), and signal intensity–time curves and vascular volume transfer constant (K^TRANS) from dynamic contrast-enhanced MRI (DCE). The reference standards were pathological complete response (pCR) at the time of surgery, and 10-year recurrence-free survival. Receiver operating characteristics analyses were performed to assess the predictive value of the MRI parameters. MRI findings and outcomes were compared between the treatment groups. Results: Seventy women were included from November 2008 to July 2012, with a median age of 49.5 years and median tumour diameter of 47 mm. Fourteen patients (20.0%) achieved pCR, while eleven (15.7%) had recurrence during the 10-year follow-up. The treatment significantly reduced tumour size, increased ADC, decreased K^TRANS, and shifted the signal intensity–time curves towards more benign shapes. The DCE parameters changed significantly more in the bevacizumab group. In the bevacizumab group, baseline K^TRANS predicted pCR (Area under curve (AUC) = 0.73), but the difference in pCR-rates between the treatment groups was not significant (p = 0.07). Only tumour size and shrinkage at 12 weeks predicted pCR (AUC = 0.71–0.85) regardless of size measuring method. No MRI parameters predicted survival. Conclusions: All MRI parameters reflected treatment response, but no parameter predicted survival or benefit from adding bevacizumab to chemotherapy.

Few studies have examined cognitive function in long-term survivors with brain metastases (BM). The aim of this study was to assess performance-based cognitive function and compare it with normative samples. Patients with ≥2-year survival after a first-time BM diagnosis completed neuropsychological tests assessing the following neurocognitive domains: processing speed, executive functioning, mental flexibility, visual learning and memory, verbal learning and memory, attention, and working memory. Test scores were converted into standardized z-scores using normative sample means and standard deviations (SD). The proportions of patients with an individual z-score of ≤−1 and ≤−1.5 SD below the normative sample means were calculated to indicate subclinical and clinically significant impairment. Forty-one patients (median age 58, 24 women) completed assessments at a median of 32 months (min–max: 26–47) after the BM diagnosis. On a group level, patients performed poorer than normative samples in tests within all domains except verbal learning and memory. The deviation was most pronounced in a subtest assessing mental flexibility. The proportion of patients with subclinical or clinically significant impairment ranged from 29% to 59% and 7% to 51% between domains, respectively. Seventy-three percent had at least subclinical and 59% had clinically significant impairment in at least 1 domain. Long-term survivors with BM performed poorer than normative samples within nearly all neurocognitive domains, particularly executive functioning and mental flexibility. This domain is important for daily living and social functioning, and clinicians should provide information about the implications of BM and tailor patient care to optimize functioning and quality of life.

Anti-VEGF (vascular endothelial growth factor) treatment improves response rates, but not progression-free or overall survival in advanced breast cancer. It has been suggested that subgroups of patients may benefit from this treatment; however, the effects of adding anti-VEGF treatment to a standard chemotherapy regimen in breast cancer patients are not well studied. Understanding the effects of the anti-vascular treatment on tumor vasculature may provide a selection of patients that can benefit. The aim of this study was to study the vascular effect of bevacizumab using clinical dynamic contrast-enhanced MRI (DCE-MRI). A total of 70 women were randomized to receive either chemotherapy alone or chemotherapy with bevacizumab for 25 weeks. DCE-MRI was performed at baseline and at 12 and 25 weeks, and in addition 25 of 70 patients agreed to participate in an early MRI after one week. Voxel-wise pharmacokinetic analysis was performed using semi-quantitative methods and the extended Tofts model. Vascular architecture was assessed by calculating the fractal dimension of the contrast-enhanced images. Changes during treatment were compared with baseline and between the treatment groups. There was no significant difference in tumor volume at any point; however, DCE-MRI parameters revealed differences in vascular function and vessel architecture. Adding bevacizumab to chemotherapy led to a pronounced reduction in vascular DCE-MRI parameters, indicating decreased vascularity. At 12 and 25 weeks, the difference between the treatment groups is severely reduced.

Prostate cancer is considered as poorly immunogenic. In a phase I/II study on de novo metastatic prostate cancer we found that a human telomerase reverse transcriptase (hTERT) vaccine induced an early immune response in most of the patients. Here we present the results from the long‐term monitoring of the immune responses and clinical outcomes. Twenty‐two men with ISUP 4 to 5 and lymph node and/or bone metastases were treated with androgen deprivation therapy (ADT), radiotherapy and the hTERT vaccine UV1 between January 2013 and July 2014. Immune response was monitored before, during and after vaccination and continued every 6 months until PSA progression. All patients had magnetic resonance imaging (MRI) at baseline, and after 6 months, 1 and 2 years, and at progression. The clinical outcome was time to progression, overall survival and prostate cancer‐specific survival. The median follow‐up was 62 months (range: 19‐101). At the last observation, nine of the 22 patients were still alive. Six have no progression, two have castration‐resistant disease treated with second‐line ADT and one has castration‐refractory disease. Median time to PSA progression was 21 months, median overall survival was 62 months and median prostate cancer‐specific survival was 84 months. Lack of immune response was an independent marker of prostate cancer death. The long‐term monitoring showed that some patients had unanticipated subsequent high immune responses without developing recurrence. This association indicates that there might be a clinical benefit of hTERT vaccination in a subgroup of men with primary metastatic hormone‐sensitive prostate cancer treated with ADT and radiotherapy.

Tumor delineation is time- and labor-intensive and prone to inter- and intraobserver variations. Magnetic resonance imaging (MRI) provides good soft tissue contrast, and functional MRI captures tis...

Purpose: To assess the safety and performance of a MRI-directed diagnostic pathway for patients with first-time suspicion of prostate cancer in a non-university hospital. Methods: Between May 2017 and December 2018 all biopsy-naive patients examined in our hospital followed a MRI-directed diagnostic work-up algorithm based on PI-RADS score. In short, PI-RADS 1–2 was generally not biopsied and PI-RADS 3–5 was reviewed by a multidisciplinary team. Patients with PI-RADS 4-5 were all referred to biopsy, either transrectal ultrasound-guided biopsy or MRI in-bore biopsy for small tumors and for sites difficult to access. PI-RADS scores were compared to the histopathology from biopsies and surgical specimens for patients who had prostatectomy. Non-biopsied patients were referred to a safety net monitoring regimen. Results: Two hundred and ninety-eight men were enrolled. 97 (33%) had PI-RADS 1–2, 44 (15%) had PI-RADS 3, and 157 (53%) had PI-RADS 4–5. 116 (39%) of the patients avoided biopsy. None of these were diagnosed with significant cancer within 2–3.5 years of safety net monitoring. Almost all high ISUP grade groups (≥ 3) were in the PI-RADS 4–5 category (98%). Prostatectomy specimens and systematic biopsies from MRI-negative areas indicated that very few clinically significant cancers were missed by the MRI-directed diagnostic pathway. Conclusion: Our findings add to evidence that a MRI-directed diagnostic pathway can be safely established in a non-university hospital. The pathway reduced the number of biopsies and reliably detected the site of the most aggressive cancers. Graphic

Background: Several imaging modalities are used in the early work-up of patients with gastrointestinal stromal tumor (GIST) receiving tyrosine kinase inhibitor (TKI) treatment and there is a need to establish whether they provide similar or complimentary information. Purpose: To compare 18F-fluorodeoxyglucose positron emission tomography (FDG PET), computed tomography (CT) and magnetic resonance imaging (MRI) as early predictors of three-month outcomes for patients with GIST receiving TKI treatment. Material and Methods: Thirty-five patients with advanced GIST were prospectively included between February 2011 and June 2017. FDG PET, contrast-enhanced CT (CECT), and MRI were performed before and early after onset of TKI treatment (range 8–18 days). Early response was categorized according to mRECIST (CT), the Choi criteria (CECT), and PERCIST (FDG PET/CT). For MRI, volumetry from T2-weighted images and change in apparent diffusion coefficient (ADC) from diffusion-weighted imaging was used. The reference standard for early assessment was the three-month mRECIST evaluation based on CT. At three months, both stable disease (SD) and partial response (PR) were categorized as response. Clinical usefulness was defined as agreement between early and three-month assessment. Results: At the three-month assessment, 91% (32/35) were responders, 37% (13/35) PR, 54% (19/35) SD, and 9% (3/35) had progressive disease (PD). Early assessment correctly predicted three-month response in 93% (27/29) for MRI, 80% (28/35) for PERCIST, 74% (26/35) for Choi, and 23% (8/35) for mRECIST. Six patients had non-FDG-avid tumors. For the FDG-avid tumors, PET/CT correctly predicted three-month response in 97% (28/29). Conclusion: MRI was superior to CECT for early assessment of TKI-treatment response in GIST. If the tumor was FDG-avid, PET and MRI were equally good. Changes in functional parameters were superior to changes in longest tumor diameter (mRECIST).

FACBC (anti-1-amino-3-F-18-fluorocyclobutane-1-carboxylic acid) is a FDA-approved PET-tracer in patients with suspected recurrent prostate cancer. In the diagnostic work-up of primary prostate cancer, accurate localization of the index tumor is needed for image-guidance of biopsies. We therefore assessed the performance of FACBC PET/CT to detect and localize the index tumor and compared it to multiparametric MRI (mpMRl) using whole-mount histopathology as reference standard. Twenty-three patients with biopsy-proven prostate cancer had FACBC PET/CT and mpMRl within two weeks prior to prostatectomy. FACBC PET/CT was acquired as 14 minutes list-mode and rebinned into seven 2-minutes intervals. Static FACBC was the acquired data from 4-6 minutes, whereas the dynamic FACBC included all seven intervals. Two radiologists and two nuclear medicine physicians independently interpreted the images and consensus was reached in case of discrepancy. Static PET detected 15 of 23 (65%) of the index tumors, dynamic PET detected 14 of 22 (64%), and MRI detected 20 of 23 (87%). To assess the extent of the tumor, the interpreters delineated the tumor in a 12 regions sector-based template. True positive, true negative, false positive and false negative sectors were recorded based on the template drawings and whole-mount histopathology. Both static and dynamic FACBC PET had sensitivity of 40% and specificity of 99%, whereas MRI had sensitivity of 81% and specificity of 100%. Our data indicate that FACBC PET/CT may be useful but that mpMRl is better for localizing the index tumor in patients with prostate cancer.

Little is known about the transport mechanism of anti-3-18F-fluorocyclobutane-1-carboxylic acid (FACBC) into prostate tumors. Because of the structural similarity to natural amino acids, FACBC is anticipated to cross the cell membrane via amino acid transporters, and preclinical studies have suggested that ASCT2, LAT1 and SNAT2 are involved. In 16 patients with intermediate or high-risk prostate cancer we matched the FACBC uptake from clinical PET to the location of punch biopsies from resected prostatectomy specimens and compared maximum standardized uptake value (SUVmax) with the gene expression of 40 amino acid transporters. The study also included immunohistochemistry for the three amino acid transporters ASCT2, LAT1 and SNAT2. Furthermore, we performed global gene expression analysis of the biopsies to investigate biological processes associated with FACBC uptake. Several amino acid transporters had a higher gene expression level than the others, but we found no significant correlations between SUVmax and the gene expression levels of any of 40 different amino acid transporters. In the immunohistochemical analyses, ASCT2 and SNAT2 were highly expressed, but not correlated to SUVmax. LAT1 had low gene- and protein expression. Global gene expression analyses identified 153 unique genes that were positively correlated to SUVmax. These genes were found to be associated with gene sets reflecting intracellular transport and high metabolic activity. Based on the study findings we propose that the uptake mechanism of FACBC is more complex than mediated by a few amino acid transporters.