MRI Assessment of Changes in Tumor Vascularization during Neoadjuvant Anti-Angiogenic Treatment in Locally Advanced Breast Cancer Patients.

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 radiogenomics reveals proliferative gene expression programs associated with distinct MRI-based hypoxia levels.

BACKGROUND AND PURPOSE: The biology behind individual hypoxia levels in patient tumors is poorly understood. Here, we used radiogenomics to identify associations between magnetic resonance imaging (MRI)-based hypoxia levels and biological processes derived from gene expression data in prostate cancer. MATERIALS AND METHODS: For 85 prostate cancer patients, MRI-based hypoxia images were constructed by combining diffusion-weighted images reflecting oxygen consumption and supply. The ability to differentiate hypoxia levels in these images was verified by comparison with matched biopsy sections stained for the hypoxia marker pimonidazole. For MRI-defined hypoxia levels, corresponding hypoxic fractions were calculated and correlated with biopsy gene expression profiles. Biological processes were predicted by gene set enrichment analysis (GSEA) and validated by immunohistochemistry (Ki67 proliferation marker, reactive stroma grade) and RT-PCR (MYC). RESULTS: Genes with correlation between expression level and hypoxic fraction were identified for 56 MRI-based hypoxia levels. At all levels, GSEA identified proliferation as the predominant biological process enriched among the correlating genes. Two independent proliferative gene signatures were developed. The Peak1 signature, upregulated at moderate/severe hypoxia, reflected MYC upregulation and high Ki67-proliferation index of cancer cells in pimonidazole-positive regions. The Peak2 signature, upregulated at mild to non-hypoxic levels, was associated with fibroblast gene signature and reactive stroma grade. High scores of both Peak1 and Peak2 indicated elevated risk of biochemical recurrence in multiple cohorts. CONCLUSION: Radiogenomics identified two gene expression programs activated at different hypoxia levels, reflecting proliferation of cancer cells and stroma cells. Genes involved in these programs could be candidate targets for intervention.

Monoparametric high-resolution diffusion weighted MRI as a possible first step in an MRI-directed diagnostic pathway for men with suspicion of prostate cancer.

Purpose: To explore if a high-resolution diffusion weighted MRI sequence (DWI-only) could be used as a first step in an MRI-directed diagnostic pathway. Methods: Prospective single center study that between December 2017 and August 2018 included 129 consecutive patients with suspicion of prostate cancer into a PI-RADS-based MRI-directed diagnostic pathway. All patients had multiparametric MRI (mpMRI). Based on only the transversal high-resolution DWI images two consultant radiologists prospectively categorized the findings as positive, equivocal, or negative for clinically significant cancer. The radiologists then interpreted the mpMRI and assigned a PI-RADS score. A third independent reader retrospectively categorized the DWI-only exams without access to the mpMRI. The interpretations of DWI-only were compared to the PI-RADS classification from mpMRI and the histopathology from the biopsies. Non-biopsied patients were followed in a safety net monitoring for 56 months. Results: Based on DWI-only, 29 (22.5%) of the exams were categorized as negative, 38 (29.5%) as equivocal and 62 (48.1%) as positive. Of the 56 patients with PI-RADS 4-5 at mpMRI, 55 were also categorized as positive at DWI-only. All patients diagnosed with clinically significant cancer were identified using DWI-only. 56 months of safety net monitoring did not reveal any clinically significant cancers among patients with exams categorized as negative or equivocal. There was high inter-reader agreement on positive findings, but less agreement on negative and equivocal findings. Conclusions: In this concept study, the monoparametric DWI-only identified all patients with clinically significant cancer in a mpMRI-directed diagnostic pathway.

Impact of human telomerase reverse transcriptase peptide vaccine combined with androgen deprivation therapy and radiotherapy in de novo metastatic prostate cancer: Long-term clinical monitoring.

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.

Prognostic significance of conventional and volumetric PET parameters with and without partial volume correction in the assessment of head and neck squamous cell carcinoma.

BACKGROUND: The optimal quantification of PET in assessment of head and neck squamous cell carcinoma (HNSCC) is still under development. The effect of partial volume correction (PVC) on the evaluation of survival in the HNSCC patients has not been investigated yet. METHODOLOGY: Pretreatment 18F-FDG-PET/CT scans of a selected group of 57 patients with advanced stage HNSCC were collected. Conventional (SUVmean and SUVmax) and volumetric [total lesion glycolysis (TLG) and metabolic tumor volume (MTV)] PET metrics were calculated. The ROVER software (ABX GmbH, Radeberg, Germany) automatically applied PVC to the PET metrics. Cox proportional hazards regression model calculated hazard ratio (HR) for assessment of predictive parameters of progression-free survival (PFS). RESULTS: In multivariate Cox regression analysis, including age, gender, race, human papillomavirus status, and stage, the only significant predictors of PFS were the volumetric PET parameters (TLG: HR, 1.003; 95% CI, 1.001-1.005; P = 0.02), pvcTLG (HR, 1.002; 95% CI, 1.001-1.004; P = 0.01) and MTV (HR, 1.050; 95% CI, 1.024-1.077; P < 0.01). The partial volume-corrected values were significantly higher than the noncorrected values (Wilcoxon sign test; P < 0.05). However, there was not a statistically significant difference between the nonpartial volume corrected and partial volume-corrected PET metrics for assessment of PFS. CONCLUSION: Volumetric PET metrics were predictors of PFS in Cox regression analysis. Applying PVC could not significantly improve the accuracy of PET metrics for assessment of PFS.

A Prospective Study of High Dose-Rate Brachytherapy or Stereotactic Body Radiotherapy of Intra-Prostatic Recurrence: Toxicity and Long Term Clinical Outcome.

Background: Up to half of patients with localized prostate cancer experience biochemical relapse within 10 years after definitive radiotherapy. The aim of this prospective study was to investigate the toxicity, dose to the organs at risk (OARs), and efficacy of dose-intensified focal salvage radiotherapy. Methods and Material: Thirty-three patients (median age 68.8 years) with histologically confirmed relapse after primary definitive radiotherapy were enrolled between 2012 and 2019. No patients had metastases at imaging or in bone marrow aspiration. Twenty-three patients were treated with high dose-rate brachytherapy to the recurrent tumor, defined at multiparametric MRI, with 3 fractions of 10 Gy with two weeks interval, and 10 patients by stereotactic body radiotherapy with 35 Gy to the local recurrence and 25 Gy to the whole prostate in 5 fractions. We used the RTOG-scoring system to grade genitourinary (GU) and gastrointestinal toxicity (GI) at three months (acute), and at 12, 24, and 36 months (late). Dose-volume histogram parameters to the local recurrence and the OARs were obtained and 2 Gy equivalent (EQD2) total dose was calculated using the linear-quadratic model with α/ß = 3 Gy. Efficacy was assessed by the progression-free interval and overall survival. Results: Median follow-up time was 81 months (range 21-115). The cumulative moderate to severe GI and GU toxicities were 3.0% (1/33) and 15.2% (5/33). Six patients had grade 1 acute GI toxicity, none had grade 2 or 3. One patient had grade 3 acute GU toxicity, two had grade 2, and fourteen had grade 1. One patient had late GI toxicity grade 2 and eight had grade 1. Four patients had late GU toxicity grade 2 and eight had grade 1. No patients had grade 3 late toxicity. The mean total D90 to the recurrent tumor was 77.7 ± 17.0 Gy. The mean total rectum D2cc was 17.0 ± 7.9 Gy and the mean total urethra D0.1cc was 29.1 ± 8.2 Gy. Twenty-eight patients had re-irradiation without androgen deprivation therapy (ADT). Nine of these are still relapse-free and 10 had a recurrence-free interval longer than 2 years. Conclusion: The toxicity of salvage radiotherapy was mild to moderate. One-third of the patients achieved long-term stable disease without ADT and one-third had a recurrence-free interval longer than 2 years. Some patients progressed rapidly and probably did not benefit from re-irradiation.

Quantification of Tumor Hypoxia through Unsupervised Modelling of Consumption and Supply Hypoxia MR Imaging in Breast Cancer.

The purpose of the present study is to investigate if consumption and supply hypoxia (CSH) MR-imaging can depict breast cancer hypoxia, using the CSH-method initially developed for prostate cancer. Furthermore, to develop a generalized pan-cancer application of the CSH-method that doesn't require a hypoxia reference standard for training the CSH-parameters. In a cohort of 69 breast cancer patients, we generated, based on the principles of intravoxel incoherent motion modelling, images reflecting cellular density (apparent diffusion coefficient; ADC) and vascular density (perfusion fraction; fp). Combinations of the information in these images were compared to a molecular hypoxia score made from gene expression data, aiming to identify a way to apply the CSH-methodology in breast cancer. Attempts to adapt previously proposed models for prostate cancer included direct transfers and model parameter rescaling. A novel approach, based on rescaling ADC and fp data to give more nuanced response in the relevant physiologic range, was also introduced. The new CSH-method was validated in a prostate cancer cohort with known hypoxia status. The proposed CSH-method gave estimates of hypoxia that was strongly correlated to the molecular hypoxia score in breast cancer, and hypoxia as measured in pathology slices stained with pimonidazole in prostate cancer. The generalized approach to CSH-imaging depicted hypoxia in both breast and prostate cancers and requires no model training. It is easy to implement using readily available technology and encourages further investigation of CSH-imaging in other cancer entities and in other settings, with the goal being to overcome hypoxia-induced resistance to treatment.

A prognostic hypoxia gene signature with low heterogeneity within the dominant tumour lesion in prostate cancer patients.

BACKGROUND: Gene signatures measured in a biopsy have been proposed as hypoxia biomarkers in prostate cancer. We assessed a previously developed signature, and aimed to determine its relationship to hypoxia and its heterogeneity within the dominant (index) lesion of prostate cancer. METHODS: The 32-gene signature was assessed from gene expression data of 141 biopsies from the index lesion of 94 patients treated with prostatectomy. A gene score calculated from the expression levels was applied in the analyses. Hypoxic fraction from pimonidazole immunostained whole-mount and biopsy sections was used as reference standard for hypoxia. RESULTS: The gene score was correlated with pimonidazole-defined hypoxic fraction in whole-mount sections, and the two parameters showed almost equal association with clinical markers of tumour aggressiveness. Based on the gene score, incorrect classification according to hypoxic fraction in whole-mount sections was seen in one third of the patients. The incorrect classifications were apparently not due to intra-tumour heterogeneity, since the score had low heterogeneity compared to pimonidazole-defined hypoxic fraction in biopsies. The score showed prognostic significance in uni-and multivariate analysis in independent cohorts. CONCLUSIONS: Our signature from the index lesion reflects tumour hypoxia and predicts prognosis in prostate cancer, independent of intra-tumour heterogeneity in pimonidazole-defined hypoxia.

Multimodal functional imaging for early response assessment in patients with gastrointestinal stromal tumor treated with tyrosine kinase inhibitors.

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).

MRI-based automatic segmentation of rectal cancer using 2D U-Net on two independent cohorts.

BACKGROUND: 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 tissue properties that may be valuable for tumor delineation. We explored MRI-based automatic segmentation of rectal cancer using a deep learning (DL) approach. We first investigated potential improvements when including both anatomical T2-weighted (T2w) MRI and diffusion-weighted MR images (DWI). Secondly, we investigated generalizability by including a second, independent cohort. MATERIAL AND METHODS: Two cohorts of rectal cancer patients (C1 and C2) from different hospitals with 109 and 83 patients, respectively, were subject to 1.5 T MRI at baseline. T2w images were acquired for both cohorts and DWI (b-value of 500 s/mm2) for patients in C1. Tumors were manually delineated by three radiologists (two in C1, one in C2). A 2D U-Net was trained on T2w and T2w + DWI. Optimal parameters for image pre-processing and training were identified on C1 using five-fold cross-validation and patient Dice similarity coefficient (DSCp) as performance measure. The optimized models were evaluated on a C1 hold-out test set and the generalizability was investigated using C2. RESULTS: For cohort C1, the T2w model resulted in a median DSCp of 0.77 on the test set. Inclusion of DWI did not further improve the performance (DSCp 0.76). The T2w-based model trained on C1 and applied to C2 achieved a DSCp of 0.59. CONCLUSION: T2w MR-based DL models demonstrated high performance for automatic tumor segmentation, at the same level as published data on interobserver variation. DWI did not improve results further. Using DL models on unseen cohorts requires caution, and one cannot expect the same performance.

Localization of primary prostate cancer: FACBC PET/CT compared with multiparametric MRI using histopathology as reference standard.

FACBC (anti-1-amino-3-18F-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 (mpMRI) using whole-mount histopathology as reference standard. Twenty-three patients with biopsy-proven prostate cancer had FACBC PET/CT and mpMRI within two weeks prior to prostatectomy. FACBC PET/CT was acquired as 14 minutes list-mode and re-binned 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 mpMRI is better for localizing the index tumor in patients with prostate cancer.

Amino acid transporter expression and 18F-FACBC uptake at PET in primary 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.

Results from a PI-RADS-based MRI-directed diagnostic pathway for biopsy-naive patients in a non-university hospital.

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.

Prostate-Specific Membrane Antigen PET for Assessment of Primary and Recurrent Prostate Cancer with Histopathology as Reference Standard: A Systematic Review and Meta-Analysis.

Prostate-specific membrane antigen PET is a promising diagnostic tool in prostate cancer. The gold standard for the detection of prostate tumor and lymph node metastases is histopathology. The aim of the present review was to investigate accuracy measures of 68Ga/18F-labeled prostate-specific membrane antigen PET tracers in primary and recurrent prostate cancer with systematic sector-based histopathology as the reference standard. A systematic literature search was performed and 34 studies were included. Overall, prostate-specific membrane antigen PET showed high specificity, but variable sensitivity to localize known prostate cancer and detect pelvic lymph node metastases.

18F-Fluciclovine PET for Assessment of Prostate Cancer with Histopathology as Reference Standard: A Systematic Review.

The PET tracer 18F-fluciclovine (Axumin) was recently approved in the United States and Europe for men with suspected prostate cancer recurrence following prior treatment. This article summarizes studies where systematic sector-based histopathology was used as reference standard to assess the diagnostic accuracy of the tracer 18F-fluciclovine PET in patients with prostate cancer.

Impact of radiation dose on recurrence in high-risk prostate cancer patients.

BACKGROUND: Dose escalated radiation therapy (RT) combined with long-term androgen deprivation therapy (ADT) is a standard of care option for men with high-risk and locally advanced prostate cancer (PCa). However, the optimal dose of escalated RT and ADT is not known. Here we assessed the impact of radiation dose and length of ADT on biochemical recurrence in a multi-institutional cohort stratified by the Cambridge prognostic group (CPG). We hypothesized that radiation dose and length of ADT would impact outcome in similar risk groups of our patients. METHODS: Two-hundred and forty-four patients were included, 132 from Oslo University Hospital, Department of Oncology and 112 from Johns Hopkins Hospital, Department of Radiation Oncology. Biochemical recurrence was defined as prostate-specific antigen (PSA) nadir +2 ng/mL. Time to recurrence was estimated using Kaplan-Meier analysis and when stratified by CPG the log-rank test was used. Cox regression analysis was performed to identify factors associated with risk of recurrence. Site of recurrence was investigated. RESULTS: The median follow-up time was 7.4 years. The vast majority (71%) of patients were classified as high-risk (CPG 4) or very high-risk features (CPG 5). Significantly more PSA recurrences occurred in CPG 5 (41%) compared with CPG 4 (25%) (P = .04) and five-year cumulative recurrence-free survival was lower for CPG 4 and 5 (89% and 68%) compared with CPG 1, 2, and 3 (100%, 100%, and 93%). The recurrence-free survival for CPG 5 was significantly higher for prostate irradiation of 80 Gy as compared with 74 Gy (P = .011). For CPG 4 and 5 no local recurrences were detected in patients receiving 80 Gy. On stepwise Cox regression analysis neither age nor length of ADT were independent prognostic factors for recurrence free survival. CONCLUSION: Prostate dose escalation from 74 to 80 Gy decreases risk of recurrence in high-risk PCa. Further studies are needed to identify the optimal combination of ADT and RT.

Immunogenic cell death by neoadjuvant oxaliplatin and radiation protects against metastatic failure in high-risk rectal cancer.

OBJECTIVE: High rates of systemic failure in locally advanced rectal cancer call for a rational use of conventional therapies to foster tumor-defeating immunity. METHODS: We analyzed the high-mobility group box-1 (HMGB1) protein, a measure of immunogenic cell death (ICD), in plasma sampled from 50 patients at the time of diagnosis and following 4 weeks of induction chemotherapy and 5 weeks of sequential chemoradiotherapy, both neoadjuvant modalities containing oxaliplatin. The patients had the residual tumor resected and were followed for long-term outcome. RESULTS: Patients who met the main study end point-freedom from distant recurrence-showed a significant rise in HMGB1 during the induction chemotherapy and consolidation over the chemoradiotherapy. The higher the ICD increase, the lower was the metastatic failure risk (hazard ratio 0.26, 95% confidence interval 0.11-0.62, P = 0.002). However, patients who received the full-planned oxaliplatin dose of the chemoradiotherapy regimen had poorer metastasis-free survival (P = 0.020) than those who had the oxaliplatin dose reduced to avert breach of the radiation delivery, which is critical to maintain efficient tumor cell kill and in the present case, probably also protected the ongoing radiation-dependent ICD response from systemic oxaliplatin toxicity. CONCLUSION: The findings indicated that full-dose induction oxaliplatin followed by an adapted oxaliplatin dose that was compliant with full-intensity radiation caused induction and maintenance of ICD and as a result, durable disease-free outcome for a patient population prone to metastatic progression.

Inter-reader agreement of 18F-FDG PET/CT for the quantification of carotid artery plaque inflammation.

INTRODUCTION: A significant proportion of ischemic strokes are caused by emboli from unstable atherosclerotic carotid artery plaques. Inflammation is a key feature of plaque instability. Positron emission tomography/computed tomography (PET/CT) with 2-deoxy-2-(18F)-fluoro-D-glucose (18F-FDG) is a promising technique to quantify plaque inflammation, but a consensus on the methodology has not been established. High inter-reader agreement is essential if 18F-FDG PET/CT is to be used as a clinical tool for the assessment of unstable plaques and stroke risk. METHODS: We assessed the inter-reader variability of different methods for quantification of 18F-FDG uptake in 43 patients with carotid artery stenosis ≥70%. Two independent readers delineated the plaque and collected maximum standardized uptake value (SUVmax) from all axial PET slices containing the atherosclerotic plaque. RESULTS: Uptake values with and without background correction were calculated and intraclass correlation coefficients were highest for uncorrected uptake values (0.97-0.98) followed by those background corrected by subtraction (0.89-0.94) and lowest for those background corrected by division (0.74-0.79). CONCLUSION: Quantification methods without background correction have the highest inter-reader agreement for 18F-FDG PET of carotid artery plaque inflammation. The use of the single highest uptake value (max SUVmax) from the plaque will facilitate the method's clinical utility in stroke prevention.

Sex-related differences in primary metastatic site in rectal cancer; associated with hemodynamic factors?

BACKGROUND AND PURPOSE: We investigated how features relating to pelvic cavity anatomy and tumor hemodynamic factors may influence systemic failure in rectal cancer. MATERIALS AND METHODS: Rectal cancer patients (207 women, 343 men), who had been prospectively enrolled onto six cohorts and given curative-intent therapy, were analyzed for the first metastatic event. In one of the cohorts, the diameter of the inferior mesenteric vein (IMV) was assessed on diagnostic abdominal computed tomography images (n = 113). Tumor volume (n = 193) and histologic response to neoadjuvant therapy (n = 445) were recorded from diagnostic magnetic resonance images and surgical specimens, respectively. RESULTS: More women than men developed lung metastasis (p = 0.037), while the opposite was the case for liver metastasis (p = 0.040). Wider IMV diameter correlated with larger tumor volume (r = 0.481, p < 0.001) and male sex (p < 0.001). Female sex was the only adverse prognostic factor for lung metastasis. When sex, tumor volume, and histologic response were taken into consideration, poor tumor response remained the only determinant for liver metastasis (p = 0.002). CONCLUSIONS: In a diverse rectal cancer population given curative-intent treatment, women and men had different outcome with regard to the primary metastatic site. Tumor hemodynamic factors should be considered in rectal cancer risk stratification.

Toward Personalized Computer Simulation of Breast Cancer Treatment: A Multiscale Pharmacokinetic and Pharmacodynamic Model Informed by Multitype Patient Data.

The usefulness of mechanistic models to disentangle complex multiscale cancer processes, such as treatment response, has been widely acknowledged. However, a major barrier for multiscale models to predict treatment outcomes in individual patients lies in their initialization and parametrization, which needs to reflect individual cancer characteristics accurately. In this study, we use multitype measurements acquired routinely on a single breast tumor, including histopathology, MRI, and molecular profiling, to personalize parts of a complex multiscale model of breast cancer treated with chemotherapeutic and antiangiogenic agents. The model accounts for drug pharmacokinetics and pharmacodynamics. We developed an open-source computer program that simulates cross-sections of tumors under 12-week therapy regimens and used it to individually reproduce and elucidate treatment outcomes of 4 patients. Two of the tumors did not respond to therapy, and model simulations were used to suggest alternative regimens with improved outcomes dependent on the tumor's individual characteristics. It was determined that more frequent and lower doses of chemotherapy reduce tumor burden in a low proliferative tumor while lower doses of antiangiogenic agents improve drug penetration in a poorly perfused tumor. Furthermore, using this model, we were able to correctly predict the outcome in another patient after 12 weeks of treatment. In summary, our model bridges multitype clinical data to shed light on individual treatment outcomes. SIGNIFICANCE: Mathematical modeling is used to validate possible mechanisms of tumor growth, resistance, and treatment outcome.