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Purpose: The objective of this study was to present the 5-year results from a prospective, multicenter, phase 2 randomized trial of every-other-day (EOD) versus once-a-week (QW) urethra-sparing stereotactic body radiation therapy for localized prostate cancer. Methods and Materials: Between 2012 and 2015, 170 patients with cT1c-3aN0M0 prostate cancer from 9 European institutions were randomized to 36.25 Gy in 5 fractions (6.5 Gy/fraction to the urethra) delivered either EOD (arm A, n = 84) or QW (arm B, n = 86). The median follow-up was 78 months (interquartile range, 66-89 months) and 77 months (interquartile range, 66-82 months) for arms A and B, respectively. Results: Among the 165 patients treated and retained for the final analysis (arm A, n = 82; arm B, n = 83), acute toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 scale) was mild or absent, with no differences between arms. The 5-year grade 2 or greater genitourinary toxicity-free survival was 75.9% and 76.1% for arms A and B, respectively (P =.945), whereas the 5-year grade 2 or greater gastrointestinal toxicity-free survival was 89% and 92% for arms A and B, respectively (P =.596). No changes in European Organisation for Research and Treatment of Cancer QLQ-PR25 scores were observed in both arms for genitourinary, gastrointestinal, and sexual domains at 5-year follow-up compared with baseline. At the last follow-up, biochemical failure was observed in 14 patients in the EOD arm and in 7 patients in the QW arm, with a 5-year biochemical relapse-free survival rate of 92.2% and 93% for arms A and B, respectively (P =.13). Conclusions: Stereotactic body radiation therapy for prostate cancer with a 10% dose reduction to urethra was associated with a minimal effect on urinary function and quality of life regardless of an EOD or QW fractionation schedule. Biochemical control so far has been encouraging and much alike in both study arms, although longer follow-up is probably needed to assess the true value of overall treatment time on disease outcome.

Highlights • Distribution of recurrent HNSCC in relation to radiotherapy volume was evaluated. • Both p16 positive and negative HNSCC recur in high-risk treatment volume. • This indicates potential failure of multimodality imaging to disclose significant disease. • A need for biomarkers other than p16 to predict radiosensitivity continues to exist., Background Locoregional recurrence remains a major cause of failure in head and neck squamous cell carcinoma (HNSCC). Human papilloma virus (HPV)-associated HNSCCs generally have a good prognosis but may recur even after standard photon radiotherapy (RT). Another incentive in observing patterns of recurrence is increased use of highly conformal techniques such as proton therapy. We therefore studied geographic distribution of recurrent tumors in relation to the high-risk treatment volume in a cohort of patients with HNSCC receiving combined modality therapy. Methods Medical records of 508 patients diagnosed with HNSCC in 2010–2015 were reviewed. We identified a subgroup that had local and/or regional recurrence at hybrid positron emission tomography (PET)/computed tomography (CT) and/or magnetic resonance imaging (MRI). We adapted p16 as a surrogate marker for HPV-positivity and only patients with known p16 status were eligible for a detailed analysis where recurrent tumor was copied on the planning CT and the dose received by the recurrent tumor volume was determined using dose-volume histograms. Results Twenty-five patients who had received either cisplatin (n = 23) or cetuximab-enhanced (n = 2) RT were identified. 31 locoregional recurrent tumors were detected among 18 p16 negative and 7 p16 positive patients. Of recurrent tumors 14 (45%) were classified as in-field, 5 (16%) as marginal miss, and 12 (39%) as true miss. p16 positive patients had 4 in-field, 2 marginal, and 1 true miss. By contrast, p16 negative patients had 10 in-field, 3 marginal, and 11 true miss recurrences. Conclusions Both p16 positive and negative HNSCC recur in high-risk treatment volume despite the common view of high radiosensitivity of the former. Biomarkers predicting radioresistance should be characterized in p16 positive tumors before widely embarking on de-escalated CRT protocols. Another concern is how to decrease the number of true or marginal misses in p16 negative cases despite multimodality imaging-based target delineation.

The aim of this prospective single-institution clinical trial (NCT02002455) was to evaluate the potential of advanced post-processing methods for 18F-Fluciclovine PET and multisequence multiparametric MRI in the prediction of prostate cancer (PCa) aggressiveness, defined by Gleason Grade Group (GGG). 21 patients with PCa underwent PET/CT, PET/MRI and MRI before prostatectomy. DWI was post-processed using kurtosis (ADCk, K), mono- (ADCm), and biexponential functions (f, Dp, Df) while Logan plots were used to calculate volume of distribution (VT). In total, 16 unique PET (VT, SUV) and MRI derived quantitative parameters were evaluated. Univariate and multivariate analysis were carried out to estimate the potential of the quantitative parameters and their combinations to predict GGG 1 vs >1, using logistic regression with a nested leave-pair out cross validation (LPOCV) scheme and recursive feature elimination technique applied for feature selection. The second order rotating frame imaging (RAFF), monoexponential and kurtosis derived parameters had LPOCV AUC in the range of 0.72 to 0.92 while the corresponding value for VT was 0.85. The best performance for GGG prediction was achieved by K parameter of kurtosis function followed by quantitative parameters based on DWI, RAFF and 18F-FACBC PET. No major improvement was achieved using parameter combinations with or without feature selection. Addition of 18F-FACBC PET derived parameters (VT, SUV) to DWI and RAFF derived parameters did not improve LPOCV AUC.

Background To present the 18 months results from a prospective multicenter phase II randomized trial of short vs protracted urethra‐sparing stereotactic body radiotherapy (SBRT) for localized prostate cancer (PCa). Methods Between 2012 and 2015, a total of 170 PCa patients were randomized to 36.25 Gy in 5 fractions (6.5 Gy × 5 to the urethra) delivered either every other day (EOD, arm A, n = 84) or once a week (QW, arm B, n = 86). Genitourinary (GU) and gastrointestinal (GI) toxicity (CTCAE v4.0 scale), IPSS, and QoL scores were assessed at baseline, at the 5th fraction (5fx), 12th weeks (12W), and every 6 months after SBRT. The primary endpoint was biochemical control at 18 months and grade ≥ 3 toxicity (including grade ≥ 2 for urinary obstruction/retention) during the first 3 months. Results Among the 165 patients analyzed, the toxicity stopping rule was never activated during the acute phase. Maximum acute grade 2 GU toxicity rates at 5fx were 17% and 19% for arms A and B, respectively, with only 2 cases of grade 2 GI toxicity at 5fx in arm A. At month 18, grade ≥ 2 GU and GI toxicity decreased below 5% and 2% for both arms. No changes in EORTC QLQ‐PR25 scores for GU, GI, and sexual domains were observed in both arms between baseline and month 18. Four biochemical failures were observed, 2 in each arm, rejecting the null hypothesis of an unfavorable response rate ≤ 85% in favor of an acceptable ≥ 95% rate. Conclusions At 18 months, urethra‐sparing SBRT showed a low toxicity profile, with minimal impact on QoL and favorable biochemical control rates, regardless of overall treatment time (EOD vs QW)., Dose per fraction and overall treatment time can impact tolerance of prostate SBRT. Urethra‐sparing SBRT showed a low toxicity profile and minimal impact on QoL. An EOD or QW SBRT schedule had a comparable tolerance and efficacy at 18 months.

Purpose Radiation scattering from bone reconstruction materials can cause problems from prolonged healing to osteoradionecrosis. Glass fiber reinforced composite (FRC) has been introduced for bone reconstruction in craniofacial surgery but the effects during radiotherapy have not been previously studied. The purpose of this study was to compare the attenuation and back scatter caused by different reconstruction materials during radiotherapy, especially FRC with bioactive glass (BG) and titanium. Methods The effect of five different bone reconstruction materials on the surrounding tissue during radiotherapy was measured. The materials tested were titanium, glass FRC with and without BG, polyether ether ketone (PEEK) and bone. The samples were irradiated with 6 MV and 10 MV photon beams. Measurements of backscattering and dose changes behind the sample were made with radiochromic film and diamond detector dosimetry. Results An 18% dose enhancement was measured with a radiochromic film on the entrance side of irradiation for titanium with 6 MV energy while PEEK and FRC caused an enhancement of 10% and 4%, respectively. FRC‐BG did not cause any measurable enhancement. The change in dose immediately behind the sample was also greatest with titanium (15% reduction) compared with the other materials (0–1% enhancement). The trend is similar with diamond detector measurements, titanium caused a dose enhancement of up to 4% with a 1 mm sample and a reduction of 8.5% with 6 MV energy whereas FRC, FRC‐BG, PEEK or bone only caused a maximum dose reduction of 2.2%. Conclusions Glass fiber reinforced composite causes less interaction with radiation than titanium during radiotherapy and could provide a better healing environment after bone reconstruction.

Background In high-income countries, cancer is the leading cause of death among middle-aged adults. Prospective data on the effects of childhood risk exposures on subsequent cancer mortality are scarce. Methods We examined whether childhood body mass index (BMI), blood pressure, glucose and lipid levels were associated with adult cancer mortality, using data from 21,012 children enrolled aged 3–19 years in seven prospective cohort studies from the U.S., Australia, and Finland that have followed participants from childhood into adulthood. Cancer mortality (cancer as a primary or secondary cause of death) was captured using registries. Results 354 cancer deaths occurred over the follow-up. In age-, sex, and cohort-adjusted analyses, childhood BMI (Hazard ratio [HR], 1.13; 95% confidence interval [CI] 1.03–1.24 per 1-SD increase) and childhood glucose (HR 1.22; 95%CI 1.01–1.47 per 1-SD increase), were associated with subsequent cancer mortality. In a multivariable analysis adjusted for age, sex, cohort, and childhood measures of fasting glucose, total cholesterol, triglycerides, and systolic blood pressure, childhood BMI remained as an independent predictor of subsequent cancer mortality (HR, 1.24; 95%CI, 1.03–1.49). The association of childhood BMI and subsequent cancer mortality persisted after adjustment for adulthood BMI (HR for childhood BMI, 1.35; 95%CI 1.12–1.63). Conclusions Higher childhood BMI was independently associated with increased overall cancer mortality.

BackgroundSomatostatin receptors (SSTR) and chemokine receptor CXCR4 are expressed in lymphomas, while the abundance is known to be heterogeneous in different subtypes of lymphomas. Targeting tumor cells expressing these receptors might add to therapeutic opportunities while radiolabeled ligands for both imaging and therapy have been developed. The aim of this study was to establish SSTR subtype 2, 3 and 5 and also CXCR4 status immunohistochemically in six different lymphoma subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), mucosa-associated marginal B-cell lymphoma (MALT), Hodgkin lymphoma (HL) and peripheral T-cell lymphoma (PTCL).Material and MethodsThis study included a total of 103 lymphoma patients (24 DLBCL, 22 FL, 18 HL, 9 MALT, 20 MCL and 10 PTCL) diagnosed in the Southwest hospital district of Finland during 2010-2019. SSTR 2, 3 and 5 and CXCR4 expression was analyzed immunohistochemically (IHC) in lymphoma samples obtained from local archival Biobank tissue repository. Immunopositivity of each receptor was scored on a four-point scale accounting for staining intensity and proportion of positively stained tumor cells.ResultsOf different SSTR subtypes SSTR2 immunopositivity was most common and seen predominantly at the cell membrane of the malignant cells in 46-56% of DLBCL, HL and FL. CXCR4 co-expression was frequently present in these cases. SSTR3 and SSTR5 IHC were negative in DLBCL and FL but in HL SSTR expression was more heterogenous and SSTR3 and SSTR5 positivity was found in cytoplasm in 35% and 25% of cases. 2/4 blastoid MCL variants and one pleomorphic MCL variant had positive CXCR4 IHC whilst all other MCL cases (85%) were negative for all receptors. 30% (n=3) of the PTCL patients had positive SSTR5 IHC and CXCR4. MALT lymphomas were negative for all receptors.ConclusionSSTR2 and CXCR4 are found in DLBCL, FL and HL and co-expression of these receptors is common. Although in general expression of SSTRs and CXCR4 is heterogenous and very low in some subtypes such as MCL and MALT there are also patients with abundant expression. The latter are candidates for trials studying SSTR2 and/or CXCR4 based treatments in the future.

Background Persistent smoking after cancer diagnosis is associated with increased overall mortality (OM) and cancer mortality (CM). According to the 2020 Surgeon General's report, smoking cessation may reduce CM but supporting evidence is not wide. Use of deep learning-based modeling that enables universal natural language processing of medical narratives to acquire population-based real-life smoking data may help overcome the challenge. We assessed the effect of smoking status and within-1-year smoking cessation on CM by an in-house adapted freely available language processing algorithm. Materials and methods This cross-sectional real-world study included 29 823 patients diagnosed with cancer in 2009-2018 in Southwest Finland. The medical narrative, International Classification of Diseases-10th edition codes, histology, cancer treatment records, and death certificates were combined. Over 162 000 sentences describing tobacco smoking behavior were analyzed with ULMFiT and BERT algorithms. Results The language model classified the smoking status of 23 031 patients. Recent quitters had reduced CM [hazard ratio (HR) 0.80 (0.74-0.87)] and OM [HR 0.78 (0.72-0.84)] compared to persistent smokers. Compared to never smokers, persistent smokers had increased CM in head and neck, gastro-esophageal, pancreatic, lung, prostate, and breast cancer and Hodgkin's lymphoma, irrespective of age, comorbidities, performance status, or presence of metastatic disease. Increased CM was also observed in smokers with colorectal cancer, men with melanoma or bladder cancer, and lymphoid and myeloid leukemia, but no longer independently of the abovementioned covariates. Specificity and sensitivity were 96%/96%, 98%/68%, and 88%/99% for never, former, and current smokers, respectively, being essentially the same with both models. Conclusions Deep learning can be used to classify large amounts of smoking data from the medical narrative with good accuracy. The results highlight the detrimental effects of persistent smoking in oncologic patients and emphasize that smoking cessation should always be an essential element of patient counseling., Highlights • Deep learning/universal language modeling was used to extract smoking status of cancer patients. Good accuracy was observed. • Those who continue smoking after cancer diagnosis had increased CM compared to never smokers. • Recent within-1-year cessation reduced this mortality. • Detrimental effects of smoking were observed in multiple types of early- and advanced-stage cancers, including the elderly. • We conclude that smoking cessation support should always be included in cancer care.

Simple Summary Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is overexpressed in prostate cancer and correlates with the aggressiveness of the disease. PSMA is a promising target for imaging and therapeutics in prostate cancer patients validated in prospective trials. However, the role of PSMA in prostate cancer progression is poorly understood. In this review, we discuss the biology and scientific rationale behind the use of PSMA and other targets in the detection and theranostics of metastatic prostate cancer. Abstract Prostate cancer is the second most common cancer type in men globally. Although the prognosis for localized prostate cancer is good, no curative treatments are available for metastatic disease. Better diagnostic methods could help target therapies and improve the outcome. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed on malignant prostate tumor cells and correlates with the aggressiveness of the disease. PSMA is a clinically validated target for positron emission tomography (PET) imaging-based diagnostics in prostate cancer, and during recent years several therapeutics have been developed based on PSMA expression and activity. The expression of PSMA in prostate cancer can be very heterogeneous and some metastases are negative for PSMA. Determinants that dictate clinical responses to PSMA-targeting therapeutics are not well known. Moreover, it is not clear how to manipulate PSMA expression for therapeutic purposes and develop rational treatment combinations. A deeper understanding of the biology behind the use of PSMA would help the development of theranostics with radiolabeled compounds and other PSMA-based therapeutic approaches. Along with PSMA several other targets have also been evaluated or are currently under investigation in preclinical or clinical settings in prostate cancer. Here we critically elaborate the biology and scientific rationale behind the use of PSMA and other targets in the detection and therapeutic targeting of metastatic prostate cancer.

Purpose: To present the radiation therapy quality assurance results from a prospective multicenter phase 2 randomized trial of short versus protracted urethra-sparing stereotactic body radiation therapy (SBRT) for localized prostate cancer. Methods and Materials: Between 2012 and 2015, 165 patients with prostate cancer from 9 centers were randomized and treated with SBRT delivered either every other day (arm A, n = 82) or once a week (arm B, n = 83); 36.25 Gy in 5 fractions were prescribed to the prostate with (n = 92) or without (n = 73) inclusion of the seminal vesicles (SV), and the urethra planning-risk volume received 32.5 Gy. Patients were treated either with volumetric modulated arc therapy (VMAT; n = 112) or with intensity modulated radiation therapy (IMRT; n = 53). Deviations from protocol dose constraints, planning target volume (PTV) homogeneity index, PTV Dice similarity coefficient, and number of monitor units for each treatment plan were retrospectively analyzed. Dosimetric results of VMAT versus IMRT and treatment plans with versus without inclusion of SV were compared. Results: At least 1 major protocol deviation occurred in 51 patients (31%), whereas none was observed in 41. Protocol violations were more frequent in the IMRT group (P 98% (31.1 vs 30.8 Gy, P 2% (37.9 vs 38.7 Gy, P 50% (24.5% vs 33.5%, P =.0001). To achieve its goals volumetric modulated arc therapy required fewer monitor units than IMRT (2275 vs 3378, P 90% (9.1% vs 10.4%, P =.0003) and V80% (13.2% vs 15.7%, P =.0003). Conclusions: Protocol deviations with potential impact on tumor control or toxicity occurred in 31% of patients in this prospective clinical trial. Protocol deviations were more frequent with IMRT. Prospective radiation therapy quality assurance protocols should be strongly recommended for SBRT trials to minimize potential protocol deviations.

Background:Smoking cessation after a cancer diagnosis is associated with improved overall survival. Few studies have reported oncologists' cessation practice patterns, but differences between the curative and palliative settings have not been described. We aimed to study the oncologist's perceptions on patients' tobacco use, current practices and barriers to providing smoking cessation support, while distinguishing between treatment with curative (C) and palliative (P) intent. Methods:In 2019, an online 34-item survey was sent to approximately 6235 oncologists from 16 European countries. Responses were descriptively reported and compared by treatment setting. Results:Responses from 544 oncologists were included. Oncologists appeared to favour addressing tobacco in the curative setting more than in the palliative setting. Oncologists believe that continued smoking impacts treatment outcomes (C: 94%, P: 74%) and that cessation support should be standard cancer care (C: 95%, P: 63%). Most routinely assess tobacco use (C: 93%, P: 78%) and advise patients to stop using tobacco (C: 88%, P: 54%), but only 24% (P)-39% (C) routinely discuss medication options, and only 18% (P)-31% (C) provide cessation support. Hesitation to remove a pleasurable habit (C: 13%, P: 43%) and disbelieve on smoking affecting outcomes (C: 3%, P: 14%) were disparate barriers between the curative and palliative settings (p < 0.001), but dominant barriers of time, resources, education and patient resistance were similar between settings. Conclusion:Oncologists appear to favour addressing tobacco use more in the curative setting; however, they discuss medication options and/or provide cessation support in a minority of cases. All patients who report current smoking should have access to evidence-based smoking cessation support, also patients treated with palliative intent given their increasing survival.

Introduction The increased radioresistance of hypoxic cells compared to well-oxygenated cells is quantified by the oxygen enhancement ratio (OER). In this study we created a FLUKA Monte Carlo based tool for inclusion of both OER and relative biological effectiveness (RBE) in biologically weighted dose (ROWD) calculations in proton therapy and applied this to explore the impact of hypoxia. Methods The RBE-weighted dose was adapted for hypoxia by making RBE model parameters dependent on the OER, in addition to the linear energy transfer (LET). The OER depends on the partial oxygen pressure (pO2) and LET. To demonstrate model performance, calculations were done with spread-out Bragg peaks (SOBP) in water phantoms with pO2 ranging from strongly hypoxic to normoxic (0.01–30 mmHg) and with a head and neck cancer proton plan optimized with an RBE of 1.1 and pO2 estimated voxel-by-voxel using [18F]-EF5 PET. An RBE of 1.1 and the Rorvik RBE model were used for the ROWD calculations. Results The SOBP in water had decreasing ROWD with decreasing pO2. In the plans accounting for oxygenation, the median target doses were approximately a factor 1.1 lower than the corresponding plans which did not consider the OER. Hypoxia adapted target ROWDs were considerably more heterogeneous than the RBE1.1-weighted doses. Conclusion We realized a Monte Carlo based tool for calculating the ROWD. Read-in of patient pO2 and estimation of ROWD with flexibility in choice of RBE model was achieved, giving a tool that may be useful in future clinical applications of hypoxia-guided particle therapy.

Reimbursement is a key factor in defining which resources are made available to ensure quality, efficiency, availability, and access to specific health-care interventions. This Policy Review assesses publicly funded radiotherapy reimbursement systems in Europe. We did a survey of the national societies of radiation oncology in Europe, focusing on the general features and global structure of the reimbursement system, the coverage scope, and level for typical indications. The annual expenditure covering radiotherapy in each country was also collected. Most countries have a predominantly budgetary-based system. Variability was the major finding, both in the components of the treatment considered for reimbursement, and in the fees paid for specific treatment techniques, fractionations, and indications. Annual expenses for radiotherapy, including capital investment, available in 12 countries, represented between 4·3% and 12·3% (average 7·8%) of the cancer care budget. Although an essential pillar in multidisciplinary oncology, radiotherapy is an inexpensive modality with a modest contribution to total cancer care costs. Scientific societies and policy makers across Europe need to discuss new strategies for reimbursement, combining flexibility with incentives to improve productivity and quality, allowing radiation oncology services to follow evolving evidence.

// Aida Kiviniemi 1, 2 , Maria Gardberg 3 , Katri Kivinen 4 , Jussi P. Posti 5 , Ville Vuorinen 5 , Jussi Sipila 6, 7 , Melissa Rahi 5 , Matti Sankinen 5 and Heikki Minn 8 1 Department of Radiology, Medical Imaging Center of Southwest Finland, Turku University Hospital and University of Turku, Turku, Finland 2 Turku PET Center, Turku University Hospital and University of Turku, Turku, Finland 3 Department of Pathology, Turku University Hospital and University of Turku, Turku, Finland 4 TYKSLAB, Laboratory of Molecular Genetics, Turku University Hospital, Turku, Finland 5 Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital and University of Turku, Turku, Finland 6 Department of Neurology, North Karelia Central Hospital, Joensuu, Finland 7 Division of Clinical Neurosciences, Department of Neurology, Turku University Hospital and University of Turku, Turku, Finland 8 Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland Correspondence to: Aida Kiviniemi, email: aida.kiviniemi@utu.fi Keywords: glioma, somatostatin receptor, oligodendroglioma, IDH mutation, prognosis Received: February 20, 2017 Accepted: April 03, 2017 Published: April 13, 2017 ABSTRACT Somatostatin receptor subtype 2A (SSTR2A) is a potential therapeutic target in gliomas. Data on SSTR2A expression in different glioma entities, however, is particularly conflicting. Our objective was to characterize SSTR2A status and explore its impact on survival in gliomas classified according to the specific molecular signatures of the updated WHO classification. In total, 184 glioma samples were retrospectively analyzed for SSTR2A expression using immunohistochemistry with monoclonal antibody UMB-1. Double staining with CD68 was used to exclude microglia and macrophages from analyses. SSTR2A staining intensity and its localization in tumor cells was evaluated and correlated with glioma entities and survival. Diagnoses included 101 glioblastomas (93 isocitrate dehydrogenase (IDH) -wildtype, 3 IDH -mutant, 5 not otherwise specified (NOS)), 60 astrocytomas (22 IDH -wildtype, 37 IDH -mutant, 1 NOS), and 23 oligodendrogliomas (19 IDH -mutant and 1p/19q-codeleted, 4 NOS). SSTR2A expression significantly associated with oligodendrogliomas (79% SSTR2A positive) compared to IDH -mutant or IDH -wildtype astrocytomas (27% and 23% SSTR2A positive, respectively), and especially glioblastomas of which only 13% were SSTR2A positive ( p < 0.001, Fisher’s exact test). The staining pattern in glioblastomas was patchy whereas more homogeneous membranous and cytoplasmic staining was detected in oligodendrogliomas. Positive SSTR2A was related to longer overall survival in grade II and III gliomas (HR 2.7, CI 1.2–5.8, p = 0.013). In conclusion, SSTR2A expression is infrequent in astrocytomas and negative in the majority of glioblastomas where it is of no prognostic significance. In contrast, oligodendrogliomas show intense membranous and cytoplasmic SSTR2A expression, which carries potential diagnostic, prognostic, and therapeutic value.

Purpose To evaluate the expression of alanine-serine-cysteine-transporter 2 (ASCT2) and L-type amino acid transporter1 (LAT1) in prostate cancer (PCa) and their impact on uptake of 18F-1-amino-3-fluorocyclobutane-1-carboxylic acid (18F-fluciclovine) which is approved for the detection of recurrent PCa. Methods Twenty-five hormone-naïve patients with histologically confirmed PCa underwent PET/CT before prostatectomy. Dynamic imaging was performed immediately after injection of 368 ± 10 MBq of 18F-fluciclovine and the uptake in PCa was expressed as SUVmax at six sequential 4-min time frames and as tracer distribution volume (V T) using Logan plots over 0–24 min. The expression of ASCT2 and LAT1 was studied with immunohistochemistry (IHC) on a tissue microarray (TMA) containing three cores per carcinoma lesion. The TMA slides were scored independently by two trained readers based on visual intensity of ASCT2/LAT1 expression on a four-tiered scale. The correlations between ASCT2/LAT1 staining intensity, SUVmax/V T, and Gleason grade group (GGG) were assessed using Spearman’s rank correlation coefficient (ρ). Results Forty tumor foci (> 0.5 mm in diameter, max. 3 per patient) were available for TMA. In visual scoring, low, moderate, and high staining intensity of ASCT2 was observed in 4 (10%), 24 (60%), and 12 (30%) tumors, respectively. No tumors showed high LAT1 staining intensity while moderate intensity was found in 10 (25%), 25 (63%) showed low, and the remaining 5 (12%) were negative for staining with LAT1. Tumors with GGG > 2 showed significantly higher uptake of 18F-fluciclovine and higher LAT1 staining intensity (p

Background To evaluate the accuracy of 11C-acetate Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) in bladder cancer (BC) staging and monitoring response to neoadjuvant chemotherapy (NAC). Methods Eighteen patients were prospectively enrolled. Fifteen treatment naive patients underwent 11C-acetate PET/MRI before transurethral resection of bladder tumor (TUR-BT) for primary tumor evaluation. Five patients with muscle invasive BC were imaged after NAC and prior to radical cystectomy (RC) with extended pelvic lymph node dissection (ePLND) for NAC treatment response evaluation. Two patients were part of both cohorts. 11C-acetate PET/MRI findings were correlated with histopathology. Accuracy for lymph node detection was evaluated on patient and the ePLND template (10 regions) levels. Results The sensitivity, specificity and accuracy of 11C-acetate PET/MRI for the detection of muscle invasive BC was 1.00, 0.69 and 0.73 while the area under the receiver operating characteristic curve (95% confidence interval) was 0.85 (0.55–1.0), respectively. All five NAC patients underwent chemotherapy as planned and 11C-acetate PET/MRI correctly staged three patients, overstaged one and understaged one patient compared with RC and ePLND findings. A total of 175 lymph node were removed, median of 35 (range, 27–43) per patient in five patients who had RC and ePLND while 12 (7%) harboured metastases. Sensitivity, specificity, accuracy and AUC for N-staging were 0.20, 0.96, 0.80 and 0.58 on the ePLND template (10 regions) level. Conclusions 11C-acetate PET/MRI is feasible for staging of BC although sensitivity for the detection of nodal metastases is low. Monitoring response to NAC shows promise and warrants evaluation in larger studies. Trial registration ClinicalTrials.gov Identifier: NCT01918592, registered August 8 2013

The potential risks associated with cardiovascular imaging (CVI) have recently been debated, partly triggered by the rapid increase in the use of imaging procedures and new imaging modalities such as cardiac computed tomography (CT).1,2 The discussion has mainly focused only on a single-risk aspect such as radiation.3 However, the various procedures have several risks: stressors, contrast agents, invasiveness, radiation, etc. Even more important, the test must be related to the benefit of performing or not performing the test with the risk and drawbacks associated with the disease remaining undetected. We aimed to create a balanced analysis of immediate, short- and long-term risks associated with CVI in relation to the natural course of coronary artery disease (CAD) and to therapeutic interventions. The imaging tests for CAD were selected, since many CVI tests are commonly used. We analysed: (i) the risk of major cardiac events (MCEs) for each component of imaging test; (ii) the upper limit for each risk, in order to avoid underestimation of a risk; (iii) composite risks calculated for selected common diagnostic tests for CAD; (iv) the risks compared with the risk of the disease itself, to assess the potential benefits of tests; and (v) comparison with risks in regular life activities and that associated with trivial long-term prophylactic interventions such as aspirin use. This analysis is based on the data available from the literature. Data for risks related to some of the procedures are quite limited, for some variable, and for some of limited quality. Still we sought to present risk estimations from all the procedures using reliable studies and databases available from an extensive search of the literature. The detailed information about risk assessments is shown in Supplementary material. ### Definitions In the literature, risks are described in many different ways, e.g. ‘fatal, major, …

Objectives: We aimed to study the ability of contrast enhanced MRI at 1.5 T and C-11-acetate PET/CT, both individually and using fused data, to detect localized prostate cancer.Methods: Thirty-six men with untreated prostate cancer and negative for metastatic disease on pelvic CT and bone scan were prospectively enrolled. A pelvic C-11-acetate PET/CT scan was performed in all patients, and a contrast enhanced MRI scan in 33 patients (6 examinations using both endorectal coil and surface coils, and 27 examinations using surface coils only). After the imaging studies 10 patients underwent prostatectomy and 26 were treated by image guided external beam radiation treatment. Image fusion of co-registered PET and MRI data was performed based on anatomical landmarks visible on CT and MRI using an advanced in-house developed software package. PET/CT, MRI and fused PET/MRI data were evaluated visually and compared with biopsy findings on a lobar level, while a sextant approach was used for patients undergoing prostatectomy.Results: When using biopsy samples as method of reference, the sensitivity, specificity and accuracy for visual detection of prostate cancer on a lobar level by contrast enhanced MRI was 85%, 37%, 73% and that of C-11-acetate PET/CT 88%, 41%, 74%, respectively. Fusion of PET with MRI data increased sensitivity, specificity and accuracy to 90%, 72% and 85%, respectively.Conclusions: Fusion of sequentially obtained PET/CT and MRI data for the localization of prostate cancer is feasible and superior to the performance of each individual modality alone. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

We assessed the ability of C-11-acetate PET/CT, MRI, and proton MR spectroscopy (H-1-MRS) to image localized prostate cancer and detect its aggressiveness, using qualitative and quantitative approaches. Methods: Twenty-one patients with untreated localized prostate cancer, diagnosed using transrectal ultrasound-guided biopsy, were prospectively enrolled. Cancer laterality was based on the percentage of cancer and the highest Gleason score determined from biopsies. In addition to PET/CT, 3-dimensional H-1-MRS of the entire prostate volume using a quantitative approach was performed. The imaging and histologic findings of 8 patients undergoing subsequent prostatectomy were compared on a sextant level. For each lobe and sextant, standardized uptake values (SUVs) and (choline + creatine + polyamines)-to-citrate (CCP/C) ratios were obtained from C-11-acetate PET/CT and H-1-MRS, respectively. The visual and quantitative findings on PET/CT and MRI data were compared with cancer laterality and aggressiveness based on the Gleason score and with prostate-specific antigen (PSA) velocity and international risk group classification. Results: The sensitivity, specificity, and accuracy, on a lobar level using visual analysis, of C-11-acetate PET/CT were 80%, 29%, 71%, respectively, and 89%, 29%, 79%, respectively, using contrast-enhanced MRI. The sensitivity and accuracy of C-11-acetate PET/CT decreased to 64% and 63% and specificity increased to 62% when sextant analysis was performed. The agreement between prostate cancer laterality based on biopsy findings and visual interpretation of C-11-acetate PET/CT and contrast-enhanced MRI was similar at 71%. The mean SUV maximum and CCP/C maximum for the dominant tumor lesion were 5.5 and 1.48, respectively, and did not differ significantly from values in the nondominant lobe. The dominant-lesion SUVs or CCP/C values were not associated with histologically determined prostate cancer aggressiveness, nor did PSA velocity correlate with the SUV or CCP/C values from the entire gland. Conclusion: C-11-acetate PET/CT, MRI, and H-1-MRS enable detection of localized prostate cancer with comparable and limited accuracy but fail to provide information on cancer aggressiveness.

Background The relationship between the uptake of [18F]fluoroerythronitroimidazole ([18F]FETNIM), blood flow ([15O]H2O) and 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) and immunohistochemically determined biomarkers was evaluated in squamous-cell carcinomas of the head and neck (HNSCC). Methods [18F]FETNIM and [18F]FDG PET were performed on separate days on 15 untreated patients with HNSCC. Hypoxia imaging with [18F]FETNIM was coupled with measurement of tumor blood flow using [15O]H2O. Uptake of [18F]FETNIM was measured as tumor-to-plasma ratio (T/P) and fractional hypoxic volume (FHV), and that of [18F]FDG as standardized uptake value (SUV) and the metabolically active tumor volume (TV). Tumor biopsies were cut and stained for GLUT-1, Ki-67, p53, CD68, HIF-1α, VEGFsc-152, CD31 and apoptosis. The expression of biomarkers was correlated to PET findings and patient outcome. Results None of the PET parameters depicting hypoxia and metabolism correlated with the expression of the biomarkers on a continuous scale. When PET parameters were divided into two groups according to median values, a significant association was detected between [18F]FDG SUV and p53 expression (p =0.029) using median SUV as the cut-off. There was a significant association between tumor volume and the amount of apoptotic cells (p =0.029). The intensity of VEGF stained cells was associated with [18F]FDG SUV (p =0.036). Patient outcome was associated with tumor macrophage content (p =0.050), but not with the other biomarkers. HIF-1α correlated with GLUT-1 (rs =0.553, p =0.040) and Ki-67 with HIF-1α (rs =506, p =0.065). p53 correlated inversely with GLUT-1 (rs = −618, p =0.019) and apoptosis with Ki-67 (rs = −638, p =0.014). Conclusions A high uptake of [18F]FDG expressed as SUV is linked to an aggressive HNSCC phenotype: the rate of apoptosis is low and the expressions of p53 and VEGF are high. None of the studied biomarkers correlated with perfusion and hypoxia as evaluated with [15O]H2O-PET and [18F]FETNIM-PET. Increased tumor metabolism evaluated with PET may thus signify an aggressive phenotype, which should be taken into account in the management of HNSCC.

Purpose: A novel [68Ga]-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 peptide (BAY86-7548) having high affinity to bombesin receptor subtype II to detect primary and metastatic prostate carcinoma using positron emission tomography/computed tomography (PET/CT) was synthesized and evaluated for prostate cancer. Experimental Design: In this first human study with BAY86-7548, 14 men scheduled for radical prostatectomy (n = 11) or with biochemical recurrence after surgery or hormonal therapy (n = 3) were enrolled. The patients received an intravenous injection of BAY86-7548 followed by over 60-minute dynamic imaging of prostate gland (n = 10) and/or subsequent whole-body imaging (n = 14). The visual assessment of PET/CT images included evaluation of intraprostatic (12 subsextants) and pelvic nodal uptake of BAY86-7548 in 11 surgical patients and detection of potential metastatic foci in all patients. In patients with biochemical recurrence, results were compared with those of either [11C]-acetate (n = 2) or [18F]-fluoromethylcholine (n = 1) PET/CT. Results: We found a sensitivity, specificity, and accuracy of 88%, 81% and 83%, respectively, for detection of primary PCa and sensitivity of 70% for metastatic lymph nodes using histology as gold standard. BAY86-7548 correctly detected local recurrence in prostate bed and showed nodal relapse in accordance with [11C]-acetate PET/CT in 2 patients with biochemical relapse. In the third hormone refractory patient, BAY86-7548 failed to show multiple bone metastases evident on [18F]-fluoromethylcholine PET/CT. Conclusion: BAY86-7548 PET/CT is a promising molecular imaging technique for detecting intraprostatic prostate cancer. Clin Cancer Res; 19(19); 5434–43. ©2013 AACR.

Background Prostate tumours are commonly poorly oxygenated which is associated with tumour progression and development of resistance to chemotherapeutic drugs and radiotherapy. Fibroblast growth factor 8b (FGF8b) is a mitogenic and angiogenic factor, which is expressed at an increased level in human prostate tumours and is associated with a poor prognosis. We studied the effect of FGF8b on tumour oxygenation and growth parameters in xenografts in comparison with vascular endothelial growth factor (VEGF)-expressing xenografts, representing another fast growing and angiogenic tumour model. Methods Subcutaneous tumours of PC-3 cells transfected with FGF8b, VEGF or empty (mock) vectors were produced and studied for vascularity, cell proliferation, glucose metabolism and oxygenation. Tumours were evaluated by immunohistochemistry (IHC), flow cytometry, use of radiolabelled markers of energy metabolism ([18F]FDG) and hypoxia ([18F]EF5), and intratumoral polarographic measurements of pO2. Results Both FGF8b and VEGF tumours grew rapidly in nude mice and showed highly vascularised morphology. Perfusion studies, pO2 measurements, [18F]EF5 and [18F]FDG uptake as well as IHC staining for glucose transport protein (GLUT1) and hypoxia inducible factor (HIF) 1 showed that VEGF xenografts were well-perfused and oxygenised, as expected, whereas FGF8b tumours were as hypoxic as mock tumours. These results suggest that FGF8b-induced tumour capillaries are defective. Nevertheless, the growth rate of hypoxic FGF8b tumours was highly increased, as that of well-oxygenised VEGF tumours, when compared with hypoxic mock tumour controls. Conclusion FGF8b is able to induce fast growth in strongly hypoxic tumour microenvironment whereas VEGF-stimulated growth advantage is associated with improved perfusion and oxygenation of prostate tumour xenografts.

Background Tumor hypoxia is linked to invasion and metastasis but whether this associates with tumor growth rate is not well understood. We aimed to study the relationship between hypoxia evaluated with the positron emission tomography (PET) tracer [18F]EF5 and tumor growth. Our second goal was to assess the variability in the uptake of [18F]EF5 in tumor between two scans. Methods Four human head and neck squamous cell carcinoma (UT-SCC) cell lines were xenografted in flank or neck of nude mice, and tumor size was closely monitored over the study period. The tumors were clearly visible when the first [18F]EF5 scan was acquired. After an exponential growth phase, the tumors were imaged again with [18F]EF5 and also with 18F-fluorodeoxyglucose ([18F]FDG). Results There was a clear correlation between the percentage of tumor growth rate per day and the [18F]EF5 uptake in the latter scan (r = 0.766, p = 0.01). The uptake of [18F]EF5 in the first scan and the uptake of [18F]FDG did not significantly correlate with the tumor growth rate. We also observed considerable variations in the uptake of [18F]EF5 between the two scans. Conclusions The uptake of [18F]EF5 in the late phase of exponential tumor growth is associated with the tumor growth rate in mice bearing HNC xenografts.

Background High-grade gliomas (HGGs) express somatostatin receptors (SSTR), rendering them candidates for peptide receptor radionuclide therapy (PRRT). Our purpose was to evaluate the potential of 68Ga-DOTA-1-Nal3-octreotide (68Ga-DOTANOC) or 68Ga-DOTA-Tyr3-octreotide (68Ga-DOTATOC) to target SSTR subtype 2 (SSTR2) in HGGs, and to study the association between SSTR2 expression and established biomarkers. Methods Twenty-seven patients (mean age 52 years) with primary or recurrent HGG prospectively underwent 68Ga-DOTA-peptide positron emission tomography/computed tomography (PET/CT) before resection. Maximum standardized uptake values (SUVmax) and receptor binding potential (BP) were calculated on PET/CT and disruption of blood–brain barrier (BBB) from contrast-enhanced T1-weighted magnetic resonance imaging (MRI-T1-Gad). Tumor volume concordance between PET and MRI-T1-Gad was assessed by Dice similarity coefficient (DC) and correlation by Spearman’s rank. Immunohistochemically determined SSTR2 status was compared to receptor imaging findings, prognostic biomarkers, and survival with Kruskal-Wallis, Pearson chi-square, and multivariate Cox regression, respectively. Results All 19 HGGs with disrupted BBB demonstrated tracer uptake. Tumor SUVmax (2.25 ± 1.33) correlated with MRI-T1-Gad (r = 0.713, P = 0.001) although DC 0.41 ± 0.19 suggested limited concordance. SSTR2 immunohistochemistry was regarded as positive in nine HGGs (32%) but no correlation with SUVmax or BP was found. By contrast, SSTR2 expression was associated with IDH1 mutation (P = 0.007), oligodendroglioma component (P = 0.010), lower grade (P = 0.005), absence of EGFR amplification (P = 0.021), and longer progression-free survival (HR 0.161, CI 0.037 to 0.704, P = 0.015). Conclusions In HGGs, uptake of 68Ga-DOTA-peptides is associated with disrupted BBB and cannot be predicted by SSTR2 immunohistochemistry. Thus, PET/CT shows limited value to detect HGGs suitable for PRRT. However, high SSTR2 expression portends favorable outcome along with established biomarkers such as IDH1 mutation. Trial registration ClinicalTrials.gov NCT01460706