Tolerability of tariquidar - A third generation P-gp inhibitor as add-on medication to antiseizure medications in drug-resistant epilepsy.

PURPOSE: P-glycoprotein (P-gp) has been hypothesized to be involved in drug-resistance of epilepsy by actively extruding antiseizure medications (ASMs) from the brain. The P-gp inhibitor tariquidar (TQD) has been shown to effectively inhibit P-gp at the human blood-brain barrier, improving brain entry of several ASMs. A potential strategy to overcome drug-resistance is the co-administration of P-gp inhibitors such as TQD to ASMs. Here we present data on the tolerability of single-dose TQD as a potential add-on medication to ASMs. METHODS: We performed a multi-centre cohort study including drug-resistant epilepsy patients and healthy controls from the United Kingdom and Austria. TQD was administered intravenously at five different doses (2 mg/kg or 3 mg/kg of TQD were given to drug-resistant epilepsy patients and healthy controls, higher doses of TQD at 4 mg/kg, 6 mg/kg and 8 mg/kg as well as a prolonged infusion aiming at a dose of 6 mg/kg were only given to healthy controls). Adverse events were recorded and graded using the Common Terminology Criteria (CTCAE) scale. Additionally, TQD plasma concentration levels were measured and compared between drug-resistant patients and healthy controls. RESULTS: In total, 108 participants received TQD once at variable doses and it was overall well tolerated. At doses of 2 or 3 mg/kg TQD, only two of the 19 drug-resistant epilepsy patients and a third of the healthy controls (n = 14/42) reported adverse events probably related to TQD. The majority of those adverse events (96 %) were reported as mild. One drug-resistant epilepsy patient reported adverse events 24-hours after TQD administration possibly related to TQD-induced increased ASMs levels in the brain. CONCLUSIONS: TQD is an effective and well tolerated P-gp inhibitor as a single dose and could potentially be used intermittently in conjunction with ASMs to improve efficacy. This promising strategy to overcome drug-resistance in epilepsy should be investigated further in clinical randomised controlled trials.

Using prostate-specific membrane antigen positron-emission tomography to guide prostate biopsies and stage men at high-risk of prostate cancer.

OBJECTIVE: To assess whether a diagnostic pathway in which prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/computed tomography (CT) is used as a single imaging modality is feasible to guide targeted biopsy and to detect clinically significant prostate cancer (csPCa) in biopsy-naïve men at high-risk of disease. PATIENTS AND METHODS: A total of 60 men with a prostate-specific antigen (PSA) level of 20-50 ng/mL underwent 18 F-PSMA(DCFPyL)-PET/CT prior to prostate biopsies in this prospective, non-randomised cohort study. Magnetic resonance imaging (MRI) was not performed. Using a 12-segment mapping model of the prostate, PSMA-guided targeted biopsy was performed along with systematic biopsies. The detection rate of PCa and csPCa was assessed for combined systematic and targeted biopsy, and for targeted biopsy only. csPCa was defined as a prostate biopsy with an International Society of Uropathology (ISUP) Grade Group ≥2. RESULTS: Lesions suspicious for PCa in the prostate gland were observed on all PSMA-PET/CTs. A total of 27/60 men (45%) already had metastatic disease on staging 18 F-PSMA(DCFPyL)-PET/CT. Combined PSMA-guided targeted and systematic biopsies detected PCa in 56/60 (93.3%) patients, with 52 of them (92.9%) having csPCa. PSMA-guided targeted biopsy, if performed as a single biopsy modality, identified PCa in 52/60 men (86.7%) and in 27/27 men (100%) men with metastases. CONCLUSIONS: Using the PSMA-driven single imaging modality pathway in biopsy-naïve men at high-risk of PCa, a substantial number of diagnostic MRI scans could be avoided while at the same time obtaining adequate targeting, staging, and detection of csPCa.

The Influence of Long-Acting Somatostatin Analogs on 68 Ga-DOTATATE Uptake in Patients With Neuroendocrine Tumors.

PURPOSE: A high SUV max tumor-to-liver ratio (TLR) of 68 Ga-DOTATATE can be used to select patients with neuroendocrine tumors (NETs) for peptide receptor radionuclide therapy (PRRT). In addition, an SUV max TLR ≥ 8.1 is associated with increased progression-free survival in NET patients treated with somatostatin analogs (SSAs). To avoid a theoretical interaction, several guidelines recommend performing PET/CT just before the monthly administration of long-acting SSAs. We aimed to investigate the effect of SSA on the SUV max of 68 Ga-DOTATATE in patients with NET and to identify independent predictors for high SUV max TLR. PATIENTS AND METHODS: For this retrospective study, 192 68 Ga-DOTATATE PET/CT scans of 165 patients without (n = 115) and with (n = 77) SSA (octreotide or lanreotide) in the 3 months before PET/CT were collected and reviewed. The effect of SSA on SUV max values was analyzed by a maximum likelihood mixed model. RESULTS: Patients with SSA had a significantly higher median SUV max TLR than patients without SSA (4.7 [IQR], 3.1-7.7) versus 3.2 [IQR, 2.0-5.4]; P < 0.001). Multivariable logistic regression analysis showed that SSA use was an independent predictor for SUV max TLR ≥ 8.1 (odds ratio, 2.91; 95% confidence interval, 1.26-6.72; P = 0.012). CONCLUSIONS: Our data suggest that higher SSA concentrations do not have a negative effect on 68 Ga-DOTATATE uptake in tumor lesions. In addition, we found that only SSA use was associated with SUV max TLR ≥ 8.1. Our results are consistent with previously conducted studies and in line with the recently published guideline that suggests that the relatively recent use of SSA does not necessitate any delay in 68 Ga-DOTATATE PET/CT imaging.

Anatomical breast imaging-derived parameters do not provide incremental information in prediction of nonvisualization of sentinel lymph nodes on lymphoscintigraphy.

OBJECTIVE: Accurate sentinel lymph node (SLN) staging is essential for both prognosis and treatment in patients with breast cancer. However, the preoperative lymphoscintigraphy may fail to visualize the SLN. The aim of this retrospective study was to investigate whether parameters derived from anatomical breast imaging can predict SLN nonvisualization on lymphoscintigraphy. METHODS: For this retrospective study, all data of mammography, breast MRI, and lymphoscintigraphy of SLN procedures from January 2016 to April 2021 were collected and reviewed from the Amsterdam UMC database. RESULTS: A total of 758 breast cancer patients were included in this study. SLN nonvisualization on planar lymphoscintigraphy at 2-h postinjection (pi) was 29.7% and was reduced after a second injection to 7.5% at late lymphoscintigraphy 4-h pi. Multivariable analysis showed that age ≥ 70 years ( P = 0.019; OR, 1.82; 95% CI, 1.10-3.01), BMI ≥ 30 kg/m 2 ( P = 0.031; OR, 1.59; 95% CI, 1.04-2.43), and nonpalpable tumors ( P = 0.034; OR, 1.54; 95% CI, 1.03-2.04) were independent predictors of SLN nonvisualization. Differences in tumor size, Breast Imaging-Reporting and Data System classification, or breast density were not significantly associated with SLN nonvisualization. CONCLUSION: This study shows that, by using a multivariable analysis, risk factors for SLN nonvisualization in breast cancer patients during preoperative lymphoscintigraphy at 2-h pi are age ≥ 70 years, BMI ≥ 30 kg/m 2 , and nonpalpable tumors. Parameters derived from mammography or breast MRI, however, are not useful to predict SLN nonvisualization on lymphoscintigraphy.

Targeting PSMA Revolutionizes the Role of Nuclear Medicine in Diagnosis and Treatment of Prostate Cancer.

Targeting the prostate-specific membrane antigen (PSMA) protein has become of great clinical value in prostate cancer (PCa) care. PSMA positron emission tomography/computed tomography (PET/CT) is increasingly used in initial staging and restaging at biochemical recurrence in patients with PCa, where it has shown superior detection rates compared to previous imaging modalities. Apart from targeting PSMA for diagnostic purposes, there is a growing interest in developing ligands to target the PSMA-protein for radioligand therapy (RLT). PSMA-based RLT is a novel treatment that couples a PSMA-antibody to (alpha or beta-emitting) radionuclide, such as Lutetium-177 (177Lu), to deliver high radiation doses to tumor cells locally. Treatment with 177Lu-PSMA RLT has demonstrated a superior overall survival rate within randomized clinical trials as compared to routine clinical care in patients with metastatic castration-resistant prostate cancer (mCRPC). The current review provides an overview of the literature regarding recent developments in nuclear medicine related to PSMA-targeted PET imaging and Theranostics.

Standardised uptake values as determined on prostate-specific membrane antigen positron emission tomography/computed tomography is associated with oncological outcomes in patients with prostate cancer.

OBJECTIVES: To investigate the association between intraprostatic, intratumoral maximum standardised uptake values (SUVmax ) on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with prostate cancer (PCa) prior to robot-assisted radical prostatectomy (RARP) and pathology outcomes, including pathological International Society of Urological Pathology score (pISUP) and lymph node (LN) status (pN0/pN1). PATIENTS AND METHODS: A bi-centric, secondary analysis of two previous, prospective cohort studies was performed in 318 patients with biopsy confirmed PCa and who were scheduled for RARP. Before surgery, patients received a PSMA PET/CT with either 68 Ga-PSMA-11 (59% of the patients) or 18 F-PSMA (DCFPyL; 41%) as radiotracer. PET/CT images were analysed both visually and semi-quantitatively by measuring the SUVmax of the most intense suspect lesion in the prostate. The association between the SUVmax of the primary tumour and pre- and postoperative variables was analysed. RESULTS: The SUVmax was associated with clinical and biopsy preoperative variables, as well as with pISUP score and pathological tumour stage. Patients with a pISUP of ≤2 showed significantly lower SUVmax compared to patients with a pISUP of >2 for both tracers (SUVmax18 F-PSMA: median 5.1 vs 9.6, P = 0.002; SUVmax68 Ga-PSMA-11: 6.6 vs 8.6, P = 0.003). Moreover, patients with pN1 had significantly higher median SUVmax than those with pN0/pNx for both tracers (SUVmax18 F-PSMA: 7.9 vs 12.3, P = 0.04; SUVmax68 Ga-PSMA-11: 7.6 vs 12.0, P < 0.001). On multivariable logistic regression analysis, the intraprostatic SUVmax was an independent predictor of pN1 for both 68 Ga-PSMA-11 (per doubling: odds ratio [OR] 1.96, 95% confidence interval [CI] 1.27-3.01)) and 18 F-PSMA (per doubling: OR 1.79, 95% CI 1.06-3.03). CONCLUSION: Intraprostatic, intratumoral PSMA intensity on PET/CT, as semi-quantitatively expressed by SUVmax , may be a valuable innovative biomarker in patients with localised PCa, as it is highly associated with known conventional prognostic factors, such as pISUP and LN status.

Complementary and alternative medicine in children with diffuse intrinsic pontine glioma-A SIOPE DIPG Network and Registry study.

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare and aggressive childhood brainstem malignancy with a 2-year survival rate of <10%. This international survey study aims to evaluate the use of complementary and alternative medicine (CAM) in this patient population. METHODS: Parents and physicians of patients with DIPG were asked to participate in a retrospective online survey regarding CAM use during time of illness. RESULTS: Between January and May 2020, 120 parents and 75 physicians contributed to the online survey. Most physicians estimated that <50% of their patients used CAM, whereas 69% of the parents reported using CAM to treat their child during time of illness. Cannabis was the most frequently used form of CAM, followed by vitamins and minerals, melatonin, curcumin, and boswellic acid. CAM was mainly used with the intention of direct antitumor effect. Other motivations were to treat side effects of chemotherapy or to increase comfort of the child. Children diagnosed from 2016 onwards were more likely to use CAM (χ2  = 6.08, p = .014). No significant difference was found between CAM users and nonusers based on ethnicity (χ2  = 4.18, p = .382) or country of residence (χ2  = 9.37, p = .154). Almost 50% of the physicians do not frequently ask their patients about possible CAM use. CONCLUSION: This survey demonstrates that worldwide, a considerable number of patients with DIPG use CAM. Physicians should be more aware of potential CAM use and actively discuss the topic. In addition, more research is needed to gain knowledge about possible anticancer effects of CAM and (positive/negative) interactions with conventional therapies.

A phase I/II study of bevacizumab, irinotecan and erlotinib in children with progressive diffuse intrinsic pontine glioma.

INTRODUCTION: This study investigates the safety, tolerability, and preliminary efficacy of combined treatment with VEGF inhibitor bevacizumab, topoisomerase I inhibitor irinotecan, and EGFR inhibitor erlotinib in children with progressive diffuse intrinsic pontine glioma (DIPG). METHODS: Biweekly bevacizumab (10 mg/kg) and irinotecan (125 mg/m2) were combined with daily erlotinib. Two cohorts received increasing doses of erlotinib (65 and 85 mg/m2) following a 3 + 3 dose-escalation schedule, until disease progression with a maximum of one year. Dose-limiting toxicities (DLT) were monitored biweekly. Secondary progression free survival (sPFS) and overall survival (OS) were determined based on clinical and radiological response measurements. Quality of life (QoL) during treatment was also assessed. RESULTS: Between November 2011 and March 2018, nine patients with disease progression after initial radiotherapy were enrolled. Median PFS at start of the study was 7.3 months (range 3.5-10.0). In the first dose cohort, one patient experienced a DLT (grade III acute diarrhea), resulting in enrollment of three additional patients in this cohort. No additional DLTs were observed in consecutive patients receiving up to a maximum dose of 85 mg/m2. Median sPFS was 3.2 months (range 1.0-10.9), and median OS was 13.8 months (range 9.3-33.0). Overall QoL was stable during treatment. CONCLUSIONS: Daily erlotinib is safe and well tolerated in doses up to 85 mg/m2 when combined with biweekly bevacizumab and irinotecan in children with progressive DIPG. Median OS of the study patients was longer than known form literature.

The Predictive Value of Preoperative Negative Prostate Specific Membrane Antigen Positron Emission Tomography Imaging for Lymph Node Metastatic Prostate Cancer.

PURPOSE: We sought to identify a subset of patients in whom an extended pelvic lymph node dissection during robot-assisted laparoscopic radical prostatectomy for localized prostate cancer could be omitted when preoperative prostate specific membrane antigen positron emission tomography showed no lymph node metastatic prostate cancer. MATERIALS AND METHODS: A total of 434 patients who underwent prostate specific membrane antigen positron emission tomography prior to robot-assisted laparoscopic radical prostatectomy and extended pelvic lymph node dissection were retrospectively analyzed. Patients were excluded from analysis when the prostate specific membrane antigen positron emission tomography showed evidence of distant metastases. The primary outcome was whether a negative for metastases prostate specific membrane antigen positron emission tomography was able to correctly rule out pelvic lymp node metastases after extended pelvic lymph node dissection, ie its negative predictive value. RESULTS: Overall sensitivity, specificity, positive predictive value and negative predictive value of prostate specific membrane antigen positron emission tomography for the detection of pelvic lymp node metastases were 37.9%, 94.1%, 64.3% and 84.4%, respectively. The negative predictive value of prostate specific membrane antigen positron emission tomography in patients with intermediate risk prostate cancer was 91.6% (95% CI 86-97), compared to 81.4% (95% CI 77-86) in patients with high risk prostate cancer. When only assessing patients with

Management impact of 18F-DCFPyL PET/CT in hormone-sensitive prostate cancer patients with biochemical recurrence after definitive treatment: a multicenter retrospective study.

PURPOSE: The aim of this study was to investigate whether an early, accurate identification of disease using 18F-DCFPyL PET/CT imaging resulted in a change of decision on treatment management, for individual patients with biochemically recurrent (BCR), hormone-sensitive prostate cancer. METHODS: In this retrospective study, a total of 253 patients with BCR who underwent restaging 18F-DCFPyL PET/CT were assessed. Two urologists specialized in uro-oncology were asked to formulate a preferred treatment for each patient before and after knowing the results of the 18F-DCFPyL PET/CT. RESULTS: Out of 253 patients, 191 (75%) underwent robot-assisted radical prostatectomy (RARP) as primary therapy, and 62 (25%) external beam radiation therapy (EBRT). In 103/253 cases (40.7%), a preferred treatment change based on the 18F-DCFPyL PET/CT findings was reported. In patients post-RARP, a positive 18F-DCFPyL PET/CT (OR 6.21; 95%CI 2.78-13.8; p < 0.001) and positive pathological lymph node status (pN1) (OR 2.96; 95%CI 1.15-7.60; p = 0.024) were significant predictors for an intended change of management, whereas a positive surgical margin (OR 0.42; 95%CI 0.20-0.88; p = 0.022) was inversely associated with an intended change of management. CONCLUSION: In this study, we found a significant impact of 18F-DCFPyL PET/CT on the intended management of patients with biochemically recurrent hormone-sensitive prostate cancer. A positive 18F-DCFPyL PET/CT scan, positive pathological lymph node status, and a negative surgical margin status were significantly associated with increased odds of having a change of management based on 18F-DCFPyL PET/CT findings.

SUVs Are Adequate Measures of Lesional 18F-DCFPyL Uptake in Patients with Low Prostate Cancer Disease Burden.

In prostate cancer (PCa) patients, the tumor-to-blood ratio (TBR) has been validated as the preferred simplified method for lesional 18F-DCFPyL (a radiolabeled prostate-specific membrane antigen ligand) uptake quantification on PET. In contrast to SUVs, the TBR accounts for variability in arterial input functions caused by differences in total tumor burden between patients (the sink effect). However, TBR depends strongly on tracer uptake interval and has worse repeatability and is less applicable in clinical practice than SUVs. We investigated whether SUV could provide adequate quantification of 18F-DCFPyL uptake on PET/CT in a patient cohort with low PCa burden. Methods: In total, 116 patients with PCa undergoing 18F-DCFPyL PET/CT imaging were retrospectively included. All 18F-DCFPyL-avid lesions suspected of being PCa were semiautomatically delineated. SUVpeak was plotted against TBR for the most intense lesion of each patient. The correlation of SUVpeak and TBR was evaluated using linear regression and was stratified for patients undergoing PET/CT for primary staging, patients undergoing restaging at biochemical recurrence, and patients with metastatic castration-resistant PCa. Moreover, the correlation was evaluated as a function of tracer uptake time, prostate-specific antigen level, and PET-positive tumor volume. Results: In total, 436 lesions were delineated (median, 1 per patient; range, 1-66). SUVpeak correlated well with TBR in patients with PCa and a total tumor volume of less than 200 cm3 (R2 = 0.931). The correlation between SUV and TBR was not affected by disease setting, prostate-specific antigen level, or tumor volume. SUVpeak depended less on tracer uptake time than did TBR. Conclusion: For 18F-DCFPyL PET/CT, SUVpeak correlates strongly with TBR. Therefore, it is a valuable simplified, semiquantitative measurement in patients with low-volume PCa (<200 cm3). SUVpeak can therefore be applied in 18F-DCFPyL PET assessment as an imaging biomarker to characterize tumors and to monitor treatment outcomes.

The Oral Bioavailability and Metabolism of Midazolam in Stable Critically Ill Children: A Pharmacokinetic Microtracing Study.

Midazolam is metabolized by the developmentally regulated intestinal and hepatic drug-metabolizing enzyme cytochrome P450 (CYP) 3A4/5. It is frequently administered orally to children, yet knowledge is lacking on the oral bioavailability in term neonates up until 1 year of age. Furthermore, the dispositions of the major metabolites 1-OH-midazolam (OHM) and 1-OH-midazolam-glucuronide (OHMG) after oral administration are largely unknown for the entire pediatric age span. We aimed to fill these knowledge gaps with a pediatric [14 C]midazolam microtracer population pharmacokinetic study. Forty-six stable, critically ill children (median age 9.8 (range 0.3-276.4) weeks) received a single oral [14 C]midazolam microtracer (58 (40-67) Bq/kg) when they received a therapeutic continuous intravenous midazolam infusion and had an arterial line in place enabling blood sampling. For midazolam, in a one-compartment model, bodyweight was a significant predictor for clearance (0.98 L/hour) and volume of distribution (8.7 L) (values for a typical individual of 5 kg). The typical oral bioavailability in the population was 66% (range 25-85%). The exposures of OHM and OHMG were highest for the youngest age groups and significantly decreased with postnatal age. The oral bioavailability of midazolam, largely reflective of intestinal and hepatic CYP3A activity, was on average lower than the reported 49-92% for preterm neonates, and higher than the reported 21% for children> 1 year of age and 30% for adults. As midazolam oral bioavailability varied widely, systemic exposure of other CYP3A-substrate drugs after oral dosing in this population may also be unpredictable, with risk of therapy failure or toxicity.

The Role of 89Zr-Immuno-PET in Navigating and Derisking the Development of Biopharmaceuticals.

The identification of molecular drivers of disease and the compelling rise of biotherapeutics have impacted clinical care but have also come with challenges. Such therapeutics include peptides, monoclonal antibodies, antibody fragments and nontraditional binding scaffolds, activatable antibodies, bispecific antibodies, immunocytokines, antibody-drug conjugates, enzymes, polynucleotides, and therapeutic cells, as well as alternative drug carriers such as nanoparticles. Drug development is expensive, attrition rates are high, and efficacy rates are lower than desired. Almost all these drugs, which in general have a long residence time in the body, can stably be labeled with 89Zr for whole-body PET imaging and quantification. Although not restricted to monoclonal antibodies, this approach is called 89Zr-immuno-PET. This review summarizes the state of the art of the technical aspects of 89Zr-immuno-PET and illustrates why it has potential for steering the design, development, and application of biologic drugs. Appealing showcases are discussed to illustrate what can be learned with this emerging technology during preclinical and especially clinical studies about biologic drug formats and disease targets. In addition, an overview of ongoing and completed clinical trials is provided. Although 89Zr-immuno-PET is a young tool in drug development, its application is rapidly expanding, with first clinical experiences giving insight on why certain drug-target combinations might have better perspectives than others.

Phase I Trial of 131I-GMIB-Anti-HER2-VHH1, a New Promising Candidate for HER2-Targeted Radionuclide Therapy in Breast Cancer Patients.

131I-GMIB-anti-human epidermal growth factor receptor type 2 (HER2)-VHH1 is a targeted radionuclide theranostic agent directed at HER2-expressing cancers. VHH1 is a single-domain antibody covalently linked to therapeutic 131I via the linker N-succinimidyl 4-guanidino-methyl-3-iodobenzoate (SGMIB). The phase I study was aimed at evaluating the safety, biodistribution, radiation dosimetry, and tumor-imaging potential of 131I-GMIB-anti-HER2-VHH1 in healthy volunteers and breast cancer patients. Methods: In a first cohort, 6 healthy volunteers were included. The biodistribution of 131I-GMIB-anti-HER2-VHH1 was assessed using whole-body (anterior and posterior) planar images obtained at 40 min and at 2, 4, 24, and 72 h after intravenously administered (38 ± 9 MBq) 131I-GMIB-anti-HER2-VHH1. Imaging data were analyzed using OLINDA/EXM software to determine the dosimetry. Blood and urine samples were obtained over 72 h. In the second cohort, 3 patients with metastatic HER2-positive breast cancer were included. Planar whole-body imaging was performed at 2 and 24 h after injection. Additional SPECT/CT images were obtained after the whole-body images at 2 and 24 h if there was relevant uptake in known cancer lesions. Results: No drug-related adverse events were observed throughout the study. The biologic half-life of 131I-GMIB-anti-HER2-VHH1 in healthy subjects was about 8 h. After intravenous administration, the compound was eliminated from the blood with a 2.5-h half-life. The drug was eliminated primarily via the kidneys. The drug was stable in circulation, and there was no increased accumulation in the thyroid or stomach. The absorbed dose to the kidneys was 1.54 ± 0.25 mGy/MBq, and to bone marrow it was 0.03 ± 0.01 mGy/MBq. SPECT/CT imaging in patients with advanced breast cancer showed focal uptake of 131I-GMIB-anti-HER2-VHH1 in metastatic lesions. Conclusion: Because of its favorable toxicity profile and its uptake in HER2-positive lesions, this radiopharmaceutical can offer new therapeutic options to patients who have progressed on trastuzumab, pertuzumab, or trastuzmab emtansine, given its difference in mode-of-action. A dose escalation is planned in a subsequent phase I/II study to assess the therapeutic window of this compound (NCT04467515).

11C-Sorafenib and 15O-H2O PET for Early Evaluation of Sorafenib Therapy.

Sorafenib leads to clinical benefit in a subgroup of patients, whereas all are exposed to potential toxicity. Currently, no predictive biomarkers are available. The purpose of this study was to evaluate whether 11C-sorafenib and 15O-H2O PET have potential to predict treatment efficacy. Methods: In this prospective exploratory study, 8 patients with advanced solid malignancies and an indication for sorafenib treatment were included. Microdose 11C-sorafenib and perfusion 15O-H2O dynamic PET scans were performed before and after 2 wk of sorafenib therapy. The main objective was to assess whether tumor 11C-sorafenib uptake predicts sorafenib concentrations during therapy in corresponding tumor biopsy samples measured with liquid chromatography tandem mass spectrometry. Secondary objectives included determining the association of 11C-sorafenib PET findings, perfusion 15O-H2O PET findings, and sorafenib concentrations after therapeutic dosing with response. Results:11C-sorafenib PET findings did not predict sorafenib concentrations in tumor biopsy samples during therapy. In addition, sorafenib plasma and tumor concentrations were not associated with clinical outcome in this exploratory study. Higher 11C-sorafenib accumulation in tumors at baseline and day 14 of treatment showed an association with poorer prognosis and correlated with tumor perfusion (Spearman correlation coefficient = 0.671, P = 0.020). Interestingly, a decrease in tumor perfusion measured with 15O-H2O PET after only 14 d of therapy showed an association with response, with a decrease in tumor perfusion of 56% ± 23% (mean ± SD) versus 18% ± 32% in patients with stable and progressive disease, respectively. Conclusion: Microdose 11C-sorafenib PET did not predict intratumoral sorafenib concentrations after therapeutic dosing, but the association between a decrease in tumor perfusion and clinical benefit warrants further investigation.

The neurovascular unit in diffuse intrinsic pontine gliomas.

Aims: Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a median overall survival of eleven months. Lack of chemotherapy efficacy may be related to an intact blood-brain barrier (BBB). In this study we aim to investigate the neurovascular unit (NVU) in DIPG patients. Methods: DIPG biopsy (n = 4) and autopsy samples (n = 6) and age-matched healthy pons samples (n = 20) were immunohistochemically investigated for plasma protein extravasation, and the expression of tight junction proteins claudin-5 and zonula occludens-1 (ZO-1), basement membrane component laminin, pericyte marker PDGFR-ß, and efflux transporters P-gp and BCRP. The mean vascular density and diameter were also assessed. Results: DIPGs show a heterogeneity in cell morphology and evidence of BBB leakage. Both in tumor biopsy and autopsy samples, expression of claudin-5, ZO-1, laminin, PDGFR-ß and P-gp was reduced compared to healthy pontine tissues. In DIPG autopsy samples, vascular density was lower compared to healthy pons. The density of small vessels (<10 µm) was significantly lower (P<0.001), whereas the density of large vessels (≥10 µm) did not differ between groups (P = 0.404). The median vascular diameter was not significantly different: 6.21 µm in DIPG autopsy samples (range 2.25-94.85 µm), and 6.26 µm in controls (range 1.17-264.77 µm). Conclusion: Our study demonstrates evidence of structural changes in the NVU in DIPG patients, both in biopsy and autopsy samples, as well as a reduced vascular density in end-stage disease. Adding such a biological perspective may help to better direct future treatment choices for DIPG patients.

Prostate Specific Membrane Antigen Positron Emission Tomography/Computerized Tomography in the Evaluation of Initial Response in Candidates Who Underwent Salvage Radiation Therapy after Radical Prostatectomy for Prostate Cancer.

PURPOSE: We assessed predictors of short-term oncologic outcomes of patients who underwent salvage radiation therapy for biochemical recurrence after robot-assisted laparoscopic radical prostatectomy without evidence of metastases on prostate specific membrane antigen positron emission tomography/computerized tomography. MATERIALS AND METHODS: We retrospectively analyzed 194 patients with biochemical recurrence after robot-assisted laparoscopic radical prostatectomy who underwent prostate specific membrane antigen positron emission tomography/computerized tomography prior to salvage radiation therapy. Patients with lymph node or distant metastases on restaging imaging or at the time of extended pelvic lymph node dissection during robot-assisted laparoscopic radical prostatectomy were excluded, as were patients who received androgen deprivation therapy during or prior to salvage radiation therapy. A multivariable logistic regression analysis was performed to assess predictors of treatment response, defined as prostate specific antigen value ≤0.1 ng/ml after salvage radiation therapy. RESULTS: Overall treatment response after salvage radiation therapy was 75% (146/194 patients). On multivariable analysis, prostate specific antigen value at initiation of salvage radiation therapy (OR 0.42, 95% CI 0.27-0.62, p <0.001), pathological T stage (pT3a vs pT2 OR 0.28, 95% CI 0.11-0.69, p=0.006; pT3b vs pT2 OR 0.26, 95% CI 0.09-0.71, p=0.009) and local recurrent disease on imaging (OR 5.53, 95% CI 1.96-18.52, p=0.003) were predictors of treatment response. CONCLUSIONS: Salvage radiation therapy in patients without evidence of metastases on prostate specific membrane antigen positron emission tomography/computerized tomography showed a good overall treatment response of 75%. Higher treatment response rates were observed in patients with lower prostate specific antigen values at initiation of salvage radiation therapy, those with local recurrent disease on imaging and those with lower pathological T stage (pT2 vs pT3a/b).