A Novel Method Using Fine Needle Aspiration from Tumor-Draining Lymph Nodes Could Enable the Discovery of New Prognostic Markers in Patients with Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell cancer (cSCC) is the second most common form of skin cancer, characterized by abnormal, accelerated growth of squamous cells. When caught early, most cSCCs are curable. About 5 percent of the cSCC cases have advanced to such an extent, generally metastatic, that they are far more dangerous, with very poor prognosis and challenging to treat. All efforts to find biomarkers, in blood or in the tumor itself, for early identification of patients with a risk for metastasis have so far failed. The present study describes a novel method that enables the identification of lymphocyte markers in tumor-draining lymph nodes. Six patients with advanced cSCC were analyzed using a combination of a sentinel lymph node biopsy (SLNB) protocol, fine needle aspiration (FNA), and flow cytometry. Immunological results from the sentinel nodes were combined with corresponding data from peripheral blood and unfixed tumor tissues. The result demonstrates a striking difference between the subsets of T-cells from the three compartments. Our interpretation of this first pilot study is that the ability to follow specific immunological markers on lymphocytes in tumor-draining lymph nodes will enable the identification of novel prognostic biomarkers not detectable in material from blood and tumor tissues.

Primary tumour iodine avidity in relation to uptake in persistent metastatic disease in papillary and poorly differentiated thyroid cancer.

PURPOSE: Patients with persistent or recurrent papillary and poorly differentiated thyroid cancer can be effectively treated with radioiodine, if the tumour tissue is iodine-avid. However, iodine-avidity status is often unknown at the time of initial radioiodine treatment, limiting any adaptive approach. This study aimed to clarify the relationship between pre-therapeutic iodine avidity in primary tumour tissue, initial lymph node metastases and iodine uptake in subsequent metastases. METHODS: Iodine avidity was prospectively assessed pre-therapeutically in 35 patients by injection of tracer amounts of iodine-131 two days prior to surgery. Iodine concentrations in resected tissue samples were measured, enabling accurate and histologically verifiable iodine avidity data for both primary tumour and initial lymph node metastases. Iodine uptake in persistent metastatic disease was assessed by review of radiology, and treatment response was examined through journal studies. RESULTS: Out of data from 35 patients, 10 had persistent disease at presentation or during follow-up (range 19-46 months). Four patients had non-avid persistent metastatic disease, all with low iodine avidity in their primary tumours and initial lymph node metastases. Patients with low pre-therapeutic iodine avidity did not appear to have greater risk of persistent disease. CONCLUSION: The results indicate a close link between pre-therapeutically measured iodine concentrations in primary tumours with iodine avidity of any subsequent metastases.

Sentinel node-assisted neck dissection in advanced oral squamous cell carcinoma-A new protocol for staging and treatment.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is used to improve the staging of and guide treatment in patients with early-stage T1-T2 N0 oral squamous cell carcinoma (OSCC). The role of sentinel nodes (SNs) and the use of SN-technique in advanced OSCC (T3-T4 and/or N+) remain to be evaluated. This study investigates the nodal drainage and the rate of positive SNs (SNs+) in all stages of OSCC. MATERIALS AND METHODS: In total, 85 patients with T1-T4 OSCC diagnosed 2019-2021 were included. We used a prolonged interval between peritumoral injection of radionuclide and SPECT-CT to include all SNs. RESULTS: Patients with advanced OSCC presented a higher proportion of contralateral lymphatic drainage and a higher rate of SN+ compared to patients with early-stage disease. T3-T4 and N+ tumors presented a tendency for a higher rate of contralateral lymphatic drainage compared to T1-T2 and N0 tumors (p = 0.1). The prevalence of positive nodes (SNs+) was higher among patients with advanced disease, T3-T4 versus T1-T2 (p = 0.0398). CONCLUSION: SN-assisted ND enables identification and removal of all SNs + and has the potential for more accurate staging and could possibly give prognostic advantages regarding regional recurrence for all OSCC patients, especially among those with advanced disease. The precise localization of the SNs + also suggests that a more individualized ND approach might be possible in the future even for patients with advanced OSCC.

Survival Outcomes, Digital TILs, and On-treatment PET/CT During Neoadjuvant Therapy for HER2-positive Breast Cancer: Results from the Randomized PREDIX HER2 Trial.

PURPOSE: PREDIX HER2 is a randomized Phase II trial that compared neoadjuvant docetaxel, trastuzumab, and pertuzumab (THP) with trastuzumab emtansine (T-DM1) for HER2-positive breast cancer. Rates of pathologic complete response (pCR) did not differ between the two groups. Here, we present the survival outcomes from PREDIX HER2 and investigate metabolic response and tumor-infiltrating lymphocytes (TIL) as prognostic factors. PATIENTS AND METHODS: In total, 202 patients with HER2-positive breast cancer were enrolled and 197 patients received six cycles of either THP or T-DM1. Secondary endpoints included event-free survival (EFS), recurrence-free survival (RFS), and overall survival (OS). Assessment with PET/CT was performed at baseline, after two and six treatment cycles. TILs were assessed manually at baseline biopsies, while image-based evaluation of TILs [digital TILs (DTIL)] was performed in digitized full-face sections. RESULTS: After a median follow-up of 5.21 years, there was no difference between the two treatment groups in terms of EFS [HR = 1.26; 95% confidence interval (CI), 0.54-2.91], RFS (HR = 0.69; 95% CI, 0.24-1.93), or OS (HR = 0.52; 95% CI, 0.09-2.82). Higher SUVmax at cycle 2 (C2) predicted lower pCR (ORadj = 0.65; 95% CI, 0.48-0.87; P = 0.005) and worse EFS (HRadj = 1.27; 95% CI, 1.12-1.41; P < 0.001). Baseline TILs and DTILs provided additional prognostic information to clinical parameters and C2 SUVmax. CONCLUSIONS: Long-term outcomes following neoadjuvant T-DM1 were similar to neoadjuvant THP. SUVmax after two cycles of neoadjuvant therapy for HER2-positive breast cancer may be an independent predictor of both short- and long-term outcomes. Combined assessment with TILs may facilitate early selection of poor responders for alternative treatment strategies.

Primary hyperparathyroidism, a machine learning approach to identify multiglandular disease in patients with a single adenoma found at preoperative Sestamibi-SPECT/CT.

Objective: Successful preoperative image localisation of all parathyroid adenomas (PTA) in patients with primary hyperparathyroidism (pHPT) and multiglandular disease (MGD) remains challenging. We investigate whether a machine learning classifier (MLC) could predict the presence of overlooked PTA at preoperative localisation with 99mTc-Sestamibi-SPECT/CT in MGD patients. Design: This study is a retrospective study from a single tertiary referral hospital initially including 349 patients with biochemically confirmed pHPT and cured after surgical parathyroidectomy. Methods: A classification ensemble of decision trees with Bayesian hyperparameter optimisation and five-fold cross-validation was trained with six predictor variables: the preoperative plasma concentrations of parathyroid hormone, total calcium and thyroid-stimulating hormone, the serum concentration of ionised calcium, the 24-h urine calcium and the histopathological weight of the localised PTA at imaging. Two response classes were defined: patients with single-gland disease (SGD) correctly localised at imaging and MGD patients in whom only one PTA was localised on imaging. The data set was split into 70% for training and 30% for testing. The MLC was also tested on a subset of the original data based on CT image-derived PTA weights. Results: The MLC achieved an overall accuracy at validation of 90% with an area under the cross-validation receiver operating characteristic curve of 0.9. On test data, the MLC reached a 72% true-positive prediction rate for MGD patients and a misclassification rate of 6% for SGD patients. Similar results were obtained in the testing set with image-derived PTA weight. Conclusions: Artificial intelligence can aid in identifying patients with MGD for whom 99mTc-Sestamibi-SPECT/CT failed to visualise all PTAs.

A Phase II Trial of a Personalized, Dose-Intense Administration Schedule of 177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-Risk Neuroblastoma-LuDO-N.

Background: Half the children with high-risk neuroblastoma die with widespread metastases. Molecular radiotherapy is an attractive systemic treatment for this relatively radiosensitive tumor. 131I-mIBG is the most widely used form in current use, but is not universally effective. Clinical trials of 177Lutetium DOTATATE have so far had disappointing results, possibly because the administered activity was too low, and the courses were spread over too long a period of time, for a rapidly proliferating tumor. We have devised an alternative administration schedule to overcome these limitations. This involves two high-activity administrations of single agent 177Lu-DOTATATE given 2 weeks apart, prescribed as a personalized whole body radiation absorbed dose, rather than a fixed administered activity. "A phase II trial of 177Lutetium-DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma - LuDO-N" (EudraCT No: 2020-004445-36, ClinicalTrials.gov Identifier: NCT04903899) evaluates this new dosing schedule. Methods: The LuDO-N trial is a phase II, open label, multi-center, single arm, two stage design clinical trial. Children aged 18 months to 18 years are eligible. The trial is conducted by the Nordic Society for Pediatric Hematology and Oncology (NOPHO) and it has been endorsed by SIOPEN (https://www.siopen.net). The Karolinska University Hospital, is the sponsor of the LuDO-N trial, which is conducted in collaboration with Advanced Accelerator Applications, a Novartis company. All Scandinavian countries, Lithuania and the Netherlands participate in the trial and the UK has voiced an interest in joining in 2022. Results: The pediatric use of the Investigational Medicinal Product (IMP) 177Lu-DOTATATE, as well as non-IMPs SomaKit TOC® (68Ga-DOTATOC) and LysaKare® amino acid solution for renal protection, have been approved for pediatric use, within the LuDO-N Trial by the European Medicines Agency (EMA). The trial is currently recruiting. Recruitment is estimated to be finalized within 3-5 years. Discussion: In this paper we present the protocol of the LuDO-N Trial. The rationale and design of the trial are discussed in relation to other ongoing, or planned trials with similar objectives. Further, we discuss the rapid development of targeted radiopharmaceutical therapy and the future perspectives for developing novel therapies for high-risk neuroblastoma and other pediatric solid tumors.

Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients With ERBB2-Positive Breast Cancer: A Phase 2 Randomized Clinical Trial.

Importance: Trastuzumab emtansine (T-DM1) is presently approved for treatment of advanced breast cancer and after incomplete response to neoadjuvant therapy, but the potential of T-DM1 as monotherapy is so far unknown. Objective: To assess pathologic complete response (pCR) to standard neoadjuvant therapy of combination docetaxel, trastuzumab, and pertuzumab (DTP) vs T-DM1 monotherapy in patients with ERBB2 (formerly HER2)-positive breast cancer. Design, Setting, and Participants: This randomized phase 2 trial, conducted at 9 sites in Sweden, enrolled 202 patients between December 1, 2014, and October 31, 2018. Participants were 18 years or older, with ERBB2-positive tumors larger than 20 mm and/or verified lymph node metastases. Analysis was performed on an intention-to-treat basis. Interventions: Patients were randomized to receive 6 cycles of DTP (standard group) or T-DM1 (investigational group). Crossover was recommended at lack of response or occurrence of intolerable toxic effects. Assessment with fluorine 18-labeled fluorodeoxyglucose (18F-FDG) positron emission tomography combined with computed tomography (PET-CT) was performed at baseline and after 2 and 6 treatment cycles. Main Outcome and Measures: Pathologic complete response, defined as ypT0 or Tis ypN0. Secondary end points were clinical and radiologic objective response; event-free survival, invasive disease-free survival, distant disease-free survival, and overall survival; safety; health-related quality of life (HRQoL); functional and biological tumor characteristics; and frequency of breast-conserving surgery. Results: Overall, 202 patients were randomized; 197 (99 women in the standard group [median age, 51 years (range, 26-73 years)] and 98 women in the investigational group [median age, 53 years (range, 28-74 years)]) were evaluable for the primary end point. Pathologic complete response was achieved in 45 patients in the standard group (45.5%; 95% CI 35.4%-55.8%) and 43 patients in the investigational group (43.9%; 95% CI 33.9%-54.3%). The difference was not statistically significant (P = .82). In a subgroup analysis, the pCR rate was higher in hormone receptor-negative tumors than in hormone receptor-positive tumors in both treatment groups (45 of 72 [62.5%] vs 45 of 125 [36.0%]). Three patients in the T-DM1 group experienced progression during therapy. In an exploratory analysis, tumor-infiltrating lymphocytes at 10% or more (median) estimated pCR significantly (odds ratio, 2.76; 95% CI, 1.42-5.36; P = .003). Response evaluation with 18F-FDG PET-CT revealed a relative decrease of maximum standardized uptake value by equal to or greater than 68.7% (median) was associated with pCR (odds ratio, 6.74, 95% CI, 2.75-16.51; P < .001). Conclusions and Relevance: In this study, treatment with standard neoadjuvant combination DTP was equal to T-DM1. Trial Registrations: ClinicalTrials.gov Identifier: NCT02568839; EudraCT number: 2014-000808-10.

The preoperative localisation of small parathyroid adenomas improves when adding Tc-99m-Sestamibi SPECT to multiphase contrast-enhanced CT.

OBJECTIVES: To investigate the incremental value of Sestamibi SPECT combined with a non-enhanced and contrast-enhanced CT, using SPECT/CT, for the preoperative localisation of small parathyroid adenomas (PTA). METHODS: Retrospectively, 147 patients surgically cured from primary hyperparathyroidism, as verified by biochemistry 6 months postoperatively, were included. All patients had preoperatively undergone a dual time 99mTechnetium-Sestamibi SPECT (S) with multiphase CT including native (N), arterial (A) and venous (V) phases. Independently, two radiologists blinded from both the surgical and the preoperative imaging reports, sequentially performed PTA localisation starting with either [A] or [V], thereafter [A + N] or [V + N] and finally with the complete [A + N + S] or [V + N + S]. PTA localisation was reported for each image-set. The readers results were combined and the diagnostic performance for each image set was determined. Sensitivity was also calculated for the different quartiles of PTA weight distribution. RESULTS: The median adenoma weight was 315 mg. No statistically significant differences in diagnostic performance between arterial and venous based image sets were found. The net effect of adding [N] was to increase specificity. Sestamibi SPECT significantly increased the overall diagnostic accuracy for arterial- and venous-based image sets, p = 0.0008 and p = 0.001, respectively. [A + N + S] was found to have the highest diagnostic performance with 86.5% sensitivity and 94.9% overall accuracy. [A + N + S] was particularly advantageous for locating PTA in the lower weight quartiles. CONCLUSIONS: Native CT-phase and dual time point Sestamibi SPECT increase specificity and sensitivity, respectively. These, in combination with a single contrast-enhanced CT-phase is the most optimal examination protocol for preoperative localisation of PTA using SPECT/CT.

Renography with a semiautomated algorithm for diuretic decision 7 min postradiopharmaceutical administration: a feasibility study.

OBJECTIVE: The F+10 method for diuretic renography (diuretics given 10 min after the radiopharmaceutical) could be a time-conserving method. This method involves a 30-min dynamic acquisition where diuretics are administered only when necessary by the Nuclear Medicine technologist performing the examination. The purpose of this study was to assess the method's performance and to discover the optimal threshold of residual activity for a diuretic administration 7 min into the F+10 renography by reprocessing raw data from prior performed examinations with 20-min acquisitions without diuretics. METHODS: Retrospectively, raw data from 320 original examinations of adult patients performed from 2013 to 2015 were reprocessed into 7-min series and categorized as requiring diuretic or not. The diuretic decisions made by an expert panel were used as a reference. A receiver-operating characteristic curve was drawn to assess the optimal cutoff value for the residual renal activity. Sensitivity, specificity, positive and negative predictive values, as well as the Youden J index were calculated. RESULT: The experts classified 50% (160 examinations) as in need of diuretics. The receiver-operating characteristic curve demonstrated the theoretical optimal cutoff value at 7 min to be 94% of maximum activity (sensitivity 0.93, specificity 0.81, Youden J index 0.73). A clinically acceptable threshold is suggested to be 85% (sensitivity 0.99, specificity 0.59, Youden J index 0.58). CONCLUSION: Tc-mercaptoacetyltriglycine renography with the F+10 method and the threshold 85% for diuretic decision 7 min into the renography is a feasible and acceptable method in clinical practice.

PET imaging of beta-secretase 1 in the human brain: radiation dosimetry, quantification, and test-retest examination of [18F]PF-06684511.

PURPOSE: Beta-secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer's disease. [18F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [18F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [18F]PF-06684511 in healthy volunteers. METHODS: Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume (VT) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of VT were calculated as reliability measures. RESULTS: In the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 µSv/MBq). The calculated ED was 24.7 ± 0.8 µSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. VT (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRV and ICC of VT (2TCM) were 16.5% (12.4-20.5%) and 0.496 (0.291-0.644). CONCLUSION: The ED of [18F]PF-06684511 was similar to other 18F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of VT was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [18F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain. TRIAL REGISTRATION: EudraCT 2016-001110-19 (registered 2016-08-08).

Gastroparesis versus dyspepsia by intragastric meal distribution: new diagnostics and definitions ahead.

Gastroparesis often presents a challenge to the practicing gastroenterologist. Postprandial symptoms with nausea and vomiting may not only lead to nutritional and metabolic consequences, but also significant disruption of social activities that often center around food. The treatment options that affect gastric function are limited and often disappointing. The female predominance, the mostly idiopathic and idiosyncratic nature of the illness, often with some common psychiatric co-morbidity, parallels other functional disorders of the gastrointestinal tract. These parallels have provided the rationale for studies investigating alternative diagnostic features of the gastric emptying test as employed in the clinical setting. Hence, not only the regular cut-offs of 60% or 10% gastric retention of a meal at 2 and 4 h, but also a new concept, the intragastric meal distribution at time 0 (IMD0) is now introduced as a plausible diagnostic feature that should be more aligned with the patients' symptoms as they appear in close connection with the meal. Impaired gastric accommodation with absence of fundic relaxation followed by dumping of the meal into antrum is suggested to be diagnostic for functional dyspepsia and gastroparesis. The diagnostic cut-off is considered when more than 57% of the meal is distributed to the distal part of the stomach immediately on food intake. This new diagnostic feature of the gastric emptying profile lend support to better understanding of the patients' symptoms and provides a new basis for pharmacological treatment options in gastroparesis that may provide an improved quality of life in affected individuals.

Multiphase Iodine Contrast-Enhanced SPECT/CT Outperforms Nonenhanced SPECT/CT for Preoperative Localization of Small Parathyroid Adenomas.

PURPOSE: The aim of this study was to assess the value of intravenously contrast-enhanced CT in conjunction with Tc-MIBI SPECT for preoperative localization of parathyroid adenoma. METHODS: One hundred ninety-two patients with primary hyperparathyroidism were enrolled in the study between May 2015 and May 2017. The patients underwent a preoperative "one-stop shop" examination with Tc-MIBI SPECT/CT by using dual time-point (10 and 90 minutes) protocol and both nonenhanced CT and contrast-enhanced CT acquisition in the arterial and venous phase, 35 and 75 seconds, respectively, after contrast medium injection start. For 149 patients, the imaging results could be correlated to those at surgery and histopathology. RESULTS: The median adenoma weight was 330 mg. The addition of contrast-enhanced CT increased the sensitivity from 81.1% to 89.9% (P = 0.003). The specificity of nonenhanced SPECT/CT was similar to contrast-enhanced CT (96.1% vs 97.9%; P = 0.077). For patients with uniglandular disease (n = 140, 94.0%), the sensitivity increased from 86.4% to 93.6% (P = 0.021) and the specificity from 96.2% to 97.9% (P = 0.118) by adding contrast-enhanced CT. In patients with multiglandular disease (n = 9, 6.0%), adding contrast-enhanced CT improved detection sensitivity from 42.1% to 63.2%. However, these patients were few and significance was not reached (P = 0.125). CONCLUSIONS: In this cohort, with generally small parathyroid adenomas, the sensitivity in preoperative localization was greatly improved by adding contrast-enhanced CT to Tc-MIBI SPECT/CT.

Comparison of acquisition protocols for ventilation/perfusion SPECT-a Monte Carlo study.

One of the most commonly used imaging techniques for diagnosing pulmonary embolism (PE) is ventilation/perfusion (V/P) scintigraphy. The aim of this study was to evaluate the performance of the currently used imaging protocols for V/P single photon emission computed tomography (V/P SPECT) at two nuclear medicine department sites and to investigate the effect of altering important protocol parameters. The Monte Carlo technique was used to simulate 4D digital phantoms with perfusion defects. Six imaging protocols were included in the study and a total of 72 digital patients were simulated. Six dually trained radiologists/nuclear medicine physicians reviewed the images and reported all perfusion mismatch findings. The radiologists also visually graded the image quality. No statistically significant differences in diagnostic performance were found between the studied protocols, but visual grading analysis pointed out one protocol as significantly superior to four of the other protocols. Considering the study results, we have decided to harmonize our clinical protocols for imaging patients with suspected PE. The administered Technegas and macro aggregated albumin activities have been altered, a low energy all purpose collimator is used instead of a low energy high resolution collimator and the acquisition times have been lowered.

Characterization of [11C]PXT012253 as a PET Radioligand for mGlu4 Allosteric Modulators in Nonhuman Primates.

PURPOSE: Modulation of presynaptic metabotropic glutamate receptor 4 (mGlu4) by an allosteric ligand has been proposed as a promising therapeutic target in Parkinson's disease and levodopa-induced dyskinesia. A positron emission tomography (PET) ligand for an allosteric site of mGlu4 may provide evidence that a clinical drug candidate reaches and binds the target. A carbon-11-labeled PET radioligand binding an allosteric site of mGlu4, [11C]PXT012253, has been recently developed. Here, we describe the detailed characterization of this novel radiolabeled mGlu4 ligand in nonhuman primates. PROCEDURES: [11C]PXT012253 binding in the brain of cynomolgus monkeys, under the baseline and blocking conditions with the structurally different mGlu4 allosteric ligand PXT002331, currently in clinical trials for Parkinson's disease, was quantified with compartment and graphical modeling approaches using a radiometabolite-corrected plasma input function. Whole-body biodistribution of [11C]PXT012253 was then assessed using PET/x-ray computed tomography to estimate the human effective doses of [11C]PXT012253 for further clinical studies. RESULTS: [11C]PXT012253 displayed binding in mGlu4-expressing regions in the brain of cynomolgus monkeys. Brain regional time-activity curves of [11C]PXT012253 were well described in the two-tissue compartment model (2TC). Total distribution volume was stably estimated using Logan plot and multilinear analysis (MA1) although 2TC showed unstable values in some cases. Competition with PXT002331 showed high specific binding in the total distribution volume. Whole-body PET showed high accumulation of [11C]PXT012253 in the liver, kidney, heart, and brain in the initial phase. The radioligand was excreted through both the gastrointestinal and the urinary tracts. Effective dose of [11C]PXT012253 was estimated to be 0.0042 mSv/MBq. CONCLUSIONS: [11C]PXT012253 was shown to be a promising PET radioligand for mGlu4 allosteric modulators in the monkey brain. MA1 would be the choice of quantitative method. Further development of [11C]PXT012253 in human subjects is warranted.

Safety and Activity of Sorafenib in Addition to Vinflunine in Post-Platinum Metastatic Urothelial Carcinoma (Vinsor): Phase I Trial.

LESSONS LEARNED: First trial to report safety and activity of the microtubule inhibitor vinflunine plus the tyrosine kinase inhibitor sorafenib in post-platinum metastatic urothelial cancer (mUC) patients.A recommended phase II dose was identified for the treatment combination of vinflunine plus sorafenib, with main adverse events including fatigue, febrile neutropenia, neutropenia, hypertension, and hyponatremia.An overall response rate of 41% to second-line vinflunine plus sorafenib treatment in patients with platinum-resistant mUC was confirmed. BACKGROUND: Platinum-progressive metastatic urothelial carcinoma (mUC) is a clinical challenge. The tyrosine kinase inhibitor sorafenib has demonstrated varied activity in mUC. This trial was designed to examine safety and activity of vinflunine plus sorafenib in mUC. METHODS: In addition to standard dose of vinflunine (320 or 280 mg/m2), patients received sorafenib (400, 600, or 800 mg/day), in a 3 + 3 dose-escalation phase I design. RESULTS: Twenty-two patients (median age 62.5 years) were included. Five patients received vinflunine 320 mg/m2 and 17 received 280 mg/m2. The maximum tolerated dose (MTD) of sorafenib with vinflunine 280 mg/m2 was 600 mg, and with vinflunine 320 mg/m2 it was not determined, owing to toxicity. Adverse events (AEs) grades 3 + 4 consisted of neutropenia (6 patients), febrile neutropenia (5), and hyponatremia (5). The overall response rate (ORR) in the efficacy-evaluable patients was 41% (7 of 17), all partial responses evaluated by RECIST version 1.1. Median overall survival (OS) was 7.0 months (1.8-41.7). CONCLUSION: The defined recommended phase II dose (RPTD) was vinflunine 280 mg/m2 plus sorafenib 400 mg. Sorafenib was too toxic in combination with vinflunine 320 mg/m2. The ORR of 41% to this second-line combination treatment of mUC is noteworthy and supports further trials.

SPECT/CT's Advantage for Preoperative Localization of Small Parathyroid Adenomas in Primary Hyperparathyroidism.

PURPOSES: The aims of this study were to assess the performance of Tc-sestamibi SPECT/CT, with diagnostic CT quality, compared with SPECT alone for preoperative localization of parathyroid adenomas and to assess the influence of adenoma weight on the correct adenoma lateralization with SPECT/CT and with SPECT alone. METHODS: Two hundred forty-nine consecutive patients, biochemically diagnosed with primary hyperparathyroidism, were examined with a combined SPECT/CT scanner. Subsequently, 200 patients with confirmed histopathology and biochemical cure after parathyroidectomy were included in this study (16 with multiglandular disease). For each patient, the SPECT-alone data were analyzed first. Thereafter, the CT information was added, and a new evaluation was performed with the combined data. In addition, for each patient, the diagnostic confidence with each method was graded on a scale based on the presence of different image features. The preoperative diagnostic findings were then compared with the surgical and histopathologic reports. RESULTS: The distribution of adenoma weights showed a peak at 210 mg, with a median at 338 mg. The sensitivity and specificity (multiglandular disease included) for correct classification of adenomas were significantly higher for SPECT/CT, 83% and 96%, respectively, than for SPECT alone, 80% and 93% (P < 0.01). Below 210 mg, the differences between SPECT/CT and SPECT alone in accurate adenoma lateralization were more prominent. Sixty-seven percent of all adenomas were graded with the highest confidence score with SPECT/CT compared with 53% with SPECT. CONCLUSIONS: SPECT/CT yields fewer false-positive findings than SPECT alone. The advantage of SPECT/CT over SPECT alone was most apparent for correct lateralization of small adenomas (<210 mg).

Reduced acquisition times in whole body bone scintigraphy using a noise-reducing Pixon®-algorithm-a qualitative evaluation study.

BACKGROUND: Reducing scan-time while maintaining sufficient image quality is a common issue in nuclear medicine diagnostics. This matter can be addressed by different post-processing methods such as Pixon® image processing. The aim of the present study was to evaluate if a commercially available noise-reducing Pixon-algorithm applied on whole body bone scintigraphy acquired with half the standard scan-time could provide the same clinical information as full scan-time non-processed images. METHODS: Twenty patients were administered with 500 MBq (99m)Tc-diphosphonate and scanned on a Siemens Symbia T16 system. Each patient was first imaged using a standard clinical protocol and subsequently imaged using a protocol with half the standard scan-time. Half-time images were processed using a commercially available software package, Enhanced Planar Processing, from Siemens. All images were anonymized and visually evaluated with regard to clinically relevant lesion detectability by three experienced nuclear medicine physicians. The result of this evaluation was grouped into four BMI intervals to investigate the performance of the algorithm with regard to different patient size. Also, a comparison study was performed where the physicians compared the standard image and the processed half-time image corresponding to the same patient with regard to lesion detectability, image noise, and artifacts. RESULTS: The results showed that 93 % of the processed half-time images and 98 % of the standard images were rated as sufficient or good with regard to lesion detectability. The processed half-time images were predominately considered sufficient (65 %), whereas the majority of the standard images were graded as good (83 %). The performance of the algorithm was unaffected by patient size as the average grading of all half-time processed images was constant independent of patient BMI. The comparison study showed that the standard images were rated superior with regard to lesion detectability, image noise, and artifacts, in 32, 65, and 23 % of the evaluations, respectively. CONCLUSIONS: The results indicate that the Pixon Enhanced Planar Processing does not fully compensate for the loss of counts associated with reducing the scan-time in half for whole body bone scintigraphies. The findings showed that implementing the Pixon-algorithm on images acquired with half the acquisition time in overall provide sufficient clinical information regardless of patient size. The half-time processed images were predominantly graded lower in comparison to images acquired with full time protocols, and a less aggressive reduction in scan-time is therefore recommended.

Volumetric FDG-PET predicts overall and progression- free survival after 14 days of targeted therapy in metastatic renal cell carcinoma.

BACKGROUND: To determine whether changes in the metabolism of metastatic renal cell carcinoma (mRCC) assessed by F18-FDG-PET after 14 and 28 days of treatment with tyrosine kinase inhibitors can predict overall and progression- free patient survival. METHODS: Thirty-nine consecutive patients with mRCC were included prospectively and underwent PET examinations prior to and after 14 and 28 days of standard treatment with sunitinib (n=18), sorafenib (n=19) or pazopanib (n=2). The PET response was analyzed in terms of SUVmax, SULpeak, and total lesion glycolysis and a positive response (defined as a 30% reduction) compared to overall and progression- free survival. RESULTS: Thirty-five patients with at least one metabolically active metastatic lesion prior to treatment underwent additional FDG-PET examinations after 14 (n=32) and/or 28 days (n=30) of treatment. Changes in either SULpeak or total lesion glycolysis were correlated to both progression-free and overall survival (for TLG2.5 responders, HR=0.38 (95% CI: 0.18-0.83) and 0.22 (95% CI: 0.09-0.53), and for TLG50 responders, HR=0.25 (0.10-0.62) and 0.25 (95% CI: 0.11-0.57) and for SULpeak responders, HR=0.39 (95% CI: 0.17-0.91) and 0.38 (95% CI: 0.15-0.93), respectively). In contrast SUVmax response did not predict progression- free or overall survival (HR=0.43 (95% CI: 0.18-1.01) and 0.50 (95% CI: 0.21-1.19), respectively). CONCLUSIONS: Assessment of early changes in SULpeak and total lesion glycolysis undergoing treatment with tyrosine kinase inhibitors by FDG-PET can possibly predict progression- free and overall survival in patients with mRCC.

Clinical activity of sorafenib in a previously treated advanced urothelial cancer patient.

A male patient, with advanced urothelial carcinoma, who had previously received cisplatin, was treated with sorafenib off-licence for 10.7 months. Evaluation of tumour response with computed tomography scans indicated a reduction in tumour size and necrosis of the metastases within 2 months. Progression-free survival was 10.5 months. Side effects were manageable and not beyond the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 grade 2. Molecular profiling of two of the proposed targets of sorafenib, platelet-derived growth factor receptor ß and vascular endothelial growth factor receptor 2, of the patient's tumour lesion showed high and intermediate expression levels in the tumour as compared with the surrounding non-neoplastic tissue. In contrast to previous reports, we report a clinically meaningful effect of sorafenib in a patient with advanced urothelial carcinoma. Hence, it appears that a fraction of patients with this disease are sensitive to this compound. To identify subpopulations of responders, we propose that clinical trials evaluating sorafenib and other targeted drugs should be biomarker-driven and designed with endpoints that consider the mode of action of the specific compound.

Normal uptake of 68Ga-DOTA-TOC by the pancreas uncinate process mimicking malignancy at somatostatin receptor PET.

PURPOSE: To characterize a commonly occurring increased uptake by the uncinate process of the pancreas at PET/CT using 68Ga-DOTA-d-Phe1-Tyr3-octreotide (68Ga-DOTA-TOC). This tracer has replaced In pentetreotide (OctreoScan®) for somatostatin receptor scintigraphy at our laboratory. METHODS: Fifty of our first 74 PET/CT examinations with 68Ga-DOTA-TOC could be evaluated in retrospect. None of these patients had surgery or showed any pathology in the pancreas head at the concomitant CT. RESULTS: Thirty-five of the 50 examinations (70%) showed an uptake by the uncinate process sufficiently intense to be interpreted as pathologic and simulating a tumor. Mean SUVmax was 9.2. Mean SUVmean using an isoactivity cut-off of >75% and >50% was 7.8 and 6.0, respectively. Volume calculations of the uncinate process activity using these definitions gave 0.9 mL and 4.2 mL, respectively. CONCLUSION: There is a frequent physiological uptake of 68Ga-DOTA-TOC by the pancreas uncinate process. This may be caused by an accumulation of pancreatic polypeptide-containing cells expressing somatostatin receptors. If there is a normal finding at concomitant diagnostic CT, this uptake should be regarded as physiological.