First-in-human validation of a DROP-IN ß-probe for robotic radioguided surgery: defining optimal signal-to-background discrimination algorithm.

PURPOSE: In radioguided surgery (RGS), radiopharmaceuticals are used to generate preoperative roadmaps (e.g., PET/CT) and to facilitate intraoperative tracing of tracer avid lesions. Within RGS, there is a push toward the use of receptor-targeted radiopharmaceuticals, a trend that also has to align with the surgical move toward minimal invasive robotic surgery. Building on our initial ex vivo evaluation, this study investigates the clinical translation of a DROP-IN ß probe in robotic PSMA-guided prostate cancer surgery. METHODS: A clinical-grade DROP-IN ß probe was developed to support the detection of PET radioisotopes (e.g., 68 Ga). The prototype was evaluated in 7 primary prostate cancer patients, having at least 1 lymph node metastases visible on PSMA-PET. Patients were scheduled for radical prostatectomy combined with extended pelvic lymph node dissection. At the beginning of surgery, patients were injected with 1.1 MBq/kg of [68Ga]Ga-PSMA. The ß probe was used to trace PSMA-expressing lymph nodes in vivo. To support intraoperative decision-making, a statistical software algorithm was defined and optimized on this dataset to help the surgeon discriminate between probe signals coming from tumors and healthy tissue. RESULTS: The DROP-IN ß probe helped provide the surgeon with autonomous and highly maneuverable tracer detection. A total of 66 samples (i.e., lymph node specimens) were analyzed in vivo, of which 31 (47%) were found to be malignant. After optimization of the signal cutoff algorithm, we found a probe detection rate of 78% of the PSMA-PET-positive samples, a sensitivity of 76%, and a specificity of 93%, as compared to pathologic evaluation. CONCLUSION: This study shows the first-in-human use of a DROP-IN ß probe, supporting the integration of ß radio guidance and robotic surgery. The achieved competitive sensitivity and specificity help open the world of robotic RGS to a whole new range of radiopharmaceuticals.

Radioguided surgery with ß decay: A feasibility study in cervical cancer.

PURPOSE: Radioguided surgery (RGS) is a technique that helps the surgeon to achieve a tumour resection as complete as possible, by means of the intraoperative detection of particles emitted by a radiotracer that bounds to tumoural cells. This study aimed to investigate the applicability of ß-RGS for tumour resection and margin assessment in cervical cancer patients preoperatively injected with [18F]FDG, by means of Monte Carlo simulations. METHODS: Patients were retrospectively included if they had a recurrent or persistent cervical cancer, underwent preoperative PET/CT to exclude distant metastases and received radical surgery. All PET/CT images were analysed extracting tumour SUVmax, background SUVmean and tumour-to-non-tumour ratio. These values were used to obtain the expected count rate in a realistic surgical scenario by means of a Monte Carlo simulation of the ß probe, assuming the injection of 2 MBq/kg of [18F]FDG 60 min before surgery. RESULTS: Thirty-eight patients were included. A measuring time of ∼2-3 s is expected to be sufficient for discriminating the tumour from background in a given lesion, being this the time the probe has to be over the sample in order to be able to discriminate tumour from healthy tissue with a sensitivity of ∼99% and a specificity of at least 95%. CONCLUSION: This study presents the first step towards a possible application of our ß-RGS technique in cervical cancer. Results suggest that this approach to ß-RGS could help surgeons distinguish tumour margins from surrounding healthy tissue, even in a setting of high radiotracer background activity.

Role of radiomics in predicting lung cancer spread through air spaces in a heterogeneous dataset.

Background: Spread through air spaces (STAS) has been reported as a negative prognostic factor in patients with lung cancer undergoing sublobar resection. Radiomics has been recently proposed to predict STAS using preoperative computed tomography (CT). However, limitations of previous studies included the strict selection of imaging acquisition protocols, leading to results hardly applicable to daily clinical practice. The aim of this study is to test a radiomics-based prediction model of STAS in a practice-based dataset. Methods: A training cohort of 99 consecutive patients (65 STAS+ and 34 STAS-) with resected lung adenocarcinoma (ADC) was retrospectively collected. Preoperative CT images were collected from different centers regardless model and scanner manufacture, acquisition and reconstruction protocol, contrast phase and pixel size. Radiomics features were selected according to separation power and P value stability within different preprocessing setups and bootstrapping resampling. A prospective cohort of 50 patients (33 STAS+ and 17 STAS-) was enrolled for the external validation. Results: Only the five features with the highest stability were considered for the prediction model building. Radiomics, radiological and mixed radiomics-radiological prediction models were created, showing an accuracy of 0.66±0.02 after internal validation and reaching an accuracy of 0.78 in the external validation. Conclusions: Radiomics-based prediction models of STAS may be useful to properly plan surgical treatment and avoid oncological ineffective sublobar resections. This study supports a possible application of radiomics-based models on data with high variance in acquisition, reconstruction and preprocessing, opening a new chance for the use of radiomics in the prediction of STAS. Trial Registration: ClinicalTrials.gov identifier: NCT04893200.

Multimodal evaluation of 19F-BPA internalization in pancreatic cancer cells for boron capture and proton therapy potential applications.

PURPOSE: One of the obstacles to the application of Boron Neutron Capture Therapy (BNCT) and Proton Boron Fusion Therapy (PBFT) concerns the measurement of borated carriers' biodistribution. The objective of the present study was to evaluate the in vitro internalization of the 19F-labelled p-boronophenylalanine (19F-BPA) in the human cancer pancreatic cell line (PANC-1) for the potential application of BNCT and PBFT in pancreatic cancer. The 19F-BPA carrier has the advantage that its bio-distribution may be monitored in vivo using 19F-Nuclear Magnetic Resonance (19F NMR). MATERIALS AND METHODS: The 19F-BPA internalization in PANC-1 cells was evaluated using three independent techniques on cellular samples left in contact with growing medium enriched with 13.6 mM 19F-BPA corresponding to a 11B concentration of 120 ppm: neutron autoradiography, which quantifies boron; liquid chromatography hyphenated to tandem mass spectrometry and UV-Diode Array Detection (UV-DAD), which quantifies 19F-BPA molecule; and 19F NMR spectroscopy, which detects fluorine nuclei. RESULTS: Our studies suggested that 19F-BPA is internalized by PANC-1 cells. The three methods provided consistent results of about 50% internalization fraction at 120 ppm of 11B. Small variations (less than 15%) in internalization fraction are mainly dependent on the proliferation state of the cells. CONCLUSIONS: The ability of 19F NMR spectroscopy to study 19F-BPA internalization was validated by well-established independent techniques. The multimodal approach we used suggests 19F-BPA as a promising BNCT/PBFT carrier for the treatment of pancreatic cancer. Since the quantification is performed at doses useful for BNCT/PBFT, 19F NMR can be envisaged to monitor 19F-BPA bio-distribution during the therapy.

90Y-DOTA-Nimotuzumab: Synthesis of a Promising ß- Radiopharmaceutical.

BACKGROUND: Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody, nowadays used for tumour immunochemotherapy. This study aimed to label the conjugate DOTA-nimotuzumab with yttrium-90, in order to provide a ß- emitting radioimmunoconjugate (90Y-DOTA-nimotuzumab) potentially useful to assess the feasibility of a new radio-guided surgery approach. METHODS: The synthesis of 90Y-DOTA-nimotuzumab was performed in two days. Nimotuzumab was conjugated with a 50-fold excess of DOTA and then labelled with 90Y3+. The 90Y-DOTA-nimotuzumab preparation was optimized considering several parameters such as pH, temperature and reaction volume. Moreover, the 90Y-DOTA-nimotuzumab stability was evaluated in human plasma. RESULTS: The radioimmunoconjugate 90Y-DOTA-nimotuzumab was obtained with a radiochemical purity greater than 96%, and showed a good stability at 20°C as well as at 37°C in human plasma. CONCLUSIONS: The optimized conditions for a mild and easy preparation of 90Y-DOTA-nimotuzumab joined to a promising stability under physiological conditions suggest to propose this radioimmunoconjugate as a potential diagnostic radiopharmaceutical for ß- radio-guided surgery.

Technical note: A wearable radiation measurement system for collection of patient-specific time-activity data in radiopharmaceutical therapy: system design and Monte Carlo simulation results.

PURPOSE: A high level of personalization in Molecular Radiotherapy (MRT) could bring advantages in terms of treatment effectiveness and toxicity reduction. Individual organ-level dosimetry is crucial to describe the radiopharmaceutical biodistribution expressed by the patient, to estimate absorbed doses to normal organs and target tissue(s). This paper presents a proof-of-concept Monte Carlo simulation study of "WIDMApp" (Wearable Individual Dose Monitoring Apparatus), a multi-channel radiation detector and data processing system for in vivo patient measurement and collection of radiopharmaceutical biokinetic data (i.e., time-activity data). Potentially, such a system can increase the amount of such data that can be collected while reducing the need to derive it via nuclear medicine imaging. METHODS: a male anthropomorphic MIRD phantom was used to simulate photons (i.e., gamma-rays) propagation in a patient undergoing a 131 I thyroid treatment. The administered activity was set to the amount usually administered for the treatment of differentiated carcinoma while its initial distribution in different organs was assigned following the ICRP indications for the 131 I biokinetics. Using this information, the simulation computes the Time-dependent Counts Curves (TCCs) that would have been measured by seven WIDMApp-like sensors placed and oriented to face each one of five emitting organs plus two thyroid lobes. A deconvolution algorithm was then applied on this simulated data set to reconstruct the Time-Activity Curve (TAC) of each organ. Deviations of the reconstructed TACs parameters from values used to generate them were studied as a function of the deconvolution algorithm initialization parameters and assuming non-Poisson fluctuation of the TCCs data points. RESULTS: This study demonstrates that it is possible, at least in the simple simulated scenario, to reconstruct the organ cumulated activity by measuring the time dependence of counts recorded by several detectors placed at selected positions on the patient's body. The ability to perform in vivo sampling more frequently than conventional biokinetic studies increases the number of time points and therefore the accuracy in TAC estimates. In this study, an accuracy on cumulated activity of 5% is obtained even with a 20% error on the TCC data points and a 50% error on the initial guess on the parameters of the deconvolution algorithm. CONCLUSIONS: the WIDMApp approach could provide an effective tool to characterize more accurately the radiopharmaceutical biokinetics in MRT patients, reducing the need of resources of nuclear medicine departments, such as technologist and scanner time, to perform individualized biokinetics studies. The relatively simple hardware for the approach proposed would allow its application to large numbers of patients. The results obtained justify development of an actual prototype system to characterize this technique under realistic conditions.

First Ex Vivo Results of ß--Radioguided Surgery in Small Intestine Neuroendocrine Tumors with 90Y-DOTATOC.

Background: In neuroendocrine tumor (NET), complete surgery could better the prognosis. Radioguided surgery (RGS) with ß--radioisotopes is a novel approach focused on developing a new probe that, detecting electrons and operating with low background, provides a clearer delineation of the lesions with low radiation exposition for surgeons. As a first step to validate this procedure, ex vivo specimens of tumors expressing somatostatin receptors, as small intestine neuroendocrine tumor (SI-NET), were tested. Materials and Methods: SI-NET presents a high uptake of a beta-emitting radiotracer, 90Y-DOTATOC. Five SI-NET patients were enrolled after performing a 68Ga-DOTATOC positron emission tomography/computed tomography (CT) and a CT enterography; 24 h before surgery, they received 5 mCi of 90Y-DOTATOC. Results: Surgery was performed as routine. Tumors and surrounding tissue were sectioned in different samples and examined ex vivo with the beta-detecting probe. All the tumor samples showed high counts of radioactivity that was up to a factor of 18 times higher than the corresponding cutoff value, with a sensitivity of 96% and a specificity of 100%. Conclusions: These first ex vivo RGS tests showed that this probe can discriminate very effectively between tumor and healthy tissues by the administration of low activities of 90Y-DOTATOC, allowing more precise surgery.

A DROP-IN beta probe for robot-assisted 68Ga-PSMA radioguided surgery: first ex vivo technology evaluation using prostate cancer specimens.

BACKGROUND: Recently, a flexible DROP-IN gamma-probe was introduced for robot-assisted radioguided surgery, using traditional low-energy SPECT-isotopes. In parallel, a novel approach to achieve sensitive radioguidance using beta-emitting PET isotopes has been proposed. Integration of these two concepts would allow to exploit the use of PET tracers during robot-assisted tumor-receptor-targeted. In this study, we have engineered and validated the performance of a novel DROP-IN beta particle (DROP-INß) detector. METHODS: Seven prostate cancer patients with PSMA-PET positive tumors received an additional intraoperative injection of ~ 70 MBq 68Ga-PSMA-11, followed by robot-assisted prostatectomy and extended pelvic lymph node dissection. The surgical specimens from these procedures were used to validate the performance of our DROP-INß probe prototype, which merged a scintillating detector with a housing optimized for a 12-mm trocar and prograsp instruments. RESULTS: After optimization of the detector and probe housing via Monte Carlo simulations, the resulting DROP-INß probe prototype was tested in a robotic setting. In the ex vivo setting, the probe-positioned by the robot-was able to identify 68Ga-PSMA-11 containing hot-spots in the surgical specimens: signal-to-background (S/B) was > 5 when pathology confirmed that the tumor was located < 1 mm below the specimen surface. 68Ga-PSMA-11 containing (and PET positive) lymph nodes, as found in two patients, were also confirmed with the DROP-INß probe (S/B > 3). The rotational freedom of the DROP-IN design and the ability to manipulate the probe with the prograsp tool allowed the surgeon to perform autonomous beta-tracing. CONCLUSIONS: This study demonstrates the feasibility of beta-radioguided surgery in a robotic context by means of a DROP-INß detector. When translated to an in vivo setting in the future, this technique could provide a valuable tool in detecting tumor remnants on the prostate surface and in confirmation of PSMA-PET positive lymph nodes.

Radioguided surgery with ß- radiation in pancreatic Neuroendocrine Tumors: a feasibility study.

The possibility to use ß- decaying isotopes for radioguided surgery (RGS) has been recently proposed, and first promising tests on ex-vivo samples of Meningioma and intestinal Neuroendocrine Tumor (NET) have been published. This paper reports a study of the uptake of 68Ga-DOTATOC in pancreatic NETs (pNETs) in order to assess the feasibility of a new RGS approach using 90Y-DOTATOC. Tumor and healthy pancreas uptakes were estimated from 68Ga-DOTATOC PET/CT scans of 30 patients with pNETs. From the obtained SUVs (Standardised Uptake Value) and TNRs (Tumor Non tumor Ratio), an analysis algorithm relying on a Monte Carlo simulation of the detector has been applied to evaluate the performances of the proposed technique. Almost all considered patients resulted to be compatible with the application of ß--RGS assuming to administer 1.5 MBq/kg of activity of 90Y-DOTATOC 24 h before surgery, and a sampling time of few seconds. In just 2 cases the technique would have required a mildly increased amount of activity or of sampling time. Despite a high physiological uptake of 68Ga-DOTATOC in the healthy pancreas, the proposed RGS technique promises to be effective. This approach allows RGS to find application also in pancreatic diseases, where traditional techniques are not viable.

Radioguided surgery with ß radiation: a novel application with Ga68.

Radio Guided Surgery is a technique helping the surgeon in the resection of tumors: a radiolabeled tracer is administered to the patient before surgery and then the surgeon evaluates the completeness of the resection with a handheld detector sensitive to emitted radiation. Established methods rely on γ emitting tracers coupled with γ detecting probes. The efficacy of this technique is however hindered by the high penetration of γ radiation, limiting its applicability to low background conditions. To overtake such limitations, a novel approach to RGS has been proposed, relying on ß- emitting isotopes together with a dedicated ß probe. This technique has been proved to be effective in first ex-vivo trials. We discuss in this paper the possibility to extend its application cases to 68Ga, a ß+ emitting isotope widely used today in nuclear medicine. To this aim, a retrospective study on 45 prostatic cancer patients was performed, analysing their 68Ga-PSMA PET images to asses if the molecule uptake is enough to apply this technique. Despite the expected variability both in terms of SUV (median 4.1, IQR 3.0-6.1) and TNR (median 9.4, IQR 5.2-14.6), the majority of cases have been found to be compatible with ß-RGS with reasonable injected activity and probing time (5 s).

Mass spectrometry characterization of DOTA-Nimotuzumab conjugate as precursor of an innovative ß- tracer suitable in radio-guided surgery.

The aim of the present work has been the mass spectrometry characterization of the Nimotuzumab (NIM) antibody chemically modified with the bifunctional chelating agent para-S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza cyclododecanetetraacetic acid (p-SCN-Bn-DOTA). The conjugate, upon labeling with the pure ß--emitter 90Y3+, could represent a promising candidate as radiotracer for an innovative radio-guided surgery (RGS) technique, developed and patented by researchers of our group, which uses a probe system for intraoperative detection of tumor residues exploiting the selective uptake of ß--emitting tracers. The results reported in this study show that multiple DOTA molecules bind to lysine residues of both light and heavy chains of the antibody and, probably, some of them are linked to the variable region of antibody. Moreover, the new mass spectrometric analysis highlights the presence of unreacted NIM in the final product. The information obtained by this work is of fundamental importance in the perspective to utilize this conjugate as a radiocompound after its labeling with 90Y3+ radioisotope. Indeed, the conjugation efficiency and the presence of unreacted NIM affect the specific activity of the final radiotracer which binds specific receptor.

Feasibility of beta-particle radioguided surgery for a variety of "nuclear medicine" radionuclides.

PURPOSE: Beta-particle radioguided tumor resection may potentially overcome the limitations of conventional gamma-ray guided surgery by eliminating, or at least minimizing, the confounding effect of counts contributed by activity in adjacent normal tissues. The current study evaluates the clinical feasibility of this approach for a variety of radionuclides. Nowadays, the only ß- radioisotope suited to radioguided surgery is 90Y. Here, we study the ß- probe prototype capability to different radionuclides chosen among those used in nuclear medicine. METHODS: The counting efficiency of our probe prototype was evaluated for sources of electrons and photons of different energies. Such measurements were used to benchmark the Monte Carlo (MC) simulation of the probe behavior, especially the parameters related to the simulation of the optical photon propagation in the scintillation crystal. Then, the MC simulation was used to derive the signal and the background we would measure from a small tumor embedded in the patient body if one of the selected radionuclides is used. RESULTS: Based on the criterion of detectability of a 0.1 ml tumor for a counting interval of 1 s and an administered activity of 3 MBq/kg, the current probe yields a detectable signal over a wide range of Standard Uptake Values (SUVs) and tumor-to-non-tumor activity-concentration ratios (TNRs) for 31Si, 32P, 97Zr, and 188Re. Although efficient counting of 83Br, 133I, and 153Sm proved somewhat more problematic, the foregoing criterion can be satisfied for these isotopes as well for sufficiently high SUVs and TNRs.

Benchmarking Geant4 hadronic models for prompt-γ monitoring in carbon ion therapy.

PURPOSE: The real-time monitoring of the spread-out Bragg peak would allow the planned dose delivered during treatment to be directly verified, but this poses a major challenge in modern ion beam therapy. A possible method to achieve this goal is to exploit the production of secondary particles by the nuclear reactions of the beam with the patient and correlate their emission profile to the planned target volume position. In this study, we present both the production rate and energy spectra of the prompt-γ produced by the interactions of the 12 C ion beam with a polymethyl methacrylate (PMMA) target. We also assess three different Monte Carlo models for prompt-γ simulation based on our experimental data. METHODS: The experiment was carried out at the GSI Helmholtz Centre for Heavy Ion Research, Darmstadt, Germany with a 220 MeV/u 12 C ions beam impinging on a 5× 5× 20 cm3 polymethyl methacrylate beam stopping target, with the prompt-γ being detected by a hexagonally-shaped barium fluoride scintillator with a circumscribed radius of 5.4 cm and a length of 14 cm, placed at 60° and 90° with respect to the beam direction. Monte Carlo simulations were carried out with three different hadronic models from the Geant4 code: binary ion cascade (BIC), quantum molecular dynamics (QMD), and Liege intranuclear cascade (INCL++ ). RESULTS: An experimental prompt-γ yield of 1.06 × 10-2  sr-1 was measured at 90°. A good agreement was observed between the shapes of the experimental and simulated energy spectra, especially with the INCL++ physics list. The prompt-γ yield obtained with this physics list was compatible with the measurement within 2σ, with a relative difference of 26% on average. BIC and QMD physics lists proved to be less accurate than INCL++ , with the difference between the measured and simulated yields exceeding 100%. The differences between the three physics lists were ascribed to important discrepancies between the models of the physical processes producing prompt-γ emissions. CONCLUSION: In conclusion, this study provides prompt-γ yield values in agreement with previously published results for different carbon ions energies. This work demonstrates that the INCL++ physics list from Geant4 is more accurate than BIC and QMD to reproduce prompt-γ emission properties.

Design of a new tracking device for on-line beam range monitor in carbon therapy.

Charged particle therapy is a technique for cancer treatment that exploits hadron beams, mostly protons and carbon ions. A critical issue is the monitoring of the beam range so to check the correct dose deposition to the tumor and surrounding tissues. The design of a new tracking device for beam range real-time monitoring in pencil beam carbon ion therapy is presented. The proposed device tracks secondary charged particles produced by beam interactions in the patient tissue and exploits the correlation of the charged particle emission profile with the spatial dose deposition and the Bragg peak position. The detector, currently under construction, uses the information provided by 12 layers of scintillating fibers followed by a plastic scintillator and a pixelated Lutetium Fine Silicate (LFS) crystal calorimeter. An algorithm to account and correct for emission profile distortion due to charged secondaries absorption inside the patient tissue is also proposed. Finally detector reconstruction efficiency for charged particle emission profile is evaluated using a Monte Carlo simulation considering a quasi-realistic case of a non-homogenous phantom.

Monitoring of Hadrontherapy Treatments by Means of Charged Particle Detection.

The interaction of the incoming beam radiation with the patient body in hadrontherapy treatments produces secondary charged and neutral particles, whose detection can be used for monitoring purposes and to perform an on-line check of beam particle range. In the context of ion-therapy with active scanning, charged particles are potentially attractive since they can be easily tracked with a high efficiency, in presence of a relatively low background contamination. In order to verify the possibility of exploiting this approach for in-beam monitoring in ion-therapy, and to guide the design of specific detectors, both simulations and experimental tests are being performed with ion beams impinging on simple homogeneous tissue-like targets (PMMA). From these studies, a resolution of the order of few millimeters on the single track has been proven to be sufficient to exploit charged particle tracking for monitoring purposes, preserving the precision achievable on longitudinal shape. The results obtained so far show that the measurement of charged particles can be successfully implemented in a technology capable of monitoring both the dose profile and the position of the Bragg peak inside the target and finally lead to the design of a novel profile detector. Crucial aspects to be considered are the detector positioning, to be optimized in order to maximize the available statistics, and the capability of accounting for the multiple scattering interactions undergone by the charged fragments along their exit path from the patient body. The experimental results collected up to now are also valuable for the validation of Monte Carlo simulation software tools and their implementation in Treatment Planning Software packages.

Time Evolution of DOTATOC Uptake in Neuroendocrine Tumors in View of a Possible Application of Radioguided Surgery with ß- Decay.

UNLABELLED: A novel radioguided surgery (RGS) technique exploiting ß- radiation has been proposed. To develop such a technique, a suitable radiotracer able to deliver a ß- emitter to the tumor has to be identified. A first candidate is represented by 90Y-labeled DOTATOC, a compound commonly used today for peptide radioreceptor therapy. The application of this ß- RGS to neuroendocrine tumors (NET) requires study of the uptake of DOTATOC and its time evolution both in tumors and in healthy organs and evaluation of the corresponding performance of the technique. METHODS: Uptake by lesions and healthy organs (kidneys, spleen, liver and healthy muscle) was estimated on 177Lu-DOTATOC SPECT/CT scans of 15 patients affected by NET with different localizations, treated at IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. For each patient, SPECT/CT images, acquired at 0.5, 4, 20, 40, and 70 h after injection, were studied. For each lesion, the tumor-to-nontumor ratio (TNR) with respect to all healthy organs and its time evolution were studied. A subset of patients showing hepatic lesions was selected, and the TNR with respect to the nearby healthy tissue was calculated. By means of a Monte Carlo simulation of the probe for ß- RGS, the activity that is to be administered for a successful detection was estimated lesion-by-lesion. RESULTS: Uptake of DOTATOC on NETs maximized at about 24 h after injection. The cases of hepatic lesions showed a TNR with respect to the tumor margins compatible with the application of ß- RGS. In particular, 0.1-mL residuals are expected to be detectable within 1 s with 5% false-negative and 1% false-positive by administering the patient as little as 1 MBq/kg. CONCLUSION: The balance between tumor uptake and metabolic washout in healthy tissue causes the TNR to increase with time, reaching its maximum after 24 h, and this characteristic can be exploited when a radiotracer with a long half-life, such as 90Y, is used. In particular, if 90Y-DOTATOC is used with liver NET metastases, the proposed RGS technique is believed to be feasible by injecting an activity that is one third of that commonly used for PET imaging.

Toward radioguided surgery with ß- decays: uptake of a somatostatin analogue, DOTATOC, in meningioma and high-grade glioma.

UNLABELLED: A novel radioguided surgery (RGS) technique for cerebral tumors using ß(-) radiation is being developed. Checking for a radiotracer that can deliver a ß(-) emitter to the tumor is a fundamental step in the deployment of such a technique. This paper reports a study of the uptake of (90)Y-DOTATOC in meningiomas and high-grade gliomas (HGGs) and a feasibility study of the RGS technique in these types of tumor. Estimates were performed assuming the use of a ß(-) probe under development with a sensitive area 2.55 mm in radius to detect 0.1-mL residuals. METHODS: Uptake and background from healthy tissues were estimated on (68)Ga-DOTATOC PET scans of 11 meningioma patients and 12 HGG patients. A dedicated statistical analysis of the DICOM images was developed and validated. The feasibility study was performed using full simulation of emission and detection of the radiation, accounting for the measured uptake and background rate. RESULTS: All meningioma patients but one with an atypical extracranial tumor showed high uptake of DOTATOC. In terms of feasibility of the RGS technique, we estimated that by administering a 3 MBq/kg activity of radiotracer, the time needed to detect a 0.1-mL remnant with 5% false-negative and 1% false-positive rates is less than 1 s. Actually, to achieve a detection time of 1 s the required activities to administer were as low as 0.2-0.5 MBq/kg in many patients. In HGGs, the uptake was lower than in meningiomas, but the tumor-to-nontumor ratio was higher than 4, which implies that the tracer can still be effective for RGS. It was estimated that by administering 3 mBq/kg of radiotracer, the time needed to detect a 0.1-mL remnant is less than 6 s, with the exception of the only oligodendroma in the sample. CONCLUSION: Uptake of (90)Y-DOTATOC in meningiomas was high in all studied patients. Uptake in HGGs was significantly worse than in meningiomas but was still acceptable for RGS, particularly if further research and development are done to improve the performance of the ß(-) probe.

Autologous chondrocyte implantation: a comparison between an open periosteal-covered and an arthroscopic matrix-guided technique.

In this prospective study, the authors compared the Carticel method of autologous chondrocyte implantation with the Hyalograft C technique. The aim of the study was to compare the clinical outcomes of the two methods, to identify any complications and to analyse MRI images of the repair process. Seventeen patients who had received autologous chondrocyte implantation with the Carticel technique and ten treated with Hyalograft C were assessed. A statistically significant improvement was observed in both groups at six months (p < 0.001 for Carticel and p = 0.002 for Hyalograft C) and at twelve months after surgery (p < 0.001 both for Carticel and Hyalograft C), according to HSS (Hospital for Special Surgery) and ICRS (International Cartilage Repair Society) scores. There were no statistically significant differences between the two groups. MRI images obtained one year after surgery revealed the formation of well-integrated tissue similar to the surrounding healthy cartilage in most cases, in both Carticel and Hyalograft C groups. Six patients treated with Carticel technique were also assessed by second-look arthroscopy and histology of biopsies. The newly-formed tissue presented structural features similar to normal cartilage in most cases (84%). Molecular analysis was performed to assess mRNA levels of the various collagen molecules and proliferation and differentiation factors: the results showed that the implanted material undergoes progressive remodelling to regenerate hyaline cartilage. Both Carticel and Hyalograft C implantation techniques seem to lead to comparable short- and medium-term results. Moreover, this study confirmed that MRI is a valid tool in the follow-up evaluation of autologous chondrocyte implantation.

Patella resurfacing in posterior stabilised total knee arthroplasty: a follow-up study in 56 patients.

Patellar resurfacing in total knee arthroplasty (TKA) remains controversial. This study evaluates the results of resurfacing and non-resurfacing of the patella. Fifty-six patients with osteoarthritis (OA) of the knee were enrolled in a prospective randomised clinical trial using a posterior-stabilised TKA. Evaluations were done preoperatively and after 1, 3, 6, 12 and 24 months. Disease specific (Knee Society Score or KSS) and functional (patella-related activities) outcomes were measured. Patient satisfaction and anterior knee pain questionnaires were completed. No patients were lost to follow-up. No significant differences were found between groups with regard to the clinical part of the Knee Society score (KSS) not even in obese patients, the ability of performing daily activities involving the patellofemoral joint, and patient satisfaction. Significant differences were found regarding the functional section of the KSS, passive flexion, anterior knee pain and patellar tilt and subluxation. In conclusion, the authors believe that, for the implant studied, patellar resurfacing can be indicated.

Molecular and immunohistological characterization of human cartilage two years following autologous cell transplantation.

BACKGROUND: There are only a few studies concerning the cellular, biochemical, and genetic processes that occur during the remodeling of graft tissue after autologous chondrocyte transplantation. The purpose of the present study was to quantify the expression of genes encoding extracellular matrix proteins and regulatory factors that are essential for cell differentiation in cartilage biopsy specimens from patients who had this treatment two years previously. METHODS: Two cartilage biopsy specimens from each of four patients who had been treated with autologous chondrocyte transplantation and from two multiorgan donors were used. Real-time reverse transcriptase-polymerase chain reaction analysis was performed to evaluate the expression of types I, II, and X collagen; aggrecan; cathepsin B; and early growth response protein-1 (Egr-1) and Sry-type high-mobility-group box transcription factor-9 (Sox-9) mRNAs. Immunohistochemical analysis for matrix proteins and regulatory proteins was carried out on paraffin-embedded sections. RESULTS: Type-I collagen mRNA was expressed in all of the samples evaluated. Type-II collagen was present in autologous chondrocyte transplantation samples but at lower levels than in the controls. Type-X collagen messenger was undetectable. Aggrecan mRNA was present in all of the samples at lower levels than in the controls, while cathepsin-B messenger levels were higher and Egr-1 and Sox-9 mRNAs were expressed at lower levels. The immunohistochemical analysis showed slight positivity for type-I collagen in all of the sections. Type-II collagen was found in all of the samples with positivity confined inside the cells, while the controls displayed a positivity that was diffuse in the extracellular matrix. Cathepsin B was slightly positive in all of the samples, while the controls were negative. Egr-1 protein was particularly evident in the areas negative for type-II collagen. Sox-9 was positive in all samples, with evident localization in the superficial and middle layers. CONCLUSIONS: In biopsy specimens from autologous chondrocyte transplantation tissue at two years, there is evidence of the formation of new tissue, which displays varying degrees of organization with some fibrous and fibrocartilaginous features. Long-term follow-up investigations are needed to verify whether, once all of the remodeling processes are completed, the newly formed tissue will acquire the more typical features of articular cartilage.