Experimental validation of an innovative approach in biokinetics study for personalised dosimetry of molecular radiation therapy treatments.

One of today's main challenges in molecular radiation therapy is to assess an individual dosimetry that allows treatment to be tailored to the specific patient, in accordance with the current paradigm of 'personalized medicine'. The evaluation of the absorbed doses for tumor and organs at risk in molecular radiotherapy is typically based on MIRD schema acquiring few experimental points for the assessement of biokinetic parameters. WIDMApp, the wearable individual dose monitoring apparatus, is an innovative approach for internal dosimetry based on a wearable radiation detecting system for individual biokinetics sampling, a Monte Carlo simulation for particle interaction, and an unfolding algorithm for data analysis and integrated activity determination at organ level. A prototype of a WIDMApp detector element was used to record the photon emissions in a body phantom containing 3 spheres with liquid sources (18F,64Cu and99mTc) to simulate organs having different washout. Modelling the phantom geometry on the basis of a CT scan imaging, the Monte Carlo simulation computed the contribution of each emitting sphere to the signal detected in 3 positions on the phantoms surface. Combining the simulated results with the data acquired for 120 h, the unfolding algorithm deconvolved the detected signal and assessed the decay half-life (T1/2) and initial activity values (A(0)) that best reproduces the observed exponential decays. A 3%-18% level of agreement is found between the actualA(0) andT1/2values and those obtained by means of the minimization procedure based on the Monte Carlo simulation. That resulted in an estimation of the cumulated activity <15%. Moreover, WIDMApp data redundancy has been used to mitigate some experimental occurrences that happened during data taking. A first experimental test of the WIDMApp approach to internal radiation dosimetry is presented. Studies with patients are foreseen to validate the technique in a real environment.

Characterization and optimization of a ß detector for 18F radio-guided surgery.

Radio-Guided Surgery (RGS) is a nuclear medicine technique to support the surgeon during surgery towards a complete tumor resection. It is based on intraoperative detection of radiation emitted by a radio-pharmaceutical that bounds selectively to tumoral cells. In the past years, an approach that exploits ß- emitting radiotracers has been pursued to overtake some limitations of the traditional RGS based on γ emission. A particle detector dedicated to this application, demonstrating very high efficiency to ß- particles and remarkable transparency to photons, has been thus developed. As a by-product, its characteristics suggested the possibility to utilize it with ß+ emitting sources, more commonly in use in nuclear medicine. In this paper, performances of such detector on 18F liquid sources are estimated by means of Monte Carlo simulations (MC) and laboratory measurements. The experimental setup with a 18F saline solution comprised a "positron signal" spot (a 7 × 10 mm cylinder representing the tumor residual), and a surrounding "far background" volume, that represented for the detector an almost isotropic source of annihilation photons. Experimental results show good agreement with MC predictions, thus confirming the expected performances of the detector with 18F, and the validity of the developed MC simulation as a tool to predict the gamma background determined by a diffuse source of annihilation photons.

How I treat HER2-positive early breast cancer: how long adjuvant trastuzumab is needed?

Since its first approval in 2006, 1 year of adjuvant trastuzumab has been the standard of care for early-stage HER2-positive breast cancer. Nevertheless, the optimal duration of adjuvant trastuzumab was uncertain, and the standard 12-month duration has been questioned by a number of different trials. Although most of these studies were formally negative, a patient-level meta-analysis presented at the 2021 European Society for Medical Oncology (ESMO) meeting first showed the non-inferiority of 6-month trastuzumab. Through this review, we sought to take a closer look at the meta-analysis and the included trials to explain why we believe that non-inferiority should be interpreted with caution. Indeed, here we underline how the meta-analysis' results were mainly driven by the PERSEPHONE study, an old trial that tested non-standard chemo-trastuzumab regimens in a relatively low-risk population with doubtful endpoints. In summary, considering all the limitations of this analysis and the increasing use of effective anthracycline-free de-escalation strategies, we are convinced that 1-year trastuzumab should remain the standard of care.

Clinical development and current role of margetuximab for the treatment of breast cancer.

Up to 20% of breast cancers overexpress HER2, a molecular alteration conferring these tumors a particularly aggressive behavior. However, targeting HER2 has radically changed the prognosis of this disease in the last 2 decades, with multiple anti-HER2 compounds shown to improve disease outcomes both in the early and advanced setting. The latest anti-HER2 compound to be approved by the U.S. Food and Drug Administration (FDA) was margetuximab, an Fc-engineered monoclonal antibody with an improved binding to FcγRIIIA receptor, which leads to a greater antibody-dependent cellular cytotoxicity (ADCC) activation compared with trastuzumab. Margetuximab was shown to slightly improve progression-free survival compared with trastuzumab when combined with chemotherapy for the treatment of advanced HER2-positive breast cancer patients, and is now included among the available treatment options for pretreated HER2-positive breast cancer patients. In this monograph we recapitulate the clinical development, current role and future perspectives of margetuximab for the treatment of breast cancer.

Seroconversion in patients with cancer and oncology health care workers infected by SARS-CoV-2.

BACKGROUND: Patients with cancer have high risk for severe complications and poor outcome to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease [coronavirus disease 2019 (COVID-19)]. Almost all subjects with COVID-19 develop anti-SARS-CoV-2 immunoglobulin G (IgG) within 3 weeks after infection. No data are available on the seroconversion rates of cancer patients and COVID-19. PATIENTS AND METHODS: We conducted a multicenter, observational, prospective study that enrolled (i) patients and oncology health professionals with SARS-CoV-2 infection confirmed by real-time RT-PCR assays on nasal/pharyngeal swab specimens; (ii) patients and oncology health professionals with clinical or radiological suspicious of infection by SARS-CoV-2; and (iii) patients with cancer who are considered at high risk for infection and eligible for active therapy and/or major surgery. All enrolled subjects were tested with the 2019-nCoV IgG/IgM Rapid Test Cassette, which is a qualitative membrane-based immunoassay for the detection of IgG and IgM antibodies to SARS-CoV-2. The aim of the study was to evaluate anti-SARS-CoV-2 seroconversion rate in patients with cancer and oncology health care professionals with confirmed or clinically suspected COVID-19. RESULTS: From 30 March 2020 to 11 May 2020, 166 subjects were enrolled in the study. Among them, cancer patients and health workers were 61 (36.7%) and 105 (63.3%), respectively. Overall, 86 subjects (51.8%) had confirmed SARS-CoV-2 diagnosis by RT-PCR testing on nasopharyngeal swab specimen, and 60 (36.2%) had a clinical suspicious of COVID-19. Median time from symptom onset (for cases not confirmed by RT-PCR) or RT-PCR confirmation to serum antibody test was 17 days (interquartile range 26). In the population with confirmed RT-PCR, 83.8% of cases were IgG positive. No difference in IgG positivity was observed between cancer patients and health workers (87.9% versus 80.5%; P = 0.39). CONCLUSIONS: Our data indicate that SARS-CoV-2-specific IgG antibody detection do not differ between cancer patients and healthy subjects.

Feasibility study on the use of CMOS sensors as detectors in radioguided surgery with ß-- emitters.

Radioguided surgery (RGS) is a medical practice which thanks to a radiopharmaceutical tracer and a probe allows the surgeon to identify tumor residuals up to a millimetric resolution in real-time. The employment of ß- emitters, instead of γ or ß+, reduces background from healthy tissues, administered activity to the patient, and medical exposure. In a previous work the possibility of using a CMOS Imager (Aptina MT9V011), initially designed for visible light imaging, to detect ß- from 90Y or 90Sr sources has been established. Because of its possible application as counting probe in RGS, the performances of MT9V011 in clinical-like conditions were studied.1 Through horizontal scans on a collimated 90Sr source of different sizes (1, 3, 5, 7 mm), we have determined relationships between scan fit parameters and the source dimension, namely A quadratic correlation and a linear dependency of, respectively, signal integrated over scan interval, and maximum signal against source diameter, are determined. Horizontal scan measurements on a source, interposing collimators of different size, aim to determine relationships or correlations between scan fit parameters and source dimension. A quadratic correlation and a linear dependency of, respectively, signal integrated over scan interval, and maximum signal against source diameter are determined. In order to get closer to clinical conditions, agar-agar phantoms containing 90Y with different dimensions and activities were prepared. A 90Y phantom is characterized by a central spot and a ring all around, for simulating both signal (tumor) and background (surrounding healthy tissue). The relationship found between scan maximum and 90Sr source diameter is then exploited to extract the concentration ratio between spot and external ring of the 90Y phantom. This observable, defined as the ratio between the tumor and the nearby healthy tissues uptake simulates the Tumor-to-Non-tumor Ratio (TNR). With the aim of evaluating the sensor's ability to discriminate signal from background relying on the significance parameter, a further 90Y phantom, featuring a well-known and clinical-like activity will mimic the signal only condition. This result is used to extrapolate to different source sizes, after having estimated the background for various TNR. The obtained significance values suggest that the MT9V011 sensor is capable of distinguishing a signal from an estimated background, depending on the interplay among TNR, acquisition time and tumor diameter.

Tumor-non-tumor discrimination by a ß- detector for Radio Guided Surgery on ex-vivo neuroendocrine tumors samples.

This paper provides a first insight of the potential of the ß- Radio Guided Surgery (ß--RGS) in a complex surgical environment like the abdomen, where multiple sources of background concur to the signal at the tumor site. This case is well reproduced by ex-vivo samples of 90Y-marked Gastro-Entero-Pancreatic Neuroendocrine Tumors (GEP NET) in the bowel. These specimens indeed include at least three wide independent sources of background associated to three anatomical districts (mesentery, intestine, mucose). The study is based on the analysis of 37 lesions found on 5 samples belonging to 5 different patients. We show that the use of electrons, a short range particle, instead of γ particles, allows to limit counts read on a lesion to the sum of the tumor signal plus the background generated by the sole hosting district.The background on adjacent districts in the same specimen/patient is found to differ up to a factor 4, showing how the specificity and sensitivity of the ß--RGS technique can be fully exploited only upon a correct measurement of the contributing background. This locality has been used to set a site-specific cut-off algorithm to discriminate tumor and healthy tissue with a specificity of 100% and a sensitivity, on this test data sample, close to 100%. Factors influencing the sensitivity are also discussed. One of the specimens set allowed us evaluate the volume of the lesions, thus concluding that the probe was able to detect lesions as small as 0.04 mL in that particular case.

Characterisation of a ß detector on positron emitters for medical applications.

PURPOSE: Radio Guided Surgery (RGS) is a technique that helps the surgeon to achieve an as complete as possible tumor resection, thanks to the intraoperative detection of particles emitted by a radio tracer that bounds to tumoral cells. In the last years, a novel approach to this technique has been proposed that, exploiting ß- emitting radio tracers, overtakes some limitations of established γ-RGS. In this context, a first prototype of an intraoperative ß particle detector, based on a high light yield and low density organic scintillator, has been developed and characterised on pure ß- emitters, like 90Y. The demonstrated very high efficiency to ß- particles, together with the remarkable transparency to photons, suggested the possibility to use this detector also with ß+ emitting sources, that have plenty of applications in nuclear medicine. In this paper, we present upgrades and optimisations performed to the detector to reveal such particles. METHODS: Laboratory measurement have been performed on liquid Ga68 source, and were used to validate and tune a Monte Carlo simulation. RESULTS: The upgraded detector has an ~80% efficiency to electrons above ~110keV, reaching a plateau value of ~95%. At the same time, the probe is substantially transparent to photons below ~200keV, reaching a plateau value of ~3%. CONCLUSIONS: The new prototype seems to have promising characteristics to perform RGS also with ß+ emitting isotopes.

The ß- radio-guided surgery: Method to estimate the minimum injectable activity from ex-vivo test.

PURPOSE: Radio-guided surgery with ß- decays is a novel technique under investigation. One of the main advantages is its capability to detect small (⩽0.1 ml) samples after injecting the patient with low activity of radiopharmaceutical. This paper presents an experimental method to quantify this feature based on ex-vivo tests on specimens from meningioma patients. METHODS: Patients were enrolled on the basis of the standard uptake value (SUV) and the tumour-to-non-tumour activity ratio (TNR) resulted from 68Ga-DOTATOC PET exams. After injecting the patients with 93-167 MBq of 90Y-DOTATOC, 26 samples excised during surgery were analyzed with a ß- probe. The radioactivity expected on the neoplastic specimens was estimated according to the SUV found in the PET scan and the correlation with the measured counts was studied. The doses to surgeon and medical personnel were also evaluated. RESULTS: Even injecting as low as 1.4 MBq/kg of radiotracer, tumour residuals of 0.1 ml can be detected. A negligible dose to the medical personnel was confirmed. CONCLUSIONS: Radio-guided surgery with ß- decays is a feasible technique with a low radiation dose for both personnel and patient, in particular if the patient is injected with the minimum required activity. A correlation greater than 80% was observed between the measured counts and the expected activity for the lesion samples based on the individual SUV and the TNR. This makes identifiable the minimum injectable radiotracer activity for cases where 90Y is the utilized radionuclide.

Computational simulation of TEVAR in the ascending aorta for optimal endograft selection: A patient-specific case study.

Thoracic endovascular aortic repair of the ascending aorta is becoming an option for patients considered unfit for open surgery. Such an endovascular procedure requires careful pre-operative planning and the customization of prosthesis design. The patient-specific tailoring of the procedure may call for dedicated tools to investigate virtual treatment scenarios. Given such considerations, the present study shows a computational framework for choosing and deploying stent-grafts via Finite Element Analysis, by supporting the device sizing and selection in a real case dealing with the endovascular treatment of a pseudoaneurysm. In particular, three devices with various lengths and materials were examined. Two off-the-shelf devices were computationally tested: one composed of Stainless Steel rings with a nominal length of 60 mm and another one with Nitinol rings and a distal free flow extension, with a nominal length of 70 mm. In third place, a custom-made stent-graft, also with Nitinol rings and containing both proximal and distal bare extensions with a nominal length of 75 mm, was deployed. The latter solution based on patient morphology and virtually benchmarked in this simulation framework, enhanced the apposition to the wall by reducing the distance between the skirt and the vessel from more than 6 mm to less than 2 mm in the distal sealing zone. Our experience shows that in-silico simulations can help choosing the right endograft for the ascending aorta as well as the right deployment sequence. This process may also encourage vendors to develop new devices for cases where open repair is unfeasible.

First Result on the Neutrinoless Double-ß Decay of

We report the result of the search for neutrinoless double beta decay of ^{82}Se obtained with CUPID-0, the first large array of scintillating Zn^{82}Se cryogenic calorimeters implementing particle identification. We observe no signal in a 1.83 kg yr ^{82}Se exposure, and we set the most stringent lower limit on the 0νßß ^{82}Se half-life T_{1/2}^{0ν}>2.4×10^{24} yr (90% credible interval), which corresponds to an effective Majorana neutrino mass m_{ßß}<(376-770) meV depending on the nuclear matrix element calculations. The heat-light readout provides a powerful tool for the rejection of α particles and allows us to suppress the background in the region of interest down to (3.6_{-1.4}^{+1.9})×10^{-3} counts/(keV kg yr), an unprecedented level for this technique.

Search of the neutrino-less double beta decay of 82 Se into the excited states of 82 Kr with CUPID-0.

The CUPID-0 experiment searches for double beta decay using cryogenic calorimeters with double (heat and light) read-out. The detector, consisting of 24 ZnSe crystals 95 % enriched in 82 Se and two natural ZnSe crystals, started data-taking in 2017 at Laboratori Nazionali del Gran Sasso. We present the search for the neutrino-less double beta decay of 82 Se into the 0 1 + , 2 1 + and 2 2 + excited states of 82 Kr with an exposure of 5.74 kg · yr (2.24 × 10 25  emitters · yr). We found no evidence of the decays and set the most stringent limits on the widths of these processes: Γ ( 82 Se → 82 Kr 0 1 + )8.55 × 10 - 24  yr - 1 , Γ ( 82 Se → 82 Kr 2 1 + ) < 6.25 × 10 - 24  yr - 1 , Γ ( 82 Se → 82 Kr 2 2 + )8.25 × 10 - 24  yr - 1 (90 % credible interval).

Analysis of cryogenic calorimeters with light and heat read-out for double beta decay searches.

The suppression of spurious events in the region of interest for neutrinoless double beta decay will play a major role in next generation experiments. The background of detectors based on the technology of cryogenic calorimeters is expected to be dominated by α particles, that could be disentangled from double beta decay signals by exploiting the difference in the emission of the scintillation light. CUPID-0, an array of enriched Zn 82 Se scintillating calorimeters, is the first large mass demonstrator of this technology. The detector started data-taking in 2017 at the Laboratori Nazionali del Gran Sasso with the aim of proving that dual read-out of light and heat allows for an efficient suppression of the α background. In this paper we describe the software tools we developed for the analysis of scintillating calorimeters and we demonstrate that this technology allows to reach an unprecedented background for cryogenic calorimeters.

CUPID-0: the first array of enriched scintillating bolometers for 0 ν ß ß decay investigations.

The CUPID-0 detector hosted at the Laboratori Nazionali del Gran Sasso, Italy, is the first large array of enriched scintillating cryogenic detectors for the investigation of 82 Se neutrinoless double-beta decay ( 0 ν ß ß ). CUPID-0 aims at measuring a background index in the region of interest (RoI) for 0 ν ß ß at the level of 10 - 3  counts/(keV kg years), the lowest value ever measured using cryogenic detectors. CUPID-0 operates an array of Zn 82 Se scintillating bolometers coupled with bolometric light detectors, with a state of the art technology for background suppression and thorough protocols and procedures for the detector preparation and construction. In this paper, the different phases of the detector design and construction will be presented, from the material selection (for the absorber production) to the new and innovative detector structure. The successful construction of the detector lead to promising preliminary detector performance which is discussed here.

First ex vivo validation of a radioguided surgery technique with ß-radiation.

PURPOSE: A radio-guided surgery technique with ß(-)-emitting radio-tracers was suggested to overcome the effect of the large penetration of γ radiation. The feasibility studies in the case of brain tumors and abdominal neuro-endocrine tumors were based on simulations starting from PET images with several underlying assumptions. This paper reports, as proof-of-principle of this technique, an ex vivo test on a meningioma patient. This test allowed to validate the whole chain, from the evaluation of the SUV of the tumor, to the assumptions on the bio-distribution and the signal detection. METHODS: A patient affected by meningioma was administered 300MBq of (90)Y-DOTATOC. Several samples extracted from the meningioma and the nearby Dura Mater were analyzed with a ß(-) probe designed specifically for this radio-guided surgery technique. The observed signals were compared both with the evaluation from the histology and with the Monte Carlo simulation. RESULTS: we obtained a large signal on the bulk tumor (105cps) and a significant signal on residuals of ∼0.2ml (28cps). We also show that simulations predict correctly the observed yields and this allows us to estimate that the healthy tissues would return negligible signals (≈1cps). This test also demonstrated that the exposure of the medical staff is negligible and that among the biological wastes only urine has a significant activity. CONCLUSIONS: This proof-of-principle test on a patient assessed that the technique is feasible with negligible background to medical personnel and confirmed that the expectations obtained with Monte Carlo simulations starting from diagnostic PET images are correct.

Prediction of patient-specific post-operative outcomes of TAVI procedure: The impact of the positioning strategy on valve performance.

Prosthesis positioning in transcatheter aortic valve implantation procedures represents a crucial aspect for procedure success as demonstrated by many recent studies on this topic. Possible complications, device performance, and, consequently, also long-term durability are highly affected by the adopted prosthesis placement strategy. In the present work, we develop a computational finite element model able to predict device-specific and patient-specific replacement procedure outcomes, which may help medical operators to plan and choose the optimal implantation strategy. We focus in particular on the effects of prosthesis implantation depth and release angle. We start from a real clinical case undergoing Corevalve self-expanding device implantation. Our study confirms the crucial role of positioning in determining valve anchoring, replacement failure due to intra or para-valvular regurgitation, and post-operative device deformation.

First array of enriched Zn[Formula: see text]Se bolometers to search for double beta decay.

The R&D activity performed during the last years proved the potential of ZnSe scintillating bolometers to the search for neutrino-less double beta decay, motivating the realization of the first large-mass experiment based on this technology: CUPID-0. The isotopic enrichment in [Formula: see text]Se, the Zn[Formula: see text]Se crystals growth, as well as the light detectors production have been accomplished, and the experiment is now in construction at Laboratori Nazionali del Gran Sasso (Italy). In this paper we present the results obtained testing the first three Zn[Formula: see text]Se crystals operated as scintillating bolometers, and we prove that their performance in terms of energy resolution, background rejection capability and intrinsic radio-purity complies with the requirements of CUPID-0.

Pokemon proto-oncogene in oral cancer: potential role in the early phase of tumorigenesis.

OBJECTIVES: Oral squamous cell carcinoma (OSCC) represents about 90% of all oral neoplasms with a poor clinical prognosis. To improve survival of OSCC patients, it is fundamental to understand the basic molecular mechanisms characterizing oral carcinogenesis. Dysregulation of oncogenes and tumor suppressor genes seems to play a central role in tumorigenesis, including malignant transformation of the oral cavity. MATERIALS AND METHODS: We analyzed the expression levels of the pro-oncogenic transcription factor Pokemon through real-time PCR, Western blot and immunohistochemistry in tumor, and normal oral tissue samples obtained from 22 patients with OSCC. The relationship between tumor characteristics and the level of Pokemon intratumor expression was also analyzed. RESULTS: Pokemon was significantly downregulated in OSCC. In particular, both mRNA and protein levels (tumor vs normal tissue) inversely correlated with histological grading, suggesting its potential role as a prognostic factor for OSCC. Moreover, a significant inverse correlation was found between Pokemon protein expression levels (OSCC vs normal oral mucosa) and tumor size, supporting the hypothesis that Pokemon could play an important role in the early phase of tumor expansion. CONCLUSION: This work shows that reduced expression of Pokemon is a peculiar feature of OSCC. Additional studies may establish the effective role of Pokemon in oral tumorigenesis.

Simulation of transcatheter aortic valve implantation through patient-specific finite element analysis: two clinical cases.

Transcatheter aortic valve implantation (TAVI) is a minimally invasive procedure introduced to treat aortic valve stenosis in elder patients. Its clinical outcomes are strictly related to patient selection, operator skills, and dedicated pre-procedural planning based on accurate medical imaging analysis. The goal of this work is to define a finite element framework to realistically reproduce TAVI and evaluate the impact of aortic root anatomy on procedure outcomes starting from two real patient datasets. Patient-specific aortic root models including native leaflets, calcific plaques extracted from medical images, and an accurate stent geometry based on micro-tomography reconstruction are key aspects included in the present study. Through the proposed simulation strategy we observe that, in both patients, stent apposition significantly induces anatomical configuration changes, while it leads to different stress distributions on the aortic wall. Moreover, for one patient, a possible risk of paravalvular leakage has been found while an asymmetric coaptation occurs in both investigated cases. Post-operative clinical data, that have been analyzed to prove reliability of the performed simulations, show a good agreement with analysis results. The proposed work thus represents a further step towards the use of realistic computer-based simulations of TAVI procedures, aiming at improving the efficacy of the operation technique and supporting device optimization.

A novel radioguided surgery technique exploiting ß(-) decays.

The background induced by the high penetration power of the radiation is the main limiting factor of the current radio-guided surgery (RGS). To partially mitigate it, a RGS with ß(+)-emitting radio-tracers has been suggested in literature. Here we propose the use of ß(-)-emitting radio-tracers and ß(-) probes and discuss the advantage of this method with respect to the previously explored ones: the electron low penetration power allows for simple and versatile probes and could extend RGS to tumours for which background originating from nearby healthy tissue makes probes less effective. We developed a ß(-) probe prototype and studied its performances on phantoms. By means of a detailed simulation we have also extrapolated the results to estimate the performances in a realistic case of meningioma, pathology which is going to be our first in-vivo test case. A good sensitivity to residuals down to 0.1 ml can be reached within 1 s with an administered activity smaller than those for PET-scans thus making the radiation exposure to medical personnel negligible.