Monte Carlo and experimental evaluation of a Timepix4 compact gamma camera for coded aperture nuclear medicine imaging with depth resolution.

PURPOSE: We designed a prototype compact gamma camera (MediPROBE4) for nuclear medicine tasks, including radio-guided surgery and sentinel lymph node imaging with a 99mTc radiotracer. We performed Monte Carlo (MC) simulations for image performance assessment, and first spectroscopic imaging tests with a 300 µm thick silicon detector. METHODS: The hand-held camera (1 kg weight) is based on a Timepix4 readout circuit for photon-counting, energy-sensitive, hybrid pixel detectors (24.6 × 28.2 mm2 sensitive area, 55 µm pixel pitch), developed by the Medipix4 Collaboration. The camera design adopts a CdTe detector (1 or 2 mm thick) bump-bonded to a Timepix4 readout chip and a coded aperture collimator with 0.25 mm diameter round holes made of 3D printed 1-mm thick tungsten. Image reconstruction is performed via autocorrelation deconvolution. RESULTS: Geant4 MC simulations showed that, for a 99mTc source in air, at 50 mm source-collimator distance, the estimated collimator sensitivity (4 × 10-4) is 292 times larger than that of a single hole in the mask; the system sensitivity is 0.22 cps/kBq (2 mm CdTe); the lateral spatial resolution is 1.7 mm FWHM. The estimated axial longitudinal resolution is 8.2 mm FWHM at 40 mm distance. First experimental tests with a 300 µm thick Silicon pixel detector bump-bonded to a Timepix4 chip and a high-resolution coded aperture collimator showed time-over-threshold and time-of-arrival capabilities with 241Am and 133Ba gamma-ray sources. CONCLUSIONS: MC simulations and validation lab tests showed the expected performance of the MediPROBE4 compact gamma camera for gamma-ray 3D imaging.

Deep sedation for nasal septal surgery: an observational retrospective study with an inverse probability weighting model.

BACKGROUND: Septoplasty, a common surgical procedure to correct a deviated septum, can be performed under either general anesthesia or deep sedation anesthesia. The choice of anesthesia can influence the duration of anesthesia and surgical outcomes, impacting the feasibility of outpatient procedures. METHODS: The institutional review board approved the protocol, and we obtained written informed consent from all participants. This retrospective, single-center observational study analyzed data from 586 patients who underwent rhino septoplasty at Santo Stefano Hospital in Prato, Italy, from 2017 to 2021. Patients received either general anesthesia or deep sedation anesthesia. Propensity score matching and inverse probability weighting were used to balance patient characteristics. The main outcome variable was discharge time, with anesthesia time and surgical time as covariates. Statistical analysis was conducted using R software. RESULTS: Patients who received deep sedation anesthesia had a significantly shorter duration of anesthesia compared to those who received general anesthesia. A multivariate linear regression model showed that the type of anesthesia had a strong positive association with discharge time, while anesthesia time had a weaker negative association, although not statistically significant. CONCLUSIONS: Deep sedation anesthesia is associated with a shorter duration of anesthesia compared to general anesthesia during nasal septal surgery, suggesting it could be a more feasible option for outpatient procedures. However, the choice of anesthesia should be tailored to individual patient factors and surgical requirements. Further research is needed to confirm these findings and explore the potential benefits of sedation anesthesia in outpatient nasal septal surgery. QUESTION: How do general anesthesia and deep sedation anesthesia compare in terms of duration of anesthesia and surgical outcomes during nasal septal surgery? FINDINGS: Our study found that deep sedation anesthesia was associated with a shorter duration of anesthesia compared to general anesthesia in patients undergoing nasal septal surgery. However, there were no significant differences in the duration of the surgical procedure. MEANING: The findings suggest that deep sedation anesthesia could potentially make nasal septal surgery more feasible as an outpatient procedure.

Spawning time in adult polar cod (Boreogadus saida) altered by crude oil exposure, independent of food availability.

Fish early life stages are well known for their sensitivity to crude oil exposure. However, the effect of crude oil exposure on adults and their gametes during their spawning period is not well studied. Polar cod, a key arctic fish, may be at risk for crude oil exposure during this potentially sensitive life stage. Additionally, this species experiences lower food availability during their spawning season, with unknown combined consequences. In the present study, wild-caught polar cod were exposed to decreasing levels of a water-soluble fraction (WSF) of crude oil or control conditions and fed either at a low or high feed ration to assess the combined effect of both stressors. Samples were taken during late gonadal development, during active spawning (spawning window), and in the post-spawning period. Histology analysis of gonads from fish sampled during the spawning window showed that oil-exposed polar cod were more likely to have spawned compared to controls. Oil-exposed females had 947 differentially regulated hepatic genes, and their eggs had a higher polycyclic aromatic hydrocarbon body burden compared to controls. Feed ration did not consistently affect polar cod's response to oil exposure for the endpoints measured, however, did alone result in decreases in some sperm motility parameters. These results suggest that polar cod's spawning period is a sensitive life event to crude oil exposure, while feed limitation may play a minor role for this supposedly capital breeder. The effects of adult exposure to crude oil on gamete quality and the next generation warrant further investigation.

ACR TI-RADS Score combined with cytopathology classification improves the risk stratification of indeterminate thyroid nodules.

BACKGROUND: The aim of this retrospective study was the elaboration of a new diagnostic model that integrate cytological reports (2017 Bethesda System for Reporting Thyroid Cytopathology) with ultrasonographic features (based on ACR TI-RADS score) to achieve a more accurate definition of indeterminate thyroid nodule malignancy risk. METHODS: Ninety patients submitted to thyroidectomy were divided in three classes: low malignancy risk (AUS/FLUS with TI-RADS 2/TI-RADS 3 and FN/SFN with TI-RADS 2), intermediate malignancy risk (AUS/FLUS with TI-RADS 4/TI-RADS 5 and FN/SFN with TI-RADS 3/TI-RADS 4), and high malignancy risk (FN/SFN with TI-RADS 5). RESULTS: The surgical approach should be recommended in high-risk patients (81.82% of malignancies), carefully evaluated in intermediate risk (25.42%), whereas a conservative approach can be adopted in low-risk patients (0.00%). CONCLUSIONS: The integration of these two multiparametric systems in a Cyto-US score has proven to be a feasible and reliable aid to achieve a more accurate definition of malignancy risk.

Patient-specific Monte Carlo-based organ dose estimates in spiral CT via optical 3D body scanning and adaptation of a voxelized phantom dataset: proof-of-principle.

Objective. We present a method for personalized organ dose estimates obtained before the computed tomography (CT) exam, via 3D optical body scanning and Monte Carlo (MC) simulations.Approach. A voxelized phantom is derived by adapting a reference phantom to the body size and shape measured with a portable 3D optical scanner, which returns the 3D silhouette of the patient. This was used as an external rigid envelope for incorporating a tailored version of the internal body anatomy derived from a phantom dataset (National Cancer Institute, NIH, USA) matched for gender, age, weight, and height. The proof-of-principle was conducted on adult head phantoms. The Geant4 MC code provided estimates of the organ doses from 3D absorbed dose maps in the voxelized body phantom.Main results. We applied this approach for head CT scanning using an anthropomorphic voxelized head phantom derived from 3D optical scans of manikins. We compared the estimates of head organ doses with those provided by the NCICT 3.0 software (NCI, NIH, USA). Head organ doses differed up to 38% using the proposed personalized estimate and MC code, with respect to corresponding estimates calculated for the standard (non-personalized) reference head phantom. Preliminary application of the MC code to chest CT scans is shown. Real-time pre-exam personalized CT dosimetry is envisaged with adoption of a Graphics Processing Unit-based fast MC code.Significance. The developed procedure for personalized organ dose estimates before the CT exam, introduces a new approach for realistic description of size and shape of patients via voxelized phantoms specific for each patient.

The utility of intraoperative PTH dosage in primary hyperparathyroidism based on preoperative diagnosis and surgical choice.

BACKGROUND: The aim of this study was to evaluate the impact of the intraoperative PTH (ioPTH) monitoring in the success of parathyroidectomy based on the concordant or indeterminate preoperative imaging studies of localization and the performed surgical choices. METHODS: Fourthy-seven patients who received parathyroidectomy operations were divided in four groups: concordance of the imaging and ioPTH, concordance of the imaging and no ioPTH, indeterminate imaging and ioPTH and indeterminate imaging and no ioPTH. RESULTS: Overall, patients in whom ioPTH monitoring was not performed were healed in 89.47% of cases, while the percentage of recovery in patients receiving ioPTH was 85.71%. There were no differences in the changes in strategy or in the cure rates with the use of ioPTH. CONCLUSIONS: No significant differences were found, independently from the preoperative imaging agreement, in either the cure rate or in the change of intraoperative strategy using the ioPTH dosage.

Attenuation coefficient in the energy range 14-36 keV of 3D printing materials for physical breast phantoms.

Objective.To measure the monoenergetic x-ray linear attenuation coefficient,µ, of fused deposition modeling (FDM) colored 3D printing materials (ABS, PLAwhite, PLAorange, PET and NYLON), used as adipose, glandular or skin tissue substitutes for manufacturing physical breast phantoms.Approach. Attenuation data (at 14, 18, 20, 24, 28, 30 and 36 keV) were acquired at Elettra synchrotron radiation facility, with step-wedge objects, using the Lambert-Beer law and a CCD imaging detector. Test objects were 3D printed using the Ultimaker 3 FDM printer. PMMA, Nylon-6 and high-density polyethylene step objects were also investigated for the validation of the proposed methodology. Printing uniformity was assessed via monoenergetic and polyenergetic imaging (32 kV, W/Rh).Main results. Maximum absolute deviation ofµfor PMMA, Nylon-6 and HD-PE was 5.0%, with reference to literature data. For ABS and NYLON,µdiffered by less than 6.1% and 7.1% from that of adipose tissue, respectively; for PET and PLAorangethe difference was less than 11.3% and 6.3% from glandular tissue, respectively. PLAorangeis a good substitute of skin (differences from -9.4% to +1.2%). Hence, ABS and NYLON filaments are suitable adipose tissue substitutes, while PET and PLAorangemimick the glandular tissue. PLAwhitecould be printed at less than 100% infill density for matching the attenuation of glandular tissue, using the measured density calibration curve. The printing mesh was observed for sample thicknesses less than 60 mm, imaged in the direction normal to the printing layers. Printing dimensional repeatability and reproducibility was less 1%.Significance. For the first time an experimental determination was provided of the linear attenuation coefficient of common 3D printing filament materials with estimates ofµat all energies in the range 14-36 keV, for their use in mammography, breast tomosynthesis and breast computed tomography investigations.

Fabrication of 3D printed patient-derived anthropomorphic breast phantoms for mammography and digital breast tomosynthesis: Imaging assessment with clinical X-ray spectra.

PURPOSE: To design, fabricate and characterize 3D printed, anatomically realistic, compressed breast phantoms for digital mammography (DM) and digital breast tomosynthesis (DBT) x-ray imaging. MATERIALS: We realized 3D printed phantoms simulating healthy breasts, via fused deposition modeling (FDM), with a layer resolution of 0.1 mm and 100% infill density, using a dual extruder printer. The digital models were derived from a public dataset of segmented clinical breast computed tomography scans. Three physical phantoms were printed in polyethylene terephthalate (PET), acrylonitrile-butadiene-styrene (ABS), or in polylactic-acid (PLA) materials, using ABS as a substitute for adipose tissue, and PLA or PET filaments for replicating glandular and skin tissues. 3D printed phantoms were imaged at three clinical centers with DM and DBT scanners, using typical spectra. Anatomical noise of the manufactured phantoms was evaluated via the estimates of the ß parameter both in DM images and in images acquired via a clinical computed tomography (CT) scanner. RESULTS: DM and DBT phantom images showed an inner texture qualitatively similar to the images of a clinical DM or DBT exam, suitably reproducing the glandular structure of their computational phantoms. ß parameters evaluated in DM images of the manufactured phantoms ranged between 2.84 and 3.79; a lower ß was calculated from the CT scan. CONCLUSIONS: FDM 3D printed compressed breast phantoms have been fabricated using ABS, PLA and PET filaments. DM and DBT images with clinical x-ray spectra showed realistic textures. These phantoms appear promising for clinical applications in quality assurance, image quality and dosimetry assessments.

Comparisons of glandular breast dose between digital mammography, tomosynthesis and breast CT based on anthropomorphic patient-derived breast phantoms.

PURPOSE: To evaluate the bias to the mean glandular dose (MGD) estimates introduced by the homogeneous breast models in digital breast tomosynthesis (DBT) and to have an insight into the glandular dose distributions in 2D (digital mammography, DM) and 3D (DBT and breast dedicated CT, BCT) x-ray breast imaging by employing breast models with realistic glandular tissue distribution and organ silhouette. METHODS: A Monte Carlo software for DM, DBT and BCT simulations was adopted for the evaluation of glandular dose distribution in 60 computational anthropomorphic phantoms. These computational phantoms were derived from 3D breast images acquired via a clinical BCT scanner. RESULTS: g·c·s·T conversion coefficients based on homogeneous breast model led to a MGD overestimate of 18% in DBT when compared to MGD estimated via anthropomorphic phantoms; this overestimate increased up to 21% for recently computed DgNDBT conversion coefficients. The standard deviation of the glandular dose distribution in BCT resulted 60% lower than in DM and 55% lower than in DBT. The glandular dose peak - evaluated as the average value over the 5% of the gland receiving the highest dose - is 2.8 times the MGD in DM, this factor reducing to 2.6 and 1.6 in DBT and BCT, respectively. CONCLUSIONS: Conventional conversion coefficients for MGD estimates based on homogeneous breast models overestimate MGD by 18%, when compared to MGD estimated via anthropomorphic phantoms. The ratio between the peak glandular dose and the MGD is 2.8 in DM. This ratio is 8% and 75% higher than in DBT and BCT, respectively.

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.

Virtual Clinical Trials in 2D and 3D X-ray Breast Imaging and Dosimetry: Comparison of CPU-Based and GPU-Based Monte Carlo Codes.

Computational reproductions of medical imaging tests, a form of virtual clinical trials (VCTs), are increasingly being used, particularly in breast imaging research. The accuracy of the computational platform that is used for the imaging and dosimetry simulation processes is a fundamental requirement. Moreover, for practical usage, the imaging simulation computation time should be compatible with the clinical workflow. We compared three different platforms for in-silico X-ray 3D breast imaging: the Agata (University & INFN Napoli) that was based on the Geant4 toolkit and running on a CPU-based server architecture; the XRMC Monte Carlo (University of Cagliari) that was based on the use of variance reduction techniques, running on a CPU hardware; and the Monte Carlo code gCTD (University of Texas Southwestern Medical Center) running on a single GPU platform with CUDA environment. The tests simulated the irradiation of cylindrical objects as well as anthropomorphic breast phantoms and produced 2D and 3D images and 3D maps of absorbed dose. All the codes showed compatible results in terms of simulated dose maps and imaging values within a maximum discrepancy of 3%. The GPU-based code produced a reduction of the computation time up to factor 104, and so permits real-time VCT studies for X-ray breast imaging.

Breast radiotherapy with kilovoltage photons and gold nanoparticles as radiosensitizer: An in vitro study.

PURPOSE: We investigated the dose enhancement and internalization of gold nanoparticles (AuNPs) used as a radiosensitizer agent for rotational radiotherapy of breast cancer using a kilovoltage (kV) X-ray beam. METHODS: Human breast cancer cells MDA-MB-231 were incubated with or without 100 µg/mL (4.87 nM) or 200 µg/mL (9.74 nM) 15 nm AuNPs and irradiated with 100 kV, 190 kV, or 6 MV X-rays. To assess the toxicity of the AuNPs, we performed a Sulforhodamine B assay. Using atomic absorption spectroscopy, scanning electron microscopy, transmission electron microscopy, and time-lapse optical microscopy (rate of 2 frames per minute), we carried out a quantitative assessment of the amount of gold internalized by MDA-MB-231 cells and a characterization of the static and dynamical aspects of this internalization process. RESULTS: No effect of AuNPs alone was shown on cell viability. Time-lapse optical microscopy showed for the first time AuNPs cellular uptake and the dynamics of AuNPs internalization. Electron microscopy demonstrated AuNPs localization in endosomal vesicles, preferentially in the perinuclear region. After irradiation at doses up to 2 Gy, cell survival fraction curves showed increased mortality with AuNPs, with respect to irradiation without AuNPs. The highest effect of radioenhancement by AuNPs (at 9.74 nM AuNPs concentration) was observed at 190 kV showing a dose enhancement factor of 1.33 ± 0.06 (1.34 ± 0.02 at 100 kV), while at 6 MV it was 1.14 ± 0.06. CONCLUSIONS: The observed radio-sensitization effect is promising for future radio-enhanced kV radiotherapy of breast cancer and quantitatively in the order of previous observations for 15 nm AuNPs. These results of a significant dose enhancement were obtained at 15 nm AuNPs concentration as low as several nanomolar units, at dose levels typical of a single dose fraction in a radiotherapy session. Dynamical behavior of the 3D spatial distribution of 15 nm AuNPs outside the nucleus of single breast cancer cell was observed, with possible implications for future models of AuNPs sensitization.

Quick septoplasty in children: Long-term effects on nasal breathing and dentofacial morphology. A prospective cephalometric study.

OBJECTIVE: Many authors have investigated the most appropriate surgical approach to the deviated septum in childhood, considering the obligate mouth-breathing habit a possible cause of malocclusion and disharmonious development of the facial skeleton in growing kids. Nevertheless, controversies still remain about the long-term functional/esthetic results of such procedures, mainly due to the duration of the follow-up and possible confounding factors. METHODS: 111 Caucasian children (age range: 6-13 years) were submitted to a personal "Quick" septoplasty surgical technique between 2005 and 2010. Preoperative otorhinolaryngological examination using flexible nasal endoscopy, anterior active rhinomanometry (AAR), Nasal Obstruction Septoplasty Effectiveness (NOSE) questionnaire, and dentofacial evaluation (including cephalometry) were performed. Postoperative AAR, NOSE questionnaire and cephalometric assessment were carried out in all patients at the age of 18 years. Informed consent was obtained from children's parents as appropriate. RESULTS: No surgical complication was recorded. Among our patients, a significant (p <0.001) improvement of nasal breathing resistances at AAR and NOSE questionnaire scores was found after surgery. A significant improvement in cephalometric/dental parameters (gonial angle values, anterior facial height, prevalence of class I occlusion, maxillary intermolar width, and cross-bite frequency) was noticed after the follow-up with respect to preoperative conditions. CONCLUSION: The "Quick" septoplasty technique described is a practical and conservative procedure with a low complication rate that offers long-term favourable results for the correction of nasal septum deviations in children. Nasal-breathing restoration may favor a physiological and harmonious development of craniofacial and dental structures in offspring.

Efficient automated localization of ECoG electrodes in CT images via shape analysis.

PURPOSE: People with drug-refractory epilepsy are potential candidates for surgery. In many cases, epileptogenic zone localization requires intracranial investigations, e.g., via ElectroCorticoGraphy (ECoG), which uses subdural electrodes to map eloquent areas of large cortical regions. Precise electrodes localization on cortical surface is mandatory to delineate the seizure onset zone. Simple thresholding operations performed on patients' computed tomography (CT) volumes recognize electrodes but also other metal objects (e.g., wires, stitches), which need to be manually removed. A new automated method based on shape analysis is proposed, which provides substantially improved performances in ECoG electrodes recognition. METHODS: The proposed method was retrospectively tested on 24 CT volumes of subjects with drug-refractory focal epilepsy, presenting a large number (> 1700) of round platinum electrodes. After CT volume thresholding, six geometric features of voxel clusters (volume, symmetry axes lengths, circularity and cylinder similarity) were used to recognize the actual electrodes among all metal objects via a Gaussian support vector machine (G-SVM). The proposed method was further tested on seven CT volumes from a public repository. Simultaneous recognition of depth and ECoG electrodes was also investigated on three additional CT volumes, containing penetrating depth electrodes. RESULTS: The G-SVM provided a 99.74% mean classification accuracy across all 24 single-patient datasets, as well as on the combined dataset. High accuracies were obtained also on the CT volumes from public repository (98.27% across all patients, 99.68% on combined dataset). An overall accuracy of 99.34% was achieved for the recognition of depth and ECoG electrodes. CONCLUSIONS: The proposed method accomplishes automated ECoG electrodes localization with unprecedented accuracy and can be easily implemented into existing software for preoperative analysis process. The preliminary yet surprisingly good results achieved for the simultaneous depth and ECoG electrodes recognition are encouraging. Ethical approval n°NCT04479410 by "IRCCS Neuromed" (Pozzilli, Italy), 30th July 2020.

Dataset of patient-derived digital breast phantoms for in silico studies in breast computed tomography, digital breast tomosynthesis, and digital mammography.

PURPOSE: To present a dataset of computational digital breast phantoms derived from high-resolution three-dimensional (3D) clinical breast images for the use in virtual clinical trials in two-dimensional (2D) and 3D x-ray breast imaging. ACQUISITION AND VALIDATION METHODS: Uncompressed computational breast phantoms for investigations in dedicated breast CT (BCT) were derived from 150 clinical 3D breast images acquired via a BCT scanner at UC Davis (California, USA). Each image voxel was classified in one out of the four main materials presented in the field of view: fibroglandular tissue, adipose tissue, skin tissue, and air. For the image classification, a semi-automatic software was developed. The semi-automatic classification was compared via manual glandular classification performed by two researchers. A total of 60 compressed computational phantoms for virtual clinical trials in digital mammography (DM) and digital breast tomosynthesis (DBT) were obtained from the corresponding uncompressed phantoms via a software algorithm simulating the compression and the elastic deformation of the breast, using the tissue's elastic coefficient. This process was evaluated in terms of glandular fraction modification introduced by the compression procedure. The generated cohort of 150 uncompressed computational breast phantoms presented a mean value of the glandular fraction by mass of 12.3%; the average diameter of the breast evaluated at the center of mass was 105 mm. Despite the slight differences between the two manual segmentations, the resulting glandular tissue segmentation did not consistently differ from that obtained via the semi-automatic classification. The difference between the glandular fraction by mass before and after the compression was 2.1% on average. The 60 compressed phantoms presented an average glandular fraction by mass of 12.1% and an average compressed thickness of 61 mm. DATA FORMAT AND ACCESS: The generated digital breast phantoms are stored in DICOM files. Image voxels can present one out of four values representing the different classified materials: 0 for the air, 1 for the adipose tissue, 2 for the glandular tissue, and 3 for the skin tissue. The generated computational phantoms datasets were stored in the Zenodo public repository for research purposes (http://doi.org/10.5281/zenodo.4529852, http://doi.org/10.5281/zenodo.4515360). POTENTIAL APPLICATIONS: The dataset developed within the INFN AGATA project will be used for developing a platform for virtual clinical trials in x-ray breast imaging and dosimetry. In addition, they will represent a valid support for introducing new breast models for dose estimates in 2D and 3D x-ray breast imaging and as models for manufacturing anthropomorphic physical phantoms.

Normalized glandular dose coefficients for digital breast tomosynthesis systems with a homogeneous breast model.

This work aims at calculating and releasing tabulated values of dose conversion coefficients, DgNDBT, for mean glandular dose (MGD) estimates in digital breast tomosynthesis (DBT). The DgNDBT coefficients are proposed as unique conversion coefficients for MGD estimates, in place of dose conversion coefficients in mammography (DgNDM or c, g, s triad as proposed in worldwide quality assurance protocols) used together with the T correction factor. DgNDBT is the MGD per unit incident air kerma measured at the breast surface for a 0° projection and the entire tube load used for the scan. The dataset of polyenergetic DgNDBT coefficients was derived via a Monte Carlo software based on the Geant4 toolkit. Dose coefficients were calculated for a grid of values of breast characteristics (breast thickness in the range 20-90 mm and glandular fraction by mass of 1%, 25%, 50%, 75%, 100%) and the simulated geometries, scan protocols, irradiation geometries and typical spectral qualities replicated those of six commercial DBT systems (GE SenoClaire, Hologic Selenia Dimensions, GE Senographe Pristina, Fujifilm Amulet Innovality, Siemens Mammomat Inspiration and IMS Giotto Class). For given breast characteristics, target/filter combination, tube voltage and half value layer (HVL), two spectra with two HVL values have been simulated in order to permit MGD estimates from experimental HVL values via mathematical interpolation from tabulated values. The adopted breast model assumes homogenous composition of glandular and adipose tissues; it includes a 1.45 mm thick skin envelope in place of the 4-5 mm envelope commonly adopted in dosimetry protocols. The simulation code was validated versus AAPM Task group 195 Monte Carlo reference data sets (absolute differences not higher than 1.1%) and by comparison to relative dosimetry measurements with radiochromic film in a PMMA test object (differences within the maximum experimental uncertainty of 11%). The calculated coefficients show maximum relative deviations of -17.6% and +6.1% from those provided by the DBT dose coefficients adopted in the EUREF protocol and of 1.5%, on average, from data in the AAPM TG223 report. A spreadsheet is provided for interpolating the tabulated DgNDBT coefficients for arbitrary values of HVL, compressed breast thickness and glandular fraction, in the corresponding investigated ranges, for each DBT unit modeled in this work.

Open partial horizontal laryngectomy and adjuvant (chemo)radiotherapy for laryngeal squamous cell carcinoma: results from a multicenter Italian experience.

PURPOSE: To evaluate the functional and oncologic outcomes of adjuvant (chemo)radiation [(C)RT] after open partial horizontal laryngectomies (OPHLs). METHODS: Multicenter retrospective evaluation of 130 patients (116 males, 14 females) submitted between 1995 and 2017 to OPHL Types II and III for laryngeal cancer and receiving adjuvant (C)RT for one or more of the following risk factors at histopathologic examination of the surgical specimen: pT4a and/or > pN2a categories, close/positive resection margins, or presence of both perineural (PNI) and lympho-vascular invasion (LVI). The primary study endpoints were evaluation of the presence of tracheostomy and/or gastrostomy at last follow-up, and calculation of laryngo-esophageal dysfunction-free survival (LEDFS). RESULTS: Mean age of the study cohort was 60.8 ± 8.9 years (median, 62; interquartile range [IQR], 13). Mean follow-up was 50.7 ± 39.4 months (range 24-188; median, 38; IQR, 51). Adjuvant therapy consisted of CRT in 53 (41%) patients, and RT alone in 77 (59%). Five-year LEDFS was 85%. Overall survival was 71.5%, while 13% of patients remained tracheostomy- and 3% gastrostomy-dependent at the last follow-up. The only significant variable in predicting survival (p = 0.020) was tracheostomy dependence: it was maintained in 7.5% of subjects after OPHL Type II and in 34% of those submitted to OHPL Type III (p < 0.001). CONCLUSIONS: In selected patients affected by advanced laryngeal cancer, OPHLs Type II and III have a relatively good laryngeal safety profile and provide favorable oncologic outcomes even in case of need for adjuvant (C)RT.

Targeting OGG1 arrests cancer cell proliferation by inducing replication stress.

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.

Development of a chemical probe against NUDT15.

The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues.