PSMA PET as a predictive tool for sub-regional importance estimates in the parotid gland

Objective: Xerostomia (subjective dry mouth) and radiation-induced salivary gland dysfunction remain a common side effect for head-and-neck radiotherapy patients, and attempts have been made to quantify the intra-parotid dose response. Here, we aim to compare several models of parotid gland regional importance with prostate specific membrane antigen (PSMA) positron emission tomography (PET), which has high concentrations of uptake in salivary glands and has been previously suggested to relate to gland functionality. Furthermore, we develop a predictive model of Clark et al.'s relative importance using radiomic features, and demonstrate a methodology for predicting patient-specific importance deviations from the population. Approach: Intra-parotid uptake was compared with four regional importance models using [18F]DCFPyL PSMA PET images. The correlation of uptake and importance was ascertained when numerous non-overlapping sub-regions were defined, while a paired t-test was used when binary regions were defined. Radiomic PSMA PET/CT features within Clark et al.'s sub-regions were used to develop a predictive model of population importance. Main Results: Clark et al.'s relative importance regions were significantly (p < 0.02) anti-correlated with PSMA PET uptake. Van Luijk et al.'s critical regions had significantly lower (p < 0.01) uptake than in non-critical regions. Kernel Ridge Regression with principal component analysis feature selection performed best over test sets (Mean Absolute Error = 0.08. Deblurring PSMA PET images with neural blind deconvolution strengthened correlations and improved model performance. Significance: This study suggests that regions of relatively low PSMA PET concentration in parotid glands may exhibit relatively high dose-sensitivity. We've demonstrated the ability of PSMA PET radiomic features for predicting relative importance within the parotid glands.Comment: 9 Figures, 7 Table

Neural blind deconvolution for simultaneous partial volume correction and super-sampling of PSMA PET images

Objective: We aimed to simultaneously mitigate partial volume effects (PVEs) in prostate-specific membrane antigen (PSMA) positron emission tomography (PET) images while performing super-sampling. Approach: Blind deconvolution is a method of estimating the hypothetical "deblurred" image along with the blur kernel (related to the point spread function) simultaneously. Traditional maximum a posteriori blind deconvolution methods require stringent assumptions and suffer from convergence to a trivial solution. A promising method of modelling the deblurred image and kernel with independent neural networks, called "neural blind deconvolution" was demonstrated on 2D natural images in 2020. In this work, we adapt neural blind deconvolution for PVE correction of PSMA PET images, along with simultaneous super-sampling. We compare this methodology with several interpolation methods, using blind image quality metrics, and test the model's ability to predict kernels by re-running the model after applying artificial "pseudo-kernels" to deblurred images. Main Results: Our results demonstrate improvements in image quality over other interpolation methods in terms of blind image quality metrics and visual assessment. Predicted kernels were similar between patients, and the model accurately predicted several artificially-applied pseudo-kernels, Significance: The intrinsically low spatial resolution of PSMA PET leads to PVEs which negatively impact uptake quantification in small regions. The proposed method can be used to mitigate this issue, and can be straightforwardly adapted for other medical imaging modalities.Comment: 10 Figures, 4 Tables, 19 page

Bacterial Pneumonia among HIV-Infected Patients: Decreased Risk After Tobacco Smoking Cessation. ANRS CO3 Aquitaine Cohort, 2000–2007

BACKGROUND: Bacterial pneumonia is still a substantial cause of morbidity and mortality in HIV-infected patients in the era of combination Antiretroviral Therapy. The benefit of tobacco withdrawal on the risk of bacterial pneumonia has not been quantified in such populations, exposed to other important risk factors such as HIV-related immunodeficiency. Our objective was to estimate the effect of tobacco smoking withdrawal on the risk of bacterial pneumonia among HIV-infected individuals. METHODOLOGY/PRINCIPAL FINDINGS: Patients of the ANRS CO3 Aquitaine Cohort with >or= two visits during 2000-2007 and without bacterial pneumonia at the first visit were included. Former smokers were patients who stopped smoking since >or= one year. We used Cox proportional hazards models adjusted on CD4+ lymphocytes (CD4), gender, age, HIV transmission category, antiretroviral therapy, cotrimoxazole prophylaxis, statin treatment, viral load and previous AIDS diagnosis. 135 cases of bacterial pneumonia were reported in 3336 patients, yielding an incidence of 12 per thousand patient-years. The adjusted hazard of bacterial pneumonia was lower in former smokers (Hazard Ratio (HR): 0.48; P = 0.02) and never smokers (HR: 0.50; P = 0.01) compared to current smokers. It was higher in patients with <200 CD4 cells/microL and in those with 200 to 349 CD4 cells/microL (HR: 2.98 and 1.98, respectively; both P<0.01), but not in those with 350 to 499 CD4 cells/microL (HR: 0.93; P = 0.79), compared to those with >or=500 CD4 cells/microL. The interaction between CD4 cell count and tobacco smoking status was not statistically significant. CONCLUSIONS/SIGNIFICANCE: Smoking cessation dramatically reduces the risk of bacterial pneumonia, whatever the level of immunodeficiency. Smoking cessation interventions should become a key element of the clinical management of HIV-infected individuals

Image-derived input function in dynamic human PET/CT: methodology and validation with 11C-acetate and 18F-fluorothioheptadecanoic acid in muscle and 18F-fluorodeoxyglucose in brain

International audienc

Expression of C-terminal deleted p53 isoforms in neuroblastoma

The tumor suppressor gene, p53, is rarely mutated in neuroblastomas (NB) at the time of diagnosis, but its dysfunction could result from a nonfunctional conformation or cytoplasmic sequestration of the wild-type p53 protein. However, p53 mutation, when it occurs, is found in NB tumors with drug resistance acquired over the course of chemotherapy. As yet, no study has been devoted to the function of the specific p53 mutants identified in NB cells. This study includes characterization and functional analysis of p53 expressed in eight cell lines: three wild-type cell lines and five cell lines harboring mutations. We identified two transcription-inactive p53 variants truncated in the C-terminus, one of which corresponded to the p53β isoform recently identified in normal tissue by Bourdon et al. [J. C. Bourdon, K. Fernandes, F. Murray-Zmijewski, G. Liu, A. Diot, D. P. Xirodimas, M. K. Saville and D. P. Lane (2005) Genes Dev., 19, 2122–2137]. Our results show, for the first time, that the p53β isoform is the only p53 species to be endogenously expressed in the human NB cell line SK-N-AS, suggesting that the C-terminus truncated p53 isoforms may play an important role in NB tumor development

Semi-supervised learning towards automated segmentation of PET images with limited annotations: Application to lymphoma patients

The time-consuming task of manual segmentation challenges routine systematic quantification of disease burden. Convolutional neural networks (CNNs) hold significant promise to reliably identify locations and boundaries of tumors from PET scans. We aimed to leverage the need for annotated data via semi-supervised approaches, with application to PET images of diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL). We analyzed 18F-FDG PET images of 292 patients with PMBCL (n=104) and DLBCL (n=188) (n=232 for training and validation, and n=60 for external testing). We employed FCM and MS losses for training a 3D U-Net with different levels of supervision: i) fully supervised methods with labeled FCM (LFCM) as well as Unified focal and Dice loss functions, ii) unsupervised methods with Robust FCM (RFCM) and Mumford-Shah (MS) loss functions, and iii) Semi-supervised methods based on FCM (RFCM+LFCM), as well as MS loss in combination with supervised Dice loss (MS+Dice). Unified loss function yielded higher Dice score (mean +/- standard deviation (SD)) (0.73 +/- 0.03; 95% CI, 0.67-0.8) compared to Dice loss (p-value<0.01). Semi-supervised (RFCM+alpha*LFCM) with alpha=0.3 showed the best performance, with a Dice score of 0.69 +/- 0.03 (95% CI, 0.45-0.77) outperforming (MS+alpha*Dice) for any supervision level (any alpha) (p<0.01). The best performer among (MS+alpha*Dice) semi-supervised approaches with alpha=0.2 showed a Dice score of 0.60 +/- 0.08 (95% CI, 0.44-0.76) compared to another supervision level in this semi-supervised approach (p<0.01). Semi-supervised learning via FCM loss (RFCM+alpha*LFCM) showed improved performance compared to supervised approaches. Considering the time-consuming nature of expert manual delineations and intra-observer variabilities, semi-supervised approaches have significant potential for automated segmentation workflows

18F-Fluorination of Unactivated C-H Bonds in Branched Aliphatic Amino Acids: Direct Synthesis of Oncological PET Imaging Agents

A mild and selective photocatalytic C-H 18F-fluorination reaction has been developed that provides direct access to 18F-fluorinated amino acids. The biodis-tribution and uptake of three 18F-labelled leucine ana-logues via LAT1 mediated transport in several cancer cell lines is reported. PET imaging of mice bearing PC3 (pros-tate) or U87 (glioma) xenografts using 5-[18F]-fluoro-homoleucine showed high tumor uptake and excellent tumor visualization, highlighting the utility of this strat-egy for rapid tracer discovery for oncology

Optimal human papillomavirus vaccination strategies to prevent cervical cancer in low-income and middle-income countries in the context of limited resources: a mathematical modelling analysis

Introduction of human papillomavirus (HPV) vaccination has been slow in low-income and middle-income countries (LMICs) because of resource constraints and worldwide shortage of vaccine supplies. To help inform WHO recommendations, we modelled various HPV vaccination strategies to examine the optimal use of limited vaccine supplies and best allocation of scarce resources in LMICs in the context of the WHO global call to eliminate cervical cancer as a public health problem. Methods In this mathematical modelling analysis, we developed HPV-ADVISE LMIC, a transmission-dynamic model of HPV infection and diseases calibrated to four LMICs: India, Vietnam, Uganda, and Nigeria. For different vaccination strategies that encompassed use of a nine-valent vaccine (or a two-valent or four-valent vaccine assuming high cross-protection), we estimated three outcomes: reduction in the age-standardised rate of cervical cancer, number of doses needed to prevent one case of cervical cancer (NNV; as a measure of efficiency), and the incremental cost-effectiveness ratio (ICER; in 2017 international $per disability-adjusted life-year [DALY] averted). We examined different vaccination strategies by varying the ages of routine HPV vaccination and number of age cohorts vaccinated, the population targeted, and the number of doses used. In our base case, we assumed 100 Findings We predicted that HPV vaccination could lead to cervical cancer elimination in Vietnam, India, and Nigeria, but not in Uganda. Compared with no vaccination, strategies that involved vaccinating girls aged 9-14 years with two doses were predicted to be the most efficient and cost-effective in all four LMICs. NNV ranged from 78 to 381 and ICER ranged from$28 per DALY averted to $1406 per DALY averted depending on the country. The most efficient and cost-effective strategies were routine vaccination of girls aged 14 years, with or without a later switch to routine vaccination of girls aged 9 years, and routine vaccination of girls aged 9 years with a 5-year extended interval between doses and a catch-up programme at age 14 years. Vaccinating boys (aged 9-14 years) or women aged 18 years or older resulted in substantially higher NNVs and ICERs. Interpretation We identified two strategies that could maximise efforts to prevent cervical cancer in LMICs given constraints on vaccine supplies and costs and that would allow a maximum of LMICs to introduce HPV vaccination. Funding World Health Organization, Canadian Institute of Health Research, Fonds de recherche du Québec-Santé, Compute Canada, PATH, and The Bill & Melinda Gates Foundation. Translations For the French and Spanish translations of the abstract see Supplementary Materials section