Prostate-specific membrane antigen (PSMA) is a cell surface enzyme that is highly expressed in prostate cancer (PCa) and is currently being extensively explored as a promising target for molecular ...imaging in a variety of clinical contexts. Novel antibody and small-molecule PSMA radiotracers labeled with a variety of radionuclides for positron emission tomography (PET) imaging applications have been developed and explored in recent studies.
A great deal of progress has been made in defining the clinical utility of this class of PET agents through predominantly small and retrospective clinical studies. The most compelling data to date has been in the setting of biochemically recurrent PCa, where PSMA-targeted radiotracers have been found to be superior to conventional imaging and other molecular imaging agents for the detection of locally recurrent and metastatic PCa.
Early data, however, suggest that initial lymph node staging before definitive therapy in high-risk primary PCa patients may be limited, although intraoperative guidance may still hold promise. Other examples of potential promising applications for PSMA PET imaging include non-invasive characterization of primary PCa, staging and treatment planning for PSMA-targeted radiotherapeutics, and guidance of focal therapy for oligometastatic disease.
However, all of these indications and applications for PCa PSMA PET imaging are still lacking and require large, prospective, systematic clinical trials for validation. Such validation trials are needed and hopefully will be forthcoming as the fields of molecular imaging, urology, radiation oncology and medical oncology continue to define and refine the utility of PSMA-targeted PET imaging to improve the management of PCa patients.
Prostate cancer focal therapy aims to minimize the side-effects of whole gland treatments, such as radical prostatectomy and radiotherapy without compromising oncological efficacy. However, concerns ...exist regarding the multifocal nature of prostate cancer and the lack of long-term oncological data for this form of treatment. In recent years, the routine adoption of multi-parametric magnetic resonance imaging (mpMRI) of the prostate has improved our ability to select candidates for focal therapy and to accurately deliver this form of prostate cancer treatment.
We performed a review of the literature to provide a summary of the oncological and functional outcomes of men receiving primary prostate focal therapy. Furthermore, we discuss the impact of the routine implementation of mpMRI as part of the initial prostate cancer diagnostic pathway on the selection of candidates and delivery of focal therapy. Finally, we summarize knowledge gaps in the field and highlight active clinical trials in this arena.
Primary focal therapy involves the application of one of a number of energies that ablate tissue, such as cryotherapy and high intensity focused ultrasound (HIFU). Success is principally dependent on highly accurate patient selection and disease localization underpinned in large part by the routine integration of pre-biopsy mpMRI. Prospective medium-term follow-up data for primary HIFU and cryotherapy for men with intermediate-risk disease have shown acceptable cancer control with low risk of side effects and complications. Additional research is needed to clearly define an appropriate follow-up approach and to guide the management of in- and out-of-field recurrences. Multiple comparative trials with randomization against standard care are currently underway in men with intermediate- and high-risk prostate cancer.
The widespread adoption of prostate mpMRI has led to improved disease localization, enabling the performance of focal therapy as a viable treatment strategy for men with low volume intermediate-risk prostate cancer.
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Vaterite particles are prospective biocompatible carriers for PDT.The proposed carriers are capable of cellular uptake.Encapsulation increases local PS concentration inside cells ...improving phototoxicity.Vaterite particles encourage reduction of PS therapeutic dose.
The elaboration of biocompatible and biodegradable carriers for photosensitizer targeted delivery is one of the most promising approaches in a modern photodynamic therapy (PDT). This approach is aimed at reducing sides effects connected with incidental toxicity in healthy tissue whilst also enhancing drug accumulation in the tumour area. In the present work, Photosens-loaded calcium carbonate (CaCO3) submicron particles in vaterite modification are proposed as a novel platform for anticancer PDT. Fast penetration of the carriers (0.9±0.2μm in diameter) containing 0.12% (w/w) of the photosensitizer into NIH3T3/EGFP cells is demonstrated. The captured particles provide the dye localization inside the cell increasing its local concentration, compared with ⿿free⿿ Photosens solution which is uniformly distributed throughout the cell. The effect of photosensitizer encapsulation into vaterite submicron particles on cell viability under laser irradiation (670nm, 19mW/cm2, 10min) is discussed in the work. As determined by a viability assay, the encapsulation renders Photosens more phototoxic. By this means, CaCO3 carriers allow improvement of the photosensitizer effectiveness supposing, therefore, the reduction of therapeutic dose. Summation of these effects with the simplicity, upscalability and cheapness of fabrication, biocompatibility and high payload ability of the vaterite particles hold out the prospect of a novel PDT platform.
Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a ...prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations.
To evaluate factors affecting the diagnostic yield of flexible fiberoptic bronchoscopy in evaluating solitary pulmonary nodules (SPNs).
Retrospective analysis of bronchoscopies performed over a ...4-year period.
A tertiary teaching hospital.
One hundred seventy-seven patients with pulmonary nodules without endobronchial lesions who underwent bronchoscopy with brushing, washing, and transbronchial biopsy.
There were 151 malignant and 26 benign lesions. The diagnostic accuracy of bronchoscopy in malignant and benign lesions were 64% (97 of 151) and 35% (9 of 26), respectively. The yield of bronchoscopy was directly related to lesion size (p < 0.001, χ2). When lesions were grouped according to distance from the hilum, yields of bronchoscopy in central, intermediate, and peripherally located lesions were 82, 61, and 53%, respectively (p = 0.05, χ2). When we stratified distance from the hilum by lesion size, the difference in yield was not significant. However, lesions ≤ 2 cm had a diagnostic yield of 14% (2 of 14) when located in the peripheral third vs 31% (5 of 16) when located in the inner two thirds of the lung. There was a trend toward higher combined diagnostic yield in right middle and lingular lobes when compared to all other segments (p = 0.09, χ2). Transbronchial biopsy, washing, and brushing were complementary in improving the yield of bronchoscopy.
Size is the strongest determinant of diagnostic yield in bronchoscopy when evaluating SPNs. The yield of bronchoscopy is particularly low in lesions ≤ 2 cm that are located in the outer third of the lung. Thus, alternative diagnostic approaches may be preferable in this situation.
Mucosa-associated invariant T (MAIT) cells are unconventional innate-like T cells that recognize microbial riboflavin metabolites presented by the MHC class I-like protein MR1. Human MAIT cells ...predominantly express the CD8α coreceptor (CD8⁺), with a smaller subset lacking both CD4 and CD8 (double-negative, DN). However, it is unclear if these two MAIT cell subpopulations distinguished by CD8α represent functionally distinct subsets. Here, we show that the two MAIT cell subsets express divergent transcriptional programs and distinct patterns of classic T cell transcription factors. Furthermore, CD8⁺ MAIT cells have higher levels of receptors for IL-12 and IL-18, as well as of the activating receptors CD2, CD9, and NKG2D, and display superior functionality following stimulation with riboflavin-autotrophic as well as riboflavin-auxotrophic bacterial strains. DN MAIT cells display higher RORγt/T-bet ratio, and express less IFN-γ and more IL-17. Furthermore, the DN subset displays enrichment of an apoptosis gene signature and higher propensity for activation-induced apoptosis. During development in human fetal tissues, DN MAIT cells are more mature and accumulate over gestational time with reciprocal contraction of the CD8⁺ subset. Analysis of the T cell receptor repertoire reveals higher diversity in CD8⁺ MAIT cells than in DN MAIT cells. Finally, chronic T cell receptor stimulation of CD8⁺ MAIT cells in an in vitro culture system supports the accumulation and maintenance of the DN subpopulation. These findings define human CD8⁺ and DN MAIT cells as functionally distinct subsets and indicate a derivative developmental relationship.
A high-statistics data sample of the
K
+
decays is recorded by the OKA collaboration. A missing mass analysis is performed to search for a light invisible pseudoscalar axion-like particle (ALP)
a
in ...the decay
K
+
→
π
+
π
0
a
. No signal is observed, and the upper limits for the branching ratio of the decay are calculated. The
90
%
confidence level upper limit changes from
2.5
·
10
-
6
to
2
·
10
-
7
for the ALP mass from 0 to 200 MeV/
c
2
, except for the region of
π
0
mass, where the upper limit is
4.4
·
10
-
6
.
We report on the super enhancement of the 1.54 μm Er emission in erbium doped silicon-on-insulator when codoped with oxygen at a ratio of 1:1. This is attributed to a more favourable crystal field ...splitting in the substitutional tetrahedral site favoured for the singly coordinated case. The results on these carefully matched implant profiles show that optical response is highly determined by the amount and ratio of erbium and oxygen present in the sample and ratios of O:Er greater than unity are severely detrimental to the Er emission. The most efficient luminescence is forty times higher than in silicon-on-insulator implanted with Er only. This super enhancement now offers a realistic route not only for optical communication applications but also for the implementation of silicon photonic integrated circuits for sensing, biomedical instrumentation and quantum communication.
Lymphocyte migration is essential for adaptive immune surveillance. However, our current understanding of this process is rudimentary, because most human studies have been restricted to immunological ...analyses of blood and various tissues. To address this knowledge gap, we used an integrated approach to characterize tissue-emigrant lineages in thoracic duct lymph (TDL). The most prevalent immune cells in human and non-human primate efferent lymph were T cells. Cytolytic CD8+ T cell subsets with effector-like epigenetic and transcriptional signatures were clonotypically skewed and selectively confined to the intravascular circulation, whereas non-cytolytic CD8+ T cell subsets with stem-like epigenetic and transcriptional signatures predominated in tissues and TDL. Moreover, these anatomically distinct gene expression profiles were recapitulated within individual clonotypes, suggesting parallel differentiation programs independent of the expressed antigen receptor. Our collective dataset provides an atlas of the migratory immune system and defines the nature of tissue-emigrant CD8+ T cells that recirculate via TDL.
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•Comprehensive map of the human immune system in thoracic duct•Non-cytolytic effector memory CD8+ T cells primarily recirculate via thoracic duct•Cytolytic CD8+ T cells confined to intravascular circulation at steady state•Individual antigen-specific clones exhibit distinct migratory and functional capabilities
Buggert et al. provide a core signature that defines humantissue-emigrant CD8+ T cells under homeostatic conditions. They observe that cytolytic effector memory CD8+ T cells are primarily confined to peripheral blood and almost absent in thoracic duct lymph, indicating that distinct effector memory populations surveil blood and tissues.
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