Prostate-specific membrane antigen (PSMA)-ligand PET imaging provides unprecedented accuracy for whole-body staging of prostate cancer. As PSMA-ligand PET/CT is increasingly adopted in clinical ...trials and routine practice worldwide, a unified language for image reporting is urgently needed. We propose a molecular imaging TNM system (miTNM, version 1.0) as a standardized reporting framework for PSMA-ligand PET/CT or PET/MRI. miTNM is designed to organize findings in comprehensible categories to promote the exchange of information among physicians and institutions. Additionally, flowcharts integrating findings of PSMA-ligand PET and morphologic imaging have been designed to guide image interpretation. Specific applications, such as assessment of prognosis or impact on management, should be evaluated in future trials. miTNM is a living framework that evolves with clinical experience and scientific data.
Emerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current ...definitions of oligometastasis are solely numerical.
To characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC.
This was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease.
We measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC).
The frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio IRR 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p < 0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio HR 1.59; p = 0.03) and the development of CRPC (HR 1.71; p = 0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined.
Somatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration.
Oligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions.
The frequency of putative driver mutations increases across the metastatic hormone-sensitive prostate cancer spectrum and can stratify clinical outcomes. Somatic mutational profiles help in redefining oligometastasis beyond simple lesion enumeration by providing a biological definition.
Aberrant expression of long non-coding RNAs (lncRNAs) has been regarded as a critical component in bladder cancer (BC) and lncRNAs have been associated with BC development and progression although ...their overall expression and functional significance is still unclear. The aim of our study was to identify novel lncRNAs with a functional role in BC carcinogenesis. RNA-sequencing was used to identify aberrantly expressed lncRNAs in 8 normal and 72 BC samples. We identified 89 lncRNAs that were significantly dys-regulated in BC. Five lncRNAs; LINC00958, LINC01296, LINC00355, LNC-CMC1-1 and LNC-ALX1-2 were selected for further analyses. Silencing of LINC00958 or LINC01296 in vitro reduced both cell viability and migration. Knock-down of LINC00958 also affected invasion and resistance to anoikis. These cellular effects could be linked to direct/indirect regulation of protein coding mRNAs involved in cell death/survival, proliferation and cellular movement. Finally, we showed that LINC00958 binds proteins involved in regulation and initiation of translation and in post-transcriptional modification of RNA, including Metadherin, which has previously been associated with BC. Our analyses identified novel lncRNAs in BC that likely act as oncogenic drivers contributing to an aggressive cancerous phenotype likely through interaction with proteins involved in initiation of translation and/or post-transcriptional modification of RNA.
Abstract
Spongian diterpenes are a group of marine natural compounds possessing various biological activities. However, their anticancer activity is still poorly studied and understood. We isolated ...six spongian diterpenes from the marine sponge
Spongionella
sp
.
, including one new spongionellol A and five previously known molecules. The structures were elucidated using a detailed analysis MS and NMR spectra as well as by comparison with previously reported data. Two of them, namely, spongionellol A and 15,16-dideoxy-15α,17β-dihydroxy-15,17-oxidospongian-16-carboxylate-15,17-diacetate exhibited high activity and selectivity in human prostate cancer cells, including cells resistant to hormonal therapy and docetaxel. The mechanism of action has been identified as caspase-dependent apoptosis. Remarkably, both compounds were able to suppress expression of androgen receptor (AR) and AR-splice variant 7, as well as AR-dependent signaling. The isolated diterpenes effectively inhibited drug efflux mediated by multidrug-resistance protein 1 (MDR1; p-glycoprotein). Of note, a synergistic effect of the compounds with docetaxel, a substrate of p-glycoprotein, suggests resensitization of p-glycoprotein overexpressing cells to standard chemotherapy. In conclusion, the isolated spongian diterpenes possess high activity and selectivity towards prostate cancer cells combined with the ability to inhibit one of the main drug-resistance mechanism. This makes them promising candidates for combinational anticancer therapy.
Purpose
Radioguided surgery has been widely used for clinical procedures such as sentinel node resections. In the (robot-assisted) laparoscopic setting radioguidance is realized using laparoscopic ...gamma probes, which have limited maneuverability. To increase the rotational freedom, a tethered DROP-IN gamma probe was designed. Here we present the first in vivo feasibility study of this technology in prostate cancer patients.
Methods
Ten patients scheduled for a sentinel node procedure received four injections into the prostate with (indocyanine green-)
99m
Technetium-nanocolloid and underwent preoperative imaging (lymphoscintigraphy and SPECT/CT). The DROP-IN probe was inserted via the assistant port, still permitting the insertion and usage of additional laparoscopic tools.
Results
The sentinel nodes were resected using the
da Vinci
® Si robot under guidance of DROP-IN gamma tracing and fluorescence imaging. The surgeon was able to independently maneuver the DROP-IN probe using the ProGrasp® forceps of the
da Vinci
® robot and distinguish sentinel nodes from background signal (such as the injection site).
Conclusions
Overall the DROP-IN design proves to be a valuable tool for robot-assisted radioguided surgery approaches.
Management of prostate cancer patients with biochemical relapse has long hampered due to insufficient capability to detect and localize recurrent disease with available imaging modalities such as CT, ...MRI, or bone scintigraphy. Recent advances in functional imaging, namely, PET and SPEGT imaging, with novel tracers targeting the prostate-specific membrane antigen （PSMA） have led to a surge in imaging in prostate cancer patients with biochemical relapse since was able to reveal sites of recurrence in a claritv not seen before.
Prostate cancer surgery is currently being revolutionized by the use of prostate-specific membrane antigen (PSMA)-targeted radiotracers, for example,
Tc-labeled PSMA tracer analogs for radioguided ...surgery. The purpose of this study was to develop a second-generation
Tc-labeled PSMA-targeted tracer incorporating a fluorescent dye.
Several PSMA-targeted hybrid tracers were synthesized: glutamic acid-urea-lysine (EuK)-Cy5-mas
, EuK-(SO
)Cy5-mas
, EuK-Cy5(SO
)-mas
, EuK-(Ar)Cy5-mas
, and EuK-Cy5(Ar)-mas
; the Cy5 dye acts as a functional backbone between the EuK targeting vector and the 2-mercaptoacetyl-seryl-seryl-seryl (mas
) chelate to study the dye's interaction with PSMA's amphipathic entrance funnel. The compounds were evaluated for their photophysical and chemical properties and PSMA affinity. After radiolabeling with
Tc, we performed in vivo SPECT imaging, biodistribution, and fluorescence imaging on BALB/c nude mice with orthotopically transplanted PC346C tumors.
The dye composition influenced the photophysical properties (brightness range 0.3-1.5 × 10
M
× cm
), plasma protein interactions (range 85.0% ± 2.3%-90.7% ± 1.3% bound to serum, range 76% ± 0%-89% ± 6% stability in serum), PSMA affinity (half-maximal inhibitory concentration IC
range 19.2 ± 5.8-175.3 ± 61.1 nM) and in vivo characteristics (tumor-to-prostate and tumor-to-muscle ratios range 0.02 ± 0.00-154.73 ± 28.48 and 0.46 ± 0.28-5,157.50 ± 949.17, respectively; renal, splenic, and salivary retention). Even though all tracer analogs allowed tumor identification with SPECT and fluorescence imaging,
Tc-EuK-(SO
)Cy5-mas
had the most promising properties (e.g., half-maximal inhibitory concentration, 19.2 ± 5.8, tumor-to-muscle ratio, 5,157.50 ± 949.17).
Our findings demonstrate the intrinsic integration of a fluorophore in the pharmacophore in PSMA-targeted small-molecule tracers. In this design, having 1 sulfonate on the indole moiety adjacent to EuK (
Tc-EuK-(SO
)Cy5-mas
) yielded the most promising tracer candidate for imaging of PSMA.
Introduction: Radioguided surgery is an ever-evolving part of nuclear medicine. In fact, this nuclear medicine sub-discipline actively bridges non-invasive molecular imaging with surgical care. Next ...to relying on the availability of radio- and bimodal-tracers, the success of radioguided surgery is for a large part dependent on the imaging modalities and imaging concepts available for the surgical setting. With this review, we have aimed to provide a comprehensive update of the most recent advances in the field.
Areas covered: We have made an attempt to cover all aspects of radioguided surgery: 1) the use of radioisotopes that emit γ, β
+
, and/or β
−
radiation, 2) hardware developments ranging from probes to 2D cameras and even the use of advanced 3D interventional imaging solutions, and 3) multiplexing solutions such as dual-isotope detection or combined radionuclear and optical detection.
Expert opinion: Technical refinements in the field of radioguided surgery should continue to focus on supporting its implementation in the increasingly complex minimally invasive surgical setting, e.g. by accommodating robot-assisted laparoscopic surgery. In addition, hybrid concepts that integrate the use of radioisotopes with other image-guided surgery modalities such as fluorescence or ultrasound are likely to expand in the future.
Purpose
To explore circulating tumor cell (CTCs) counts in different stages of prostate cancer (PC) in association with tumor burden, metastatic pattern and conventional serum biomarkers. Overall ...survival (OS) analyses were conducted with respect to optimized CTC cutoff levels.
Methods
Circulating tumor cell counts were assessed in healthy controls (
n
= 15) as well as in locally advanced high risk (LAPC,
n
= 20), metastatic castration resistant (mCRPC,
n
= 40) and taxane-refractory (mTRPC,
n
= 15) PC patients. CTCs were detected using the CellSearch™ System.
Results
In metastatic PC (mPC), CTC counts were significantly increased compared to LAPC (
p
< 0.001). In LAPC, CTCs were at control level (
p
= 0.66). Patients with both bone and visceral lesions revealed the highest median CTC count (
p
= 0.004), whereas patients with sole soft tissue metastases displayed CTC counts comparable to controls (
p
= 0.16). No correlation was observed between CTC counts and osseous tumor burden assessed by bone lesion count (
p
= 0.54) or bone scan index (
p
= 0.81). CTC counts revealed a positive correlation with alkaline phosphatase (
p
< 0.001) and lactate dehydrogenase (
p
< 0.001) as well as a negative association with hemoglobin (
p
= 0.004) and PSA-doubling time (
p
= 0.01). Kaplan–Meier analyses demonstrated a cohort adjusted cutoff level of 3 CTCs with a shorter OS in case of ≥3 CTCs compared to <3 CTCs (
p
= 0.001), a cutoff level applicable in mCRPC (
p
= 0.003) but not in mTRPC patients (
p
= 0.054).
Conclusions
Circulating tumor cell counts are applicable as a prognostic molecular marker, especially in mCRPC patients harboring bone metastases with or without visceral metastases. For clinical practice, mPC patients with elevated CTC counts in combination with short PSA-DT, high alkaline phosphatase and lactate dehydrogenase levels as well as low hemoglobin levels are at high risk of disease progression and limited OS.
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