Spread Of Prostate Cancer Research Articles

Which Therapeutic Treatment Option is Best for Prostate Cancer?

Prostate cancer (PC) is the second most common cancer among men in the developed world. PC spreads very slowly and is often detected late, so it requires much more rigorous treatment options than if it had been detected early. As with most cancer treatments, all these treatment options have their fair share of advantages and disadvantages. After a prostate cancer diagnosis, an assigned oncologist and multi-disciplinary team (MDT) come up with a treatment option that gives the patient a fighting chance considering the stage of the cancer. However, there is no go-to treatment option, and it is important to consider what the patient wants; if there are certain side effects, such as incontinence, that the patient is steadfastly against, it’s important for the MDT to honour this as much as possible.

Possibilities of radiological methods of diagnosis of metastatic castration-resistant prostate cancer (Review Article).

Abstract Metastatic castration-resistant prostate cancer (mCRPC) is characterized by the progression of the tumor process when it becomes unresponsive to androgen-deprivation therapy. The incidence of bone metastases in these patients reaches up to 90%. Imaging modalities play a pivotal role in the diagnosis of this oncological condition. Computed tomography (CT) and magnetic resonance imaging (MRI) offer advantages in anatomical visualization; however, they face limitations in assessing the efficacy of prostate cancer treatment. Scintigraphy is applicable in screening for skeletal bone metastatic involvement but has limitations in assessing disease progression. Positron emission tomography combined with computed tomography (PET/CT) and single-photon emission computed tomography (SPECT/CT) are utilized for early detection of local or systemic spread of prostate cancer. The assessment of quantitative data on radiopharmaceutical uptake using PSMA PET imaging is used for predicting the efficacy of antitumor therapy. With the introduction of the radiopharmaceutical 177Lu-PSMA into clinical practice, the perspective of conducting radionuclide therapy with simultaneous efficacy evaluation through hybrid imaging methods has emerged. The capabilities of imaging modalities in assessing bone metastases present a particular interest for research and systematization of the data obtained to develop optimal parameters for conducting radioligand therapy and evaluating its efficacy. Aims: To explore the capabilities of imaging modalities in diagnosing metastatic castration-resistant prostate cancer. Conclusions: The analyzed literature data indicate that imaging methods for diagnosing mCRPC vary in sensitivity and specificity, have their advantages and disadvantages, which underscores the necessity for a comprehensive approach in their utilization. The development and advancement of methods for quantitative assessment of treatment efficacy, identification of prognostic markers can influence a more informed choice of treatment tactics and radiopharmaceutical selection, potentially leading to an increase in overall survival.

Rita Levi-Montalcini: From Persecution to the Nobel Prize and an Honorary Degree From a Canadian University.

Rita Levi-Montalcini (RLM) is recognized as a prestigious and renowned researcher of her time. She was the fourth woman to earn the Nobel Prize in Physiology and Medicine in 1986 for the discovery of nerve growth factor (NGF). We review her biography and scientific discovery, and provide an example of why her discovery is still important. She had a special relationship with McGill University, Canada, which we describe. We searched for articles and books about her for biographical and scientific material and met with Dr. Claudio Cuello, Former Chair of McGill's Faculty of Medicine. RLM was born in 1909 in Turin, Italy, where she had studied medicine. She started her career in research. Because of the anti-Jewish racial laws in Italy in 1938, she went underground and continued her projects in her bedroom. After the war, she visited St. Louis, USA, and conducted research there. Her experiments confirmed that tumors release a factor that causes nerve growth and cancer proliferation. Initially, scientists responded to this discovery with skepticism, but after its purification in 1959 and determination of its protein structure in 1971, NGF became widely accepted.Currently, crosstalk between cancers and nerves is poorly understood. The example of prostate cancer shows that surgical or chemical denervation of sympathetic nerves prevents the initiation of prostate tumors, whereas inhibition of parasympathetic nerve signaling reduces the spread of prostate cancer. McGill University awarded RLMa doctoral degree in 2011. It was the first time in itshistory that the University awarded an honorary doctorate outside of Canada, and the second one outside of Quebec.Through her discovery of NGF, RLM exemplified the power of passion and determination despite the obstacles she faced. Her relentless dedication has led to remarkable achievements.

From Tumor to Bone: Growth Factor Receptors as Key Players in Cancer Metastasis.

This review article explores the intricate correlation between growth factors and bone metastases, which play a crucial role in the development of several types of malignancies, namely breast, prostate, lung, and renal cancers. The focal point of our discussion is on crucial receptors for growth factors, including Epidermal Growth Factor Receptor (EGFR), Transforming Growth Factor-β (TGFβ), Vascular Endothelial Growth Factor Receptor (VEGFR), and Fibroblast Growth Factor Receptor (FGFR). These receptors, which are essential for cellular activities including growth, differentiation, and survival, have important involvement in the spread of cancer and the interactions between tumors and the bone environment. We discuss the underlying mechanisms of bone metastases, with a specific emphasis on the interaction between growth factor receptors and the bone microenvironment. EGFR signaling specifically enhances the process of osteoclast development and the formation of osteolytic lesions, especially in breast and lung malignancies. TGFβ receptors have a role in both osteolytic and osteoblastic metastases by releasing TGFβ, which attracts cancer cells and promotes bone remodeling. This is a crucial element in the spread of prostate cancer to the bones. The functions of FGFR and VEGFR in the processes of bone formation and tumor angiogenesis, respectively, highlight the complex and diverse nature of these interactions. The review emphasizes the possibility of targeted therapeutics targeting these receptors to interrupt the cycle of tumor development and bone degradation. Therapeutic approaches include focusing on the VEGF/VEGFR, EGF/EGFR, FGF/FGFR, and TGFβ/TGFβR pathways. These include a variety of compounds, such as small molecule inhibitors and monoclonal antibodies, which have shown potential to interfere with tumor-induced alterations in bone. The text discusses clinical trials and preclinical models, offering insights into the effectiveness and constraints of various treatments. Ultimately, this study provides a succinct but thorough summary of the present knowledge and treatment strategies focused on growth factor receptors in bone metastases. This highlights the significance of comprehending the signaling of growth factor receptors in the microenvironment where tumors spread to the bones, as well as the possibility of using targeted therapies to enhance the results for cancer patients with bone metastases. The advancement of treating bone metastases hinges on the development of treatments that specifically target the intricate relationships between malignancies and bone.

Aberrant Super-Enhancer Landscape in Enzalutamide-Resistant Prostate Cancer Cells.

Background: Castration-resistant prostate cancer (CRPC), which has developed resistance to next-generation antiandrogens, such as enzalutamide (Enz), is a lethal disease. Furthermore, transcriptional regulation by super enhancers (SEs) is crucial for the growth and spread of prostate cancer, as well as drug resistance. The functions of SEs, a significant class of noncoding DNA cis-regulatory elements, have been the subject of numerous recent studies in the field of cancer research. Materials and Methods: The goal of this research was to identify SEs associated with Enz resistance in C4-2B cells using chromatin immunoprecipitation sequencing and cleavage under targets and tagmentation (CUT&Tag). Using HOMER analysis to predict protein/gene-binding motifs, we identified master transcription factors (TFs) that may bind to SE sites. Using small interfering RNA, WST-1 assays, and qRT-PCR, we then confirmed the associations between TFs of SEs and Enz resistance. Results: A total of 999 SEs were screened from C4-2B EnzR cells in total. Incorporating analysis with RNA-seq data revealed 41 SEs to be strongly associated with the promotion of Enz resistance. In addition, we finally predicted that master TFs bind to SE-binding regions. Subsequently, we selected zinc finger protein 467 (ZFP467) and SMAD family member 3 to confirm the functional connections of master TFs with Enz resistance through SEs (ZNF467). Conclusions: In this study, SMAD3 and ZNF467 were found to be closely related to Enz-resistant CRPC. Our research uncovered a sizable group of SEs linked to Enz resistance in prostate cancer, dissected the mechanisms underlying SE Enz resistance, and shed light on potential clinical uses for SEs.

Role of Ga68 Prostate-Specific Membrane Antigen Positron Emission Tomography-Computed Tomography in Prostate Cancer Imaging

AbstractThe introduction of prostate-specific membrane antigen (PSMA) in clinical practice has revolutionized the evaluation of biochemical recurrence (BCR) of prostate cancer after curative-intent treatment. The high expression of this glycoprotein in prostate cancer cells makes PSMA imaging superior to the current conventional staging methods, namely bone scanning and computed tomography. The high capability of PSMA imaging for identifying very small previously undetected lesions has been widely demonstrated in the literature, leading to a rethinking of patient management by treating physicians. The usual and predictable patterns of spread in prostate cancer are still more prevalent, such as spread to pelvic lymph nodes and bone metastasis, but different patterns of disease spread are becoming more commonly recognized with higher reliability because PSMA imaging allows the detection of more usual and unusual lesions than conventional imaging. The expanding use of PSMA positron emission tomography (PET) has also revealed PSMA ligand uptake in diverse nonprostatic diseases, which raised questions about the specificity of this imaging modality. It is important for the reading physician to recognize and understand the usual disease spread, the most prevalent unusual sites of relapse, and the nonprostatic conditions which are PSMA avid not only to heighten the relevancy of reports but also to improve imaging consultancy in multispecialty oncologic practice. This article aims to brief the role of PSMA PET in the initial staging of multitude of clinical scenarios, BCR, castration-resistant prostate cancer, usual and unusual patterns of recurrence and metastatic spread diagnosed with PSMA PET, normal variants, pitfalls, and nonprostatic disorders showing PSMA expression.

Molecular testing of prostate cancer: timing, methods and consequences

Metastatic prostate cancer is a heterogeneous disease. To date, however, treatment decisions are often based on the extent and symptom burden of the tumour, concomitant diseases, and the patient's wishes. Molecular pathology aspects are rarely taken into account. Declining costs and the increasing use of next-generation sequencing (NGS) have led to an increase in molecular testing and a better understanding of the significance of molecular alterations for the development and spread of prostate cancer. More consistent germline testing reveals hereditary predispositions. Following the approval of olaparib for the treatment of BRCA1/2 mutated, castration-resistant prostate cancer, further targeted therapeutic approaches are currently under development. In our review article, we provide an overview of current molecular testing in prostate cancer and discuss possible consequences.

The Role of Adipocytokines and their Receptors in Prostate Cancer: Adiponectin May Protect Against Progression.

Obesity is correlated with an increased risk of developing malignancies, including prostate cancer. Adipocytokines, such as leptin and adiponectin, are a family of hormones derived from adipose tissue that are involved not only in metabolism, but also in the development and progression of various malignancies. However, little is known about their role in prostate cancer. This study aimed to determine how leptin, adiponectin, and their receptors impact the spread of prostate cancer. We first performed immunohistochemical analysis of prostate cancer tissue microarrays to detect leptin, leptin receptor (Ob-R), adiponectin, and adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2). Wound healing assays and western blot analysis were then performed in human prostate cancer cell lines. Immunohistochemistry showed that prostate tissue was not significantly positive for adiponectin. However, its expression tended to decrease according to the International Society of Urological Pathology (ISUP) grade of prostate cancer (p=0.056). In prostate cancer cell lines, administration of the synthetic adiponectin AdipoRon suppressed cell migration as well as the expression of phospho-NF-[Formula: see text]B and cyclooxygenase-2, whereas leptin stimulated these effects. Adiponectin expression tended to be suppressed according to ISUP grade in prostate cancer tissues. In vitro, tumor cell migration was induced by leptin but suppressed by adiponectin. Targeting adipocytokines could be a novel treatment strategy for prostate cancer.

Unusual Sites of Visceral Spread in Prostate Cancer: A Prostate-Specific Membrane Antigen-Based Theranostic Imaging Series.

Prostate cancer commonly metastasizes to lymphatic and skeletal systems with lesser frequency to visceral organs; however, uncommon visceral sites have also been found and reported as case reports. We present a series of uncommon metastatic visceral spread in prostate cancer on prostate-specific membrane antigen-based diagnostic and posttherapeutic imaging modalities.

Atypical neoplastic solitary focal uptake of 18F-PSMA-1007 in PET/CT in patients with biochemically recurrent prostate cancer

It is established that prostate-specific membrane antigen (PSMA), despite its name, is expressed in many tissues other than the prostate gland, both within physiological conditions and in various pathological processes. Additionally, apart from prostate cancer, other malignant tumors are characterized by increased PSMA expression which, according to many authors, is associated with neoangiogenesis. These factors are reflected in the results of PSMA-radioligand imaging and require comprehensive approach to image interpretation including evaluation of computed tomography and magnetic resonance semiotics. In addition, rare cases of distant visceral prostate cancer metastasis in the form of solitary lesions also should be considered during interpretation of the results of radiologic imaging including positron emission tomography/computed tomography.We present two clinical cases in which positron emission tomography/computed tomography revealed solitary foci of pathological 18F-PSMA-1007 uptake outside the areas of typical metastatic spread (with exception of advanced disease) of prostate cancer, specifically in the stomach wall and the left cerebellar hemisphere. In the first case histological examination results revealed a metachronous low grade neuroendocrine tumor of the stomach, in the second case a metastatic lesion of the cerebellum was diagnosed as part of the underlying disease.

Intra-prostatic tumour evolution, steps in metastatic spread and histogenomic associations revealed by integration of multi-region whole-genome sequencing with histopathological features.

Extension of prostate cancer beyond the primary site by local invasion or nodal metastasis is associated with poor prognosis. Despite significant research on tumour evolution in prostate cancer metastasis, the emergence and evolution of cancer clones at this early stage of expansion and spread are poorly understood. We aimed to delineate the routes of evolution and cancer spread within the prostate and to seminal vesicles and lymph nodes, linking these to histological features that are used in diagnostic risk stratification. We performed whole-genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and lymph nodes of five treatment-naive patients with locally advanced disease. We spatially mapped the clonal composition of cancer across the prostate and the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes in each individual by analysing a total of > 19,000 copy number corrected single nucleotide variants. In each patient, we identified sample locations corresponding to the earliest part of the malignancy. In patient 10, we mapped the spread of cancer from the apex of the prostate to the seminal vesicles and identified specific genomic changes associated with the transformation of adenocarcinoma to amphicrine morphology during this spread. Furthermore, we show that the lymph node metastases in this patient arose from specific cancer clones found at the base of the prostate and the seminal vesicles. In patient 15, we observed increased mutational burden, altered mutational signatures and histological changes associated with whole genome duplication. In all patients in whom histological heterogeneity was observed (4/5), we found that the distinct morphologies were located on separate branches of their respective evolutionary trees. Our results link histological transformation with specific genomic alterations and phylogenetic branching. These findings have implications for diagnosis and risk stratification, in addition to providing a rationale for further studies to characterise the genetic changes causally linked to morphological transformation. Our study demonstrates the value of integrating multi-region sequencing with histopathological data to understand tumour evolution and identify mechanisms of prostate cancer spread.

Prevalence of bilateral loco-regional spread in unilateral pelvic PSMA PET positive recurrent prostate cancer.

Defining the best surgical template for salvage lymph node dissection (SLND) in patients exhibiting unilateral prostate cancer (PCa) recurrence in pelvic lymph nodes (LNs) is an unmet need. We assessed the risk of missing contralateral nodal recurrence in patients with unilateral positive PSMA-PET who were treated with bilateral PSMA-radioguided (RGS) SLND. Patients who consecutively underwent bilateral PSMA-radioguided SLND for PCa recurrence between April 2014 and January 2023 were identified. We compared PSMA PET findings with the number and the location of PCa LN metastases of the final pathological report. Univariable logistic regression models to try to predict contralateral missed disease were performed. Sixty patients were identified. At PSMA-RGS, the median PSA level was 0.71 ng/mL (IQR: 0.38-2.28). At PSMA-PET pre-SLND, 49 (82%) patients had unilateral exclusively pelvic lesions, 2 (3%) had unilateral positive nodes at the level of the common iliac arteries, and 9 (15%) had unilateral positive nodes in both levels. Final pathology revealed unilateral LN involvement in 43 (72%), a negative report in 3 (5%), and bilateral positive lesions in 14 (23%) patients. In the univariable logistic regression models, none of the tested factors showed influence on missing contralateral lesions. Four patients out of 35 (11%) with one positive LN at PSMA-PET had bilateral PCa recurrence. Patients with one-sided positive LNs on PSMA PET can be considered for a unilateral PSMA-radioguided SLND template with the caveat that about a quarter of patients ultimately have bilateral positive LNs. Larger prospective randomized trials are needed to confirm our findings.

Expression of microRNA-379 reduces metastatic spread of prostate cancer.

Prostate cancer (PCa) is the most common type of cancer in males, and the metastatic form is a leading cause of death worldwide. There are currently no curative treatments for this subset of patients. To decrease the mortality of this disease, greater focus must be placed on developing therapeutics to reduce metastatic spread. We focus on dissemination to the bone since this is both the most common site of metastatic spread and associated with extreme pain and discomfort for patients. Our strategy is to exploit microRNAs (miRNAs) to disrupt the spread of primary PCa to the bone. PCa cell lines were transduced to overexpress microRNA-379 (miR-379). These transduced PCa cells were assessed using cell growth, migration, colony formation and adhesion assays. We also performed in vivo intracardiac injections to look at metastatic spread in NSG mice. A cytokine array was also performed to identify targets of miR-379 that may drive metastatic spread. PCa cells with increased levels of miR-379 showed a significant decrease in proliferation, migration, colony formation, and adhesion to bone cells in vitro. In vivo miR-379 overexpression in PC3 cells significantly decreased metastatic spread to bone and reduced levels of miR-379 were seen in patients with metastases. We identified GDF-15 to be secreted from osteoblasts when grown in conditioned media from PCa cells with reduced miR-379 levels. Taken together, our in vitro and in vivo functional assays support a role for miR-379 as a tumour suppressor. A potential mechanism is unravelled whereby miR-379 deregulation in PCa cells affects the secretion of GDF-15 from osteoblasts which in turn facilitates the metastatic establishment in bone. Our findings support the potential role of miR-379 as a therapeutic solution for prostate cancer.

Combination of DNA methylation biomarkers with multiparametric magnetic resonance and ultrasound imaging fusion biopsy to detect the local spread of prostate cancer.

This study aimed to investigate the extent of field cancerization adjacent to index lesions in prostate cancer (PCa) by measuring DNA methylation of selected tumor suppressor genes in the perifocal tissue of PCa not visible on multiparametric magnetic resonanse imaging (mpMRI) for the safe zone of focal therapy identification. A total of 272 patients were enrolled in this study, 44 patients' tissue biosamples were included in the field cancerization research, and 272 urine samples were included in the urine-based test development. Targeted biopsies were performed using the mpMRI/ultrasoundimage fusion system. Quantitative analysis revealed significantly higher DNA methylation levels of RARB, RASSF1, GSTP1 &APC genes in the index lesion compared with perifocal tissue samples 10 mm away from it (p < 0.0001). Notably, the RARB, GSTP1 & APC and RARB, RASSF1, GSTP1 & APC biomarker combinations exhibited the highest sensitivity and specificity comparing the extent of DNA methylation in index lesions and noncancerous prostate tissues 20 mm away (both area under the curve [AUC] = 0.98; p < 0.0001). The analysis of the potential urinary biomarkers showed that the combination of all four DNA methylation biomarkers with prostate-specific antigen (PSA) or PSA density (PSAD) in the blood significantly improves the detection of clinically significant PCa (csPCa). The combination of the four-biomarker test with PSAD allowed the identification of csPCa with ≥90% sensitivity and specificity. Thus, this study suggests that for focal therapy by region target hemi-ablation, the safe distance from the index lesion is no less than 10 mm. Noninvasive urine DNA methylation tests in combination with PSAD could be used for further follow-up of the patients, but larger prospective studies with external validation are needed.

Direct anti-tumoral effects of sulfated fucans isolated from echinoderms: a possible role of neuropilin-1/β1 integrin endocytosis and focal adhesion kinase (FAK) degradation.

Hypercoagulability, a major complication of metastatic cancers, has usually been treated with heparins from natural sources, or with their synthetic derivatives, which are under intense investigation in clinical oncology. However, the use of heparin has been challenging for patients with risk of severe bleeding. While the systemic administration of heparins, in pre-clinical models, has shown primarily attenuating effects on metastasis, their direct effect on established solid tumors has generated contradictory outcomes. We investigated the direct antitumoral properties of two sulfated fucans isolated from marine echinoderms, FucSulf1 and FucSulf2, which exhibit anticoagulant activity with mild hemorrhagic potential. Unlike heparin, sulfated fucans significantly inhibited tumor cell proliferation (by ~30-50 percent), and inhibited tumor migration and invasion in vitro. We found that FucSulf1 and FucSulf2 interacted with fibronectin (FN) as efficiently as heparin, leading to loss of prostate cancer and melanoma cell spreading. The sulfated fucans increased the endocytosis of β1 integrin and neuropilin-1 (NRP-1) chains, two cell receptors implicated in FN-dependent adhesion. The treatment of cancer cells with both sulfated fucans, but not with heparin, also triggered intracellular focal adhesion kinase (FAK) degradation, with a consequent overall decrease in activated FAK levels. Finally, only sulfated fucans inhibited the growth of B16-F10 melanoma cells implanted in the dermis of syngeneic C57/BL6 mice. FucSulf1 and FucSulf2 arise from this study as candidates for the design of possible alternatives to long-term treatments of cancer patients with heparins, with the advantage of also controlling local growth and invasion of malignant cells.

Multi-institutional Development and Validation of Contouring Guidelines for Para-aortic Elective Nodal Irradiation in Prostate Cancer Based on Patterns of Involvement on Targeted Molecular Imaging Positron Emission Tomography/Computed Tomography

Molecular imaging better identifies anatomic regions of metastatic spread of prostate cancer compared with conventional imaging, resulting in para-aortic (PA) nodal metastases being increasingly identified. Consequently, some radiation oncologists electively treat the PA lymph node region in patients with gross or high risk of PA nodal involvement. The anatomic locations of at-risk PA lymph nodes for prostate cancer are unknown. Our objective was to use molecular imaging to develop guidelines for the optimal delineation of the PA clinical target volume (CTV) in patients with prostate cancer. We conducted a multi-institutional retrospective cohort study of patients with prostate cancer undergoing 18F-fluciclovine or 18F-DCFPyL prostate-specific membrane antigen positron emission tomography (PET)/computed tomography (CT). Images of patients with PET-positive PA nodes were imported into the treatment planning system, avid nodes were contoured, and measurements were taken in relation to anatomic landmarks. A contouring guideline that encompassed the location of ≥95% of PET-positive PA nodes was created using descriptive statistics and then validated in an independent data set. Five hundred fifty-nine patients had molecular PET/CT imaging in the development data set (78% 18F-fluciclovine, 22% prostate-specific membrane antigen). Seventy-six patients (14%) had evidence of PA nodal metastasis. We determined that expanding the CTV to 1.8 cm left of the aorta, 1.4 cm right of the inferior vena cava (IVC), 7 mm posterior to the aorta/IVC or to the vertebral body, and superiorly to the T11/T12 vertebral interface, with the anterior border 4 mm anterior to the aorta/IVC and inferior border at the bifurcation of the aorta/IVC, resulted in coverage of ≥95% of PET-positive PA nodes. When the guideline was used in the independent validation data set (246 patients with molecular PET/CT imaging, of whom 31 had PA nodal metastasis), 97% of nodes were encompassed, thereby validating our guideline. We used molecular PET/CT imaging to determine the anatomic locations of PA metastases to develop contouring guidelines for creating a prostate cancer PA CTV. Although the optimal patient selection and clinical benefits of PA radiation therapy remain uncertain, our results will aid in delineating the optimal target when PA radiation therapy is pursued.

The Androgen Regulation of Matrix Metalloproteases in Prostate Cancer and Its Related Tumor Microenvironment

Prostate cancer represents the most common type of cancer among males and the second leading cause of cancer death in men in Western society. In most cases (~70%), PC has a slow and symptom-free growth, whereas it is more aggressive in the remaining patients. Current PC therapies prevalently target the proliferative function of the androgen receptor and may only be effective within short periods, beyond which the disease will progress to metastatic and castration-resistant phenotype. Preclinical and clinical studies are aimed at investigating the molecular basis for prostate cancer spreading. Although considerable efforts have been made to dissect the programs that foster prostate cancer spreading, few biomarkers predictive of metastatic phenotype have yet been identified and few therapeutic options are available for treatment of the metastatic disease. In the present paper, we will discuss innovative aspects of prostate cancer biology, which impinge on the role of cancer-associated fibroblasts and the released matrix metalloproteinases in the disease progression. Investigating these aspects might allow the discovery of clinically actionable biomarkers to target in the advanced stages of prostate cancer.

Development and External Validation of a Novel Nomogram to Predict the Probability of Pelvic Lymph-node Metastases in Prostate Cancer Patients Using Magnetic Resonance Imaging and Molecular Imaging with Prostate-specific Membrane Antigen Positron Emission Tomography

BackgroundPreoperative assessment of the probability of pelvic lymph-node metastatic disease (pN1) is required to identify patients with prostate cancer (PCa) who are candidates for extended pelvic lymph-node dissection (ePLND). ObjectiveTo develop a novel intuitive prognostic nomogram for predicting pathological lymph-node (pN) status in contemporary patients with primary diagnosed localized PCa, using preoperative clinical and histopathological parameters, magnetic resonance imaging (MRI), and prostate-specific membrane antigen (PSMA) positron emission tomography (PET). Design, setting, and participantsIn total, 700 eligible patients who underwent robot-assisted radical prostatectomy and ePLND were included in the model-building cohort. The external validation cohort consisted of 305 surgically treated patients. Logistic regression with backward elimination was used to select variables for the Amsterdam-Brisbane-Sydney nomogram. Outcome measurements and statistical analysisPerformance of the final model was evaluated using the area under the receiver operating characteristic curve (AUC), calibration plots, and decision-curve analyses. Models were subsequently validated in an external population. Results and limitationsThe Amsterdam-Brisbane-Sydney nomogram included initial prostate-specific antigen value, MRI T stage, highest biopsy grade group (GG), biopsy technique, percentage of systematic cores with clinically significant PCa (GG ≥2), and lymph-node status on PSMA-PET. The AUC for predicting pN status was 0.81 (95% confidence interval [CI] 0.78–0.85) for the final model. On external validation, the Amsterdam-Brisbane-Sydney nomogram showed superior discriminative ability to the Briganti-2017 and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms (AUC 0.75 [95% CI 0.69–0.81] vs 0.67 [95% CI 0.61–0.74] and 0.65 [95% CI 0.58–0.72], respectively; p < 0.05), and similar discriminative ability to the Briganti-2019 nomogram (AUC 0.78 [95% CI 0.71–0.86] vs 0.80 [95% CI 0.73–0.86]; p = 0.76). The Amsterdam-Brisbane-Sydney nomogram showed excellent calibration on external validation, with an increased net benefit at a threshold probability of ≥4%. ConclusionsThe validated Amsterdam-Brisbane-Sydney nomogram performs superior to the Briganti-2017 and MSKCC nomograms, and similar to the Briganti-2019 nomogram. Furthermore, it is applicable in all patients with newly diagnosed unfavorable intermediate- and high-risk PCa. Patient summaryWe developed and validated the Amsterdam-Brisbane-Sydney nomogram for the prediction of prostate cancer spread to lymph nodes before surgery. This nomogram performs similar or superior to all presently available nomograms.

Peritoneal Carcinomatosis of Prostate Cancer with PSMA-targeted 18F-DCFPyL PET/CT

HomeRadiology: Imaging CancerVol. 5, No. 2 PreviousNext Images in CancerFree AccessPeritoneal Carcinomatosis of Prostate Cancer with PSMA-targeted 18F-DCFPyL PET/CTRonald Woodruff , Cameron Henry, Phillip SchererRonald Woodruff , Cameron Henry, Phillip SchererAuthor AffiliationsFrom the Philadelphia College of Osteopathic Medicine, 4170 City Avenue, Philadelphia, PA 19131 (R.W.); and Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tenn (C.H., P.S.).Address correspondence to R.W. (email: [email protected]).Ronald Woodruff Cameron HenryPhillip SchererPublished Online:Mar 17 2023https://doi.org/10.1148/rycan.220174MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Prostate cancer is the second most common cause of cancer-related death in men. Metastatic spread of prostate cancer frequently involves the bones (84%) and, less commonly, distant lymph nodes (10.6%) and the liver (10.2%) (1). Peritoneal spread of prostate adenocarcinoma is rarely described in the literature, especially without evidence of bony spread or other distant metastatic involvement (2,3). The cause of peritoneal involvement of prostate cancer is poorly understood. While treatment options such as surgical intervention combined with medical therapy have proven effective in preventing local disease recurrence, studies have proposed that laparoscopic prostatectomies may increase the risk of iatrogenic seeding of the peritoneum, causing disease recurrence later in life (4). Cases of peritoneal involvement in the absence of surgical intervention have also been reported, possibly revealing hematogenous or lymphatic spread as a cause. Visceral involvement in prostate cancer is known to be a poor prognostic indicator. Clinicians should consider this diagnosis when performing imaging for patients with a history of prostate adenocarcinoma (Figure).Prostate-specific membrane antigen–targeted fluorine 18 (18F) 2-(3-{1-carboxy-5-[(6-18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (DCFPyL) PET/CT images in an 88-year-old man with a history of prostate adenocarcinoma who presented with worsening fatigue and abdominal distention for over a year. The patient was treated 15 years prior with prostatectomy (Gleason score was 3 + 4 = 7) and continued to receive medical management. Despite treatment, the patient’s prostate-specific antigen level was elevated to 917.61 ng/mL. For restaging, imaging was performed. (A) Coronal PET image shows diffuse intense uptake throughout the peritoneum and omentum. (B, C) Axial PET/CT images show peritoneal nodularity (white arrow), ascites (red arrow), and extensive omental nodularity and stranding (blue arrows), with no evidence of skeletal metastasis. Histologic sample of the mesentery helped confirm prostate adenocarcinoma. No further genetic or histologic testing aided the patient’s diagnosis.Download as PowerPointOpen in Image Viewer Disclosures of conflicts of interest: R.W. No relevant relationships. C.H. Leadership or fiduciary role in Society of Cardiovascular Computed Tomography (SCCT) FiRST committee. P.S. No relevant relationships.Keywords: PET/CT, Prostate, Peritoneum, Omentum, Mesentery, MetastasesAuthors declared no funding for this work.

Nano-Hydroxyapatite/PLGA Mixed Scaffolds as a Tool for Drug Development and to Study Metastatic Prostate Cancer in the Bone.

(1) Background: Three-dimensional (3D) in vitro, biorelevant culture models that recapitulate cancer progression can help elucidate physio-pathological disease cues and enhance the screening of more effective therapies. Insufficient research has been conducted to generate in vitro 3D models to replicate the spread of prostate cancer to the bone, a key metastatic site of the disease, and to understand the interplay between the key cell players. In this study, we aim to investigate PLGA and nano-hydroxyapatite (nHA)/PLGA mixed scaffolds as a predictive preclinical tool to study metastatic prostate cancer (mPC) in the bone and reduce the gap that exists with traditional 2D cultures. (2) Methods: nHA/PLGA mixed scaffolds were produced by electrospraying, compacting, and foaming PLGA polymer microparticles, +/- nano-hydroxyapatite (nHA), and a salt porogen to produce 3D, porous scaffolds. Physicochemical scaffold characterisation together with an evaluation of osteoblastic (hFOB 1.19) and mPC (PC-3) cell behaviour (RT-qPCR, viability, and differentiation) in mono- and co-culture, was undertaken. (3) Results: The results show that the addition of nHA, particularly at the higher-level impacted scaffolds in terms of mechanical and degradation behaviour. The nHA 4 mg resulted in weaker scaffolds, but cell viability increased. Qualitatively, fluorescent imaging of cultures showed an increase in PC-3 cells compared to osteoblasts despite lower initial PC-3 seeding densities. Osteoblast monocultures, in general, caused an upregulation (or at least equivalent to controls) in gene production, which was highest in plain scaffolds and decreased with increases in nHA. Additionally, the genes were downregulated in PC3 and co-cultures. Further, drug toxicity tests demonstrated a significant effect in 2D and 3D co-cultures. (4) Conclusions: The results demonstrate that culture conditions and environment (2D versus 3D, monoculture versus co-culture) and scaffold composition all impact cell behaviour and model development.