Objectives To provide an outline of the existing data on penile intraepithelial neoplasia (PeIN), as well as a narrative review on imiquimod (IQ; a toll‐like receptor 7 agonist) treatment and immune ...microenvironment markers that may predict response to treatment. Methods A narrative review of the literature from 2000 to the present was conducted on PubMed, and we describe the most relevant data and cross references. Results The incidence of PeIN is increasing. Local therapy with IQ may offer an easy applicable treatment with complete response rates of up to 63% but can be associated with considerable side‐effects. There is no conclusive data on the optimal treatment schedule for PeIN, but evaluation of treatment results for other human papillomavirus‐related pre‐malignancies suggest three times a week for a duration up to 16 weeks. There are no published studies concerning the PeIN immune microenvironment. However, findings from the few studies on penile cancer and pre‐cancerous vulvar and cervical lesions imply that specific immune cell subpopulations can serve as future predictors for successful immunomodulation treatments such as IQ. Conclusions Overall, limited data are available on IQ treatment for PeIN and no published data exists on the PeIN immune microenvironment. Further translational studies are warranted to gain more understanding on the pathophysiology of PeIN and potential predictors of progression and of response to topical treatments.
Targeted real-time imaging during robot-assisted radical prostatectomy provides information on the localisation and extent of prostate cancer. We assessed the safety and feasibility of the ...prostate-specific membrane antigen (PSMA)-targeted fluorescent tracer OTL78 in patients with prostate cancer.
In this single-arm, phase 2a, feasibility trial with an adaptive design was carried out in The Netherlands Cancer Institute, Netherlands. Male patients aged 18 years or older, with PSMA PET-avid prostate cancer with an International Society of Urological Pathology (ISUP) grade group of 2 or more, who were scheduled to undergo robot-assisted radical prostatectomy with or without extended pelvic lymph node dissection were eligible. All patients had a robot-assisted radical prostatectomy using OTL78. Based on timing and dose, patients received a single intravenous infusion of OTL78 (0·06 mg/kg 1–2 h before surgery dose cohort 1, 0·03 mg/kg 1–2 h before surgery dose cohort 2, or 0·03 mg/kg 24 h before surgery dose cohort 3). The primary outcomes, assessed in all enrolled patients, were safety and pharmacokinetics of OTL78. This study is completed and is registered in the European Trial Database, 2019-002393-31, and the International Clinical Trials Registry Platform, NL8552, and is completed.
Between June 29, 2020, and April 1, 2021, 19 patients were screened for eligibility, 18 of whom were enrolled. The median age was 69 years (IQR 64–70) and median prostate-specific antigen concentration was 15 ng/mL (IQR 9·3–22·0). In 16 (89%) of 18 patients, robot-assisted radical prostatectomy was accompanied by an extended pelvic lymph node dissection. Three serious adverse events occurred in one (6%) patient: an infected lymphocele, a urosepsis, and an intraperitoneal haemorrhage. These adverse events were considered unrelated to the administration of OTL78 or intraoperative fluorescence imaging. No patient died, required a dose reduction, or required discontinuation due to drug-related toxicity. The dose-normalised maximum serum concentration (Cmax/dose) in patients was 84·1 ng/mL/mg for the 0·03 mg/kg dose and 79·6 ng/mL/mg for the 0·06 mg/kg dose, the half-life was 5·1 h for the 0·03 mg/kg dose and 4·7 h for the 0·06 mg/kg dose, the volume of distribution was 22·9 L for the 0·03 mg/kg dose and 19·5 L for the 0·06 mg/kg dose, and the clearance was 3·1 L/h for the 0·03 mg/kg dose and 3·0 L/h for the 0·06 mg/kg dose.
This first-in-patient study showed that OTL78 was well tolerated and had the potential to improve prostate cancer detection. Optimal dosing was 0·03 mg/kg, 24 h preoperatively. PSMA-directed fluorescence imaging allowed real-time identification of visually occult prostate cancer and might help to achieve complete oncological resections.
On Target Laboratories.
Purpose
Currently, approximately 11–38% of prostate cancer (PCa) patients undergoing radical prostatectomy have a positive surgical margin (PSM) on histopathology. Cerenkov luminescence imaging (CLI) ...using
68
Ga-prostate-specific membrane antigen (
68
Ga-PSMA) is a novel technique for intraoperative margin assessment. The aim of this first-in-man study was to investigate the feasibility of intraoperative
68
Ga-PSMA CLI
.
In this study, feasibility was defined as the ability to distinguish between a positive and negative surgical margin, imaging within 45 min and low radiation exposure to staff.
Methods
Six patients were included in this ongoing study. Following perioperative i.v. injection of ~ 100 MBq
68
Ga-PSMA, the prostate was excised and immediately imaged ex vivo. Different acquisition protocols were tested, and hotspots on CLI images from the intact prostate were marked for comparison with histopathology.
Results
By using an acquisition protocol with 150 s exposure time, 8 × 8 binning and a 550 nm shortpass filter, PSMs and negative surgical margins (NSMs) were visually correctly identified on CLI in 3 of the 5 patients. Two patients had a hotspot on CLI from cancer < 0.1 mm from the excision margin.
Conclusion
Overall, the study showed that
68
Ga-PSMA CLI is a feasible and low-risk technique for intraoperative margin assessment in PCa. The remaining patients in this ongoing study will be used to assess the diagnostic accuracy of the technique.
Trial registration: NL8256 registered at www.trialregister.nl on 04/11/20109.
Fibro-osseous pseudotumors of the digits (FOPD) is a rare self-limiting lesion composed of bland looking hypercellular fibrous tissue and bone.
USP6 rearrangement is a consistent genetic finding in ...aneurysmal bone cyst, nodular fasciitis, myositis ossificans and giant cell lesions of small bones.
We report herein the occurrence of USP6 rearrangement in fibro-osseous pseudotumors of the digits using fluorescence in situ hybridization analysis (FISH).
Of the five patients included, three were female and two were male. The age ranged from 33 to 72 years (mean 48 years). Lesions arose in the palm (n = 2), thenar (n = 1), middle finger (n = 1) and great toe (n = 1). All patients underwent resection.
Four cases (80%) harbored USP6 rearrangements showing that fibro-osseous pseudotumors of digits belongs to the spectrum of clonal transient neoplasms including aneurysmal bone cyst, nodular fasciitis, myositis ossificans and giant cell lesion of small bones.
•We identified USP6 rearrangements in fibro-osseous pseudotumors of the digits.•They therefore belong to the group of clonal transient neoplasms including nodular fasciitis and myositis ossificans.•USP6 FISH can be helpful when considering malignancy on clinicopathological grounds.
The aim of this study was to assess the association between radiological and histopathological response after neoadjuvant radiotherapy (nRT) in soft tissue sarcoma (STS), as well as the prognostic ...value of the different response evaluation methods on the oncological outcome.
A retrospective cohort of patients with localized STS of the extremity and trunk wall, treated with nRT followed by resection were included. The radiological response was assessed by RECIST 1.1 (RECIST) and MR-adapted Choi (Choi), histopathologic response was evaluated according to the EORTC-STBSG recommendations. Oncological outcome parameters of interest were local recurrence-free survival (LRFS), disease metastases-free survival (DMFS), and overall survival (OS).
For 107 patients, complete pre- and postoperative pathology and imaging datasets were available. Most tumors were high-grade (77%) and the most common histological subtypes were undifferentiated pleomorphic sarcoma/not otherwise specified (UPS/NOS, 40%), myxoid liposarcoma (MLS, 21%) and myxofibrosarcoma (MFS, 16%). When comparing RECIST to Choi, the response was differently categorized in 58%, with a higher response rate (CR + PR) with Choi. Radiological responders showed a significant lower median percentage of viable cells (RECIST p = .050, Choi p = .015) and necrosis (RECIST p < .001), and a higher median percentage of fibrosis (RECIST p = .005, Choi p = .008), compared to radiological non-responders (SD + PD). RECIST, Choi, fibrosis, and viable cells were not significantly associated with altered oncological outcome, more necrosis was associated with poorer OS (p = .038).
RECIST, Choi and the EORTC-STBSG response score show incongruent results in response evaluation. The radiological response was significantly correlated with a lower percentage of viable cells and necrosis, but a higher percentage of fibrosis. Apart from necrosis, radiological nor other histopathological parameters were associated with oncologic outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Solitary fibrous tumor is a mesenchymal tumor of fibroblastic type, which can affect any region of the body. Recently, a recurrent gene fusion NAB2-STAT6 has been identified as molecular hallmark. ...The NAB2-STAT6 fusion leads to EGR1 activation and transcriptional deregulation of EGR1-dependent target genes and is a driving event in initiation of SFT. In this study, we report the clinicopathologic and RT-PCR findings and evaluated expression of STAT6 and EGR1 protein in a cohort of 28 SFTs.
28 patients with a median age of 54 years were included with SFTs originating at different sites, most occurring in the lung and pleura (9, 32%), 5 in soft tissues of the lower extremities (18%) and 5 in the head and neck (18%). For detection of the NAB2-STAT6 fusion gene, RT-PCR was performed using RNA extracted from formalin-fixed and paraffin-embedded tissues. Immunohistochemistry was performed on all cases with antibodies against STAT6 and EGR1.
All patients were treated by surgery, 3 with adjuvant chemo- or radiotherapy. Follow-up data of 18 patients could be obtained of which 2 patients died of metastatic disease 13 months and 52 years after first diagnosis. Sixteen patients have no evidence of disease with a median follow up of 29.5 months (range 7 - 120 months). NAB2-STAT6 fusion transcripts were found in 19/28 cases (68%). The most common fusion was between NAB2 exon 4 and STAT6 exon 3 (11/19, 58%), mainly occurring in pleuropulmonary lesions. All cases showed strong nuclear expression of STAT6 (28/28, 100%) while EGR1 showed low-level variable nuclear expression in all samples, comparable with the EGR1 expression results of the control group.
The identification of the NAB2-STAT6 fusion in SFTs can provide important diagnostic information, especially in cases with aberrant morphology or when biopsy material is limited. STAT6 immunohistochemistry is another useful tool in diagnosing SFT. EGR1 immunohistochemistry indicates low-level protein expression in accordance with EGR1 activation due to distorted NAB2 activity.
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_224.
Objective
To determine the diagnostic accuracy of the hybrid tracer indocyanine green (ICG)-Technetium-99 m(
99m
Tc)-nanocolloid compared to sequential tracers of
99m
Tc-nanocolloid and free-ICG in ...detecting tumor-positive lymph nodes (LN) during primary surgery in prostate cancer (PCa) patients.
Introduction
Image-guided surgery strategies can help visualize individual lymphatic drainage patterns and sentinel lymph nodes (SLNs) in PCa patients. For lymphatic mapping radioactive, fluorescent and hybrid tracers are being clinically exploited. In this prospective randomized phase II trial, we made a head-to-head comparison between ICG-
99m
Tc-nanocolloid (hybrid group) and
99m
Tc-nanocolloid and subsequent free-ICG injection (sequential group).
Methods
PCa patients with a >5% risk of lymphatic involvement according to the 2012 Briganti nomogram and planned for prostatectomy were included and randomized (1:1) between ultrasound-guided intraprostatic tracer administration of ICG-
99m
Tc-nanocolloid (
n
= 69) or
99m
Tc-nanocolloid (
n
= 69) 5 h before surgery. Preoperative lymphoscintigraphy and SPECT/CT were performed to define the locations of the SLNs. Additionally, all participants in the sequential group received an injection of free-ICG at time of surgery. Subsequently, all (S)LNs were dissected using fluorescence guidance followed by an extended pelvic lymph node dissection (ePLND). The primary outcome was the total number of surgically removed (S)LNs and tumor-positive (S)LNs.
Results
The total number of surgically removed (S)LN packages was 701 and 733 in the hybrid and sequential groups, respectively (
p
= 0.727). The total number of fluorescent LNs retrieved was 310 and 665 nodes in the hybrid and sequential groups, respectively (
p
< 0.001). However, no statistically significant difference was observed in the corresponding number of tumor-positive nodes among the groups (44 vs. 33;
p
= 0.470). Consequently, the rate of tumor-positive fluorescent LNs was higher in the hybrid group (7.4%) compared to the sequential group (2.6%;
p
= 0.002), indicating an enhanced positive predictive value for the hybrid approach. There was no difference in complications within 90 days after surgery (
p
= 0.78).
Conclusions
The hybrid tracer ICG-
99m
Tc-nanocolloid improved the positive predictive value for tumor-bearing LNs while minimizing the number of fluorescent nodes compared to the sequential tracer approach. Consequently, the hybrid tracer ICG-
99m
Tc-nanocolloid enables the most reliable and minimal invasive method for LN staging in PCa patients.
In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells ...adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target.
Understanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007.
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