The accuracy and intra- and interobserver variability of PSMA PET/CT for the local staging of primary prostate cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA) positron emission tomography/ computed tomography (PET/CT) is recognized as the most accurate imaging modality for detection of metastatic high-risk prostate cancer (PCa). Its role in the local staging of disease is yet unclear. We assessed the intra- and interobserver variability, as well as the diagnostic accuracy of the PSMA PET/CT based molecular imaging local tumour stage (miT-stage) for the local tumour stage assessment in a large, multicentre cohort of patients with intermediate and high-risk primary PCa, with the radical prostatectomy specimen (pT-stage) serving as the reference standard. METHODS: A total of 600 patients who underwent staging PSMA PET/CT before robot-assisted radical prostatectomy was studied. In 579 PSMA positive primary prostate tumours a comparison was made between miT-stage as assessed by four nuclear physicians and the pT-stage according to ISUP protocol. Sensitivity, specificity and diagnostic accuracy were determined. In a representative subset of 100 patients, the intra-and interobserver variability were assessed using Kappa-estimates. RESULTS: The sensitivity and specificity of the PSMA PET/CT based miT-stage were 58% and 59% for pT3a-stage, 30% and 97% for ≥ pT3b-stage, and 68% and 61% for overall ≥ pT3-stage, respectively. No statistically significant differences in diagnostic accuracy were found between tracers. We found a substantial intra-observer agreement for PSMA PET/CT assessment of ≥ T3-stage (k 0.70) and ≥ T3b-stage (k 0.75), whereas the interobserver agreement for the assessment of ≥ T3-stage (k 0.47) and ≥ T3b-stage (k 0.41) were moderate. CONCLUSION: In a large, multicentre study evaluating 600 patients with newly diagnosed intermediate and high-risk PCa, we showed that PSMA PET/CT may have a value in local tumour staging when pathological tumour stage in the radical prostatectomy specimen was used as the reference standard. The intra-observer and interobserver variability of assessment of tumour extent on PSMA PET/CT was moderate to substantial.

99mTcPSMA-radioguided surgery in oligorecurrent prostate cancer: the randomised TRACE-II trial.

OBJECTIVE: To investigate whether combination treatment of prostate-specific membrane antigen (PSMA)-based radioguided surgery (RGS) with short-term androgen deprivation therapy (ADT) improves oncological outcomes in men with oligorecurrent prostate cancer (PCa) as compared to treatment with short-term ADT only. METHODS: The TRACE-II study is an investigator-initiated, prospective, randomised controlled clinical trial. Patients (aged >18 years) with hormone-sensitive recurrent PCa after radical prostatectomy or radiotherapy (brachytherapy or external beam radiotherapy), with involvement of ≤2 lymph nodes or local oligorecurrent disease within the pelvis as determined by PSMA positron emission tomography (PET)/computed tomography (CT) are randomly assigned in a 1:1 ratio between 6-month ADT (Arm A) or 6-month ADT plus RGS (Arm B). The primary objective is to determine clinical progression-free survival (CPFS) at 24 months. After PSMA-RGS, CPFS is defined as the time between the start of treatment and the appearance of a re-recurrence (any N1 or M1) as suggested by PSMA-PET/CT or symptoms related to progressive PCa, or death from any cause. The secondary objectives include metastasis-free survival at 2, 5 and 10 years, biochemical progression-free survival at 2 years, and patient-reported quality of life at 2, 5 and 10 years. A total of 60 patients, 30 per arm, will be included. The trial is powered (80%) to detect at least a 30% absolute difference in CPFS between the two study arms in the period 2 years after randomisation. We expect to enrol the required participants in 3 years. The study has an expected duration of 5 years in total. CONCLUSIONS: Combining RGS with short-term ADT might be oncologically beneficial for patients with oligorecurrent PCa. In this first randomised controlled trial, we are investigating the potential oncological benefits of this combined treatment, while also focusing on maintaining quality of life.

First-in-patient study of OTL78 for intraoperative fluorescence imaging of prostate-specific membrane antigen-positive prostate cancer: a single-arm, phase 2a, feasibility trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: On Target Laboratories.

Management of Benign Phyllodes Tumors: A Dutch Population-Based Retrospective Cohort Between 1989 and 2022.

BACKGROUND: Phyllodes tumors (PTs) are rare tumors of the breast. The current National Comprehensive Cancer Network (NCCN) guidelines recommend excision of benign PTs, accepting close or positive margins. Controversy about the optimal treatment for benign PTs remains, especially regarding the preferred margin width after surgical excision and the need for follow-up evaluation. METHODS: A nationwide retrospective study analyzed the Dutch population from 1989 to 2022. All patients with a diagnosis of benign PT were identified through a search in the Dutch nationwide pathology databank (Palga). Information on age, year of diagnosis, size of the primary tumor, surgical treatment, surgical margin status, and local recurrence was collected. RESULTS: The study enrolled 1908 patients with benign PT. The median age at diagnosis was 43 years (interquartile range [IQR], 34-52 years), and the median tumor size was 30 mm (IQR, 19-40 mm). Most of the patients (95%) were treated with breast-conserving surgery (BCS). The overall local recurrence rate was 6.2%, and the median time to local recurrence was 31 months (IQR, 15-61 months). Local recurrence was associated with bilaterality of the tumor (odds ratio [OR], 4.91; 95% confidence interval [CI], 2.95-28.30) and positive margin status (OR, 2.51; 95% CI 1.36-4.63). The local recurrence rate was 8.9% for the patients with positive excision margins and 4.0% for the patients with negative excision margins. Notably, for 27 patients (22.6%) who experienced a local recurrence, histologic upgrading of the recurrent tumor was reported, 7 (5.9%) of whom had recurrence as malignant lesions. CONCLUSIONS: This nationwide series of 1908 patients showed a low local recurrence rate of 6.2% for benign PT, with higher recurrence rates following positive margins.

A hybrid radioactive and fluorescence approach is more than the sum of its parts; outcome of a phase II randomized sentinel node trial in prostate cancer patients.

OBJECTIVE: To determine the diagnostic accuracy of the hybrid tracer indocyanine green (ICG)-Technetium-99 m(99mTc)-nanocolloid compared to sequential tracers of 99mTc-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-99mTc-nanocolloid (hybrid group) and 99mTc-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-99mTc-nanocolloid (n = 69) or 99mTc-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-99mTc-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-99mTc-nanocolloid enables the most reliable and minimal invasive method for LN staging in PCa patients.

The prognostic value of lymph node staging with prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and extended pelvic lymph node dissection in node-positive patients with prostate cancer.

OBJECTIVES: To investigate whether patients with suspected pelvic lymph node metastases (molecular imaging [mi] N1) on staging prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) had a different oncological outcome compared to those in whom the PSMA PET/CT did not reveal any pelvic lymph node metastases (miN0). PATIENTS AND METHODS: All patients with pelvic lymph node metastatic (pN1) disease after robot-assisted radical prostatectomy (RARP) and extended pelvic lymph node dissection (ePLND) between January 2017 and December 2020 were included. To assess predictors of biochemical progression of disease after RARP, a multivariable Cox regression analysis was performed, including number of tumour-positive lymph nodes, diameter of the largest nodal metastasis, and extranodal extension. RESULTS: In total, 145 patients were diagnosed with pN1 disease after ePLND. The median biochemical progression-free survival in patients with miN0 on PSMA PET/CT was 13.7 months, compared to 7.9 months in patients with miN1 disease (P = 0.006). On multivariable Cox regression analysis, both number of tumour-positive lymph nodes (>2 vs 1-2: hazard ratio [HR] 1.97; P = 0.005) and diameter of the largest nodal metastasis (HR 1.12; P < 0.001) were significant independent predictors of biochemical progression of disease. CONCLUSION: Patients in whom pelvic lymph node metastases were suspected on preoperative PSMA imaging (miN1), patients diagnosed with >2 tumour-positive lymph nodes, and patients with a larger diameter of the largest nodal metastasis had a significantly increased risk of biochemical disease progression after surgery.

Correlation of radiological and histopathological response after neoadjuvant radiotherapy in soft tissue sarcoma.

BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.

The impact of drainage pathways on the detection of nodal metastases in prostate cancer: a phase II randomized comparison of intratumoral vs intraprostatic tracer injection for sentinel node detection.

INTRODUCTION: Previous studies indicated that location and amount of detected sentinel lymph nodes (SLNs) in prostate cancer (PCa) are influenced where SLN-tracer is deposited within the prostate. To validate whether intratumoral (IT) tracer injection helps to increase identification of tumor-positive lymph nodes (LNs) better than intraprostatic (IP) tracer injection, a prospective randomized phase II trial was performed. METHODS: PCa patients with a > 5% risk of lymphatic involvement were randomized between ultrasound-guided transrectal injection of indocyanine green-[99mTc]Tc-nanocolloid in 2 depots of 1 mL in the tumor (n = 55, IT-group) or in 4 depots of 0.5 mL in the peripheral zone of the prostate (n = 58, IP-group). Preoperative lymphoscintigraphy and SPECT/CT were used to define the location of the SLNs. SLNs were dissected using combination of radio- and fluorescence-guidance, followed by extended pelvic LN dissection and robot-assisted radical prostatectomy. Outcome measurements were number of tumor-bearing SNs, tumor-bearing LNs, removed nodes, number of patients with nodal metastases, and metastasis-free survival (MFS) of 4-7-year follow-up data. RESULTS: IT-injection did not result in significant difference of removed SLNs (5.0 vs 6.0, p = 0.317) and histologically positive SLNs (28 vs 22, p = 0.571). However, in IT-group, the SLN-positive nodes were 73.7% of total positive nodes compared to 37.3% in IP-group (p = 0.015). Moreover, significantly more node-positive patients were found in IT-group (42% vs 24%, p = 0.045), which did not result in worse MFS. In two patients (3.6%) from whom the IT-tracer injection only partly covered intraprostatic tumor spread, nodal metastases in ePLND without tumor-positive SNs were yielded. CONCLUSIONS: The percentage-positive SLNs found after IT-injection were significantly higher compared to IP-injection. Significantly more node-positive patients were found using IT-injection, which did not affect MFS. IT-injection failed to detect nodal metastases from non-index satellite lesions. Therefore, we suggest to combine IT- and IP-tracer injections in men with visible tumor on imaging.

Diagnostic Laparoscopy and Abdominal Cytology Reliably Detect Peritoneal Metastases in Patients with Urachal Adenocarcinoma.

BACKGROUND: Urachal adenocarcinoma (UrAC) is a rare malignancy that can cause peritoneal metastases (PM). Analogous to other enteric malignancies, selected patients with limited PM of UrAC can be treated by cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). OBJECTIVE: The aim of this study was to address the value of diagnostic laparoscopy (DLS) and abdominal cytology (ACyt) for the detection and evaluation of the extent of PM in patients with UrAC. METHODS: A consecutive series of cN0M0 patients with UrAC who underwent DLS with or without ACyt at a tertiary referral center between 2000 and 2018 was assessed. Patients were staged with computed tomography (CT) and/or positron emission tomography (PET)/CT or bone scan. DLS was performed to rule out PM and to evaluate the extent and resectability of PM if seen on imaging. Sensitivity and specificity values were calculated for imaging, DLS, ACyt, and the combination of DLS and ACyt. RESULTS: Thirty-two patients with UrAC underwent DLS. ACyt was obtained in 19 patients. Four patients had suspicion of PM on imaging. In the 28 patients who were PM-negative on imaging, DLS and ACyt revealed PM in 6 (21%) patients, of whom 5 had macroscopically visible PM; 1 patient had positive ACyt without visible PM. Sensitivity of combined DLS/ACyt for the detection of PM was 91%, with a specificity of 100%, whereas sensitivity of imaging was 36%. DLS correctly predicted resectability in all patients. CONCLUSION: Combined DLS/ACyt proved an effective tool to detect occult PM and to evaluate the extent of PM to select UrAC patients for possible treatment with CRS/HIPEC.

68Ga-PSMA Cerenkov luminescence imaging in primary prostate cancer: first-in-man series.

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 68Ga-prostate-specific membrane antigen (68Ga-PSMA) is a novel technique for intraoperative margin assessment. The aim of this first-in-man study was to investigate the feasibility of intraoperative 68Ga-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 68Ga-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 68Ga-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 pseudotumor of digits - Expanding the spectrum of clonal transient neoplasms harboring USP6 rearrangement.

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.

Myositis ossificans - Another condition with USP6 rearrangement, providing evidence of a relationship with nodular fasciitis and aneurysmal bone cyst.

Myositis ossificans is defined as a self-limiting pseudotumor composed of reactive hypercellular fibrous tissue and bone. USP6 rearrangements have been identified as a consistent genetic driving event in aneurysmal bone cyst and nodular fasciitis. It is therefore an integral part of the diagnostic workup when dealing with (myo)fibroblastic lesions of soft tissue and bone. Two cases of myositis ossificans with USP6 rearrangement were published so far. We determine herein the incidence of USP6 rearrangement in myositis ossificans using USP6 fluorescence in situ hybridization analysis (FISH). Of the 11 cases included, seven patients were female and four were male. Age ranged from 6 to 56 years (mean 27 years). Lesions were located in the thigh (n = 5), knee (n = 1), lower leg (n = 1), lower arm (n = 1), perineum (n = 1), gluteal (n = 1) and thoracic wall (n = 1). All assessable cases except one (8/9) showed rearrangement of USP6 providing evidence that myositis ossificans is genetically related to nodular fasciitis and aneurysmal bone cyst.

Multifocal occurrence of extra-abdominal desmoid type fibromatosis - A rare manifestation. A clinicopathological study of 6 sporadic cases and 1 hereditary case.

Desmoid-type fibromatosis, also called desmoid tumor, is a locally aggressive myofibroblastic neoplasm that usually arises in deep soft tissue with significant potential for local recurrence. It displays an unpredictable clinical course. ß-Catenin, the genetic key player of desmoid tumors shows nuclear accumulation due to mutations that prevent its degradation leading to activation of Wnt signaling and myofibroblastic cell proliferation. The corresponding hot spot mutations are located in exon 3 of the CTNNB1 gene or alternatively, in the APC tumor suppressor gene, most often as a germline mutation. Multifocal desmoid tumors are very rare and clinical characteristics are poorly understood. Here we present six sporadic and one familial case of multifocal desmoid tumors. Four female and three male patients, aged between 7 and 30 years (mean 18.4 years) were identified in a cohort of 1392 cases. Tumors were located in (distal) extremities, thorax, breast, abdominal wall, shoulder, and neck. Four cases showed a CTNNB1 mutation and one an APC germline mutation. In two sporadic cases no CTNNB1 mutation was identified. Four patients showed (multiple) recurrences and one patient was lost to follow-up. In conclusion, multifocal desmoid tumors are a very rare disease and may occur in sporadic cases that are characterized by recurrent CTNNB1 mutations. However, the underlying pathogenesis of multifocal desmoid tumors remains poorly understood with often aggressive clinical behavior and challenging therapeutical management.

Mutational analysis using Sanger and next generation sequencing in sporadic spindle cell hemangiomas: A study of 19 cases.

Spindle cell hemangioma (SCH) is a distinct vascular soft-tissue lesion characterized by cavernous blood vessels and a spindle cell component mainly occurring in the distal extremities of young adults. The majority of cases harbor heterozygous mutations in IDH1/2 sporadically or rarely in association with Maffucci syndrome. However, based on mosaicism and accordingly a low percentage of lesional cells harboring a mutant allele, detection can be challenging. We tested 19 sporadic SCHs by Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), conventional next generation sequencing (NGS), and NGS using a single molecule molecular inversion probes (smMIP)-based library preparation to compare their diagnostic value. Out of 10 cases tested by Sanger sequencing and 2 analyzed using MLPA, 4 and 1, respectively, revealed a mutation in IDH1 (p.R132C). The 7 remaining negative cases and additional 6 cases were investigated using smMIP/NGS, showing hot spot mutations in IDH1 (p.R132C) (8 cases) and IDH2 (3 cases; twice p.R172S and once p.R172G, respectively). One case was negative. Owing to insufficient DNA quality and insufficient coverage, 2 cases were excluded. In total, in 16 out of 17 cases successfully tested, an IDH1/2 mutation was found. Given that IDH1/2 mutations were absent in 161 other vascular lesions tested by smMIP/NGS, the mutation can be considered as highly specific for SCH.

Soft tissue angiofibroma: Clinicopathologic, immunohistochemical and molecular analysis of 14 cases.

Soft tissue angiofibroma is rare and has characteristic histomorphological and genetic features. For diagnostic purposes, there are no specific antibodies available. Fourteen lesions (6 females, 8 males; age range 7-67 years) of the lower extremities (12) and trunk (2) were investigated by immunohistochemistry, including for the first time NCOA2. NCOA2 was also tested in a control group of other spindle cell lesions. The known fusion-genes (AHRR-NCOA2 and GTF2I-NCOA2) were examined using RT-PCR in order to evaluate their diagnostic value. Cases in which no fusion gene was detected were additionally analysed by RNA sequencing. All cases tested showed nuclear expression of NCOA2. However, this was not specific since other spindle cell neoplasms also expressed this marker in a high percentage of cases. Other variably positive markers were EMA, SMA, desmin and CD34. STAT6 was negative in the cases tested. By RT-PCR for the most frequently observed fusions, an AHRR-NCOA2 fusion transcript was found in 9/14 cases. GTF2I-NCOA2 was not detected in the remaining cases (n = 3). RNA sequencing revealed three additional positive cases; two harbored a AHRR-NCOA2 fusion and one case a novel GAB1-ABL1 fusion. Two cases failed molecular analysis due to poor RNA quality. In conclusion, the AHRR-NCOA2 fusion is a frequent finding in soft tissue angiofibroma, while GTF2I-NCOA2 seems to be a rare genetic event. For the first time, we report a GAB1-ABL1 fusion in a soft tissue angiofibroma of a child. Nuclear expression of NCOA2 is not discriminating when compared with other spindle cell neoplasms.

Myxoid liposarcoma of the foot: a study of 8 cases.

INTRODUCTION: Myxoid liposarcoma is the only translocation-associated liposarcoma subtype. It classically originates in the deep soft tissues of the thigh. At distal sites of the extremities, this tumor is exceedingly rare. We present a series of 8 cases occurring in the foot/ankle. RESULTS: Two female and 6 male patients, aged between 32 and 77 years (mean, 54.3 years), were identified. Tumor size ranged from 1.1 to 10 cm (mean, 6.8 cm). Two lesions eroded bone. All tumors were treated by excision and 7 by (neo)adjuvant radiotherapy. R0 status was reached in 2 cases with 1 case followed by metastasis in the groin. All other cases were documented with R1 (n=2) or R2 (n=4) resection status. In 1 patient, the follow-up status was unknown. All other patients were alive 15-135 (mean, 55.8) months after initial diagnosis. We conclude that myxoid liposarcoma at acral sites are exceedingly rare, and in this series, prognosis was good irrespective of resection status. Clinicians and pathologists have to be aware because this sarcoma type shows a peculiar clinical behavior with high radio- and chemosensitivity and metastatic spread to extrapulmonary sites.

Agent-based modeling of the prostate tumor microenvironment uncovers spatial tumor growth constraints and immunomodulatory properties.

Inhibiting androgen receptor (AR) signaling through androgen deprivation therapy (ADT) reduces prostate cancer (PCa) growth in virtually all patients, but response may be temporary, in which case resistance develops, ultimately leading to lethal castration-resistant prostate cancer (CRPC). The tumor microenvironment (TME) plays an important role in the development and progression of PCa. In addition to tumor cells, TME-resident macrophages and fibroblasts express AR and are therefore also affected by ADT. However, the interplay of different TME cell types in the development of CRPC remains largely unexplored. To understand the complex stochastic nature of cell-cell interactions, we created a PCa-specific agent-based model (PCABM) based on in vitro cell proliferation data. PCa cells, fibroblasts, "pro-inflammatory" M1-like and "pro-tumor" M2-like polarized macrophages are modeled as agents from a simple set of validated base assumptions. PCABM allows us to simulate the effect of ADT on the interplay between various prostate TME cell types. The resulting in vitro growth patterns mimic human PCa. Our PCABM can effectively model hormonal perturbations by ADT, in which PCABM suggests that CRPC arises in clusters of resistant cells, as is observed in multifocal PCa. In addition, fibroblasts compete for cellular space in the TME while simultaneously creating niches for tumor cells to proliferate in. Finally, PCABM predicts that ADT has immunomodulatory effects on macrophages that may enhance tumor survival. Taken together, these results suggest that AR plays a critical role in the cellular interplay and stochastic interactions in the TME that influence tumor cell behavior and CRPC development.

Real-world data on malignant and borderline phyllodes tumors of the breast: A population-based study of all 921 cases in the Netherlands (1989 -2020).

AIM: The aim of our study is to analyze patterns in treatment and outcome in a population-based series of patients with borderline and malignant phyllodes tumors (PT). MATERIAL AND METHODS: Data on all patients with a borderline or malignant PT (1989-2020) were extracted from the Netherlands Cancer Registry and the Dutch nationwide pathology databank (Palga) and retrospectively analyzed. RESULTS: We included 921 patients (borderline PT n = 452 and malignant PT n = 469). Borderline PT patients more often had breast-conserving surgery (BCS) as final surgery (81 vs. 46%). BCS rates for borderline PT increased over time (OR 1.08 per year, 95%CI 1.04 - 1.13, P < 0.001). In malignant PT adjuvant radiotherapy was given in 14.7%; this rate increased over time (OR 1.07 per year, 95%CI 1.02 - 1.13, P = 0.012). Local recurrence rate (5-year estimate of cumulative incidence) was 8.7% (95%CI 6.0-11.4) for borderline PT and 11.7% (95%CI 8.6-14.8) for malignant PT (P = 0.187) and was related to tumor size ≥ 20 mm (HR 10.6 (95%CI 1.5-76.8) and positive margin (HR 3.0 (95%CI 1.6-5.6), p < 0.001), but not to negative margin width (HR 1.3 ( 95%CI 0.7-2.3), p = 0.350)). Distant metastasis occurred only in malignant PT with a 5-year cumulative incidence of 4.7% (95%CI 3.3 - 6.1). CONCLUSION: This population-based series showed an increase in BCS in borderline PT and an increase in adjuvant radiotherapy in malignant PT over time. We identified malignant PT, BCS, larger tumor size and positive final margins as possible risk factors for local recurrence. Small but negative margins can be accepted.

Strong Correlation Between SUVmax on PSMA PET/CT and Numeric Drop-In γ-Probe Signal for Intraoperative Identification of Prostate Cancer Lesions.

Prostate-specific membrane antigen (PSMA) PET is used to select patients with recurrent prostate cancer for metastasis-directed therapy. A surgical approach can be achieved through radioguided surgery (RGS), using a Drop-In γ-probe that traces lesions that accumulate the radioactive signal. With the aim of guiding patient selection for salvage surgery, we studied the correlation between the SUVmax of lesions on preoperative PSMA PET/CT and their intraoperative counts/s measured using the Drop-In γ-probe. Methods: A secondary analysis based on the prospective, single-arm, and single-center feasibility study was conducted (NCT03857113). Patients (n = 29) with biochemical recurrence after previous curative-intent therapy and a maximum of 3 suggestive lesions within the pelvis on preoperative PSMA PET/CT were included. Patients treated with androgen deprivation therapy within 6 mo before surgery were excluded. All patients received an intravenous injection of 99mTc-PSMA-I&S 1 d before surgery. Radioguidance was achieved using a Drop-In γ-probe. Correlation was determined using the Spearman rank correlation coefficient (ρs). Subgroup analysis was based on the median SUVmax Results: In total, 33 lesions were visible on the PSMA PET/CT images, with a median overall SUVmax of 6.2 (interquartile range [IQR], 4.2-9.7). RGS facilitated removal of 31 lesions. The median Drop-In counts/s were 134 (IQR, 81-220) in vivo and 109 (IQR, 72-219) ex vivo. The intensity of the values correlated with SUVmax (ρs = 0.728 and 0.763, respectively; P < 0.001). Subgroup analysis based on median SUVmax in the group with an SUVmax of less than 6 showed no statistically significant correlation with the numeric signal in vivo (ρs = 0.382; P = 0.221) or the signal-to-background-ratio (ρs = 0.245; P = 0.442), whereas the group with an SUVmax of 6 or more showed respective statistically significant positive correlations (ρs = 0.774 [P < 0.001] and ρs = 0.647 [P = 0.007]). Conclusion: Our findings indicate that there is a direct relation between SUVmax on PSMA PET/CT and the readout recorded by the surgical Drop-In probe, thereby indicating that SUVmax can be used to select patients for PSMA RGS. For more definitive subgroup definitions for treatment recommendations, further studies are necessary to validate the present findings.