Publications by authors named "Daniela Ferraro"

39 Publications

Ga-PSMA-11 PET imaging in patients with ongoing androgen deprivation therapy for advanced prostate cancer.

Ann Nucl Med 2021 Jun 29. Epub 2021 Jun 29.

Department of Urology, University Hospital Zürich, University of Zürich, Zurich, Switzerland.

Purpose: Prostate-specific membrane antigen (PSMA) targeted positron emission tomography (PET) imaging significantly improved the detection of recurrent prostate cancer (PCa). However, the value of PSMA PET imaging in patients with advanced hormone-sensitive or hormone-resistant PCa is still largely unknown. The aim of this study was to analyze the detection rate and distribution of lesions using PSMA PET imaging in patients with advanced PCa and ongoing androgen deprivation therapy (ADT).

Methods: A total of 84 patients diagnosed with hormone-sensitive or hormone-resistant PCa who underwent Ga-PSMA-11 PET/magnetic resonance imaging (MRI) or computer tomography (CT) under ongoing ADT were retrospectively analyzed. We assessed the detection of PSMA-positive lesions overall and for three PSA subgroups (0 to < 1 ng/mL, 1 to < 20 ng/mL and > 20 ng/mL). In addition, PSMA-positive findings were stratified by localization (prostatic fossa, pelvic, para-aortic, mediastinal/supraclavicular and axillary lymph nodes, bone lesions and visceral lesions) and hormone status (hormone-sensitive vs. hormone-resistant). Furthermore, we assessed how many patients would be classified as having oligometastatic disease (≤ 3 lesions) and theoretically qualify for metastasis-directed radiotherapy (MDRT) in a personalized patient management.

Results: We detected PSMA-positive lesions in 94.0% (79 of 84) of all patients. In the three PSA subgroups detection rates of 85.2% (0 to < 1 ng/mL, n = 27), 97.3% (1 to < 20 ng/mL, n = 37) and 100% (> 20 ng/mL, n = 20) were observed, respectively. PSMA-positive visceral metastases were observed only in patients with a PSA > 1 ng/mL. Detection of PSMA-positive lesions did not significantly differ between patients with hormone-sensitive and hormone-resistant PCa. Oligometastatic PCa was detected in 19 of 84 patients (22.6%). Almost all patients, 94.7% (n = 18) would have been eligible for MDRT.

Conclusions: In this study, we observed an overall very high detection rate of 94% using PSMA PET imaging in patients with advanced PCa and ongoing ADT. Even in a majority of patients with very low PSA values < 1 ng/ml PSMA-positive lesions were found.
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http://dx.doi.org/10.1007/s12149-021-01646-zDOI Listing
June 2021

Diagnostic performance of Ga-PSMA-11 PET/MRI-guided biopsy in patients with suspected prostate cancer: a prospective single-center study.

Eur J Nucl Med Mol Imaging 2021 Feb 23. Epub 2021 Feb 23.

Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Purpose: Ultrasound-guided biopsy (US biopsy) with 10-12 cores has a suboptimal sensitivity for clinically significant prostate cancer (sigPCa). If US biopsy is negative, magnetic resonance imaging (MRI)-guided biopsy is recommended, despite a low specificity for lesions with score 3-5 on Prostate Imaging Reporting and Data System (PIRADS). Screening and biopsy guidance using an imaging modality with high accuracy could reduce the number of unnecessary biopsies, reducing side effects. The aim of this study was to assess the performance of positron emission tomography/MRI with Ga-labeled prostate-specific membrane antigen (PSMA-PET/MRI) to detect and localize primary sigPCa (ISUP grade group 3 and/or cancer core length ≥ 6 mm) and guide biopsy.

Methods: Prospective, open-label, single-center, non-randomized, diagnostic accuracy study including patients with suspected PCa by elevation of prostate-specific antigen (PSA) level and a suspicious lesion (PIRADS ≥3) on multiparametric MRI (mpMRI). Forty-two patients underwent PSMA-PET/MRI followed by both PSMA-PET/MRI-guided and section-based saturation template biopsy between May 2017 and February 2019. Primary outcome was the accuracy of PSMA-PET/MRI for biopsy guidance using section-based saturation template biopsy as the reference standard.

Results: SigPCa was found in 62% of the patients. Patient-based sensitivity, specificity, negative and positive predictive value, and accuracy for sigPCa were 96%, 81%, 93%, 89%, and 90%, respectively. One patient had PSMA-negative sigPCa. Eight of nine false-positive lesions corresponded to cancer on prostatectomy and one in six false-negative lesions was negative on prostatectomy.

Conclusion: PSMA-PET/MRI has a high accuracy for detecting sigPCa and is a promising tool to select patients with suspicion of PCa for biopsy.

Trial Registration: This trial was retrospectively registered under the name "Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) Guided Biopsy in Men with Elevated PSA" (NCT03187990) on 06/15/2017 ( https://clinicaltrials.gov/ct2/show/NCT03187990 ).
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http://dx.doi.org/10.1007/s00259-021-05261-yDOI Listing
February 2021

A pilot study on lung cancer detection based on regional metabolic activity distribution in digital low-dose 18F-FDG PET.

Br J Radiol 2021 Mar 2;94(1119):20200244. Epub 2021 Feb 2.

Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland.

Objectives: To investigate the potential of automatic lung cancer detection on submillisievert dose F-fludeoxyglucose (F-FDG) scans using different positron emission tomography (PET) parameters, as a primary step towards a potential new indication for F-FDG PET in lung cancer screening.

Methods: We performed a retrospective cohort analysis with 83 patients referred for F-FDG PET/CT, including of 34 patients with histology-proven lung cancer and 49 patients without lung disease. Aside clinical standard PET images (PET) two additional low-dose PET reconstructions were generated, using only 15 s and 5 s of the 150 s list mode raw data of the full-dose PET, corresponding to 10% and 3.3% of the original F-FDG activity. The lungs were subdivided into three segments on each side, and each segment was classified as normal or containing cancer. The following standardized uptake values (SUVs) were extracted from PET per lung segment: SUV, SUV, SUV, SUV and SUV. A multivariate linear regression model was used and cross-validated. The accuracy for lung cancer detection was tested with receiver operating characteristics analysis and T-statistics was used to calculate the weight of each parameter.

Results: The T-statistics showed that SUV was the most important discriminative factor for lung cancer detection. The multivariate model achieved an area under the curve of 0.97 for full-dose PET, 0.85 for PET with PET reconstructions resulting in a still high sensitivity the PET reconstruction of 80%.

Conclusion: This pilot study indicates that segment-based, quantitative PET parameters of low-dose PET reconstructions could be used to automatically detect lung cancer with high sensitivity.

Advances In Knowledge: Automated assessment of PET parameters in low-dose PET may aid for an early detection of lung cancer.
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http://dx.doi.org/10.1259/bjr.20200244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011269PMC
March 2021

Whole-body parametric [F]-FDG PET/CT improves interpretation of a distant lesion as venous embolus in a lung cancer patient.

Eur J Nucl Med Mol Imaging 2021 06 15;48(6):2047-2048. Epub 2021 Jan 15.

Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Rämistrasse 100, 8091, Zürich, Switzerland.

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http://dx.doi.org/10.1007/s00259-020-05176-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113174PMC
June 2021

Improved oncological outcome after radical prostatectomy in patients staged with Ga-PSMA-11 PET: a single-center retrospective cohort comparison.

Eur J Nucl Med Mol Imaging 2021 04 19;48(4):1219-1228. Epub 2020 Oct 19.

Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Rämistrasse 100, 8091, Zürich, Switzerland.

Background: Positron emission tomography (PET) targeting the prostate-specific membrane antigen (PSMA) has superior sensitivity over conventional imaging (CI) to stage prostate cancer (PCa) and therefore is increasingly used in staging to stratify patients before radical therapy. Whether this improved diagnostic accuracy translates into improved outcome after radical prostatectomy (RPE) has not yet been shown. Therefore, the aim of this study was to compare the oncological outcome after RPE between patients that underwent preoperative staging with CI or PSMA-PET for intermediate and high-risk PCa.

Methods: We retrospectively selected all patients that underwent RPE for intermediate- or high-risk PCa at our institution before PSMA-PET introduction (between March 2014 and September 2016) and compared the oncologic outcome of patients staged with PSMA-PET (between October 2016 and October 2018). Oncological pre-surgical risk parameters (age, PSA, D'Amico score, biopsy-ISUP, and cT stage) were compared between the groups. Oncological outcome was determined as PSA persistence, nerve-sparing rate, and surgical margin status. Wilcoxon rank-sum, Fisher's, and chi-square tests where used for statistical testing.

Results: One hundred five patients were included, 53 in the CI group and 52 in the PSMA-group. Patients in the PSMA group had higher ISUP grade (p < 0.001) and D'Amico score (p < 0.05). The rate of free surgical margins and PSA persistence after RPE was 64% and 17% for the CI and 77% and 6% for the PSMA group (p = 0.15 and 0.13, respectively). Subgroup analysis with high-risk patients revealed PSA persistence in 7% (3/44) in the PSMA group and 25% (7/28) in the CI group (p = 0.04). Limitations include the retrospective design and choline-PET for some patients in the CI group.

Conclusion: Immediate outcome after RPE was not worse in the PSMA group compared with the CI group, despite a higher-risk cohort. In a comparison of only high-risk patients, PSMA-PET staging was associated with a significantly lower rate of postsurgical PSA persistence.
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http://dx.doi.org/10.1007/s00259-020-05058-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041683PMC
April 2021

Prostate-specific Membrane Antigen PET: Therapy Response Assessment in Metastatic Prostate Cancer.

Radiographics 2020 Sep-Oct;40(5):1412-1430. Epub 2020 Aug 7.

From the Departments of Radiology (F.G.B., M.A.Q., R.F.N., P.R.D., E.C.Z., L.B.C., J.F.G.M., C.A.B.) and Oncology (D.A.B.), Hospital Sírio-Libanês, Rua Dona Adma Jafet 115, São Paulo, SP, CEP 01308-060, Brazil (F.G.B., M.A.Q., R.F.N., P.R.D., E.C.Z., L.B.C., J.F.G.M., C.A.B.); Department of Radiology and Oncology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil (M.A.Q., D.A.B., J.F.G.M., C.A.B.); and Department of Nuclear Medicine, University Hospital of Zurich, Zurich, Switzerland (D.A.F.).

Therapy response assessment is a critical step in cancer management, leading clinicians to optimize the use of therapeutic options during the course of the disease. Imaging is a pivotal biomarker for therapy response evaluation in oncology and has gained wider use through the development of reproducible data-based guidelines, of which the Response Evaluation Criteria in Solid Tumors is the most successful example. Disease-specific criteria have also been proposed, and the Prostate Cancer Working Group 3 criteria are the mainstay for prostate cancer (PC). However, conventional imaging evaluation in metastatic PC has several limitations, including the inability to detect small-volume disease, the high prevalence of bone (nonmeasurable) lesions at imaging, and the established role of serum prostate-specific antigen (PSA) levels as the biomarker of choice for response assessment and disease progression. In addition, there are an increasing number of newer treatment options with various effects on imaging features. Prostate-specific membrane antigen (PSMA) PET has improved patient selection for newer treatments, such as metastasis-directed therapy (MDT) or radionuclide therapy. The role of PSMA PET in response assessment for many metastatic PC therapeutic options (MDT, androgen deprivation therapy, chemotherapy, radionuclide therapy, and immunotherapy) is an evolving issue, with emerging data showing good correlation with PSA levels and clinical outcome. However, there are specific implications of each therapy (especially androgen deprivation therapy and immunotherapy) on PSMA expression by PC cells, leading to potential pitfalls and inaccuracies that must be known by radiologists. Despite some limitations, PSMA PET is addressing gaps left by conventional imaging methods (eg, CT and bone scanning) and nonimaging biomarkers (PSA levels) in metastatic PC therapy response assessment, a role that can be improved with advances like refinement of interpretation criteria and whole-body tumor burden quantification. RSNA, 2020See discussion on this article by Barwick and Castellucci.
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http://dx.doi.org/10.1148/rg.2020200058DOI Listing
July 2021

Immunohistochemical PSMA expression patterns of primary prostate cancer tissue are associated with the detection rate of biochemical recurrence with Ga-PSMA-11-PET.

Theranostics 2020 15;10(14):6082-6094. Epub 2020 May 15.

Department of Nuclear Medicine, University Hospital Zürich, University of Zürich, Zurich, Switzerland.

Prostate-specific membrane antigen (PSMA) targeted PET has a high detection rate for biochemical recurrence (BCR) of prostate cancer (PCa). Nevertheless, even at high prostate-specific antigen (PSA) levels (> 3 ng/ml), a relevant number of PSMA-PET scans are negative, mainly due to PSMA-negative PCa. Our objective was to investigate whether PSMA-expression patterns of the primary tumour on immunohistochemistry (IHC) are associated with PSMA-PET detection rate of recurrent PCa. Retrospective institutional review board approved single-centre analysis of patients who had undergone Ga-PSMA-11-PET for BCR after radical prostatectomy (RPE) between 04/2016 and 07/2019, with tumour specimens available for PSMA-IHC. Clinical information (age, PSA-level, ongoing androgen deprivation therapy (ADT), Gleason score) and PSMA-IHC of the primary tumour were collected and their relationship to results from PSMA-PET (positive/negative) was investigated using a multiple logistic regression analysis. 120 PSMA-PET scans in 74 patients were available for this analysis. Overall detection rate was 62% (74/120 scans), with a mean PSA value at scan time of 0.99 ng/ml (IQR 0.32-4.27). Of the clinical factors, only PSA-level and ADT were associated with PSMA-PET positivity. The percentage of PSMA-negative tumour area on IHC (PSMA) had a significant association to PSMA-PET negativity (OR = 2.88, < 0.001), while membranous PSMA-expression showed no association ( = 0.73). The positive predictive value of PSMA ≥ 50% for a negative PSMA-PET was 85% (13/11) and for a PSMA of 80% or more, 100% (9/9). PSMA-negative tumour area on IHC exhibited the strongest association with negative PSMA-PET scans, beside PSA-level and ADT. Even at very high PSA levels, PSMA-PET scans were negative in most of the patients with PSMA ≥ 50%.
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http://dx.doi.org/10.7150/thno.44584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255040PMC
May 2021

Metal artifact reduction in Ga-PSMA-11 PET/MRI for prostate cancer patients with hip joint replacement using multiacquisition variable-resonance image combination.

Eur J Hybrid Imaging 2020 Apr 9;4(1). Epub 2020 Apr 9.

Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland.

Background: PET/MRI has a high potential in oncology imaging, especially for tumor indications where high soft tissue contrast is crucial such as genitourinary tumors. One of the challenges for PET/MRI acquisition is handling of metal implants. In addition to conventional methods, more innovative techniques have been developed to reduce artifacts caused by those implants such as the selective multiacquisition variable-image combination (MAVRIC-SL). The aim of this study is to perform a quantitative and qualitative assessment of metal artifact reduction in Ga-PSMA-11 PET/MRI for prostate cancer patients with hip joint replacement using a selective MAVRIC-SL sequence for the whole pelvis.

Methods: We retrospectively analyzed data of 20 men with 37 metal hip implants diagnosed with PCA, staged or restaged by Ga-PSMA-11 PET/MRI from June 2016 to December 2017. Each signal cancellation per side or metal implant was analyzed on the reference sequence LAVA-FLEX, as well as T1-weighted fast spin echo (T1w-FSE) sequence and MAVRIC-SL. Two independent reviewers reported on a four-point scale whether abnormal pelvic Ga-PSMA-11 uptake could be assigned to an anatomical structure in the tested sequences.

Results: The smallest averaged signal void was observed on MAVRIC-SL sequences with a mean artifact size of 26.17 cm (range 12.63 to 42.93 cm, p < 0.001). The best image quality regarding anatomical assignment of pathological PSMA uptakes in the pelvis by two independent readers was noted for MAVRIC-SL sequences, followed by T1w-FSE with excellent interreader agreement.

Conclusions: MAVRIC-SL sequence allows better image quality in the surrounding of hip implants by reducing MR signal voids and increasing so the accuracy of anatomical assignment of pathological Ga-PSMA-11 uptake in the pelvis over LAVA-FLEX and T1w-FSE sequences.
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http://dx.doi.org/10.1186/s41824-020-00075-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218168PMC
April 2020

Ga-PSMA-11 dose reduction for dedicated pelvic imaging with simultaneous PET/MR using TOF BSREM reconstructions.

Eur Radiol 2020 Jun 14;30(6):3188-3197. Epub 2020 Feb 14.

Department of Nuclear Medicine, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland.

Objectives: When increasing the PET acquisition time to match the longer MRI protocol in simultaneous PET/MR, the injected PET tracer dose can possibly be lowered to reduce radiation exposure. Moreover, applying new commercially available time-of-flight (TOF) block sequential regularized expectation maximization (BSREM)-based reconstruction algorithms could allow for further dose reductions. The purpose of this study was to find the minimal dose of the tracer targeting the prostate specific membrane antigen (Ga-PSMA-11) for a dedicated 15-min pelvic PET/MR scan that still matches the image quality of a reference 3-min scan at 100% (150 MBq) dose.

Methods: In this retrospective analysis, 25 patients were included. PET emission datasets were edited to simulate stepwise reductions of injected tracer dose. Reference TOF ordered subset expectation maximum (OSEM) and new TOF BSREM reconstructions were performed and differences in the resulting PET images were visually and quantitatively assessed.

Results: Visually, TOF BSREM reconstructions with relatively high regularization parameter (β) values are preferred. Quantitatively, however, high β-values result in lower lesion maximum standardized uptake values (SUV) compared to the reference. A β-value of 550 was considered the optimal compromise for the lowest possible 10% dose reconstructions, resulting in comparable visual assessment and lesion SUV.

Conclusions: This study indicates that the injected Ga-PSMA-11 tracer dose for a standard 3-min PET scan can be reduced to approximately 10% (15 MBq) when the PET acquisition time is matched to the 15-min pelvic MRI protocol, and when reconstructed with TOF BSREM using β = 550. This decreases the effective dose from 3.54 to 0.35 mSv.

Key Points: • Low-dose dedicated pelvicGa-PSMA-11 PET/MR reduces radiation exposure for patients. • Retrospective study investigating the minimal dose needed for adequate image quality for 15-min PET frames over the pelvis showed using quantitative and qualitative analysis that a substantial dose reduction is possible without significant loss of image quality when using the TOF BSREM reconstruction algorithm. • With the introduction of low-dose pelvicGa-PSMA-11 PET/MR, new potential applications ofGa-PSMA-11 PET for local staging or investigation of equivocal MRI findings could become applicable, even for patients without confirmed prostate cancer.
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http://dx.doi.org/10.1007/s00330-020-06667-2DOI Listing
June 2020

Prostate Cancer: Prostate-specific Membrane Antigen Positron-emission Tomography/Computed Tomography or Positron-emission Tomography/Magnetic Resonance Imaging for Staging.

Top Magn Reson Imaging 2020 Feb;29(1):59-66

Department of Nuclear Medicine, University Hospital Zürich, University of Zürich, Zürich, Switzerland.

Positron-emission tomography (PET) with prostate-specific membrane antigen (PSMA) has been increasingly used to image prostate cancer in the last decade. In the staging setting several studies have already been published suggesting PSMA PET can be a valuable tool. They, however, did not translate into recommendations by guidelines. Both PSMA PET/computed tomography (CT) and PET/magnetic resonance imaging have been investigated in the staging setting, showing higher detection rate of prostate cancer lesions over the conventional imaging work-up and some studies already showed an impact on disease management. The aim of this review is to provide an overview of the existing published data regarding PSMA PET for staging prostate cancer, with emphasis on PET/magnetic resonance imaging. Despite the fact that PSMA is a relatively new tool and not officially recommended for staging yet, there are >50 original studies in the literature assessing PSMA PET performance in the staging setting of prostate cancer, and some meta-analyses.
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http://dx.doi.org/10.1097/RMR.0000000000000229DOI Listing
February 2020

[Advances in Oncology 2019].

Rev Med Suisse 2020 Jan;16(676-7):72-77

Centre coordonné d'oncologie, CHUV, 1011 Lausanne.

Driven by highly specialized medicine, research and the quest for personalization of treatments, oncology witnessed substantial advances in 2019. This year numerous treatments have consolidated their importance and broadened their indications. Multiple innovative treatments, currently under study, brought hope for future advances, while biomarkers, such as PD-L1, microsatellite instability (MSI), tumor mutational burden (TMB), BRCA1/2 gene mutations, and homologous recombination deficiency (HRD) allowed better selection and customization of available treatments. This article provides an overview of this year's advances in oncology.
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January 2020

Artificial intelligence for detecting small FDG-positive lung nodules in digital PET/CT: impact of image reconstructions on diagnostic performance.

Eur Radiol 2020 Apr 10;30(4):2031-2040. Epub 2019 Dec 10.

Department of Nuclear Medicine, University Hospital Zurich, Rämistrasse 100, CH-8091, Zurich, Switzerland.

Objectives: To evaluate the diagnostic performance of a deep learning algorithm for automated detection of small F-FDG-avid pulmonary nodules in PET scans, and to assess whether novel block sequential regularized expectation maximization (BSREM) reconstruction affects detection accuracy as compared to ordered subset expectation maximization (OSEM) reconstruction.

Methods: Fifty-seven patients with 92 F-FDG-avid pulmonary nodules (all ≤ 2 cm) undergoing PET/CT for oncological (re-)staging were retrospectively included and a total of 8824 PET images of the lungs were extracted using OSEM and BSREM reconstruction. Per-slice and per-nodule sensitivity of a deep learning algorithm was assessed, with an expert readout by a radiologist/nuclear medicine physician serving as standard of reference. Receiver-operator characteristic (ROC) curve of OSEM and BSREM were assessed and the areas under the ROC curve (AUC) were compared. A maximum standardized uptake value (SUV)-based sensitivity analysis and a size-based sensitivity analysis with subgroups defined by nodule size was performed.

Results: The AUC of the deep learning algorithm for nodule detection using OSEM reconstruction was 0.796 (CI 95%; 0.772-0.869), and 0.848 (CI 95%; 0.828-0.869) using BSREM reconstruction. The AUC was significantly higher for BSREM compared to OSEM (p = 0.001). On a per-slice analysis, sensitivity and specificity were 66.7% and 79.0% for OSEM, and 69.2% and 84.5% for BSREM. On a per-nodule analysis, the overall sensitivity of OSEM was 81.5% compared to 87.0% for BSREM.

Conclusions: Our results suggest that machine learning algorithms may aid detection of small F-FDG-avid pulmonary nodules in clinical PET/CT. AI performed significantly better on images with BSREM than OSEM.

Key Points: • The diagnostic value of deep learning for detecting small lung nodules (≤ 2 cm) in PET images using BSREM and OSEM reconstruction was assessed. • BSREM yields higher SUVof small pulmonary nodules as compared to OSEM reconstruction. • The use of BSREM translates into a higher detectability of small pulmonary nodules in PET images as assessed with artificial intelligence.
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http://dx.doi.org/10.1007/s00330-019-06498-wDOI Listing
April 2020

Impact of Ga-PSMA-11 PET staging on clinical decision-making in patients with intermediate or high-risk prostate cancer.

Eur J Nucl Med Mol Imaging 2020 03 4;47(3):652-664. Epub 2019 Dec 4.

Department of Nuclear Medicine, University Hospital Zürich, University of Zürich, Rämistrasse 100, 8091, Zürich, Switzerland.

Background: Accurate staging is of major importance to determine the optimal treatment modality for patients with prostate cancer. Positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) is a promising technique that outperformed conventional imaging in the detection of nodal and distant metastases in previous studies. However, it is still unclear whether the superior sensitivity and specificity also translate into improved patient management. The aim of this study was to assess the performance of Ga-PSMA-11 PET for staging of intermediate and high-risk prostate cancer and its potential impact on disease management.

Methods: In this retrospective analysis, 116 patients who underwent Ga-PSMA-11 PET/CT or MRI scans for staging of their intermediate or high-risk prostate cancer between April 2016 and May 2018 were included. The potential impact of Ga-PSMA-11 PET staging on patient management was assessed within a simulated multidisciplinary tumour board where hypothetical treatment decisions based on clinical information and conventional imaging alone was determined. This treatment decision was compared with the treatment recommendation based on clinical information and Ga-PSMA-11 PET imaging.

Results: The primary tumour was positive on Ga-PSMA-11 PET in 113 patients (97%). Nodal metastases were detected in 28 patients (24%) and bone metastases in 14 patients (12%). Compared with clinical staging and conventional imaging, Ga-PSMA-11 PET resulted in new information in 42 of 116 patients (36%). In 32 of 116 patients (27%), this information would most likely have changed the management into a different therapy modality (15 patients, 13%) or adjusted treatment details (e.g. modification of radiotherapy field or lymph node dissection template; 17 patients, 14%).

Conclusion: Information from Ga-PSMA-11 PET staging has the potential to change the management in more than a fourth of the patients who underwent PET staging for their intermediate to high-risk prostate cancer. Whether these more personalized Ga-PSMA-11 PET-based treatment decisions will improve patient outcome needs further investigation.
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http://dx.doi.org/10.1007/s00259-019-04568-1DOI Listing
March 2020

Ga-PSMA-11 PET has the potential to improve patient selection for extended pelvic lymph node dissection in intermediate to high-risk prostate cancer.

Eur J Nucl Med Mol Imaging 2020 01 14;47(1):147-159. Epub 2019 Sep 14.

Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Rämistrasse 100, 8091, Zürich, Switzerland.

Introduction: Radical prostatectomy with extended pelvic lymph node dissection (ePLND) is a curative treatment option for patients with clinically significant localised prostate cancer. The decision to perform an ePLND can be challenging because the overall incidence of lymph node metastasis is relatively low and ePLND is not free of complications. Using current clinical nomograms to identify patients with nodal involvement, approximately 75-85% of ePLNDs performed are negative. The aim of this study was to assess the added value of Ga-PSMA-11 PET in predicting lymph node metastasis in men with intermediate- or high-risk prostate cancer.

Methods: Ga-PSMA-11 PET scans of 60 patients undergoing radical prostatectomy with ePLND were reviewed for qualitative (visual) assessment of suspicious nodes and assessment of quantitative parameters of the primary tumour in the prostate (SUV, total activity (PSMA) and PSMA positive volume (PSMA)). Ability of quantitative PET parameters to predict nodal metastasis was assessed with receiver operating characteristics (ROC) analysis. A multivariable logistic regression model combining PSA, Gleason score, visual nodal status on PET and primary tumour PSMA was built. Net benefit at each risk threshold was compared with five nomograms: MSKCC nomogram, Yale formula, Roach formula, Winter nomogram and Partin tables (2016).

Results: Overall, pathology of ePLND specimens revealed 31 pelvic metastatic lymph nodes in 12 patients. Ga-PSMA-11 PET visual analysis correctly detected suspicious nodes in 7 patients, yielding a sensitivity of 58% and a specificity of 98%. The area under the ROC curve for primary tumour SUV was 0.70, for PSMA 0.76 and for PSMA 0.75. The optimal cut-off for nodal involvement was PSMA > 49.1. The PET model including PSA, Gleason score and quantitative PET parameters had a persistently higher net benefit compared with all clinical nomograms.

Conclusion: Our model combining PSA, Gleason score and visual lymph node analysis on Ga-PSMA-11 PET with PSMA of the primary tumour showed a tendency to improve patient selection for ePLND over the currently used clinical nomograms. Although this result has to be validated, Ga-PSMA-11 PET showed the potential to reduce unnecessary surgical procedures in patients with intermediate- or high-risk prostate cancer.
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http://dx.doi.org/10.1007/s00259-019-04511-4DOI Listing
January 2020

[Side effects of immune checkpoint inhibitors: diagnosis and management].

Rev Med Suisse 2019 May;15(651):1010-1016

Service d'immuno-oncologie, Département d'oncologie, CHUV, 1011 Lausanne.

New oncological approaches using immune checkpoint inhibitors aim to reinvigorate lymphocytes against the tumor. The prognosis of cancer has been significantly improved by these treatments, which nonetheless lead to a new spectrum of immune-related side effects. The most frequent are skin rash, colitis, thyroid dysfunction, hypophysitis, hepatitis and pneumonitis. Early detection of these toxicities is crucial to determine the etiology and to introduce a temporary immunosuppressive therapy, allowing resolution of toxicity in most of cases. A multidisciplinary team is essential for optimal management.
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May 2019

Endothelial cell-derived nidogen-1 inhibits migration of SK-BR-3 breast cancer cells.

BMC Cancer 2019 Apr 4;19(1):312. Epub 2019 Apr 4.

Department of Oncology, St. Claraspital, Kleinriehenstrasse 30, 4016, Basel, Switzerland.

Background: The tumour microenvironment is a critical regulator of malignant cancer progression. While endothelial cells have been widely studied in the context of tumour angiogenesis, their role as modulators of cancer cell invasion and migration is poorly understood.

Methods: We have investigated the influence of endothelial cells on the invasive and migratory behaviour of human cancer cells in vitro.

Results: Upon exposure to culture supernatants of endothelial cells, distinct cancer cells, such as SK-BR-3 cells, showed significantly increased invasion and cell migration concomitant with changes in cell morphology and gene expression reminiscent of an epithelial-mesenchymal transition (EMT). Interestingly, the pro-migratory effect on SK-BR-3 cells was significantly enhanced by supernatants obtained from subconfluent, proliferative endothelial cells rather than from confluent, quiescent endothelial cells. Systematically comparing the supernatants of subconfluent and confluent endothelial cells by quantitative MS proteomics revealed eight candidate proteins that were secreted at significantly higher levels by confluent endothelial cells representing potential inhibitors of cancer cell migration. Among these proteins, nidogen-1 was exclusively expressed in confluent endothelial cells and was found to be necessary and sufficient for the inhibition of SK-BR-3 cell migration. Indeed, SK-BR-3 cells exposed to nidogen-1-depleted endothelial supernatants showed increased promigratory STAT3 phosphorylation along with increased cell migration. This reflects the situation of enhanced SK-BR-3 migration upon stimulation with conditioned medium from subconfluent endothelial cells with inherent absence of nidogen-1 expression.

Conclusion: The identification of nidogen-1 as an endothelial-derived inhibitor of migration of distinct cancer cell types reveals a novel mechanism of endothelial control over cancer progression.
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http://dx.doi.org/10.1186/s12885-019-5521-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449935PMC
April 2019

First Clinicopathologic Evidence of a Non-PSMA-Related Uptake Mechanism for Ga-PSMA-11 in Salivary Glands.

J Nucl Med 2019 09 8;60(9):1270-1276. Epub 2019 Feb 8.

Department of Nuclear Medicine, University Hospital Zürich, University of Zürich, Switzerland

The intense accumulation of prostate-specific membrane antigen (PSMA) radioligands in salivary glands is still not well understood. It is of concern for therapeutic applications of PSMA radioligands, because therapeutic radiation will damage these glands. A better understanding of the uptake mechanism is, therefore, crucial to find solutions to reduce toxicity. The aim of this study was to investigate whether the accumulation of PSMA-targeting radioligands in submandibular glands (SMGs) can be explained with PSMA expression levels using autoradiography (ARG) and immunohistochemistry (IHC). All patients gave written informed consent for further utility of the biologic material. The SMG of 9 patients, pancreatic tissue of 4 patients, and prostate cancer (PCA) lesions of 9 patients were analyzed. Tissue specimens were analyzed by means of PSMA-IHC (using an anti-PSMA-antibody and an immunoreactivity score system [IRS]) and ARG using Lu-PSMA-617 (with quantification of the relative signal intensity compared with a PSMA-positive standard). The SUV in salivary glands, pancreas, and PCA tissues were quantified in 60 clinical Ga-PSMA-11 PET scans for recurrent disease as well as the 9 primary tumors selected for ARG and IHC. PCA tissue samples revealed a wide range of PSMA staining intensity on IHC (IRS = 70-300) as well as in ARG (1.3%-22% of standard). This variability on PCA tissue could also be observed in Ga-PSMA-11 PET (SUV, 4.4-16) with a significant correlation between ARG and SUV ( < 0.001, = 0.897). On IHC, ARG, and Ga-PSMA-11 PET, the pancreatic tissue was negative (IRS = 0, ARG = 0.1% ± 0.05%, SUV of 3.1 ± 1.1). The SMG tissue displayed only focal expression of PSMA limited to the intercalated ducts on IHC (IRS = 10-15) and a minimal signal on ARG (1.3% ± 0.9%). In contrast, all SMG showed a high Ga-PSMA-11 accumulation on PET scans (SUV 23.5 ± 5.2). Our results indicate that the high accumulation of PSMA radioligands in salivary glands does not correspond to high PSMA expression levels determined using ARG and IHC. These findings provide evidence, that the significant accumulation of PSMA radioligands in SMG is not primarily a result of PSMA-mediated uptake.
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http://dx.doi.org/10.2967/jnumed.118.222307DOI Listing
September 2019

68Ga-PSMA-11 PET/MR Can Be False Positive in Normal Prostatic Tissue.

Clin Nucl Med 2019 04;44(4):e291-e293

Department of Nuclear Medicine, University Hospital Zürich, University of Zürich

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein expressed in the cytosol of normal prostate tissue and highly overexpressed on the membrane of prostate cancer, therefore increasingly used to image prostate cancer. We report a case of a 65-year-old man with two focal PSMA-positive areas on a Ga-PSMA-11 PET/MR, one corresponding to a prostate carcinoma (Gleason score 4 + 3) and another region without any evidence of malignancy, but with corresponding high PSMA-expression on immunohistochemistry.
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http://dx.doi.org/10.1097/RLU.0000000000002473DOI Listing
April 2019

Ga-PSMA-11 PET/MR Detects Local Recurrence Occult on mpMRI in Prostate Cancer Patients After HIFU.

J Nucl Med 2019 08 25;60(8):1118-1123. Epub 2019 Jan 25.

Department of Urology, University Hospital Zürich, Zürich, Switzerland.

High-intensity focused ultrasound (HIFU) is a promising new modality for the treatment of localized prostate cancer (PCa). Follow-up of patients is recommended with biopsies and multiparametric MRI (mpMRI). However, mpMRI in the postinterventional setting is often false-negative. It was our aim to investigate if the new tracer targeting the prostate-specific membrane antigen (Ga-PSMA-11) could be used to localize recurrent disease with PET/MR in patients with discrepant findings between mpMRI and template biopsies. Interim analysis was performed of the first 10 patients scanned between September 2016 and May 2018 with positive template biopsy and negative mpMRI after HIFU from an ongoing clinical trial (NCT02265159). All patients underwent Ga-PSMA-11 PET/MRI within 3 mo. Four prostatic quadrants were defined, and for every quadrant suspicion for recurrence was rated on a 5-point Likert scale from definitely no recurrence (1) to highly suspected of recurrence (5), with 4 used as a cutoff for suspected disease based on PET/MRI by a masked reader. Ga-PSMA-11 uptake of suspected lesions and background areas was measured with the SUV The apparent diffusion coefficient values of lesions and background were given for each segment. PET/MRI scans were compared with the template biopsy results, including corresponding Gleason scores (GS), number of positive cores, and tumor length. The quadrant-based sensitivity, specificity, and positive and negative predictive values for PET/MRI were 55%, 100%, 100%, and 85%, respectively. Patient-based PET/MRI was negative in 4 cases with GS 3 + 4 and a tumor length between 0.1 and 3 mm. All tumor lesions with GS 4 + 3 or higher were detected on PET/MRI. Our preliminary results indicate that Ga-PSMA-11-PET/MR has the potential to localize PCa recurrence after HIFU occult on mpMRI.
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http://dx.doi.org/10.2967/jnumed.118.221564DOI Listing
August 2019

Impact of different image reconstructions on PET quantification in non-small cell lung cancer: a comparison of adenocarcinoma and squamous cell carcinoma.

Br J Radiol 2019 Apr 26;92(1096):20180792. Epub 2019 Feb 26.

1 Department of Nuclear Medicine, University Hospital Zurich / University of Zurich , Switzerland.

Objective:: Positron emission tomography (PET) using F-fludeoxyglucose (F-FDG) is an established imaging modality for tumor staging in patients with non-small cell lung cancer (NSCLC). There is a growing interest in using F-FDG PET for therapy response assessment in NSCLC which relies on quantitative PET parameters such as standardized uptake values (SUV). Different reconstruction algorithms in PET may affect SUV. We sought to determine the variation of SUV in patients with NSCLC when using ordered subset expectation maximization (OSEM) and block sequential regularized expectation maximization (BSREM) in latest-generation digital PET/CT, including a subanalysis for adenocarcinoma and squamous cell carcinoma.

Methods:: A total of 58 patients (34 = adenocarcinoma, 24 = squamous cell carcinoma) who underwent a clinically indicated F-FDG PET/CT for staging were reviewed. PET images were reconstructed with OSEM and BSREM reconstruction with noise penalty strength β-levels of 350, 450, 600, 800 and 1200. Lung tumors maximum standardized uptake value (SUV) were compared.

Results:: Lung tumors SUV were significantly lower in adenocarcinomas compared to squamous cell carcinomas in all reconstructions evaluated (all p < 0.01). Comparing BSREM to OSEM, absolute SUV differences were highest in lower β-levels of BSREM with + 2.9 ± 1.6 in adenocarcinoma and + 4.0 ± 2.9 in squamous cell carcinoma (difference between histology; p-values > 0.05). There was a statistically significant difference of the relative increase of SUV in adenocarcinoma (mean + 34.8%) and squamous cell carcinoma (mean 23.4%), when using BSREM instead of OSEM (p < 0.05).

Conclusion:: In NSCLC the relative change of SUV when using BSREM instead of OSEM is significantly higher in adenocarcinoma as compared to squamous cell carcinoma.

Advances In Knowledge:: The impact of BSREM on SUV may vary in different histological subtypes of NSCLC. This highlights the importance for careful standardization of β-value used for serial F-FDG PET scans when following-up NSCLC patients.
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http://dx.doi.org/10.1259/bjr.20180792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540860PMC
April 2019

Automated detection of lung cancer at ultralow dose PET/CT by deep neural networks - Initial results.

Lung Cancer 2018 12 3;126:170-173. Epub 2018 Nov 3.

Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Switzerland. Electronic address:

Objectives: We evaluated whether machine learning may be helpful for the detection of lung cancer in FDG-PET imaging in the setting of ultralow dose PET scans.

Materials And Methods: We studied the performance of an artificial neural network discriminating lung cancer patients (n = 50) from controls (n = 50) without pulmonary malignancies. A total of 3936 PET slices including images in which the lung tumor is visually present and image slices of patients with no lung cancer were exported. The diagnostic performance of the artificial neural network based on clinical standard dose PET images (PET) as well as with a tenfold (PET) and thirtyfold (PET) reduced radiation dose (∼0.11 mSv) was assessed.

Results: The area under the curve of the deep learning algorithm for lung cancer detection was 0.989, 0.983 and 0.970 for standard dose images (PET), and reduced dose PET, and PET reconstruction, respectively. The artificial neural network achieved a sensitivity of 95.9% and 91.5% and a specificity of 98.1% and 94.2%, at standard dose and ultralow dose PET, respectively.

Conclusion: Our results suggest that machine learning algorithms may aid fully automated lung cancer detection even at very low effective radiation doses of 0.11 mSv. Further improvement of this technology might improve the specificity of lung cancer screening efforts and could lead to new applications of FDG-PET.
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http://dx.doi.org/10.1016/j.lungcan.2018.11.001DOI Listing
December 2018

Clinical impact of Ga-PSMA-11 PET on patient management and outcome, including all patients referred for an increase in PSA level during the first year after its clinical introduction.

Eur J Nucl Med Mol Imaging 2019 Apr 28;46(4):889-900. Epub 2018 Nov 28.

Department of Nuclear Medicine, University Hospital Zürich, University of Zürich, Rämistrasse 100, 8091, Zürich, Switzerland.

Purpose: The fast-increasing use of positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) ligand for the imaging of prostate cancer (PCA) biochemical recurrence has led to a rapid change in treatment concepts. Since the superiority of Ga-PSMA-11 PET in detecting recurrent PCA is well established, the aim of our study was to assess its effect on management and outcome in all patients imaged during the first year after its introduction into clinical routine.

Methods: Of 327 patients imaged, 223 were referred for recurrent PCA and gave written informed consent for further analysis of their data for this retrospective consecutive cohort analysis. Twenty patients were lost to further follow-up. The rate of detection of recurrence by Ga-PSMA-11 PET was based on the clinical reports. Management before the availability of PET diagnostic information was assessed according to guidelines (therapy option without Ga-PSMA-11 PET). In the 203 patients with follow-up 6 months after Ga-PSMA-11 PET, the therapies effectively implemented as well as follow-up PSA levels were evaluated, with a PSA value of <0.2 ng/ml representing a complete response and a decrease in PSA value of at least 50% from baseline representing a partial response.

Results: Ga-PSMA-11 PET was positive and identified recurrence in 166 of the 223 patients (74%), with a detection rate of 50% for recurrent disease at low PSA values of <0.5 ng/ml. Ga-PSMA-11 PET led to a change in management in 122 of the 203 patients (60%). A substantial increase in the use of metastasis-targeted treatment and a reduction in the use of systemic treatment were observed, with 59 of the 203 patients (29%) undergoing targeted radiotherapy (RTXa) only, and 20 patients (10%) undergoing RTXa with hormonal therapy as the two most frequently selected therapy options. The proportion of patients in whom systemic therapy was selected decreased from 60% (133 of 223 patients) to 34% (70 of 203 patients) on the basis of the information provided by the Ga-PSMA-11 PET scan. PSMA PET-directed metastasis-targeted treatment led to a complete response after 6 months in 45% of patients.

Conclusion: The high rate of recurrence detection by PSMA PET was confirmed and PSMA PET led to a change in management in 60% of patients. Focal therapy for PSMA-positive lesions is a promising approach with complete responses in 45% of patients.
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http://dx.doi.org/10.1007/s00259-018-4203-0DOI Listing
April 2019

Bone marrow uptake of F-fluorodeoxyglucose in Hodgkin lymphoma without bone involvement: comparison between patients with and without B symptoms.

Radiol Bras 2018 Mar-Apr;51(2):76-80

MD, PhD, Division of Nuclear Medicine, Instituto do Câncer do Estado de São Paulo (Icesp), São Paulo, SP, Brazil.

Objective: To compare the degree of benign bone marrow uptake of F-fluorodeoxyglucose (F-FDG) between Hodgkin lymphoma patients with and without B symptoms.

Materials And Methods: We analyzed the medical charts of 74 Hodgkin lymphoma patients who underwent F-FDG positron emission tomography/computed tomography (PET/CT) prior to the initiation of therapy between October 2010 and September 2013. In all of the patients, the bone marrow biopsy was negative and the F-FDG PET/CT images did not suggest bone marrow involvement. Of the 74 patients evaluated, 54 presented inflammatory (B) symptoms and 20 did not. Regions of interest (ROIs) were drawn on the sternum, the proximal thirds of the humeri, the proximal thirds of the femora, and both iliac wings (totaling seven ROIs per patient). To compare the patients with and without B symptoms, in terms of standardized uptake values (SUVs) for the seven ROIs, we used the Mann-Whitney U test.

Results: For six of the ROIs, the SUVs were higher in the patients with B symptoms than in those without, and the difference was statistically significant ( < 0.05). There was also a tendency toward a statistically significant difference between the two groups in terms of the SUV for the right iliac wing ROI ( = 0.06).

Conclusion: In our sample, the presence of B symptoms was associated with increased F-FDG uptake in bone marrow.
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http://dx.doi.org/10.1590/0100-3984.2016.0201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935399PMC
May 2018

Different Polyubiquitinated Bodies in Human Dendritic Cells: IL-4 Causes PaCS During Differentiation while LPS or IFNα Induces DALIS During Maturation.

Sci Rep 2017 05 12;7(1):1844. Epub 2017 May 12.

Department of Molecular Medicine, Pathologic Anatomy Unit, University of Pavia, Via Forlanini 16, 27100, Pavia, Italy.

Two types of polyubiquitin-reactive cytoplasmic bodies, particulate cytoplasmic structures (PaCS) and dendritic cell (DC) aggresome-like induced structures (DALIS), were analyzed by electron microscopy, immunocytochemistry, immunoblotting, and flow cytometry in DC obtained from human blood monocytes incubated with GM-CSF plus IL-4 (IL4-DC), GM-CSF plus IFNα (IFN-DC), or GM-CSF alone (GM-DC), with or without LPS maturation. PaCS developed as monomorphic aggregates of proteasome-reactive barrel-like particles only in ribosomes-rich cytoplasmic areas of differentiating IL4-DC. In contrast, DALIS formed as vesicular bodies storing K63-linked ubiquitinated proteins by coalescence of increased endosomal structures, in IFN-DC or after LPS maturation of GM-DC. DALIS-forming cells showed incomplete morphological and functional DC-type differentiation when compared to PaCS-forming IL4-DC. PaCS and DALIS may have different function as well as different origin and cytochemistry. DALIS may be a transient accumulation site of potentially antigenic polyubiquitinated proteins during their processing and presentation. PaCS are found under physiologic or pathologic conditions associated with increased/deranged protein synthesis and increased ubiquitin-proteasome activity. Given its high heat-shock protein content PaCS may work as a quality control structure for newly synthesized, cytosolic proteins. This comparative analysis suggests that PaCS and DALIS have distinctive roles in DC.
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http://dx.doi.org/10.1038/s41598-017-02090-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431999PMC
May 2017

Correction: Dependence of the Ce(iii)/Ce(iv) ratio on intracellular localization in ceria nanoparticles internalized by human cells.

Nanoscale 2017 04;9(15):5021

Department of Molecular Medicine, Human Physiology Unit, University of Pavia, 27100 Pavia, Italy.

Correction for 'Dependence of the Ce(iii)/Ce(iv) ratio on intracellular localization in ceria nanoparticles internalized by human cells' by Daniela Ferraro, et al., Nanoscale, 2017, 9, 1527-1538.
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http://dx.doi.org/10.1039/c7nr90069dDOI Listing
April 2017

Dependence of the Ce(iii)/Ce(iv) ratio on intracellular localization in ceria nanoparticles internalized by human cells.

Nanoscale 2017 01;9(4):1527-1538

Department of Molecular Medicine, Human Physiology Unit, University of Pavia, 27100 Pavia, Italy.

CeO nanoparticles (CNPs) have been investigated as promising antioxidant agents with significant activity in the therapy of diseases involving free radicals or oxidative stress. However, the exact mechanism responsible for CNP activity has not been completely elucidated. In particular, in situ evidence of modification of the oxidative state of CNPs in human cells and their evolution during cell internalization and subsequent intracellular distribution has never been presented. In this study we investigated modification of the Ce(iii)/Ce(iv) ratio following internalization in human cells by X-ray absorption near edge spectroscopy (XANES). From this analysis on cell pellets, we observed that CNPs incubated for 24 h showed a significant increase in Ce(iii). By coupling on individual cells synchrotron micro-X-ray fluorescence (μXRF) with micro-XANES (μXANES) we demonstrated that the Ce(iii)/Ce(iv) ratio is also dependent on CNP intracellular localization. The regions with the highest CNP concentrations, suggested to be endolysosomes by transmission electron microscopy, were characterized by Ce atoms in the Ce(iv) oxidation state, while a higher Ce(iii) content was observed in regions surrounding these areas. These observations suggest that the interaction of CNPs with cells involves a complex mechanism in which different cellular areas play different roles.
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http://dx.doi.org/10.1039/c6nr07701cDOI Listing
January 2017

Resveratrol analogue 4,4'-dihydroxy-trans-stilbene potently inhibits cancer invasion and metastasis.

Sci Rep 2016 Feb 1;6:19973. Epub 2016 Feb 1.

Department of Molecular Medicine, Immunology and General Pathology Unit, University of Pavia, Pavia, Italy.

We investigated the preventive effects of resveratrol analogue 4,4'-dihydroxy-trans-stilbene (DHS) on cancer invasion and metastasis. Two different in vivo approaches of mouse and zebrafish lung cancer invasion models were employed in our study. The in vitro results showed that DHS displays potent inhibition on anchorage-dependent or -independent cell growth of LLC cells, leading to impairment of the cell cycle progression with reduction of cell numbers arresting at the G1 phase, an evident accumulation of pre-G1 events correlated with apoptotic behaviour. In addition, DHS induces a marked inhibition of LLC cell migration and matrigel invasion. In a murine lung cancer model, tumour volume, cell proliferation, and tumour angiogenesis were significantly inhibited by DHS. Importantly, liver metastatic lesions were significantly reduced in DHS-treated mice. Similarly, DHS significantly inhibits lung cancer cell dissemination, invasion and metastasis in a zebrafish tumour model. These findings demonstrate that DHS could potentially be developed as a novel therapeutic agent for treatment of cancer and metastasis.
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http://dx.doi.org/10.1038/srep19973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734289PMC
February 2016

Overestimation of nanoparticles-induced DNA damage determined by the comet assay.

Nanotoxicology 2016 09 26;10(7):861-70. Epub 2016 Jan 26.

a Department of Molecular Medicine , Human Physiology Unit, University of Pavia , Pavia , Italy and.

The increasing use of engineered nanoparticles (NPs) in a wide range of commercial products raises concern about the possible risks that NPs pose to human health. Many aspects of the interaction between living cells and NPs are still unclear, and a reliable assessment of NP genotoxicity would be important. One of the most common tests used for genotoxicity is the comet assay, a sensitive method measuring DNA damage in individual cells. The assay was originally developed for soluble molecules, but it is also used in the assessment of genotoxicity of NPs. However, concerns have been raised recently about the reliability of this test in the case of NPs, but no conclusive results have been presented. Using nuclei isolated from human epithelial cells incubated with NPs, we obtained clear evidence of overestimation of NP genotoxicity by the comet assay in the case of CeO2, TiO2, SiO2, and polystyrene NPs. Removal of the NPs in the cytoplasm was effective in eliminating this genotoxicity overestimation (ex post damage) and determining the actual damage produced by the NPs during incubation with the cells (ex ante damage). This method could improve significantly the determination of NP genotoxicity in eukaryotic cells.
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http://dx.doi.org/10.3109/17435390.2015.1130274DOI Listing
September 2016

Non-invasive method distinguishes chronic telogen effluvium from mild female pattern hair loss: clinicopathological correlation.

Int J Dermatol 2016 Jul 29;55(7):e373-9. Epub 2015 Dec 29.

Department of Pathology, Medical School, State University of Campinas, Campinas, Brazil.

Background: The distinction between chronic telogen effluvium (CTE) and female pattern hair loss (FPHL) is important because of their different prognosis and treatment. Non-invasive methods have been described to be useful in differentiating FPHL from CTE. This prospective study investigated the use of the washing method to differentiate CTE from mild FPHL.

Methods: Twenty patients with CTE and 17 with FPHL were recruited and followed for 18 months. The diagnosis was established through clinical, laboratory, and histological studies. The patients were asked to abstain from washing their hair for 5 days and then shampoo and collect all hair shed in the process. Hair shafts were then counted and divided into two groups: up to 3 cm in length or longer.

Results: In the CTE group, the mean hair count was high (438), and in all cases, <10% were short. In patients with FPHL, the mean count was not as high (215) and in only one patient, short hairs comprised <10% of the total. The greater the number of long hairs, the higher was the density of terminal follicles seen histologically. The CTE group presented a greater number of patients with serum iron values <70 μg/dl. Ferritin levels ranged from 6.98 to 128.33, average of 66.65 (CTE), and 16.5-304.8, average of 114.97 ng/ml (FPHL), but no significant differences were found.

Conclusion: The washing test can be useful to avoid biopsy procedures. Iron serum levels are possibly an additional parameter that may improve CTE diagnosis if combined with an earlier test.
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http://dx.doi.org/10.1111/ijd.13200DOI Listing
July 2016

Reply to Gerlee and Altrock: Diffusion and population size in game theory models of cancer.

Proc Natl Acad Sci U S A 2015 May 4;112(21):E2744. Epub 2015 May 4.

Department of Biomedicine, University of Basel, CH-4058, Basel, Switzerland.

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http://dx.doi.org/10.1073/pnas.1505648112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450390PMC
May 2015