Publications by authors named "Thomas Horn"

229 Publications

Regional Lymph Node Metastasis on PSMA PET Correlates with Decreased BCR-Free and Therapy-free Survival after Radical Prostatectomy: A Retrospective Single-Center Single-Arm Observational Study.

J Urol 2021 Feb 4:101097JU0000000000001596. Epub 2021 Feb 4.

Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Purpose: To address the impact of preoperative PSMA PET (prostate specific membrane antigen positron emission tomography) findings prior to radical prostatectomy (RP) and pelvic lymph node dissection (PLND) on biochemical recurrence (BCR) and time to adjuvant or salvage treatment.

Materials And Methods: Between 2013 and 2017, 64 intermediate- and 166 high-risk (n=230) prostate cancer (PCa) patients received Ga-PSMA-11 PET followed by RP and PLND. BCR-free and therapy-free survival was determined. For all time to event analyses, uni- and multivariable Cox's proportional hazards models and univariable Kaplan-Meier analyses were applied, with a significance threshold of p <0.05.

Results: The overall sensitivity, specificity, positive predictive value and negative predictive value of PSMA PET for pN1 disease was 48.5%, 95.7%, 82.1% and 82.2%, respectively. Median follow up was 30.2 months. BCR occurred in 50.4% (n=116) of patients and adjuvant or salvage treatment was performed in 46.5% (n=107). Worst BCR-free and therapy-free survival was observed in pN1 patients who also exhibited PSMA PET positive LN, followed by pN1 patients without PSMA PET positive LN and patients without evidence of LN metastasis on histology and PSMA PET (median BCR-free survival 1.7 vs. 7.5 vs. >36 months, median therapy-free survival 2.6 vs. 8.9 vs. >36 months).

Conclusions: Patients with positive LN on PSMA PET prior to RP have to expect early BCR and adjuvant/salvage therapy, despite thorough PLND. Therefore, results from PSMA PET can be used for patients' consultation, more stringent follow-up as well as for planning of neo-/adjuvant therapy.
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http://dx.doi.org/10.1097/JU.0000000000001596DOI Listing
February 2021

Outcomes of palliative cystectomy in patients with locally advanced pT4 bladder cancer.

Urol Oncol 2021 Jan 8. Epub 2021 Jan 8.

Department of Urology, Technical University of Munich, Rechts der Isar Medical Center, Munich, Germany.

Background: Radical cystectomy (Cx) is the standard of care for muscle-invasive bladder cancer (BCa). In locally advanced pT4 BCa the oncologic outcome is inexplicit but Cx may be necessary for palliation.

Objectives: The aim of this retrospective study was to evaluate the outcomes of Cx performed in patients with locally advanced pT4 BCa and to identify patient subgroups with improved outcome.

Methods: Between 2008 and 2017, we identified 76 of 905 patients who underwent Cx for pT4 BCa at a single tertiary referral center. The physical patients' status was estimated according to the American Society of Anesthesiologists (ASA) classification. For the classification of postoperative complication rates, the Clavien-Dindo grading was used. Time-to-event variables with log-rank statistics were calculated with the use of the Kaplan-Meier method.

Results: Median age was 74 years (range 42-90). Preoperatively, the physical status was estimated poor in 40 (52%) patients (ASA-score of ≥3). Overall, 19 (25%) patients had pT4b BCa, 41 (54%) patients were lymph node positive (c/pN+) and 14 (18%) patients had distant metastases (c/pM+). Within 30 and 90 days after surgery, 21% and 30% of the patients, respectively, developed severe complications (Clavien-Dindo grade ≥3). Overall, 30- and 90-day mortality rates were 9% and 11%, respectively. Moreover, 86% and 75% of patients who died within 30 and 90 days after surgery, respectively, had an ASA-score ≥3. At a median postoperative follow-up of 8 months (range 0-85), 53 (70%) patients have died. During the follow-up period, 46% of the patients died due to progressive disease, 16% died of a noncancer-specific cause, and for 8% of the patients, the reason remains unknown. Median overall survival (OS) and cancer-specific survival were 13.0 and 16.0 months, respectively. In subgroup analyses ASA-score ≥3 and hemoglobin <11.7 g/dl was significantly associated with poor OS. No statistically significant differences were detected between subgroups.

Conclusion: Cx performed in patients with locally advanced pT4 BCa is associated with an increased mortality rate within 90 days postoperatively. Our study revealed that the ASA-score is a relevant and easily available tool to rate the patient´s condition and estimate postoperative outcome.
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http://dx.doi.org/10.1016/j.urolonc.2020.11.042DOI Listing
January 2021

Salvage Surgery in Patients with Local Recurrence After Radical Prostatectomy.

Eur Urol 2020 Dec 11. Epub 2020 Dec 11.

Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background: Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, isolated local recurrence after radical prostatectomy (RP) can be delineated accurately.

Objective: To describe and evaluate surgical technique, biochemical response, and therapy-free survival (TFS) after salvage surgery in patients with local recurrence in the seminal vesicle bed.

Design, Setting, And Participants: We retrospectively assessed 40 patients treated with open salvage surgery in two centres (11/2014-02/2020). All patients presented with biochemical recurrence (BCR) after RP with a singular local recurrence at PSMA PET imaging. Thirty-three (82.5%) patients received previous salvage radiation therapy.

Surgical Procedure: Open salvage surgery with PSMA radioguidance.

Measurements: Prostate-specific antigen (PSA) nadir and percentage of patients with complete biochemical response (cBR) without further treatment (PSA < 0.2 ng/ml) after 6-16 wk were assessed. BCR-free survival and TFS were calculated using Kaplan-Meier estimates. Clavien-Dindo complications were evaluated.

Results And Limitations: Prior to salvage surgery, median PSA was 0.9 ng/ml (interquartile range [IQR]: 0.5-1.7 ng/ml). Postoperatively, median PSA nadir was 0.1 ng/ml (IQR: 0-0.4 ng/ml). In 31 (77.5%) patients, cBR was observed. During the median follow-up of 24.4 months, 22 (55.0%) patients experienced BCR and 12 (30.0%) received further therapy. At 1 yr of follow-up, BCR-free survival rate was 62.2% and TFS rate was 88.3%. Three (7.5%) Clavien-Dindo grade III complications were observed. The main limitations are the retrospective design, short follow-up, and lack of a control group.

Conclusions: Salvage surgery of local recurrence within the seminal vesicle bed is feasible. It may present an opportunity in selected, locally recurrent patients to prolong BCR-free survival and increase TFS. Further studies are needed to confirm our findings.

Patient Summary: We looked at the outcomes from prostate cancer patients with locally recurrent disease after radical prostatectomy and radiotherapy. We found that surgery in well-selected patients may be an opportunity to prolong treatment-free survival.
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http://dx.doi.org/10.1016/j.eururo.2020.11.012DOI Listing
December 2020

Matched-pair comparison of Ga-PSMA-11 and F-rhPSMA-7 PET/CT in patients with primary and biochemical recurrence of prostate cancer: frequency of non-tumor related uptake and tumor positivity.

J Nucl Med 2020 Dec 4. Epub 2020 Dec 4.

Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Germany, Germany.

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are a new class of prostate cancer theranostic agents. F-rhPSMA-7, offers the advantages of F-labelling and low urinary excretion compared with Ga-PSMA-11. Here, we compare frequency of non-tumor related uptake and tumor positivity with Ga-PSMA-11 and F-rhPSMA-7 in patients with primary or recurrent prostate cancer. This retrospective matched-pair comparison matched 160 F-rhPSMA-7 with 160 Ga-PSMA-11 PET/CT studies for primary staging ( = 33) and biochemical recurrence ( = 127) according to clinical characteristics. Two nuclear medicine physicians reviewed all scans, first, identifying all PET-positive lesions, then differentiating lesions suspicious for prostate cancer from those that were benign, based on known pitfalls and ancillary information from CT. For each region, SUV of the lesion with the highest PSMA-ligand uptake was noted. Tumor positivity rates were determined and SUV were compared separately for each tracer. F-rhPSMA-7 and Ga-PSMA-11 PET revealed 566 and 289 PSMA-ligand positive lesions, respectively. Of these, 379 and 100 lesions, equaling 67.0 % and 34.6 % of all PSMA-positive lesions were considered benign, respectively. The distribution of their etiology was similar (42%, 24%, 25% in F-rhPSMA-7 vs. 32%, 24%, 38% in Ga-PSMA-11 for ganglia, bone and unspecific lymph nodes, respectively). All primary tumors were positive with both agents ( = 33 each) while slightly more metastatic lesions were observed with Ga-PSMA-11 in both disease stages (113 for F-rhPSMA-7 and 124 for Ga-PSMA-11). SUV of F-rhPSMA-7 and Ga-PSMA-11 did not differ ( > 0.05) in local recurrence or primary prostate cancer, however, the tumor-to-bladder ratio was significantly higher with F-rhPSMA-7 (4.9±5.3 vs 2.2±3.7, = 0.02 for local recurrence and 9.8±9.7 vs 2.3±2.6, < 0.001 for primary prostate cancer). The tumor positivity rate was consistently high for Ga-PSMA-11 and F-rhPSMA-7. Both tracers revealed a considerable number of areas of uptake that were reliably identified as benign by trained physicians making use of corresponding morphological imaging and known PSMA pitfalls. These were more frequent with F-rhPSMA-7. However, the matched-pair comparison could have introduced a source of bias. Adequate reader training can allow physicians to differentiate benign uptake from disease and be able to benefit from the logistical and clinical advantages of F-rhPSMA-7.
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http://dx.doi.org/10.2967/jnumed.120.251447DOI Listing
December 2020

Role of Human 15-Lipoxygenase-2 in the Biosynthesis of the Lipoxin Intermediate, 5S,15S-diHpETE, Implicated with the Altered Positional Specificity of Human 15-Lipoxygenase-1.

Biochemistry 2020 Oct 13;59(42):4118-4130. Epub 2020 Oct 13.

Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, California 95064, United States.

The oxylipins, 5S,12S-dihydroxy-6E,8Z,10E,14Z-eicosatetraenoic acid (5S,12S-diHETE) and 5S,15S-dihydroxy-6E,8Z,11Z,13E-eicosatetraenoic acid (5S,15S-diHETE), have been identified in cell exudates and have chemotactic activity toward eosinophils and neutrophils. Their biosynthesis has been proposed to occur by sequential oxidations of arachidonic acid (AA) by lipoxygenase enzymes, specifically through oxidation of AA by h5-LOX followed by h12-LOX, h15-LOX-1, or h15-LOX-2. In this work, h15-LOX-1 demonstrates altered positional specificity when reacting with 5S-HETE, producing 90% 5S,12S-diHETE, instead of 5S,15S-diHETE, with kinetics 5-fold greater than that of h12-LOX. This is consistent with previous work in which h15-LOX-1 reacts with 7S-HDHA, producing the noncanonical, DHA-derived, specialized pro-resolving mediator, 7S,14S-diHDHA. It is also determined that oxygenation of 5S-HETE by h15-LOX-2 produces 5S,15S-diHETE and its biosynthetic / flux is 2-fold greater than that of h15-LOX-1, suggesting that h15-LOX-2 may have a greater role in lipoxin biosynthesis than previously thought. In addition, it is shown that oxygenation of 12S-HETE and 15S-HETE by h5-LOX is kinetically slow, suggesting that the first step in the biosynthesis of both 5S,12S-diHETE and 5S,15S-diHETE is the production of 5S-HETE.
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http://dx.doi.org/10.1021/acs.biochem.0c00622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721368PMC
October 2020

The case of a painful blue thumb.

JAAD Case Rep 2020 Oct 31;6(10):1053-1055. Epub 2020 Jul 31.

Upstate Dermatology, Greer, South Carolina.

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http://dx.doi.org/10.1016/j.jdcr.2020.06.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509360PMC
October 2020

Optimized production strategy of the major capsid protein HPV 16L1 non-assembly variant in E. coli.

Protein Expr Purif 2020 11 16;175:105690. Epub 2020 Jul 16.

Institute of Medical Virology, University of Tübingen, Elfriede-Aulhorn-Str. 06, D-72076, Tübingen, Germany. Electronic address:

The capsid of human papillomavirus (HPV) consists of two capsid proteins - the major capsid protein L1 and the minor capsid protein L2. Assembled virus-like particles, which only consist of L1 proteins, are successfully applied as prophylactic vaccines against HPV infections. The capsid subunits are L1-pentamers, which are also reported to protect efficiently against HPV infections in animals. The recombinant production of L1 has been previously shown in E. coli, yeast, insect cells, plants and mammalian cell culture. Principally, in E. coli-based expression system L1 shows high expression yields but the protein is largely insoluble. In order to overcome this problem reported strategies address fusion proteins and overexpression of bacterial chaperones. However, an insufficient cleavage of the fusion proteins and removal of co-purified chaperones can hamper subsequent down streaming. We report a significant improvement in the production of soluble L1-pentamers by combining (I) a fusion of a N-terminal SUMO-tag to L1, (II) the heterologous co-expression of the chaperon system GroEL/ES and (III) low expression temperature. The fusion construct was purified in a 2-step protein purification including efficient removal of GroEL/ES and complete removal of the N-terminal SUMO-tag. The expression strategy was transferred to process-controlled high-cell-density fermentation with defined media according to the guidelines of good manufacturing practice. The produced L1 protein is highly pure (>95%), free of DNA (260:280 = 0.5) and pentameric. The production strategy yielded 5.73 mg of purified L1-pentamers per gram dry biomass. The optimized strategy is a suitable alternative for high yield L1-pentamer production and purification as a cheaper process for vaccine production.
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http://dx.doi.org/10.1016/j.pep.2020.105690DOI Listing
November 2020

A phase 2, multicenter, placebo-controlled study of single-dose squaric acid dibutyl ester to reduce frequency of outbreaks in patients with recurrent herpes labialis.

J Am Acad Dermatol 2020 Dec 11;83(6):1807-1809. Epub 2020 Apr 11.

Squarex, LLC, Pine Springs, Minnesota. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.04.021DOI Listing
December 2020

STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy.

Int J Mol Sci 2020 Feb 7;21(3). Epub 2020 Feb 7.

Department of Urology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.

The JAK-STAT signalling pathway regulates cellular processes like cell division, cell death and immune regulation. Dysregulation has been identified in solid tumours and STAT3 activation is a marker for poor outcome. The aim of this study was to explore potential therapeutic strategies by targeting this pathway in bladder cancer (BC). High STAT3 expression was detected in 51.3% from 149 patient specimens with invasive bladder cancer by immunohistochemistry. Protein expression of JAK, STAT and downstream targets were confirmed in 10 cell lines. Effects of the JAK inhibitors Ruxolitinib and BSK-805, and STAT3/5 inhibitors Stattic, Nifuroxazide and SH-4-54 were analysed by cell viability assays, immunoblotting, apoptosis and cell cycle progression. Treatment with STAT3/5 but not JAK1/2 inhibitors reduced survival, levels of phosphorylated STAT3 and Cyclin-D1 and increased apoptosis. Tumour xenografts, using the chicken chorioallantoic membrane (CAM) model responded to Stattic monotherapy. Combination of Stattic with Cisplatin, Docetaxel, Gemcitabine, Paclitaxel and CDK4/6 inhibitors showed additive effects. The combination of Stattic with the oncolytic adenovirus XVir-N-31 increased viral replication and cell lysis. Our results provide evidence that inhibitors against STAT3/5 are promising as novel mono- and combination therapy in bladder cancer.
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http://dx.doi.org/10.3390/ijms21031106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043223PMC
February 2020

F-rhPSMA-7 PET for the Detection of Biochemical Recurrence of Prostate Cancer After Radical Prostatectomy.

J Nucl Med 2020 05 13;61(5):696-701. Epub 2019 Dec 13.

Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

F-labeled prostate-specific membrane antigen (PSMA) PET tracers are increasingly used in preference to Ga-PSMA-11 for restaging biochemical recurrence (BCR) of prostate cancer. They are associated with longer half-lives, larger-scale production, and lower positron range than their Ga-labeled counterparts. Here, we describe the efficacy of an F-labeled radiohybrid PSMA, rhPSMA-7, a novel theranostic PSMA-targeting agent for imaging BCR of prostate cancer. Datasets from 261 consecutive patients with noncastrate BCR after radical prostatectomy who underwent F-rhPSMA-7 PET/CT at our institution between June 2017 and March 2018 were reviewed retrospectively. All lesions suspected of being recurrent prostate cancer were recorded. The detection rate for sites of presumed recurrence was correlated with patients' prostate-specific antigen (PSA) level, primary Gleason score, and prior therapy (androgen deprivation therapy and external-beam radiation therapy). The 261 patients had a median PSA level of 0.96 ng/mL (range, 0.01-400 ng/mL). The median injected activity of F-rhPSMA-7 was 336 MBq, with a median uptake time of 76 min. In total, 211 patients (81%) showed pathologic findings on F-rhPSMA-7 PET/CT. The detection rates were 71% (42/59), 86% (44/51), 86% (42/49), and 95% (76/80) at PSA levels of 0.2 to <0.5 ng/mL, 0.5 to <1 ng/mL, 1 to <2 ng/mL, and ≥2 ng/mL, respectively. In 32% patients (7/22) with a PSA of less than 0.2 ng/mL, suggestive lesions were present. F-rhPSMA-7 PET/CT revealed local recurrence in 43% of patients (113). Lymph node metastases were present in the pelvis in 42% of patients (110), in the retroperitoneum in 17% (45), and in a supradiaphragmatic location in 8.0% (21). Bone and visceral metastases were detected in 21% (54) and 3.8% (10), respectively. Detection efficacy was not influenced by prior external-beam radiation therapy (79.1% vs. 82.1%, = 0.55), androgen deprivation therapy within the 6 mo preceding imaging (80.6% vs. 80.9%, = 0.54), or primary Gleason score (77.9% for ≤7 vs. 82.6% for ≥8, = 0.38). F-rhPSMA-7 PET/CT offers high detection rates in early BCR after radical prostatectomy, especially among patients with low PSA values.
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http://dx.doi.org/10.2967/jnumed.119.234914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198386PMC
May 2020

Histologically Confirmed Diagnostic Efficacy of F-rhPSMA-7 PET for N-Staging of Patients with Primary High-Risk Prostate Cancer.

J Nucl Med 2020 05 13;61(5):710-715. Epub 2019 Dec 13.

Department of Nuclear Medicine, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

F-rhPSMA-7 (radiohybrid prostate-specific membrane antigen [PSMA]) is a novel ligand for PET imaging. Here, we present data from a retrospective analysis using PET/CT and PET/MRI examinations to investigate the efficacy of F-rhPSMA-7 PET for primary N-staging of patients with prostate cancer (PC) compared with morphologic imaging (CT or MRI) and validated by histopathology. Data from 58 patients with high-risk PC (according to the D'Amico criteria) who were staged with F-rhPSMA-7 PET/CT or PET/MRI at our institution between July 2017 and June 2018 were reviewed. The patients had a median prescan prostate-specific antigen value of 12.2 ng/mL (range, 1.2-81.6 ng/mL). The median injected activity of F-rhPSMA-7 was 327 MBq (range, 132-410 MBq), with a median uptake time of 79.5 min (range, 60-153 min). All patients underwent subsequent radical prostatectomy and extended pelvic lymph node dissection. The presence of lymph node metastases was determined by an experienced reader independently for both the PET and the morphologic datasets using a template-based analysis on a 5-point scale. Patient-level and template-based results were both compared with histopathologic findings. Lymph node metastases were present in 18 patients (31.0%) and were located in 52 of 375 templates (13.9%). Receiver-operating-characteristic analyses showed F-rhPSMA-7 PET to perform significantly better than morphologic imaging on both patient-based and template-based analyses (areas under curve, 0.858 vs. 0.649 [ = 0.012] and 0.765 vs. 0.589 [ < 0.001], respectively). On patient-based analyses, the sensitivity, specificity, and accuracy of F-rhPSMA-7 PET were 72.2%, 92.5%, and 86.2%, respectively, and those of morphologic imaging were 50.0%, 72.5%, and 65.5%, respectively. On template-based analyses, the sensitivity, specificity, and accuracy of F-rhPSMA-7 PET were 53.8%, 96.9%, and 90.9%, respectively, and those of morphologic imaging were 9.6%, 95.0%, and 83.2%, respectively. F-rhPSMA-7 PET is superior to morphologic imaging for N-staging of high-risk primary PC. The efficacy of F-rhPSMA-7 is similar to published data for Ga-PSMA-11.
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http://dx.doi.org/10.2967/jnumed.119.234906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198390PMC
May 2020

FRET in a Polymeric Nanocarrier: IR-780 and IR-780-PDMS.

Biomacromolecules 2019 11 18;20(11):4065-4074. Epub 2019 Oct 18.

Nanomedicine Research Lab CLINAM , University Hospital Basel, University of Basel , Bernoullistrasse 20 , Basel CH-4056 , Switzerland.

We introduce a method to monitor the integrity of micellar nanocarriers using a novel fluorescent dye, IR-780-PDMS and Förster resonance energy transfer (FRET) as a readout. In addition, these dye-loaded nanocarriers can be used as a phototoxic agent in vitro. Mainly, a nanocarrier was designed, based on a previously described amphiphilic ABA-copolymer (Pip-PMOXA-PDMS-PMOXA-Pip) scaffold that incorporates the fluorescent FRET dye partners IR-780-PDMS (donor) and IR-780 (acceptor). The confirmation of FRET (that only occurs when donor and acceptor are in the required close proximity of less than ∼10 nm) in the nanocarriers is used to prove that the acceptor dye (IR-780) is still contained in its hydrophobic core. We measured such FRET signals of the nanocarriers also upon cellular uptake into HeLa cells using fluorescence-lifetime imaging microscopy (FLIM). Confocal laser scanning microscopy after incubation with nanocarriers demonstrated the intracellular uptake of the particles and their localization in an intracellular granular pattern. To demonstrate the intactness of the nanocarriers by detection of FRET we measured the fluorescence lifetime (FLIM) of the donor dye. FLIM showed that both types of lifetimes, that of the quenched donor, and that of the unquenched donor were present, in a granular pattern and homogeneously in the cytosol, respectively, indicating the presence of intracellular intact and disintegrated micellar nanocarriers. These data show that the herewith-described FRET method allows monitoring the intactness of nanocarriers while en route to the target, and also that the cargo is delivered and released within a potential target cell. In addition, near-infrared (NIR) irradiation of IR-780-loaded micellar nanocarriers leads to photocytotoxicity, which we demonstrated in in vitro experiments. Our findings open potential avenues in photodynamic therapy (PDT) of cancer.
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http://dx.doi.org/10.1021/acs.biomac.9b00823DOI Listing
November 2019

Enhanced In Vivo Delivery of Stem Cells using Microporous Annealed Particle Scaffolds.

Small 2019 09 13;15(39):e1903147. Epub 2019 Aug 13.

Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

Delivery to the proper tissue compartment is a major obstacle hampering the potential of cellular therapeutics for medical conditions. Delivery of cells within biomaterials may improve localization, but traditional and newer void-forming hydrogels must be made in advance with cells being added into the scaffold during the manufacturing process. Injectable, in situ cross-linking microporous scaffolds are recently developed that demonstrate a remarkable ability to provide a matrix for cellular proliferation and growth in vitro in three dimensions. The ability of these scaffolds to deliver cells in vivo is currently unknown. Herein, it is shown that mesenchymal stem cells (MSCs) can be co-injected locally with microparticle scaffolds assembled in situ immediately following injection. MSC delivery within a microporous scaffold enhances MSC retention subcutaneously when compared to cell delivery alone or delivery within traditional in situ cross-linked nanoporous hydrogels. After two weeks, endothelial cells forming blood vessels are recruited to the scaffold and cells retaining the MSC marker CD29 remain viable within the scaffold. These findings highlight the utility of this approach in achieving localized delivery of stem cells through an injectable porous matrix while limiting obstacles of introducing cells within the scaffold manufacturing process.
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http://dx.doi.org/10.1002/smll.201903147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761037PMC
September 2019

Matched-Pair Comparison of Ga-PSMA-11 PET/CT and F-PSMA-1007 PET/CT: Frequency of Pitfalls and Detection Efficacy in Biochemical Recurrence After Radical Prostatectomy.

J Nucl Med 2020 01 28;61(1):51-57. Epub 2019 Jun 28.

Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.

F-labeled prostate-specific membrane antigen (PSMA)-ligand PET has several principal advantages over Ga-PSMA-11. The purpose of this retrospective study was to evaluate the frequency of non-tumor-related uptake and the detection efficacy comparing Ga-PSMA-11 PET/CT and F-PSMA-1007 PET/CT in recurrent prostate cancer (PC) patients. The study included 102 patients with biochemically recurrent PC after radical prostatectomy undergoing F-PSMA-1007 PET/CT imaging. On the basis of various clinical variables, patients with corresponding Ga-PSMA-11 PET/CT scans were matched. All PET/CT scans ( = 204) were reviewed by 1 nuclear medicine physician. First, all PET-positive lesions were noted. Then, lesions suspected of being recurrent PC were differentiated from lesions attributed to a benign origin on the basis of known pitfalls and information from CT. For each region, the SUV of the lesion with the highest PSMA-ligand uptake was noted. Detection rates were determined, and SUV was compared separately for Ga-PSMA-11 and F-PSMA-1007. In total, F-PSMA-1007 PET and Ga-PSMA-11 PET revealed 369 and 178 PSMA-ligand-positive lesions, respectively. F-PSMA-1007 PET revealed approximately 5 times more lesions attributed to a benign origin than did Ga-PSMA-11 PET (245 vs. 52 lesions, respectively). The benign lesions most frequently observed were ganglia, unspecific lymph node, and bone lesions, at a rate of 43%, 31%, and 24% for F-PSMA-1007 PET and 29%, 42%, and 27% for Ga-PSMA-11 PET, respectively. The SUV of lesions attributed to a benign origin was significantly higher ( < 0.0001) for F-PSMA-1007 PET. Further, a similar number of lesions was attributed to recurrent PC (124/369 for F-PSMA-1007 PET and 126/178 for Ga-PSMA-11 PET). The number of lesions with increased PSMA-ligand uptake attributed to a benign origin is considerably higher for F-PSMA-1007 PET than for Ga-PSMA-11 PET. This finding indicates the need for sophisticated reader training emphasizing known pitfalls and reporting within the clinical context.
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http://dx.doi.org/10.2967/jnumed.119.229187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954457PMC
January 2020

[50 years of systemic therapy of urinary bladder cancer].

Aktuelle Urol 2019 Aug 26;50(4):358-365. Epub 2019 Jun 26.

Technische Universität München, Klinikum rechts der Isar, Urologische Klinik und Poliklinik, München.

This review summarises the treatment strategies of the last five decades for metastatic urothelial cancer. The introduction of combination chemotherapy in the mid-1980s led to clinically significant response rates and prolonged survival. Two years ago, the results of a phase-3 clinical trial with the PD1 inhibitor pembrolizumab for second-line treatment of metastatic urothelial carcinoma were published. These data were the first to show an overall survival benefit in comparison with a conventional chemotherapy with vinflunine, docetaxel or paclitaxel. Currently, PD1/PD-L1 inhibitors are also tested within randomized phase-3-trials for first-line treatment using different approaches either as a monotherapy or a combination with conventional chemotherapy or CTLA-4 inhibitors. Whereas data from single-arm phase-2 clinical trials have already been published, first phase-3 data are expected in 2019.
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http://dx.doi.org/10.1055/a-0945-8340DOI Listing
August 2019

Invasive species reduces parasite prevalence and neutralizes negative environmental effects on parasitism in a native mosquito.

J Anim Ecol 2019 08 24;88(8):1215-1225. Epub 2019 May 24.

Tyson Research Center, Washington University in St. Louis, Eureka, Missouri.

Invasive species research often focuses on direct effects of invasion on native ecosystems and less so on complex effects such as those influencing host-parasite interactions. However, invaders could have important effects on native host-parasite dynamics. Where infectious stages are ubiquitous and native host-pathogen specificity is strong, invasive less-competent hosts may reduce the pool of infectious stages, effectively reducing native host-parasite encounter rate. Alternatively, invasive species could alter transmission via changes in native species abundance. Biotic and abiotic environmental factors can also impact disease dynamics by altering host or parasite condition. However, little is known about potential interactive effects of invasion and environmental context on native species disease dynamics. Moreover, experimental examinations of the mechanisms driving dilution effects are limited, but serve to provide tests of predictions leading to diversity-disease relationships. Using field and laboratory experiments, we tested competing hypotheses that an invasive species reduces the prevalence of a native parasite in its host by removing infectious propagules from the environment or by reducing native host abundance. In addition, we evaluated the role of detritus quantity as a resource base in mediating effects of the invasive species. Native parasite prevalence was reduced when the invasive species was present. Prevalence was also higher in high detritus habitats, although this effect was lost when the invasive species was present. The invasive species significantly reduced infectious propagules from the aquatic habitats. Presence of the invasive species had no effect on the native species abundance; thus, the reduction in parasitism was not due to changes in host density but through a reduction in infectious propagule encounters. We conclude that an invasive species can facilitate a native species by reducing parasite prevalence via a dilution effect and that these effects can be modified by resource level. Reductions in parasitism may have ripple effects throughout the community, altering the strength of competitive interactions, predation rates or coinfection with other pathogens. We advocate considering potential positive effects of invasive species on recipient communities, in addition to effects of invasions on host-parasite interactions to gain a broader understanding of the complex consequences of invasion.
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http://dx.doi.org/10.1111/1365-2656.13004DOI Listing
August 2019

Single Lesion on Prostate-specific Membrane Antigen-ligand Positron Emission Tomography and Low Prostate-specific Antigen Are Prognostic Factors for a Favorable Biochemical Response to Prostate-specific Membrane Antigen-targeted Radioguided Surgery in Recurrent Prostate Cancer.

Eur Urol 2019 10 12;76(4):517-523. Epub 2019 Apr 12.

Department of Urology, Technical University of Munich, Munich, Germany; Martini-Klinik and Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background: Prostate-specific membrane antigen (PSMA)-ligand positron emission tomography (PET) allows detection of metastatic prostate cancer (PC) lesions at low prostate-specific antigen (PSA) values. To facilitate their intraoperative detection during salvage surgery, we recently introduced PSMA-targeted radioguided surgery (RGS).

Objective: To describe the outcome of a large cohort of patients treated with PSMA-targeted RGS and to establish prognostic factors.

Design, Setting, And Participants: A total of 121 consecutive patients with recurrent PC as defined by PSMA-ligand PET (median PSA: 1.13ng/ml) underwent PSMA-targeted RGS.

Outcome Measurements And Statistical Analysis: The frequency of a complete biochemical response (cBR; PSA <0.2ng/ml) without additional treatment and the duration of biochemical recurrence-free survival (bRFS, time from PSMA-targeted RGS with PSA <0.2ng/ml without further treatment) were evaluated and correlated with preoperatively available clinical variables.

Results And Limitations: In almost all patients (120/121, 99%) metastatic tissue could be removed. A cBR was achieved in 77 patients (66%). The chance of cBR was highest in patients with both low preoperative PSA and a single lesion (38/45: 84%). Median bRFS was 6.4mo in the whole patient cohort and 19.8mo for patients with cBR. Significantly longer median bRFS was observed in patients with a low preoperative PSA value (p=0.004, hazard ratio 1.48, 95% confidence interval 1.13-1.93) and with a single lesion in preoperative PSMA-ligand PET (14.0 vs 2.5mo, p=0.002).

Conclusions: PSMA-targeted RGS leads to a remarkable interval of bRFS in a subset of patients. The frequency of cBR and the duration of bRFS were highest in patients with a low preoperative PSA value and a single lesion on PSMA-ligand PET.

Patient Summary: Prostate-specific membrane antigen radioguided surgery delays disease progression in selected patients with recurrent prostate cancer after radical prostatectomy. Patients with a single lesion of recurrence and a low prostate-specific antigen value had the best outcome.
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http://dx.doi.org/10.1016/j.eururo.2019.03.045DOI Listing
October 2019

Phosphoramitoids-A submonomer approach to sequence defined N-substituted phosphoramidate polymers.

Biopolymers 2019 Apr 13;110(4):e23268. Epub 2019 Mar 13.

The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California.

There is a growing interest in new methods to generate bio-inspired, chemically diverse, sequence-defined synthetic polymers. Solid-phase submonomer approaches offer facile access to these types of materials, since they take advantage of readily available synthons. Submonomer approaches to date have been applied to peptidomimetics with oligo-amide backbones. Here we extend the approach to a phosphorous-containing backbone, where N-substituted phosphoramidate oligomers are constructed from a set of amine submonomers, diphenyl H-phosphonate, and cyclohexane diol. The key chemical steps in chain elongation are a chain extension reaction based on H-phosphonate (P III) chemistry, and a side chain attachment step based on the Atherton-Todd reaction. Cheap, stable chemical reagents are used without heating, all reaction times are 30 minutes or less and open to air, and no main-chain protecting groups are required. Phosphoramitoid tetramers and pentamers displaying a variety of side chain functionalities were synthesized by a three-step solid-phase submonomer method, typically with >85% crude purities.
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http://dx.doi.org/10.1002/bip.23268DOI Listing
April 2019

Comment on: "Exam of the future or exam of future cheating? Ethical issues surrounding the American Board of Dermatology's new certification examination".

J Am Acad Dermatol 2020 03 15;82(3):e89. Epub 2019 Feb 15.

American Board of Dermatology, Newton, Massachusetts.

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http://dx.doi.org/10.1016/j.jaad.2019.01.088DOI Listing
March 2020

Goji Who? Morphological and DNA Based Authentication of a "Superfood".

Front Plant Sci 2018 18;9:1859. Epub 2018 Dec 18.

Molecular Cell Biology, Karlsruhe Institute of Technology, Karlsruhe, Germany.

"Goji" ( and ) is a generic name for medical plants with a long historical background in the traditional Chinese medicine. With the emerging trend of "Superfoods" several years ago, Goji berries soon became an established product in European countries and not only are the most popular product of traditional Chinese medicine outside of China but to this day one of the symbols of the entire "Superfood" trend. However, since Goji is an umbrella term for different plant species that are closely related, mislabeling and adulterations (unconsciously or purposely) are possible. We carefully verified the identity of Goji reference plant material based on morphological traits, mainly floral structures of several inflorescences of each individual, in order to create a robust background for the downstream applications that were used on those reference plants and additionally on commercial Goji products. We report morphological and molecular based strategies for the differentiation of and . The two different Goji species vary significantly in seed size, with an almost double average seed area in compared to . Differences could be traced on the molecular level as well; using the psbA-trnH barcoding marker, we detected a single nucleotide substitution that was used to develop an easy one-step differentiation tool based on ARMS (amplification refractory mutation system). Two diagnostic primers used in distinct multiplex PCRs yield a second diagnostic band in a subsequent gel electrophoresis for or , respectively. Our ARMS approach is a strong but simple tool to trace either of the two different Goji species. Both the morphological and the molecular analysis showed that all of the tested commercial Goji products contained fruits of the species var. , leading to the assumption that consumer protection is satisfactory.
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http://dx.doi.org/10.3389/fpls.2018.01859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305467PMC
December 2018

The potent and selective cyclin-dependent kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile combination partner in preclinical cancer models.

Oncotarget 2018 Oct 16;9(81):35226-35240. Epub 2018 Oct 16.

Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, MA, USA.

Inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) is associated with robust antitumor activity. Ribociclib (LEE011) is an orally bioavailable CDK4/6 inhibitor that is approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer, in combination with an aromatase inhibitor, and is currently being evaluated in several additional trials. Here, we report the preclinical profile of ribociclib. When tested across a large panel of kinase active site binding assays, ribociclib and palbociclib were highly selective for CDK4, while abemaciclib showed affinity to several other kinases. Both ribociclib and abemaciclib showed slightly higher potency in -dependent cells than in -dependent cells, while palbociclib did not show such a difference. Profiling CDK4/6 inhibitors in large-scale cancer cell line screens confirmed that loss of function is a negative predictor of sensitivity. We also found that routinely used cellular viability assays measuring adenosine triphosphate levels as a proxy for cell numbers underestimated the effects of CDK4/6 inhibition, which contrasts with assays that assess cell number more directly. Robust antitumor efficacy and combination benefit was detected when ribociclib was added to encorafenib, nazartinib, or endocrine therapies in patient-derived xenografts.
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http://dx.doi.org/10.18632/oncotarget.26215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219668PMC
October 2018

Positron-emission tomography imaging in urological oncology: Current aspects and developments.

Int J Urol 2018 11 13;25(11):912-921. Epub 2018 Aug 13.

Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Positron-emission tomography/computed tomography combining both functional and morphological information has emerged as a powerful tool in oncological imaging within the past decades. The most commonly used radiotracer in oncology visualizing metabolic information is 2-[18F]fluoro-2-deoxy-d-glucose. However, the use of 2-[18F]fluoro-2-deoxy-d-glucose in urological oncology is challenging, as it is limited by physiological excretion through the urinary system. Therefore, it is only useful when applied to specific indications in selected patients with urological malignancy; for example, for detection of residual disease in the post-chemotherapy management of patients with seminoma. Despite initial promising results in bladder cancer, no relevant additional diagnostic value with positron-emission tomography using 2-[18F]fluoro-2-deoxy-d-glucose or choline-based tracers could be obtained, and should therefore be used with caution or only within clinical trials. In prostate cancer, however, a paradigm shift in imaging can be observed after development of new tracers that target the prostate-specific membrane antigen. Biochemical recurrent prostate cancer has become a clinically widely accepted indication for prostate-specific membrane antigen ligand positron-emission tomography/computed tomography, with several studies showing superior detection efficacy compared with conventional imaging. For primary high-risk prostate cancer, growing evidence suggests well-improved staging. The present review aimed to provide an overview of the current status of positron-emission tomography imaging in cancer of the urogenital system including the latest advances in Ga-labeled and F-labeled positron-emission tomography agents targeting the prostate-specific membrane antigen for positron-emission tomography imaging of prostate cancer.
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http://dx.doi.org/10.1111/iju.13779DOI Listing
November 2018

Chronic Inflammation Promotes Skin Carcinogenesis in Cancer-Prone Discoid Lupus Erythematosus.

J Invest Dermatol 2019 01 17;139(1):62-70. Epub 2018 Jul 17.

Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

High-risk skin cancer is a rare, but severe, complication associated with discoid lupus erythematosus (DLE). Chronic scar, inflammation, UVR, and immunosuppressive medications are proposed explanations for this heightened skin cancer risk; however, the exact mechanism driving skin carcinogenesis in DLE is unknown. The distinct co-localization of multiple independent skin cancers with areas of active inflammation in two DLE patients followed over 8 years strongly suggested that lupus inflammation promotes skin carcinogenesis in DLE. To investigate this clinical observation, we subjected lupus-prone MRL/lpr and control (MRL/n) mice to a skin carcinogenesis protocol. Skin tumors developed preferentially within the cutaneous lupus inflammation without scarring in MRL/lpr mice (P < 0.01). The inflammation in MRL/lpr skin was characterized by the accumulation of regulatory T cells, mast cells, M2 macrophages, and markedly elevated transforming growth factor-β1 and IL-6 levels, which have been linked to tumor promotion. Tacrolimus treatment reduced skin inflammation and blocked cancer development in MRL/lpr mice (P = 0.0195). A similar tumor-promoting immune environment was detected in SCCs and the perilesional skin of cancer-prone DLE patients. Therefore, discoid lupus inflammation promotes skin cancer in high-risk DLE patients, and blocking the inflammation may be critical for preventing this life-threatening complication of DLE.
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http://dx.doi.org/10.1016/j.jid.2018.06.185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309656PMC
January 2019

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens.

Cancer Cell 2018 06;33(6):1033-1047.e5

Agenus Inc., Lexington, MA 02421, USA. Electronic address:

The co-engagement of fragment crystallizable (Fc) gamma receptors (FcγRs) with the Fc region of recombinant immunoglobulin monoclonal antibodies (mAbs) and its contribution to therapeutic activity has been extensively studied. For example, Fc-FcγR interactions have been shown to be important for mAb-directed effector cell activities, as well as mAb-dependent forward signaling into target cells via receptor clustering. Here we identify a function of mAbs targeting T cell-expressed antigens that involves FcγR co-engagement on antigen-presenting cells (APCs). In the case of mAbs targeting CTLA-4 and TIGIT, the interaction with FcγR on APCs enhanced antigen-specific T cell responses and tumoricidal activity. This mechanism extended to an anti-CD45RB mAb, which led to FcγR-dependent regulatory T cell expansion in mice.
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http://dx.doi.org/10.1016/j.ccell.2018.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292441PMC
June 2018

Determination of Autoantibody Isotypes Increases the Sensitivity of Serodiagnostics in Rheumatoid Arthritis.

Front Immunol 2018 24;9:876. Epub 2018 Apr 24.

Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) are the most commonly used diagnostic markers of rheumatoid arthritis (RA). These antibodies are predominantly of the immunoglobulin (Ig) M (RF) or IgG (ACPA) isotype. Other subtypes of both antibodies-particularly IgA isotypes and other autoantibodies-such as RA33 antibodies-have been repeatedly reported but their diagnostic value has still not been fully elucidated. Here, we investigated the prevalence of IgA, IgG, and IgM subtypes of RF, ACPA, and RA33 antibodies in patients with RA. To determine the diagnostic specificity and sensitivity sera from 290 RA patients (165 early and 125 established disease), 261 disease controls and 100 healthy subjects were tested for the presence of IgA, IgG, and IgM isotypes of RF, ACPA, and RA33 by EliA™ platform (Phadia AB, Uppsala, Sweden). The most specific antibodies were IgG-ACPA, IgA-ACPA, and IgG-RF showing specificities >98%, closely followed by IgG- and IgA-RA33 while IgM subtypes were somewhat less specific, ranging from 95.8% (RA33) to 90% (RF). On the other hand, IgM-RF was the most sensitive subtype (65%) followed by IgG-ACPA (59.5%) and IgA-RF (50.7%). Other subtypes were less sensitive ranging from 35 (IgA-ACPA) to 6% (IgA-RA33). RA33 antibodies as well as IgA-RF and IgA-ACPA were found to increase the diagnostic sensitivity of serological testing since they were detected also in seronegative patients reducing their number from 109 to 85. Moreover, analyzing IgM-RF by EliA™ proved more sensitive than measuring RF by nephelometry and further reduced the number of seronegative patients to 76 individuals. Importantly, among antibody positive individuals, RA patients were found having significantly more antibodies (≥3) than disease controls which generally showed one or two antibody species. Thus, increasing the number of autoantibodies in serological routine testing provides valuable additional information allowing to better distinguish between RA and other rheumatic disorders, also in patients not showing antibodies in current routine diagnostics. In conclusion, testing for multiple autoantibody specificities increases the diagnostic power of autoimmune diagnostics and could further support physicians in clinical decision-making.
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http://dx.doi.org/10.3389/fimmu.2018.00876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929149PMC
July 2019

Synthetic biology-based cellular biomedical tattoo for detection of hypercalcemia associated with cancer.

Sci Transl Med 2018 04;10(437)

Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.

Diagnosis marks the beginning of any successful therapy. Because many medical conditions progress asymptomatically over extended periods of time, their timely diagnosis remains difficult, and this adversely affects patient prognosis. Focusing on hypercalcemia associated with cancer, we aimed to develop a synthetic biology-inspired biomedical tattoo using engineered cells that would (i) monitor long-term blood calcium concentration, (ii) detect onset of mild hypercalcemia, and (iii) respond via subcutaneous accumulation of the black pigment melanin to form a visible tattoo. For this purpose, we designed cells containing an ectopically expressed calcium-sensing receptor rewired to a synthetic signaling cascade that activates expression of transgenic tyrosinase, which produces melanin in response to persistently increased blood Ca We confirmed that the melanin-generated color change produced by this biomedical tattoo could be detected with the naked eye and optically quantified. The system was validated in wild-type mice bearing subcutaneously implanted encapsulated engineered cells. All animals inoculated with hypercalcemic breast and colon adenocarcinoma cells developed tattoos, whereas no tattoos were seen in animals inoculated with normocalcemic tumor cells. All tumor-bearing animals remained asymptomatic throughout the 38-day experimental period. Although hypercalcemia is also associated with other pathologies, our findings demonstrate that it is possible to detect hypercalcemia associated with cancer in murine models using this cell-based diagnostic strategy.
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http://dx.doi.org/10.1126/scitranslmed.aap8562DOI Listing
April 2018

Treatment of carcinoma in situ of the urinary bladder with an alpha-emitter immunoconjugate targeting the epidermal growth factor receptor: a pilot study.

Eur J Nucl Med Mol Imaging 2018 07 11;45(8):1364-1371. Epub 2018 Apr 11.

European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe, Germany.

Purpose: Patients with carcinoma in situ (CIS) of the bladder refractory to bacillus Calmette-Guérin (BCG) treatment are usually treated with cystectomy. Therefore, new treatment options with preservation of the urinary bladder are needed. The objective of the study was to investigate the feasibility, safety and efficacy of a novel targeted alpha-emitter immunotherapy for CIS after BCG treatment failure.

Methods: A pilot study was conducted in 12 patients (age range 64-86 years, ten men, two women) with biopsy-proven CIS of the bladder refractory to BCG treatment. The patients were treated intravesically with a single instillation (one patient was treated twice) of the alpha-emitter Bi coupled to an anti-EGFR antibody (366-821 MBq). The primary aims of the study were to determine the feasibility of treatment with the Bi-immunoconjugate and evaluation of adverse effects. Therapeutic efficacy was monitored by histological mapping of the urinary bladder 8 weeks after treatment and at different time points thereafter.

Results: The study proved that intravesical instillation of the Bi-immunoconjugate targeting EGFR is feasible. No adverse effects were observed and all blood and urine parameters determined remained in their normal ranges. Therapeutic efficacy was considered satisfactory, in that three of the 12 patients showed no signs of CIS 44, 30 and 3 months after treatment.

Conclusion: Intravesical instillation of Bi-anti-EGFR monoclonal antibody was well tolerated and showed therapeutic efficacy. Repeated instillation and/or instillation of higher activities of the Bi-immunoconjugate might lead to better therapeutic outcomes. A phase I clinical trial is planned.
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http://dx.doi.org/10.1007/s00259-018-4003-6DOI Listing
July 2018

Technetium-based Prostate-specific Membrane Antigen-radioguided Surgery in Recurrent Prostate Cancer.

Eur Urol 2019 04 4;75(4):659-666. Epub 2018 Apr 4.

Department of Nuclear Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany.

Background: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) can visualize metastatic lesions in recurrent prostate cancer (PC). However, reliable identification of small and/or atypically localized lesions during salvage surgery procedures is challenging.

Objective: To describe the technique, feasibility, and short-term outcomes of Technetium (Tc)-based PSMA-radioguided surgery (Tc-PSMA-RGS) for removal of recurrent PC lesions.

Design, Setting, And Participants: Thirty-one consecutive patients with evidence of recurrent PC on Ga-PSMA N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N'-diacetic acid (Ga-PSMA-11) PET after radical prostatectomy undergoing Tc-PSMA-RGS were retrospectively analyzed.

Surgical Procedure: Salvage surgery with intraoperative radioguidance using a gamma probe was performed after intravenous application of Tc-PSMA investigation and surgery (mean activity 571 MBq, mean time to surgery 19.7h).

Measurements: Radioactive rating (positive vs negative) of resected tissue was compared with the findings of postoperative histopathological analysis. Best prostate-specific antigen (PSA) response without additional treatment was determined after 8-16 wk postoperatively. Biochemical recurrence- and treatment-free survival was evaluated.

Results And Limitations: In total, 132 tissue specimens were removed, of which 58 showed metastatic involvement on histological analysis. On a specimen basis, radioactive rating yielded a sensitivity of 83.6% (confidence interval [CI]: 70.9-91.5%), a specificity of 100%, and an accuracy of 93.0% (CI: 85.5-96.7%). With Tc-PSMA-RGS, all lesions visualized on preoperative Ga-PSMA-11 PET could be removed. Moreover, Tc-PSMA-RGS detected additional metastases as small as 3mm in two patients. Thirteen patients suffered from complications related to surgery (Clavien-Dindo grade 1: 12 patients; grade 3a: one patient). A PSA reduction below 0.2 ng/ml was observed in 20 patients. Thirteen patients remained biochemical recurrence free after a median follow-up of 13.8 (range: 4.6-18.3) mo. Twenty patients continued to be treatment free after a median follow-up of 12.2 (range: 5.5-18.3) mo.

Conclusions: As a new technique for surgical guidance, Tc-PSMA-RGS is feasible, and has been proved to be of high value for successful intraoperative detection and removal of metastatic lesions in PC patients scheduled for salvage surgery. Its long-term impact on outcome has to be evaluated.

Patient Summary: In this report, we evaluated a novel technique to identify metastatic lesions intraoperatively in patients with recurrent prostate cancer to facilitate surgical removal. After intravenous injection of radioactive molecules that specifically bind to prostate cancer cells that show increased expression of the prostate-specific membrane antigen, we were able to detect and remove these metastatic lesions during surgery. Following salvage surgery, 41.9% of patients remained biochemical recurrence free (median follow-up of 13.8 mo) and 64.5% continued to be treatment free (median follow-up of 12.2 mo).
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http://dx.doi.org/10.1016/j.eururo.2018.03.013DOI Listing
April 2019

Landscape Physiognomy Influences Abundance of the Lone Star Tick, Amblyomma americanum (Ixodida: Ixodidae), in Ozark Forests.

J Med Entomol 2018 06;55(4):982-988

Tyson Research Center, Washington University, St. Louis, MO.

The lone star tick, Amblyomma americanum Linnaeus (Ixodida: Ixodidae), is emerging as an important human disease vector in the United States. While some recent studies have modeled broad-scale (regional or county-level) distribution patterns of A. americanum, less is known about how local-scale habitat characteristics drive A. americanum abundance. Such local-scale information is vital to identify targets for tick population control measures within land management units. We investigated how habitat features predict host-seeking A. americanum adult and nymph abundance within a 12-ha oak-hickory forest plot in the Missouri Ozarks. We trapped ticks using CO2-baited traps at 40 evenly spaced locations for three 24-h periods during the summer of 2015, and we measured biotic and abiotic variables surrounding each location. Of 2,008 A. americanum captured, 1,009 were nymphs, and 999 were adults. We observed spatial heterogeneity in local tick abundance (min = 0 ticks, max = 112 ticks, mean = 16.7 ticks per trap night). Using generalized linear mixed models, we found that both nymphs and adults had greater abundance in valleys as well as on northern-facing aspects. Moreover, nymph abundance was negatively related to temperature variance, while adult abundance had a negative relationship with elevation. These results demonstrate that managers in this region may be able to predict local tick abundance through simple physiognomic factors and use these parameters for targeted management action.
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http://dx.doi.org/10.1093/jme/tjy038DOI Listing
June 2018