Monitoring Deforestation in Rainforests Using Satellite Data: A Pilot Study from Kalimantan, Indonesia

Monitoring large forest areas is presently feasible with satellite remote sensing as opposed to time-consuming and expensive ground surveys as alternative. This study evaluated, for the first time, the potential of using freely available medium resolution (30 m) Landsat time series data for deforestation monitoring in tropical rainforests of Kalimantan, Indonesia, at sub-annual time scales. A simple, generic, data-driven algorithm for deforestation detection based on a consecutive anomalies criterion was proposed. An accuracy assessment in the spatial and the temporal domain was carried out using high-confidence reference sample pixels interpreted with the aid of multi-temporal very high spatial resolution image series. Results showed a promising spatial accuracy, when three consecutive anomalies were required to confirm a deforestation event. Recommendations in tuning the algorithm for different operational use cases were provided within the context of satisfying REDD+ requirements, depending on whether spatial accuracy or temporal accuracy need to be optimized

Architektur für ein System zur Dokumentanalyse im Unternehmenskontext - Integration von Datenbeständen, Aufbau- und Ablauforganisation

Workflowmanagementsysteme werden im Bürobereich verstärkt zur effizienten Geschäftsprozeßabwicklung eingesetzt. Das bereits Mitte der 70er Jahre propagierte papierlose Büro bleibt jedoch gegenwärtig immer noch Utopie. Dieser Widerspruch liegt darin begründet, daß die Handhabung von papierintensiven Vorgängen in hohem Maße abhängig ist von einer Identifkation und Aufbereitung der in den Dokumenten enthaltenen Informationen. Allerdings müssen solche Daten z.B. bei eingehender Post immer noch von Hand eingegeben werden. In diesem Dokument wird die Architektur eines System vorgestellt, das diesen Medienbruch überwinden soll. Techniken aus dem Gebiet der Dokumentanalyse und des Dokumentverstehens werden in den Workftowkontext integriert und nutzen das dort verfügbare Wissen zur Steigerung der Erkennungsqualität. Das Architekturdokument beruht auf einer ebenfalls dokumentierten Anforderungsanalyse (DFKI Dokument D-97-05). Es enthält eine statische und eine dynamische Beschreibung der benötigten Klassenkategorien und erklärt deren Funktionalität anhand eines umfassenden Beispiels

Molecular imaging and biochemical response assessment after a single cycle of [225Ac]Ac-PSMA-617/[177Lu]Lu-PSMA-617 tandem therapy in mCRPC patients who have progressed on [177Lu]Lu-PSMA-617 monotherapy

Rationale: Despite the promising results of prostate-specific membrane antigen (PSMA)-targeted 177Lu radioligand therapy in metastatic castration-resistant prostate carcinoma (mCRPC), some patients do not respond and other patients with initially good response develop resistance to this treatment. In this study, we investigated molecular imaging and biochemical responses after a single cycle of [225Ac]Ac-PSMA-617/[177Lu]Lu-PSMA-617 tandem therapy in patients who had progressed on [177Lu]Lu-PSMA-617 monotherapy. Methods: Seventeen patients with mCRPC were included in a retrospective, monocenter study. Molecular imaging-based response was assessed by modified PERCIST criteria using the whole-body total lesion PSMA (TLP) and molecular tumour volume (MTV) derived from [68Ga]Ga-PSMA-11 PET/CT. Biochemical response was evaluated according to PCWG3 criteria using the prostate-specific antigen (PSA) serum value. Concordance and correlation statistics as well as survival analyses were performed. Results: Based on the molecular imaging-based response assessment, 5 (29.4%) patients showed partial remission and 7 (41.2%) had stable disease. The remaining 5 (29.4%) patients had further progression, four with an increase in TLP/MTV of >30% and one with stable TLP/MTV but appearance of new metastases. Based on the biochemical response assessment, 5 (29.4%), 8 (47.1%), and 4 (23.5%) patients showed partial remission, stable disease, and progressive disease, respectively. A comparison of the response assessment methods showed a concordance of 100% (17/17) between TLP and MTV and 70.6% (12/17) between TLP/MTV and PSA. Patients with partial remission, independently assessed by each method, had better overall survival (OS) than patients with either stable or progressive disease. The difference in OS was statistically significant for the molecular imaging response assessment (median OS not reached vs. 8.3 m, p = 0.044), but not for the biochemical response assessment (median OS 18.1 m vs. 9.4 m, p = 0.468). Conclusion: Based on both assessment methods, [225Ac]Ac-PSMA-617/[177Lu]Lu-PSMA-617 tandem therapy is an effective treatment for the highly challenging cohort of patients with mCRPC who have progressed on [177Lu]Lu-PSMA-617 monotherapy. Molecular imaging response and biochemical PSA response were mostly concordant, though a considerable number of cases (29.4%) were discordant. Molecular imaging response reflecting the change in total viable tumour burden appears to be superior to PSA change in estimating survival outcome after tandem therapy

Addition of Standard Enzalutamide Medication Shows Synergistic Effects on Response to [177Lu]Lu-PSMA-617 Radioligand Therapy in mCRPC Patients with Imminent Treatment Failure—Preliminary Evidence of Pilot Experience

Well-received strong efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) does not prevent patients from either early or eventual disease progression under this treatment. In this study, we investigated co-medication with enzalutamide as a potential re-sensitizer for PSMA-RLT in patients with imminent treatment failure on standard 177Lu-based PSMA-RLT. Ten mCRPC patients who exhibited an insufficient response to conventional [177Lu]Lu PSMA-617 RLT received oral medication of enzalutamide 160 mg/d as an adjunct to continued PSMA RLT. Prostate-specific antigen (PSA) and standard toxicity screening lab work-up were performed to assess the treatment efficacy and safety in these individuals. The mean PSA increase under PSMA-RLT before starting the re-sensitizing procedure was 22.4 ± 26.5%. After the introduction of enzalutamide medication, all patients experienced a PSA decrease, –43.4 ± 20.0% and –48.2 ± 39.0%, after one and two cycles of enzalutamide-augmented PSMA-RLT, respectively. A total of 70% of patients (7/10) experienced partial remission, with a median best PSA response of –62%. Moreover, 5/6 enzalutamide-naïve patients and 2/4 patients who had previously failed enzalutamide exhibited a partial remission. There was no relevant enzalutamide-induced toxicity observed in this small cohort. This pilot experience suggests the synergistic potential of adding enzalutamide to PSMA-RLT derived from the intra-individual comparison of 177Lu-based PSMA-RLT ± enzalutamide

Renal Safety of [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Compromised Baseline Kidney Function

Background: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is an effective antitumor-treatment in metastatic castration-resistant prostate carcinoma (mCRPC). Concerns of potential nephrotoxicity are based on renal tubular PSMA expression and the resulting radiopharmaceutical retention during RLT, but data confirming clinically significant renal toxicity are still lacking. In this study, patients with significantly impaired baseline kidney function before initiation of therapy were investigated for treatment-associated nephrotoxicity and the potential relationship with administered activities of [177Lu]Lu-PSMA-617. Methods: Twenty-two mCRPC patients with impaired renal function (glomerular filtration rate (GFR) ≤ 60 mL/min) who received more than two cycles of [177Lu]Lu-PSMA-617 RLT (median 5 cycles and median 6-week time interval between consecutive cycles) were analyzed in this study. Patients were treated within a prospective patient registry (REALITY Study, NCT04833517). Cumulative administered activities ranged from 17.1 to 85.6 GBq with a median activity of 6.5 GBq per cycle. Renal function was closely monitored during and after PSMA-RLT. Results: Mean pre-treatment GFR was 45.0 ± 10.7 mL/min. After two (22/22 patients), four (20/22 patients), and six cycles (10/22 patients) of RLT, a significant increase of GFR was noted (each p < 0.05). End-of-treatment GFR (54.1 ± 16.7 mL/min) was significantly higher than baseline GFR (p = 0.016). Only one patient experienced deterioration of renal function (change of CTCAE grade 2 to 3). The remaining patients showed no significant reduction of GFR, including follow-up assessments (6, 9, and 12 months), and even showed improved (10/22 patients) or unchanged (11/22 patients) CTCAE-based renal impairment grades during and after the end of PSMA-RLT. No significant correlation between the change in GFR and per-cycle (p = 0.605) or cumulative (p = 0.132) administered activities were found. Conclusions: As pre-treatment chronic kidney failure did not lead to detectable RLT-induced deterioration of renal function in our study, the nephrotoxic potential of [177Lu]Lu-PSMA-617 RLT may be overestimated and not of clinical priority in the setting of palliative treatment in mCRPC. We suggest not to categorically exclude patients from enrolment to PSMA-RLT due to renal impairment

Response Assessment and Prediction of Progression-Free Survival by 68Ga-PSMA-11 PET/CT Based on Tumor-to-Liver Ratio (TLR) in Patients with mCRPC Undergoing 177Lu-PSMA-617 Radioligand Therapy

At present, little is known about the molecular imaging-based response assessment of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with 177Lutetium (177LuPSMA-617 RLT) in metastatic castration-resistant prostate cancer (mCRPC). Our study evaluated the response to RLT using both molecular imaging and biochemical response assessments, and their potential prediction of progression-free survival (PFS). Fifty-one consecutive patients given two cycles of RLT at 6-week intervals were analyzed retrospectively. 68Ga-PSMA-11 PET/CT was obtained about 2 weeks prior to the first and 4–6 weeks after the second cycle. Molecular imaging-based response using SUVpeak and tumor-to-liver ratio (TLR) was determined by modified PERCIST criteria. ∆TLR and ∆SUV were significantly correlated with ∆PSA (p < 0.001, each). After a median follow-up of 49 months, the median PFS (95% CI) was 8.0 (5.9–10.1) months. In univariate analysis, responders showing partial remission (PRPSA and PRTLR) had significantly (p < 0.001, each) longer PFS (median: 10.5 and 9.3 months) than non-responders showing either stable or progressive disease (median: 4.0 and 3.5 months). Response assessment using SUVpeak failed to predict survival. In multivariable analysis, response assessment using TLR was independently associated with PFS (p < 0.001), as was good performance status (p = 0.002). Molecular imaging-based response assessment with 68Ga-PSMA11 PET/CT using normalization of the total lesion PSMA over healthy liver tissue uptake (TLR) could be an appropriate biomarker to monitor RLT in mCRPC patients and to predict progression-free survival (PFS) of this treatment modalit

A Structure-Activity Relationship Study of Bimodal BODIPY-Labeled PSMA-Targeting Bioconjugates

The aim of this study was to identify a high-affinity BODIPY peptidomimetic that targets the prostate-specific membrane antigen (PSMA) as a potential bimodal imaging probe for prostate cancer. For the structure-activity study, several BODIPY (difluoroboron dipyrromethene) derivatives with varying spacers between the BODIPY dye and the PSMA Glu-CO-Lys binding motif were prepared. Corresponding affinities were determined by competitive binding assays in PSMA-positive LNCaP cells. One compound was identified with comparable affinity (IC50=21.5±0.1 nM) to Glu-CO-Lys-Ahx-HBED-CC (PSMA-11) (IC50=18.4±0.2 nM). Radiolabeling was achieved by Lewis-acid-mediated 19F/18F exchange in moderate molar activities (∼0.7 MBq nmol−1) and high radiochemical purities (>99 %) with mean radiochemical yields of 20–30 %. Cell internalization of the 18F-labeled high-affinity conjugate was demonstrated in LNCaP cells showing gradual increasing PSMA-mediated internalization over time. By fluorescence microscopy, localization of the high-affinity BODIPY-PSMA conjugate was found in the cell membrane at early time points and also in subcellular compartments at later time points. In summary, a high-affinity BODIPY-PSMA conjugate has been identified as a suitable candidate for the development of PSMA-specific dual-imaging agents

Proof-of-Concept Study of the NOTI Chelating Platform: Preclinical Evaluation of 64Cu-Labeled Mono- and Trimeric c(RGDfK) Conjugates

Purpose We recently developed a chelating platform based on the macrocycle 1,4,7-triazacyclononane with up to three five-membered azaheterocyclic arms for the preparation of 68Ga- and 64Cu-based radiopharmaceuticals. Based on this platform, the chelator scaffold NOTI-TVA with three additional carboxylic acid groups for bioconjugation was synthesized and characterized. The primary aims of this proof-of-concept study were (1) to evaluate if trimeric radiotracers on the basis of the NOTI-TVA 6 scaffold can be developed, (2) to determine if the additional substituents for bioconjugation at the non-coordinating NH atoms of the imidazole residues of the building block NOTI influence the metal binding properties, and (3) what influence multiple targeting vectors have on the biological performance of the radiotracer. The cyclic RGDfK peptide that specifically binds to the αvß3 integrin receptor was selected as the biological model system. Procedures Two different synthetic routes for the preparation of NOTI-TVA 6 were explored. Three c(RGDfK) peptide residues were conjugated to the NOTI-TVA 6 building block by standard peptide chemistry providing the trimeric bioconjugate NOTI-TVA-c(RGDfK)3 9. Labeling of 9 with [64Cu]CuCl2 was performed manually at pH 8.2 at ambient temperature. Binding affinities of Cu-8, the Cu2+ complex of the previously described monomer NODIA-Me-c(RGDfK) 8, and the trimer Cu-9 to integrin αvß3 were determined in competitive cell binding experiments in the U-87MG cell line. The pharmacokinetics of both 64Cu-labeled conjugates [64Cu]Cu-8 and [64Cu]Cu-9 were determined by small-animal PET imaging and ex vivo biodistribution studies in mice bearing U-87MG xenografts. Results Depending on the synthetic route, NOTI-TVA 6 was obtained with an overall yield up to 58 %. The bioconjugate 9 was prepared in 41 % yield. Both conjugates [64Cu]Cu-8 and [64Cu]Cu-9 were radiolabeled quantitatively at ambient temperature in high molar activities of Am ~ 20 MBq nmol−1 in less than 5 min. Competitive inhibitory constants IC50 of c(RDGfK) 7, Cu-8, and Cu-9 were determined to be 159.5 ± 1.3 nM, 256.1 ± 2.1 nM, and 99.5 ± 1.1 nM, respectively. In small-animal experiments, both radiotracers specifically delineated αvß3 integrin-positive U-87MG tumors with low uptake in non-target organs and rapid blood clearance. The trimer [64Cu]Cu-9 showed a ~ 2.5-fold higher tumor uptake compared with the monomer [64Cu]Cu-8. Conclusions Functionalization of NOTI at the non-coordinating NH atoms of the imidazole residues for bioconjugation was straightforward and allowed the preparation of a homotrimeric RGD conjugate. After optimization of the synthesis, required building blocks to make NOTI-TVA 6 are now available on multi-gram scale. Modifications at the imidazole groups had no measurable impact on metal binding properties in vitro and in vivo suggesting that the NOTI scaffold is a promising candidate for the development of 64Cu-labeled multimeric/multifunctional radiotracers

Efficacy and Safety of [225Ac]Ac-PSMA-617 Augmented [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Highly Advanced mCRPC with Poor Prognosis

The use of 225Ac in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), either as monotherapy or in combination with 177Lu, is a promising therapy approach in patients with metastatic castration-resistant prostate carcinoma (mCRPC). In this study, we report the efficacy and safety of [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT in 177Lu-naive mCRPC patients (n = 15) with poor prognosis (presence of visceral metastases, high total tumor burden with diffuse bone metastases or a short PSA doubling time of <2 months). Biochemical (by PSA serum value) and molecular imaging response (by [68Ga]Ga-PSMA-11 PET/CT) was assessed after two cycles of [177Lu]Lu-PSMA-617 RLT, with at least one [225Ac]Ac-PSMA-617 augmentation. In addition, PSA-based progression-free survival (PSA-PFS), overall survival (OS) and toxicity (according to CTCAE) were analyzed. We observed a biochemical- and molecular imaging-based partial remission in 53.3% (8/15) and 66.7% (10/15) of patients, respectively. The median PSA-PFS and OS was 9.1 and 14.8 months, respectively. No serious acute adverse events were recorded. Two out of fifteen patients experienced grade 3 anemia. No other grade 3/4 toxicities were observed. RLT-related xerostomia (grade 1/2) was recorded in 2/15 patients. Our data showed a high clinical efficacy with a favorable side effects profile of [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT in this highly challenging patient cohort

177 Lu-PSMA-617 radioligand therapy of metastatic castration-resistant prostate cancer: Initial 254-patient results from a prospective registry (REALITY Study)

Purpose Preliminary data from retrospective analyses and recent data from large randomized controlled trials suggest safety and efcacy of radioligand therapy (RLT) targeting prostate-specifc membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC). Limited data on this modality have been published regarding large samples treated in everyday practice. Methods We analyzed prospectively collected registry data regarding lutetium-177 (177Lu)-PSMA-617 RLT of 254 consecu tive men with mCRPC seen in everyday academic practice. Since 177Lu-PSMA-617 was experimental salvage treatment following failure of individually appropriate conventional therapies, patients were generally elderly and heavily pretreated (median age 70 years; prior taxanes 74.0%, 188/254), with late–end-stage disease (visceral metastasis in 32.7%, 83/254). Primary endpoints were response to RLT, defned by changes from baseline serum prostate-specifc antigen (PSA) concen tration, PSA progression-free survival (PSA-PFS), and overall survival (OS), estimated with Kaplan–Meier statistics, and caregiver-reported and patient-reported safety. Unless noted, median (minimum–maximum) values are given. Results Patients received 3 (1–13) 177Lu-PSMA-617 activities (6.5 [2.5–11.6] GBq/cycle) every 5.7 (3.0–11.0) weeks. Best response was≥50% PSA reduction in 52.0% of patients (132/254). PSA-PFS was 5.5 (95% confdence interval [95%CI] 4.4–6.6) months and OS, 14.5 (95%CI 11.5–17.5) months. In multivariable Cox proportional-hazards modeling, response to the initial≤2 RLT administrations was the strongest signifcant prognosticator related to OS (hazard ratio 3.7 [95%CI 2.5–5.5], p<0.001). No RLT-related deaths or treatment discontinuations occurred; the most frequent RLT-related Grade 3/4 adverse events were anemia (18/254 patients, 7.1%), thrombocytopenia (11/254, 4.3%), and lymphopenia (7/254, 2.8%). RLT-related xerostomia, all grade 1/2, was noted in 53/254 (20.9%). Conclusions In a large, prospectively observed “real-world” cohort with late-stage/end-stage mCRPC and conventional treatment failure, 177Lu-PSMA-617 RLT was efective, safe, and well-tolerated. Early biochemical disease control by such therapy was associated with better OS. Prospective study earlier in the disease course may be warranted