Biomarkers of bone metabolism in [223Ra] RaCl2 therapy - association with extent of disease and prediction of overall survival.

BACKGROUND: The alpha-emitting radionuclide therapy [223Ra]RaCl2 (Radium-223) improves overall survival (OS) and time to symptomatic skeletal event (SSE) in patients with metastatic castration-resistant prostate cancer (mCRPC). Evidence suggests that the effect of Radium-223 is partly exerted through an impact on the surrounding bone matrix. We hypothesized that bone metabolism markers (BMM) could provide predictive information regarding response to Radium-223. Accordingly, the aim of this study was to investigate changes in BMM during Radium-223 therapy and evaluate association with clinical outcome. METHODS: Prospective study of BMM in patients with mCRPC receiving Radium-223. Blood samples were collected before each administration of Radium-223 and the following BMM were quantified; bone-specific alkaline phosphatase (BALP), osteocalcin, procollagen type I N-propeptide (PINP), C-terminal telopeptide of type I collagen (CTX), C-terminal cross-linking telopeptide of type I collagen generated by matrix metalloproteinases (CTX-MMP), tartrate-resistant acid phosphatase isoform 5b (TRACP5b), receptor-activated nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and sclerostin. Clinical outcomes were scintigraphic progression during/after therapy, change in bone scan index (BSI), occurrence of SSE, and OS. RESULTS: A total of 55 mCRPC patients were included. There was a significant linear association between skeletal extent of disease and CTX-MMP, PINP, BALP, and osteocalcin. No significant association between dynamics in BSI and BMM were detected. Median OS for the cohort was 14 months (95% CI: 10.7-16.8). Baseline levels of Log2-CTX-MMP (HR = 2.15 (95%CI: 1.1-4.1)) and Log2-BALP (HR = 1.59 (95%CI: 1.1-2.1)) were associated with OS. Patients with increasing CTX-MMP during therapy had significantly shorter OS (Median OS = 4 mo. (95%CI: 2.3-5.7)) than patients with stable or decreasing CTX-MMP (Median OS = 12 mo. (95%CI: 10.1-13.9), P < 0.001). CONCLUSION: BMM are significantly associated with scintigraphic extent of skeletal disease and OS in patients with mCRPC. Particularly, the bone resorption marker CTX-MMP is a promising surrogate marker for prediction of outcome in patients receiving Radium-223 therapy and could potentially improve selection of patients for therapy and assessment of response. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03247010. Registered 10th of August 2017, https://clinicaltrials.gov/study/NCT03247010?term=NCT03247010&rank=1 .

Phase II study of uPAR-PET/CT for staging of primary breast cancer in comparison with ultrasound and fine needle biopsies.

Accurate initial staging of patients with breast cancer is essential for planning optimal treatment strategies. However, currently, no imaging modality is able to detect lymph node metastases preoperatively with sufficient reliability; therefore, the N status depends on the sentinel node procedure for ~ 70% of patients. In a prospective clinical trial of breast cancer patients, we compared head-to-head uPAR-PET/CT with current standard-of-care, ultrasound (US) and fine needle biopsy (FNB) as staging methods. Forty-nine patients (48 women and 1 man) with biopsy-proven early breast cancer underwent uPAR-PET/CT prior to surgery. All image data were analyzed by two separate teams, each consisting of a highly experienced certified specialist in nuclear medicine and a highly experienced certified specialist in radiology for visualization of primary tumor lesions and detection of lymph node and distant metastases. Histopathological assessment and verification of malignancy in the excised tissues (primary tumors and lymph nodes) were considered standard-of-truth. On a per patient basis, uPAR PET/CT demonstrated a sensitivity of 94% [CI: 83-99%] for detecting the primary tumor (both teams). For the detection of axillary lymph nodes the pooled sensitivity of uPAR PET/CT was 33.3% [CI: 16.5-54.0%], specificity 87.0% [CI: 66.4-97.2%] and accuracy 58.0% [CI: 43.2-71.8%]. In comparison, the standard-of-care preoperative clinical staging algorithm with US and FNB had a sensitivity of 41% [CI: 22-61%] and specificity of 100% [CI: 85-100%] for axillary lymph node metastases. We conclude that the results do not support the use of uPAR PET/CT for staging in breast cancer patients. However, the finding that 94% of primary tumors were uPAR-PET positive may be encouraging for pursuing uPAR theranostics in localized disease. Additionally, other potential applications, such as using uPAR-PET as a prognostic imaging biomarker of tumor aggressiveness, remain to be investigated.

Routine Use of [64Cu]Cu-DOTATATE PET/CT in a Neuroendocrine Tumor Center: Referral Patterns and Image Results of 2,249 Consecutive Scans.

The role of somatostatin receptor (SSTR) PET/CT, using 68Ga-based tracers or [64Cu]Cu-DOTATATE (64Cu-DOTATATE), in the management of patients with neuroendocrine neoplasm (NEN) is guided by appropriate use criteria (AUC). In this study, we performed systematic analyses of referral patterns and image findings of routine 64Cu-DOTATATE PET/CT scans to support AUC development. Methods: We included all clinical routine 64Cu-DOTATATE PET/CT scans performed between April 10, 2018 (start of clinical use), and May 2, 2022, at Copenhagen University Hospital-Rigshospitalet. We reviewed the referral text and image report of each scan and classified the indication according to clinical scenarios as listed in the AUC. Results: In total, 1,290 patients underwent 2,249 64Cu-DOTATATE PET/CT scans. Monitoring of patients with NEN seen both on conventional imaging and on SSTR PET without clinical evidence of progression was the most common indication (defined as "may be appropriate" in the AUC) and accounted for 703 (31.3%) scans. Initial staging after NEN diagnosis ("appropriate" in the AUC) and restaging after curative-intent surgery ("may be appropriate" in the AUC) accounted for 221 (9.8%) and 241 (10.7%) scans, respectively. Selection of patients eligible for peptide receptor radionuclide therapy ("appropriate" in the AUC) and restaging after peptide receptor radionuclide therapy completion ("appropriate" in the AUC) accounted for 95 (4.2%) and 115 (5.1%) scans, respectively. The number of scans performed for indications not defined in the AUC was 371 (16.5%). Image result analysis revealed no disease in 669 scans (29.7%), stable disease in 582 (25.9%), and progression in 461 (20.5%). In 99 of the 461 (21.5%) scans, progression was detected on PET but not on CT. Conclusion: Our study provided real-life data that may contribute to support development of 64Cu-DOTATATE/SSTR PET/CT guidelines including AUC. Some scenarios listed as "may be appropriate" in the current AUC were frequent in our data. Monitoring of patients with NEN without clinical evidence of progression was the most frequent indication for 64Cu-DOTATATE PET/CT, in which disease progression was detected in more than one third, and a large proportion was visible by PET only. We therefore conclude that this scenario could potentially be classified as appropriate.

Prospective phase II trial of [68Ga]Ga-NOTA-AE105 uPAR-PET/MRI in patients with primary gliomas: Prognostic value and Implications for uPAR-targeted Radionuclide Therapy.

BACKGROUND: Treatment of patients with low-grade and high-grade gliomas is highly variable due to the large difference in survival expectancy. New non-invasive tools are needed for risk stratification prior to treatment. The urokinase plasminogen activator receptor (uPAR) is expressed in several cancers, associated with poor prognosis and may be non-invasively imaged using uPAR-PET. We aimed to investigate the uptake of the uPAR-PET tracer [68Ga]Ga-NOTA-AE105 in primary gliomas and establish its prognostic value regarding overall survival (OS), and progression-free survival (PFS). Additionally, we analyzed the proportion of uPAR-PET positive tumors to estimate the potential number of candidates for future uPAR-PRRT. METHODS: In a prospective phase II clinical trial, 24 patients suspected of primary glioma underwent a dynamic 60-min PET/MRI following the administration of approximately 200 MBq (range: 83-222 MBq) [68Ga]Ga-NOTA-AE105. Lesions were considered uPAR positive if the tumor-to-background ratio, calculated as the ratio of TumorSUVmax-to-Normal-BrainSUVmean tumor-SUVmax-to-background-SUVmean, was ≥ 2.0. The patients were followed over time to assess OS and PFS and stratified into high and low uPAR expression groups based on TumorSUVmax. RESULTS: Of the 24 patients, 16 (67%) were diagnosed with WHO grade 4 gliomas, 6 (25%) with grade 3, and 2 (8%) with grade 2. Two-thirds of all patients (67%) presented with uPAR positive lesions and 94% grade 4 gliomas. At median follow up of 18.8 (2.1-45.6) months, 19 patients had disease progression and 14 had died. uPAR expression dichotomized into high and low, revealed significant worse prognosis for the high uPAR group for OS and PFS with HR of 14.3 (95% CI, 1.8-112.3; P = 0.011), and HR of 26.5 (95% CI, 3.3-214.0; P = 0.0021), respectively. uPAR expression as a continuous variable was associated with worse prognosis for OS and PFS with HR of 2.7 (95% CI, 1.5-4.8; P = 0.0012), and HR of 2.5 (95% CI, 1.5-4.2; P = 0.00073), respectively. CONCLUSIONS: The majority of glioma patients and almost all with grade 4 gliomas displayed uPAR positive lesions underlining the feasibility of 68Ga-NOTA-AE105 PET/MRI in gliomas. High uPAR expression is significantly correlated with worse survival outcomes for patients. Additionally, the high proportion of uPAR positive gliomas underscores the potential of uPAR-targeted radionuclide therapy in these patients. TRAIL REGISTRATION: EudraCT No: 2016-002417-21; the Scientific Ethics Committee: H-16,035,303; the Danish Data Protection Agency: 2012-58-0004; clinical trials registry: NCT02945826, 26Oct2016, URL: https://classic. CLINICALTRIALS: gov/ct2/show/NCT02945826 .

Development of Polar BODIPY-Tetrazines for Rapid Pretargeted Fluorescence Imaging.

Polar BODIPY-tetrazine dyes were developed and clicked in vivo to a preaccumulated trans-cyclooctene-modified anti-TAG72 monoclonal antibody CC49 (CC49-TCO). The in vivo click performance was evaluated using an in-house developed ex vivo blocking assay. All tested polar BODIPY structures exhibited excellent in vivo binding, confirming that the turn-on tetrazine dyes successfully clicked in vivo to pretargeted CC49-TCO. Fluorescence imaging showed high tumor-to-muscle ratios of 4:1. This proof-of-concept study indicates that the pretargeting concept based on turn-on probes could be used for cancer treatments, such as photodynamic or -thermal therapy.

Detection of infective endocarditis with [64Cu]Cu-DOTATATE positron emission tomography/computed tomography: a case series.

Background: Infective endocarditis (IE) is a serious and fatal condition, with prosthetic valve endocarditis representing the worst prognosis. The recommended nuclear imaging modality 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) has limitations. In this case series, we present two patients with IE scanned with a novel PET tracer [64Cu]Cu-DOTATATE ([64Cu]Cu-[1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetra acetic acid]-d-Phe1, Tyr3-octreotate). Case summary: An 84-year-old female patient (Patient 1) with a biological mitral valve prosthesis (MVP) was admitted acutely from the outpatient clinic. Transoesophageal echocardiography showed vegetations on the MVP. The patient underwent [64Cu]Cu-DOTATATE PET/CT, which showed uptake at the site of infection. The patient underwent surgical valve replacement. The post-operative period was without significant complications, and the patient was discharged home. In another case, a 72-year-old male patient (Patient 2) with a medical history of mild mitral valve stenosis, aortic valve stenosis, and gastrointestinal stromal tumour was admitted to the hospital for back and abdominal pain and subfebrile episodes. Transoesophageal echocardiography showed large vegetations in the native aortic valve. The patient underwent [64Cu]Cu-DOTATATE PET/CT, which showed no uptake at the site of the suspected infection. The patient underwent surgical valve replacement. The post-operative period was characterized by Candida albicans sternitis, and after prolonged hospitalization, the patient died of respiratory failure as a complication of sepsis. Discussion: In conclusion, this is the first case series presenting two patients with definite IE (modified Duke criteria), who were scanned with the novel [64Cu]Cu-DOTATATE PET/CT. Patient 1, with endocarditis in the MVP, showed an uptake of the tracer, while Patient 2, with native aortic valve endocarditis, did not show any uptake.

3D whole body preclinical micro-CT database of subcutaneous tumors in mice with annotations from 3 annotators.

A pivotal animal model for development of anticancer molecules is mice with subcutaneous tumors, grown by injection of xenografted tumor cells, where micro-Computed Tomography (µCT) of the mice is used to analyze the efficacy of the anticancer molecule. Manual delineation of the tumor region is necessary for the analysis, which is time-consuming and inconsistent, highlighting the need for automatic segmentation (AS) tools. This study introduces a preclinical µCT database, comprising 452 whole-body scans from 223 individual mice with subcutaneous tumors, spanning ten diverse µCT datasets conducted between 2014 and 2020 on a preclinical PET/CT scanner, making it the hitherto largest dataset of its kind. Each tumor is annotated manually by three expert annotators, allowing for robust model development. Inter-annotator agreement was analyzed, and we report an overall annotation agreement of 0.903 ± 0.046 (mean ± std) Fleiss' Kappa and a mean deviation in volume estimation of 0.015 ± 0.010 cm3 (6.9% ± 4.7), which establishes a human baseline accuracy for delineation of subcutaneous tumors, while showing good inter-annotator agreement.

An in situ depot for the sustained release of a TLR7/8 agonist in combination with a TGFß inhibitor promotes anti-tumor immune responses.

Cancer curing immune responses against heterogeneous solid cancers require that a coordinated immune activation is initiated in the antigen avid but immunosuppressive tumor microenvironment (TME). The plastic TME, and the poor systemic tolerability of immune activating drugs are, however, fundamental barriers to generating curative anticancer immune responses. Here, we introduce the CarboCell technology to overcome these barriers by forming an intratumoral sustained drug release depot that provides high payloads of immune stimulatory drugs selectively within the TME. The CarboCell thereby induces a hot spot for immune cell training and polarization and further drives and maintains the tumor-draining lymph nodes in an anticancer and immune activated state. Mechanistically, this transforms cancerous tissues, consequently generating systemic anticancer immunoreactivity. CarboCell can be injected through standard thin-needle technologies and has inherent imaging contrast which secure accurate intratumoral positioning. In particular, here we report the therapeutic performance for a dual-drug CarboCell providing sustained release of a Toll-like receptor 7/8 agonist and a transforming growth factor-ß inhibitor in preclinical tumor models in female mice.

[68Ga]Ga-DOTAGA-Glu(FAPi)2 Shows Enhanced Tumor Uptake and Theranostic Potential in Preclinical PET Imaging.

The use of fibroblast activation protein inhibitors (FAPis) for positron emission tomography (PET) imaging in cancer has garnered significant interest in recent years, yielding promising results in preclinical and clinical settings. FAP is predominantly expressed in pathological conditions such as fibrosis and cancer, making it a compelling target. An optimized approach involves using FAPi homodimers as PET tracers, which enhance tumor uptake and retention, making them more effective candidates for therapy. Here, a UAMC-1110 inhibitor-based homodimer, DOTAGA-Glu(FAPi)2, was synthesized and radiolabeled with gallium-68, and its efficacy was evaluated in vivo for PET imaging in an endogenously FAP-expressing xenografted mouse model, U87MG. Notably, 45 min post-injection, the mean uptake of [68Ga]Ga-DOTAGA-Glu(FAPi)2 was 4.7 ± 0.5% ID/g in the tumor with low off-target accumulation. The ex vivo analysis of the FAP expression in the tumors confirmed the in vivo results. These findings highlight and confirm the tracer's potential for diagnostic imaging of cancer and as a theranostic companion.

European Neuroendocrine Tumor Society (ENETS) 2024 guidance paper for the management of well-differentiated small intestine neuroendocrine tumours.

Both the incidence and prevalence of well-differentiated neuroendocrine tumours from the small intestine (Si-NET) are gradually increasing. Most patients have non-functioning tumours with subtle GI symptoms and tumours are often discovered incidentally by endoscopy or at advanced disease stages by imaging depicting mesenteric lymph node and /or liver metastases while around 30% of the patients present with symptoms of the carcinoid syndrome. Adequate biochemical assessment and staging including functional imaging is crucial for treatment-related decision-making that should take place in an expert multidisciplinary team setting. Preferably, patients should be referred to specialised ENETS Centres of Excellence or centres of high expertise in the field. This guidance paper provides the current evidence and best knowledge for the management of Si-NET grade (G) 1-3 following 10 key questions of practical relevance for the diagnostic and therapeutic decision making.

Development of Peptide-Based Probes for Molecular Imaging of the Postsynaptic Density in the Brain.

The postsynaptic density (PSD) comprises numerous scaffolding proteins, receptors, and signaling molecules that coordinate synaptic transmission in the brain. Postsynaptic density protein 95 (PSD-95) is a master scaffold protein within the PSD and one of its most abundant proteins and therefore constitutes a very attractive biomarker of PSD function and its pathological changes. Here, we exploit a high-affinity inhibitor of PSD-95, AVLX-144, as a template for developing probes for molecular imaging of the PSD. AVLX-144-based probes were labeled with the radioisotopes fluorine-18 and tritium, as well as a fluorescent tag. Tracer binding showed saturable, displaceable, and uneven distribution in rat brain slices, proving effective in quantitative autoradiography and cell imaging studies. Notably, we observed diminished tracer binding in human post-mortem Parkinson's disease (PD) brain slices, suggesting postsynaptic impairment in PD. We thus offer a suite of translational probes for visualizing and understanding PSD-related pathologies.

HER2-targeted, enzyme-activated liposomes show superior in vivo efficacy in an ovarian cancer model.

Liposomes carrying chemotherapeutic drugs can accumulate passively in solid tumors at high levels. However, additional targeting of the liposomes towards e.g. receptors expressed on cancer cells may improve their interaction and therapeutic properties. In this study, we designed a liposomal delivery system, which utilizes the intrinsic characteristics of HER2-positive tumors to ensure efficient delivery of oxaliplatin to the cancer cells. On the liposome surface, trastuzumab, an antibody specific to the HER2 receptor, was shown to facilitate internalization by the cancer cells. A polyethylene glycol (PEG) layer on the liposome surface provides protection from mononuclear phagocyte system uptake. To optimize the interaction between liposomes and cancer cells, a protease-sensitive cleavable peptide linker was inserted at the base of each PEG. The PEG layer is then cleaved off by intra- and extracellular matrix metalloproteinases (MMPs) upon accumulation in the tumor. Our data demonstrate that the removal of PEG significantly destabilizes the liposomes and leads to substantial oxaliplatin release. The proposed beneficial effect of combining antibody-mediated internalization with MMP sensitivity was confirmed in a series of in vivo studies using ovarian cancer xenograft models. The results demonstrated that HER2-targeted MMP-sensitive liposomes have superior anticancer activity compared to non-targeted and non-cleavable liposomes.

Impressive Response to TANDEM Peptide Receptor Radionuclide Therapy with 177Lu/225AcDOTA-LM3 Somatostatin Receptor Antagonist in a Patient with Therapy-Refractory, Rapidly Progressive Neuroendocrine Neoplasm of the Pancreas.

The present report describes the history of a 58-year-old woman with a rapidly progressing neuroendocrine pancreatic tumor (initially G2) presenting with extensive liver, bone, and lymph node metastases. Previous treatments included chemotherapy, hemithyroidectomy for right lobe metastasis, Peptide Receptor Radionuclide Therapy (PRRT) with [177Lu]Lu-DOTATATE, Lanreotide, Everolimus, and liver embolization. Due to severe disease progression, after a liver biopsy revealing tumor grade G3, PRRT with the somatostatin receptor antagonist LM3 was initiated. [68Ga]GaDOTA-LM3 PET/CT showed intense tracer uptake in the liver, pancreatic tumor, lymph nodes, and bone metastases. Three TANDEM-PRRT cycles using [177Lu]LuDOTA-LM3 and [225Ac]AcDOTA-LM3, administered concurrently, resulted in significant improvement, notably in liver metastases, hepatomegaly reduction, the complete regression of bone and lymph node metastases, and primary tumor improvement. Partial remission was confirmed by positron emission tomography/computed tomography, chest-abdomen-pelvis contrast-enhanced computed tomography, and magnetic resonance of the abdomen, with marked clinical improvement in pain, energy levels, and quality of life, enabling full resumption of physical activity.

Effects of Peptide Receptor Radiotherapy in Patients with Advanced Paraganglioma and Pheochromocytoma: A Nation-Wide Cohort Study.

INTRODUCTION: Pheochromocytomas and paragangliomas are rare neuroendocrine tumours that originate from chromaffin cells within the adrenal medulla or extra-adrenal sympathetic ganglia. Management of disseminated or metastatic pheochromocytomas and paragangliomas continues to pose challenges and relies on limited evidence. METHOD: In this study, we report retrospective data on median overall survival (OS) and median progression-free survival (PFS) for all Danish patients treated with peptide receptor radionuclide therapy (PRRT) with 177Lu-Dotatate or 90Y-Dotatate over the past 15 years. One standard treatment of PRRT consisted of 4 consecutive cycles with 8-14-week intervals. RESULTS: We included 28 patients; 10 were diagnosed with pheochromocytoma and 18 with paraganglioma. Median age at first PRRT was 47 (IQR 15-76) years. The median follow-up time was 31 (IQR 17-37) months. Eight patients died during follow-up. Median OS was 72 months, and 5-year survival was 65% with no difference between pheochromocytoma and paraganglioma. Patients with germline mutations had better survival than patients without mutations (p = 0.041). Median PFS after the first cycle of PRRT was 30 months. For patients who previously received systemic treatment, the median PFS was 19 months, compared with 32 months for patients with no previous systemic treatment (p = 0.083). CONCLUSIONS: The median OS of around 6 years and median PFS of around 2.5 years found in this study are comparable to those reported in previous studies employing PRRT. Based on historical data, the efficacy of PRRT may be superior to 131I-MIBG therapy, and targeted therapy with sunitinib and PRRT might therefore be considered as first-line treatment in this patient group.

Investigation of imaging the somatostatin receptor by opening the blood-brain barrier with melittin - A feasibility study using positron emission tomography and [64Cu]Cu-DOTATATE.

DOTATATE is a somatostatin peptide analog used in the clinic to detect somatostatin receptors which are highly expressed on neuroendocrine tumors. Somatostatin receptors are found naturally in the intestines, pancreas, lungs, and brain (mainly cortex). In vivo measurement of the somatostatin receptors in the cortex has been challenging because available tracers cannot cross the blood-brain barrier (BBB) due to their intrinsic polarity. A peptide called melittin, a main component of honeybee venom, has been shown to disrupt plasma membranes and increase the permeability of biological membranes. In this study, we assessed the feasibility of using melittin to facilitate the passage of [64Cu]Cu-DOTATATE through the BBB and its binding to somatostatin receptors in the cortex. Evaluation included in vitro autoradiography on Long Evans rat brains to estimate the binding affinity of [64Cu]Cu-DOTATATE to the somatostatin receptors in the cortex and an in vivo evaluation of [64Cu]Cu-DOTATATE binding in NMRI mice after injection of melittin. This study found an in vitro Bmax = 89 ± 4 nM and KD = 4.5 ± 0.6 nM in the cortex, resulting in a theoretical binding potential (BP) calculated as Bmax/KD ≈ 20, which is believed suitable for in vivo brain PET imaging. However, the in vivo results showed no significant difference between the control and melittin injected mice, indicating that the honeybee venom failed to open the BBB. Additional experiments, potentially involving faster injection rates are required to verify that melittin can increase brain uptake of non-BBB permeable PET tracers. Furthermore, an evaluation of whether a venom with a narrow therapeutic range can be used for clinical purposes needs to be considered.

Poly(ADP-ribose) polymerase (PARP)-targeted PET imaging in non-oncology application: a pilot study in preclinical models of nonalcoholic steatohepatitis.

Poly(ADP-ribose) polymerase (PARP) activation often indicates a disruptive signal to lipid metabolism, the physiological alteration of which may be implicated in the development of non-alcoholic fatty liver disease. The objective of this study was to evaluate the capability of [68Ga]DOTA-PARPi PET to detect hepatic PARP expression in a non-alcoholic steatohepatitis (NASH) mouse model. In this study, male C57BL/6 mice were subjected to a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for a 12-week period to establish preclinical NASH models. [68Ga]DOTA-PARPi PET imaging of the liver was conducted at the 12-week mark after CDAHFD feeding. Comprehensive histopathological analysis, covering hepatic steatosis, inflammation, fibrosis, along with blood biochemistry, was performed in both NASH models and control groups. Despite the induction of severe inflammation, steatosis and fibrosis in the liver of mice with the CDAHFD-NASH model, PET imaging of NASH with [68Ga]-DOTA-PARPi did not reveal a significantly higher uptake in NASH models compared to the control. This underscores the necessity for further development of new chelator-based PARP1 tracers with high binding affinity to enable the visualization of PARP1 changes in NASH pathology.

Responses to Medical Treatment in 192 Patients with Pancreatic Neuroendocrine Neoplasms Referred to the Copenhagen Neuroendocrine Tumour Centre in 2000-2020.

BACKGROUND: Given the rarity and heterogeneity of pancreatic neuroendocrine neoplasms (pNEN), treatment algorithms and sequencing are primarily guided by expert opinions with limited evidence. AIM: To investigate overall survival (OS), median progression-free survival (mPFS), and prognostic factors associated with the most common medical treatments for pNEN. METHODS: Retrospective single-center study encompassing patients diagnosed and monitored between 2000 and 2020 (n = 192). RESULTS: Median OS was 36 (95% CI: 26-46) months (99 months for grade (G) 1, 62 for G2, 14 for G3, and 10 for neuroendocrine carcinomas). Patients treated with somatostatin analogues (SSA) (n = 59, median Ki-67 9%) had an mPFS of 28 months. Treatment line (HR (first line as reference) 4.1, 95% CI: 1.9-9.1, p ≤ 0.001) emerged as an independent risk factor for time to progression. Patients with a Ki-67 index ≥10% (n = 28) had an mPFS of 27 months. Patients treated with streptozocin/5-fluorouracil (STZ/5FU) (n = 70, first-line treatment n = 68, median Ki-67 10%) had an mPFS of 20 months, with WHO grade serving as an independent risk factor (HR (G1 (n = 8) vs. G2 (n = 57)) 2.8, 95% CI: 1.1-7.2, p-value = 0.031). Median PFS was 21 months for peptide receptor radionuclide therapy (PRRT) (n = 41, first line n = 2, second line n = 29, median Ki-67 8%), 5 months for carboplatin and etoposide (n = 66, first-line treatment n = 60, median Ki-67 80%), and 3 months for temozolomide-based therapy (n = 56, first-line treatment n = 17, median Ki-67 30%). CONCLUSION: (1) Overall survival was, as expected, highly dependent on grade; (2) median PFS for SSA was around 2.5 years without difference between tumors with Ki-67 above or below 10%; (3) STZ/5FU as first-line treatment exhibited a superior mPFS of 20 months compared to what has historically been reported for targeted treatments; (4) PRRT in G2 pNEN achieved an mPFS similar to first-line chemotherapy; and (5) limited treatment efficacy was observed in high-grade tumors when treated with carboplatin and etoposide or temozolomide.

Prognostic Thresholds of Mitotic Count and Ki-67 Labeling Index for Recurrence and Survival in Lung Atypical Carcinoids.

Atypical carcinoid (AC) is a rare neuroendocrine neoplasm of the lung, which exhibits a varying malignant potential. In this study, we aimed to identify the prognostic thresholds of the mitotic count and Ki-67 labeling index for recurrence and survival in AC. We retrospectively reviewed 78 patients who had been radically resected for AC and calculated said thresholds using time-dependent receiver operating characteristic curves and the Youden index. We then dichotomized the patients into groups of above or below these thresholds and estimated the cumulative incidences of the groups using the Aalen-Johansen estimator. We compared the groups using univariable and multivariable Fine-Gray subdistribution hazard models. Our findings show that more patients recurred and died from this disease if their mitotic count exceeded three and four mitoses per 2 mm2, respectively, or if their Ki-67 labeling index exceeded 14% and 11%, respectively. Both thresholds independently predicted survival (p < 0.001 and p = 0.015, respectively). These thresholds may serve as a valuable tool for clinicians and researchers in making treatment plans and predicting outcomes for patients with AC.

uPAR (PLAUR) Marks Two Intra-Tumoral Subtypes of Glioblastoma: Insights from Single-Cell RNA Sequencing.

Urokinase plasminogen activator receptor (uPAR) encoded by the PLAUR gene is known as a clinical marker for cell invasiveness in glioblastoma multiforme (GBM). It is additionally implicated in various processes, including angiogenesis and inflammation within the tumor microenvironment. However, there has not been a comprehensive study that depicts the overall functions and molecular cooperators of PLAUR with respect to intra-tumoral subtypes of GBM. Using single-cell RNA sequencing data from 37 GBM patients, we identified PLAUR as a marker gene for two distinct subtypes in GBM. One subtype is featured by inflammatory activities and the other subtype is marked by ECM remodeling processes. Using the whole-transcriptome data from single cells, we are able to uncover the molecular cooperators of PLAUR for both subtypes without presuming biological pathways. Two protein networks comprise the molecular context of PLAUR, with each of the two subtypes characterized by a different dominant network. We concluded that targeting PLAUR directly influences the mechanisms represented by these two protein networks, regardless of the subtype of the targeted cell.

Prognostic thresholds of fluorine-18 fluorodeoxyglucose-positron emission tomography mean and maximum standardized uptake values for survival and nodal involvement in lung neuroendocrine neoplasms.

OBJECTIVES: The mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax) on fluorine-18 fluorodeoxyglucose-positron emission tomography are prognostic biomarkers for survival and nodal involvement in non-small-cell lung cancer but their prognostic value in lung neuroendocrine neoplasms (NENs) remains unexplored. In this study, we aimed to examine whether they are also prognostic biomarkers for survival and nodal involvement in lung NENs. METHODS: We retrospectively studied patients with typical carcinoid, atypical carcinoid or large cell neuroendocrine carcinoma who had been radically resected at our institution between 2008 and 2020. We measured SUVmean and SUVmax on all primary tumours and lymph nodes that were clinically and/or pathologically involved. We dichotomized the patients into groups of high or low SUVmean and SUVmax of the primary tumour using time-dependent receiver operating characteristic curves and compared their overall survival using Kaplan-Meier curves and Cox models. Lastly, we predicted the patients' pathological nodal status with SUVmean and SUVmax of the lymph nodes using binomial logistic models. RESULTS: The study included 245 patients. Patients died earlier if their SUVmean of the primary tumour exceeded 3.9 [hazard ratio 1.97, 95% confidence interval (CI) 1.27-3.04, P = 0.002] or SUVmax exceeded 5.3 (hazard ratio 1.85, 95% CI 1.20-2.87, P = 0.006). Likewise, patients had a higher risk of pathological nodal involvement if their SUVmean of the lymph nodes exceeded 3.3 (odds ratio 10.00, 95% CI 2.59-51.01, P = 0.002) or SUVmax exceeded 4.2 (odds ratio 4.00, 95% CI 1.20-14.65, P = 0.028). CONCLUSIONS: The fluorine-18 fluorodeoxyglucose-positron emission tomography SUVmean and SUVmax are strong prognostic biomarkers for survival and nodal involvement in lung NENs and could be important guides for making treatment decisions.