Minimal Uptake Research Articles

Glycoprotein Receptor CEACAM5-Targeted Intraoperative Molecular Imaging Tracer in Non-Small Cell Lung Cancer

BackgroundIntraoperative molecular imaging has emerged as a potential tool in addressing challenges faced during lung cancer surgery by localizing small lesions, ensuring negative margins, and identifying synchronous cancers. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) glycoprotein has emerged as a potential target in fluorescent labeling of non-small cell lung cancer given the high antigen density in tumor cells and absence of expression in normal parenchyma. The goal of our study was to determine whether anti-CEACAM5 targeted near-infrared fluorochrome could be a suitable target in non-small cell lung cancer. MethodsThe CEACAM5 expression was evaluated in AB-12 (known negative control), HT29 (known positive control), and H460 (non-small cell lung cancer) cell lines by polymerase chain reaction. SGM-101, a CEACAM5 antibody, coupled with a BM-104 near-infrared fluorescent tracer was evaluated with dose escalation, in vitro cellular localization, and immunofluorescence microscopy. Subsequently, in vivo validation was performed in 52 athymic nude xenografts. ResultsPolymerase chain reaction analysis demonstrated 3000x relative expression of CEACAM5 in HT-29 cells compared with AB-12. The H460 cells showed 1000x relative expression compared with AB12 (P < .05). Both HT29 and H460 cells showed tracer internalization with signal to background ratio of 4.5 (SD 0.34) whereas there was minimal uptake by AB12 cells with signal to background ratio 1.1 (SD 0.1; P < .05). There was linear fluorescence increase with increasing tracer dosing in receptor expressing cell lines. In preclinical models, HT-29 and H460 cells lines produced near-infrared fluorescence with average tumor to background ratio of 3.89 (SD 0.25) irrespective of tumor size compared with no fluorescence by AB12 tumors (P < .05). The CEACAM5 expressing tumors had excellent dye uptake compared with AB12 tumors. ConclusionsCEACAM5 serves as a possible receptor for targeted intraoperative molecular imaging resections in lung cancer. This study sets a path for evaluation of CEACAM5 targets in future clinical trials.

Preclinical evaluation of FAP-2286 for fibroblast activation protein targeted radionuclide imaging and therapy

PurposeFibroblast activation protein (FAP) is a membrane-bound protease that has limited expression in normal adult tissues but is highly expressed in the tumor microenvironment of many solid cancers. FAP-2286 is a FAP-binding peptide coupled to a radionuclide chelator that is currently being investigated in patients as an imaging and therapeutic agent. The potency, selectivity, and efficacy of FAP-2286 were evaluated in preclinical studies.MethodsFAP expression analysis was performed by immunohistochemistry and autoradiography on primary human cancer specimens. FAP-2286 was assessed in biochemical and cellular assays and in in vivo imaging and efficacy studies, and was further evaluated against FAPI-46, a small molecule–based FAP-targeting agent.ResultsImmunohistochemistry confirmed elevated levels of FAP expression in multiple tumor types including pancreatic, breast, and sarcoma, which correlated with FAP binding by FAP-2286 autoradiography. FAP-2286 and its metal complexes demonstrated high affinity to FAP recombinant protein and cell surface FAP expressed on fibroblasts. Biodistribution studies in mice showed rapid and persistent uptake of 68Ga-FAP-2286, 111In-FAP-2286, and 177Lu-FAP-2286 in FAP-positive tumors, with renal clearance and minimal uptake in normal tissues. 177Lu-FAP-2286 exhibited antitumor activity in FAP-expressing HEK293 tumors and sarcoma patient-derived xenografts, with no significant weight loss. In addition, FAP-2286 maintained longer tumor retention and suppression in comparison to FAPI-46.ConclusionIn preclinical models, radiolabeled FAP-2286 demonstrated high tumor uptake and retention, as well as potent efficacy in FAP-positive tumors. These results support clinical development of 68Ga-FAP-2286 for imaging and 177Lu-FAP-2286 for therapeutic use in a broad spectrum of FAP-positive tumors.

CD133 as a Biomarker for an Autoantibody-to-ImmunoPET Paradigm for the Early Detection of Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor for which there are no screening methods sensitive enough to facilitate early, effective intervention. We propose targeting the neuroendocrine tumor neoantigen CD133 via antibody-based early detection and PET (immunoPET) to facilitate earlier and more accurate detection of SCLC. Methods: RNA sequencing datasets, immunohistochemistry, flow cytometry, and Western blots were used to quantify CD133 expression in healthy and SCLC patients. CD133 was imaged invivo using near-infrared fluorescence (NIRF) immunoimaging, and 89Zr immunoPET. Anti(α)-CD133 autoantibody levels were measured in SCLC patient plasma using antibody microarrays. Results: Across 6 publicly available datasets, CD133 messenger RNA was found to be higher in SCLC tumors than in other tissues, including healthy or normal adjacent lung and non-SCLC samples. Critically, the upregulation of CD133 messenger RNA in SCLC was associated with a significant increase (hazard ratio, 2.62) in death. CD133 protein was expressed in primary human SCLC, in SCLC patient-derived xenografts, and in both SCLC cell lines tested (H82 and H69). Using an H82 xenograft mouse model, we first imaged CD133 expression with NIRF. Both invivo and ex vivo NIRF clearly showed that a fluorophore-tagged αCD133 homed to lung tumors. Next, we validated the noninvasive visualization of subcutaneous and orthotopic H82 xenografts via immunoPET. An αCD133 antibody labeled with the positron-emitting radiometal 89Zr demonstrated significant accumulation in tumor tissue while producing minimal uptake in healthy organs. Finally, plasma αCD133 autoantibodies were found in subjects from cohort studies up to 1 year before SCLC diagnosis. Conclusion: In light of these findings, we conclude that the presence of αCD133 autoantibodies in a blood sample followed by CD133-targeted 89Zr-immunoPET could be an effective early detection screening strategy for SCLC.

Evaluation of 134Ce as a PET imaging surrogate for antibody drug conjugates incorporating 225Ac

IntroductionThe in vivo generator 134Ce/134La has the potential to serve as a PET imaging surrogate for both alpha-emitting 225Ac and 227Th radionuclides due to the unique CeIII/CeIV redox couple and the relatively long half-life of 134Ce. The purpose of this study was to demonstrate the compatibility of 134Ce with DOTA-based antibody drug conjugates, which would act as therapeutic agents when incorporating 225Ac. MethodsThe in vivo biodistributions of [134Ce]Ce-DOTA and [134Ce]Ce-citrate were assayed by microPET imaging over 25 h in Swiss Webster mice to determine the in vivo stability of the [134Ce]Ce-DOTA complex. L3-edge X-ray absorption spectroscopy measurements were used to confirm the Ce oxidation state and the formation of a fully coordinated Ce-DOTA complex. The in vivo biodistribution of [134Ce]Ce-DOTA-Trastuzumab was assayed over 147 h by microPET imaging in SK-OV-3 tumor-bearing NOD SCID mice to evaluate tumor uptake and in vivo stability. Mice were euthanized at 214 h after administration of the radiolabeled antibody conjugate, and imaged 1 h later. An ex vivo biodistribution experiment was then performed in order to corroborate the PET images. Results[134Ce]Ce-DOTA displayed rapid renal elimination and high in vivo stability over 25 h, with negligible bone and liver uptake, in comparison to [134Ce]Ce-citrate. L3-edge X-ray absorption spectroscopy experiments confirmed the 3+ oxidation state within the stable Ce-DOTA complex. MicroPET images of [134Ce]Ce-DOTA-Trastuzumab displayed elevated tumor uptake over 214 h, with minimal bone and liver uptake analogous to previously reported [225Ac]Ac-DOTA-Trastuzumab biodistribution results, and the ex vivo biodistribution of [134Ce]Ce-DOTA-Trastuzumab corroborated the final PET images. ConclusionThese results demonstrate that 134Ce allows for long-term tumor targeting with DOTA-based antibody drug conjugates and may therefore be used to trace antibody drug conjugates incorporating 225Ac.

Quantifying intraventricular drug delivery utilizing programmable ventriculoperitoneal shunts as the intraventricular access device.

Programmable ventriculoperitoneal shunts (pVP shunts) are increasingly utilized for intraventricular chemotherapy, radioimmunotherapy, and/or cellular therapy. Shunt adjustments allow optimization of drug concentrations in the thecal space with minimization in the peritoneum. This report assesses the success of the pVP shunt as an access device for intraventricular therapies. Quantifying intrathecal drug delivery using scintigraphy by pVP shunt model has not been previously reported. We performed a single-institution, retrospective analysis on patients with CNS tumors and pVP shunts from 2003 to 2020, noting shunt model. pVP flow was evaluated for consideration of compartmental radioimmunotherapy (cRIT) using In-111-DTPA scintigraphy. Scintigraphy studies at 2-4h and at 24h quantified ventricular-thecal and peritoneal drug activity. Twenty-two CSF flow studies were administered to 15 patients (N = 15) with diagnoses including medulloblastoma, metastatic neuroblastoma, pineoblastoma, and choroid plexus carcinoma. Six different types of pVP models were noted. 100% of the studies demonstrated ventriculo-thecal drug activity. 27% (6 of 22) of the studies had no peritoneal uptake visible by imaging. 73% (16 of 22) of the studies had minimal relative peritoneal uptake (< 12%). 27% (6 of 22) of the studies demonstrated moderate relative peritoneal uptake (12-37%). No studies demonstrated peritoneal uptake above 37%. All patients had successful drug delivery of In-111-DTPA to the ventriculo-thecal space. 73% of the patients had minimal relative (< 12%) peritoneal drug uptake. Though efficacy varies by shunt model, low numbers preclude conclusions regarding model superiority. CSF flow scintigraphy studies assesses drug distribution of In-111-DTPA, informing CSF flow for delivery of intraventricular therapies.

Improving 18F-FDG PET Imaging Using Canola Oil For Evaluation Of Cardiac Sarcoidosis

Objective The incidence and prevalence of cardiac sarcoidosis (CS) is increasing significantly, likely due to improved noninvasive diagnostic methods such as 18F-FDG PET imaging and a higher index of suspicion among clinicians. Cardiac PET for diagnosis of CS requires a strict low carbohydrate diet which even if adhered to can still lead to false positives. One protocol that has been explored with mixed results is consuming a beverage high in fat to improve myocardial suppression. Our objective was to evaluate if a new diet preparation protocol using canola oil can improve 18F-FDG PET imaging. Methods In patients undergoing evaluation for CS with 18F-FDG PET and inadequate myocardial suppression on a prior study, we administered 1 cup of canola oil (224 grams of fat) 1 hour before repeating the study in addition to our standard diet. The repeat study was compared to the prior to determine if there was improved myocardial suppression. Canola oil was specifically chosen as we considered it to be most palatable to drink in a large quantity in one sitting. Results Our study protocol showed that all four patients had an improvement in myocardial suppression (Figure 1). Patient A is a 60-year old man with CS who underwent a PET-CT 3 months after initiating treatment which showed increased myocardial FDG uptake. The repeat scan with the canola oil protocol demonstrated less FDG myocardial uptake with an SUV max of 5.9 (previously 11.3). Similarly, Patient B is a 63-year old man with CS who initiated treatment and had a PET scan at 3 months showing increased FDG uptake with the repeat scan using our protocol showing decreased myocardial FDG uptake with an SUV of 3.1 (previously 12.8). Patient C is a 50-year old man with pulmonary sarcoidosis whose initial PET scan showed diffuse FDG uptake (SUV 6.4) and repeat with the protocol showed minimal FDG uptake (SUV 3.0). Finally, Patient D is a 54-year old man with frequent PVCs and MRI showing patchy late gadolinium enhancement whose initial PET_CT showed patchy FDG uptake (SUV 7.5) and repeat scan with the protocol showed no evidence of sarcoidosis (SUV 1.3). Overall the only side effect was steatorrhea for up to one day after canola oil consumption. Conclusion In patients undergoing evaluation for CS with 18F-FDG PET who have inadequate myocardial suppression, canola oil may improve imaging characteristics and decrease false positives. The incidence and prevalence of cardiac sarcoidosis (CS) is increasing significantly, likely due to improved noninvasive diagnostic methods such as 18F-FDG PET imaging and a higher index of suspicion among clinicians. Cardiac PET for diagnosis of CS requires a strict low carbohydrate diet which even if adhered to can still lead to false positives. One protocol that has been explored with mixed results is consuming a beverage high in fat to improve myocardial suppression. Our objective was to evaluate if a new diet preparation protocol using canola oil can improve 18F-FDG PET imaging. In patients undergoing evaluation for CS with 18F-FDG PET and inadequate myocardial suppression on a prior study, we administered 1 cup of canola oil (224 grams of fat) 1 hour before repeating the study in addition to our standard diet. The repeat study was compared to the prior to determine if there was improved myocardial suppression. Canola oil was specifically chosen as we considered it to be most palatable to drink in a large quantity in one sitting. Our study protocol showed that all four patients had an improvement in myocardial suppression (Figure 1). Patient A is a 60-year old man with CS who underwent a PET-CT 3 months after initiating treatment which showed increased myocardial FDG uptake. The repeat scan with the canola oil protocol demonstrated less FDG myocardial uptake with an SUV max of 5.9 (previously 11.3). Similarly, Patient B is a 63-year old man with CS who initiated treatment and had a PET scan at 3 months showing increased FDG uptake with the repeat scan using our protocol showing decreased myocardial FDG uptake with an SUV of 3.1 (previously 12.8). Patient C is a 50-year old man with pulmonary sarcoidosis whose initial PET scan showed diffuse FDG uptake (SUV 6.4) and repeat with the protocol showed minimal FDG uptake (SUV 3.0). Finally, Patient D is a 54-year old man with frequent PVCs and MRI showing patchy late gadolinium enhancement whose initial PET_CT showed patchy FDG uptake (SUV 7.5) and repeat scan with the protocol showed no evidence of sarcoidosis (SUV 1.3). Overall the only side effect was steatorrhea for up to one day after canola oil consumption. In patients undergoing evaluation for CS with 18F-FDG PET who have inadequate myocardial suppression, canola oil may improve imaging characteristics and decrease false positives.

Miscanthus × giganteus Phytoremediation of Soil Contaminated with Trace Elements as Influenced by the Presence of Plant Growth-Promoting Bacteria

The phytoremediation of industrial crops is becoming popular for the revitalization of land contaminated by trace elements (TEs). This approach combines biomass production with the improvement of soil health. To implement phytoremediation and derive sufficient dry biomass, crop production must be adequately supported by agricultural practices, including the application of bioinoculants. The current study aims to test the influence of several plant growth-promoting bacteria (PGPB), isolated from TEs-contaminated soil—i.e., Stenotrophomonas maltophilia KP-13, Bacillus altitudinis KP-14, and Pseudomonas fluorescens KP-16 and their consortia on the phytoremediation of the industrial crop M. × giganteus cultivated in the same TEs-contaminated soil. Contrary to expectations, the effects of PGPB on the biomass harvest were low. The most significant increase was detected in leaf biomass treated with a consortium of tested PGPBs. More significant effects were detected in the uptake of individual TEs. The phytoparameters of translocation factor, comprehensive bioconcentration index and uptake index were used to characterize the behavior of the TEs; Cr; Mn; Ni; Cu; Zn; Sr; V; and Pb in the presence of isolates. Plants treated with PGPB strains accumulated minimal concentrations of Cu and Pb in their aboveground biomass, while a tendency for Zn accumulation in the leaves and stems, and Sr accumulation in the leaves was observed. The obtained results reveal the combinations of isolates that lead to the minimal uptake of TEs into the stems and the simultaneous increase in DW. This study provides more insight into the leading factors of phytoremediation supported by PGPB and can be helpful when M. × giganteus is grown on TEs-contaminated soils of different origins.

Angiotensinogen uptake and stimulation of oxidative stress in human pigment retinal epithelial cells

We previously reported that isolated proximal tubules (PT) internalize the precursor protein angiotensinogen and that the 125Iodine-labeled protein accumulated in the nuclear and mitochondrial fractions of the PT cells; however, whether internalization of angiotensinogen occurs in non-renal epithelial cells is unknown. Therefore, the present study assessed the cellular uptake of 125I-angiotensinogen in human retinal pigment ARPE-19 epithelial cells, a widely utilized cell model for the assessment of retinal injury, inflammation and oxidative stress. ARPE-19 cells, maintained in serum-free media to remove extracellular sources of bovine serum angiotensinogen and renin, were incubated with 125Iodine-angiotensinogen at 37 °C and revealed the time-dependent uptake of angiotensinogen over 24 h. In contrast, incubation with labelled Ang II, Ang-(1−7) or Ang I revealed minimal cellular uptake. Subcellular fractionation following a 4-hour uptake of 125I-angiotensinogen revealed that the majority of the labeled protein localized to the nuclear fraction with lower accumulation in the mitochondrial and cytosolic fractions. Finally, we show that addition of angiotensinogen (2 nM) to the ARPE-19 cells increased oxidative stress as assessed by DCF fluorescence that was blocked by pretreatment of the cells with either the NADPH oxidase 1/4 inhibitor GKT137831, apocynin or atorvastatin, but not the AT1 receptor antagonist losartan. In contrast, treatment of the cells with Angiotensin II at an equivalent dose to angiotensinogen failed to stimulate oxidative stress. We conclude that human retinal pigment cells internalize angiotensinogen to elicit an increase in oxidative stress through a pathway that appears distinct from the Ang II-AT1 receptor axis.

18F]FDG uptake in axillary lymph nodes and deltoid muscle after COVID-19 mRNA vaccination: a cohort study to determine incidence and contributing factors using a multivariate analysis.

PurposeReactive FDG uptake in the axillary lymph nodes (ALN) and deltoid muscle (DM) after COVID-19 mRNA vaccination has been recognized, although the actual situation in the Japanese population remains unknown. To determine the incidence of reactive FDG uptake and its contributing factors, we retrospectively studied a cohort of subjects who were vaccinated at our hospital.MethodsWhole-body FDG-PET/CT examinations performed in 237 subjects out of 240 subjects with a definite history of COVID-19 vaccination (BNT162b2; BioNTech-Pfizer) were analyzed. Positivity and SUVmax of FDG uptake in the ALN and DM ipsilateral to vaccination, various subject characteristics, and the grade of the pathological FDG-PET/CT findings were evaluated using a multivariate analysis.ResultsFDG uptake in the ALN and DM ipsilateral to vaccination was seen in about 60% of the subjects even soon (0–4 days) after the first vaccination, with percentages reaching 87.5% and 75.0%, respectively, after the second vaccination. DM uptake had almost disappeared at around 2 weeks, while ALN uptake persisted for 3 weeks or longer. A multivariate analysis showed that a short duration since vaccination, a younger age, a female sex, and a low FDG-PET/CT grade (minimal pathological FDG uptake) contributed significantly to positive ALN uptake, while a short duration since vaccination and a female sex were the only significant contributors to positive DM uptake. This study is the first to identify factors contributing to positive FDG uptake in ALN and DM after COVID-19 vaccination.ConclusionA high incidence of FDG uptake in ALN and DM was observed after vaccination. ALN uptake seemed to be associated with a younger age, a female sex, and minimal pathological FDG uptake. After vaccination, an acute inflammatory reaction in DM followed by immune reaction in ALN linked to humoral immunity may be speculated.

The water uptake, thermal and mechanical properties, and aging resistance to thermo‐oxidation of phenylboronic acid‐modified benzoxazine‐glass fiber composites

AbstractPolybenzoxazines, also known as Benzoxazine (Bz) is one kind of high‐performance thermoset polymers. It manifests several advantages when used for thermal protection applications, such as thermal and dimensional stabilities, low rate of moisture absorption and near zero volatility in curing process. However, benzoxazine shows its drawbacks in terms of curing temperature, char yield at elevated temperature, and resin toughness. Thus, modification of Bz matrix would be essential in order to improve these unfavorable properties. In this study, a facile synthesis of phenylboronic acid‐modified (PBA) benzoxazine (PBz) and glass fibers (GF) composites with varied PBA ratios were prepared. Briefly, GF fabrics were impregnated with each of Bz or PBz/acetone solution and baked to form B‐staged prepregs. Then, the prepregs were stacked, molded and cured in a hot‐pressing machine to form composites. The present study shows the 10 wt% PBA modified‐Bz/GF composite is the optimal formulation as it exhibits minimal water uptake, enhanced char yield, decent thermomechanical stability in terms of glass transition temperature, exceptional interlaminar shear strength (ILSS) and highest flexural strength. Moreover, the PBz 10/GF composite subject to thermo‐oxidative aging still maintains good levels of shear and flexural properties for potential service as thermal protection layer.

Hospital-based ovarian cancer patient traceback program results in minimal genetic testing uptake

ObjectiveTo determine the feasibility of hospital-based genetic counseling and testing (GC/T) Traceback for Ovarian Cancer (OC) patients, as proposed by the Division of Cancer Prevention and the Division of Cancer Control and Population Sciences, National Cancer Institute. MethodsLiving patients with OC were sent a letter explaining the availability of guideline-supported GC/T for at least BRCA1/2 and surrogates of deceased patients were called on the telephone. Outcomes of contact attempts were systematically recorded and statistically described. Results598 Traceback-eligible OC patients diagnosed from 2006 to 2016 were identified (163 presumed-living and 435 deceased). Two living patients called our office and scheduled an appointment for GC/T after receiving a letter. For surrogates of prior patients, successful contact occurred in 25% of call attempts. Fourteen individuals (2 living patients and 12 surrogates) underwent genetic counseling. Of those 14, 10 individuals consented to genetic testing and 5 followed through with sample collection. None of these individuals had pathogenic variants (PVs). When surrogate call notes were reviewed, 58% reflected positive responses to contact, however 42% were noted to have negative or indifferent responses, which were most common among spouses. Total time spent for hospital-based Traceback was 109 h. ConclusionsOverall, hospital-based Traceback via letter and telephone contact of surrogates is time-intensive and results in minimal uptake of GC/T. To practically execute this type of outreach program, health systems should consider collection of alternative contact information to allow for electronic communication of patient surrogates. Our study also underscores the importance of timely GC/T while patients are in active cancer care.

What a difference a methylene makes: replacing Glu with Asp or Aad in the Lys-urea-Glu pharmacophore of PSMA-targeting radioligands to reduce kidney and salivary gland uptake.

The aim of this study was to investigate the effect of replacing Glu in the Lys-urea-Glu PSMA-targeting pharmacophore of [68Ga]Ga-HTK03041 with a close analog on the uptake of kidneys, salivary glands and PSMA-expressing tumor xenografts.Methods: HTK03161, HTK03149 and HTK03189A/B were obtained by replacing Glu in HTK03041 with Asp, Aad (L-2-aminoadipic acid) and Api (2-aminopimelic acid), respectively. PSMA binding affinities were measured by competition binding assays. PET imaging and biodistribution studies of 68Ga-labeled ligands were performed in LNCaP tumor-bearing mice. The best candidate HTK03149 was selected and radiolabeled with 177Lu, and SPECT imaging and biodistribution studies were performed in LNCaP tumor-bearing mice. Radiation dosimetry calculation was conducted using the OLINDA software. Radioligand therapy study was performed in LNCaP tumor-bearing mice treated with [177Lu]Lu-HTK03149 (9.3-148 MBq), [177Lu]Lu-PSMA-617 (37 MBq) or natLu-HTK03149 (500 pmol).Results: PSMA binding affinities (Ki) of Ga-HTK03161, Ga-HTK03149, Ga-HTK03189A and Lu-HTK03149 were 3.88±0.66, 6.99±0.80, 550±35.7 and 1.57±0.42 nM, respectively. PET imaging showed that all 68Ga-labeled HTK03161, HTK03149 and HTK03189A/B were excreted mainly via the renal pathway and had minimal uptake in all organs/tissues including kidneys and salivary glands. Tumor xenografts were clearly visualized in PET images of [68Ga]Ga-HTK03161 and [68Ga]Ga-HTK03149 but were barely visualized using [68Ga]Ga-HTK03189A/B. Tumor uptake values for [68Ga]Ga-HTK03161, [68Ga]Ga-HTK03149, [68Ga]Ga-HTK0189A and [68Ga]Ga-HTK03189B were 12.7±1.91, 19.1±6.37, 2.10±0.28 and 0.67±0.15 %IA/g, respectively at 1h post-injection, and their average kidney and salivary gland uptake values were 2.13-4.41 and 0.20-0.23 %IA/g, respectively. Longitudinal SPECT imaging studies showed that [177Lu]Lu-HTK03149 was excreted mainly through the renal pathway with high uptake in LNCaP tumors and minimal uptake in all normal organs/tissues. The tumor uptake of [177Lu]Lu-HTK03149 peaked at 4h post-injection (20.9±2.99 %IA/g) and the uptake was sustained over time. Compared to [177Lu]Lu-PSMA-617, [177Lu]Lu-HTK03149 had 145% increase in tumor absorbed dose but 70% less in kidney absorbed dose, leading to an 7.1-fold increase in tumor-to-kidney absorbed dose ratio. Radioligand therapy studies showed that only half of the [177Lu]Lu-PSMA-617 injected dosage was needed for [177Lu]Lu-HTK03149 to achieve the same median survival.Conclusion: Replacing Glu in the PSMA-targeting Lys-urea-Glu pharmacophore of [68Ga]Ga-HTK03041 with Asp and Aad generates [68Ga]Ga-HTK03161 and [68Ga]Ga-HTK03149, respectively, and the new derivatives retain high uptake in LNCaP tumors and have minimal uptake in normal organs/tissues including kidneys and salivary glands. [177Lu]Lu-HTK03149 also retain high uptake in LNCaP tumors and has minimal uptake in normal organs/tissues, and is, therefore, promising for clinical translation to treat prostate cancer.

Impact of primary tumor size, standardized uptake values of primary tumor, and the most avid neck node on baseline 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography upon disease recurrence in head-and-neck oropharyngeal squamous cell carcinoma using standardized imaging protocol

The purpose of this prospective study was to find the impact of primary tumor size (Ts), standardized uptake values (SUVmax) of primary tumor, and the most avid neck node on disease recurrence in patients with head-and-neck (HN) oropharyngeal squamous cell carcinoma (HNOP-SCC). We included patients with HNOP-SCC (without distant metastasis – M0 disease) who had pre- and post-treatment 18-fluoro-2-deoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) using strict standardized imaging protocol from 2017 to 2019. Based on follow-up 18FDG PET/CT findings patients were categorized as disease free (no or minimal 18FDG uptake ≤ background over surgical bed and no distant metastasis) and disease recurrence (18FDG uptake > background over surgical bed with or without nodal and/or distant metastasis). Ts and SUVmax of primary tumor and the most avid neck node were compared and impact of these was studied upon disease recurrence. A total of 112 patients were included. No significant difference was seen in mean age (overall: 60 ± 14 year), gender distribution (overall M: F: 69:31%), body mass index (overall: 25.20 ± 5.82), and history of diabetes (overall: 19%) between disease free and disease recurrence groups. Similarly, no significant difference was observed for fasting blood sugar (overall: 110 ± 28 mg%), 18FDG dose (overall: 169 ± 37 MBq) and uptake period (overall: 70 ± 12 min) between two groups ensuring strict adherence to standardized imaging protocol. Significant difference (P < 0.05) was observed between disease free and disease recurrence for Ts (25 ± 10 mm vs. 33 ± 14 mm), SUVmax of primary tumor (6.2 ± 6.8 vs. 9.3 ± 7.2) and the most avid neck node (2.1 ± 3.3 vs. 4.7 ± 5.9) and median follow-up (13 ± 12 vs. 08 ± 13 months), respectively. Using receiver operating characteristic analysis, Ts >29 mm, baseline tumor SUVmax >4.6 and nodal SUVmax >6.2 were found independent predictors for disease recurrence. Nodal SUVmax >6.2 was found an independent predictor of shortest DFS than Ts and tumor SUVmax. We conclude that, in HNOP-SCC, primary Ts (>29 mm), SUVmax of primary tumor (>4.6), and the most avid neck node (>6.2) in baseline 18FDG PET/CT using standardized imaging protocol are the independent predictors of disease recurrence. Furthermore, SUVmax >6.2 of the most avid node predicts the shortest DFS than primary Ts and SUVmax of primary tumor.

18F-labeled Dimer-Sansalvamide A Cyclodecapeptide: A Novel Diagnostic Probe to Discriminate Pancreatic Cancer from Inflammation in a Nude Mice Model.

Early detection of pancreatic cancer has been a long-standing challenge. Inflammatory mass is the main source of false-positive findings in 18F-labeled fluorodeoxyglucose (18F-FDG) positron emission tomography / computed tomography (PET/CT). Heat shock protein 90 (Hsp90) is an established biomarker overexpressed in pancreatic cancer. We modified a Dimer-Sansalvamide A cyclodecapeptide by conjugating it with the bifunctional chelator NOTA (1,4,7-triazacyclononane-1,4,7-trisacetic acid), yielding 18F-NOTA-Dimer-Sansalvamide A cyclodecapeptide (18F-NOTA-Dimer-San A). The binding specificity of the probe was confirmed by in vitro cell uptake assays in Hsp90-positive PL45 pancreatic cancer cells. Hsp90 expression was imaged via MicroPET in pancreatic cancer xenografts and inflammation in mice. All of the mice received an intravenous injection of 18F-NOTA-Dimer-San A, and images were acquired at 1 and 2 hour time points. The novel probe demonstrated prominent tumor uptake in the pancreatic cancer xenografts (4.00 ± 0.88 %ID/g, 5.80 ± 0.94 %ID/g), and the inflammatory thigh showed minimal uptake (0.85 ± 0.01 %ID/g, 1.50 ± 0.20 %ID/g) at 1 and 2 hours after injection, respectively. The activity accumulation between the two groups was significantly different (P < 0.05), and the biodistribution data was consistent with the images. Moreover, immunohistochemistry (IHC) confirmed that the expression of Hsp90 was positive in PL45 pancreatic cancer but negative in the muscles next to the tumor and inflammatory muscles. We concluded that 18F-NOTA-Dimer-San A PET might allow non-invasive imaging for Hsp90 expression in tumors and has the potential to discriminate pancreatic cancer from inflammatory mass.

Integrating the Choosing Wisely 5 Questions into Family Meetings in the Intensive Care Unit: A Randomized Controlled Trial Investigating the Effect on Family Perceived Involvement in Decision-Making.

Family members often act as surrogate decision makers for patients in the intensive care unit (ICU). The use of printed prompts may assist with families feeling empowered to fulfill this role. Prospective, randomized controlled trial in 3 ICUs in Western Australia. In the intervention arm, families received the Choosing Wisely 5 questions as printed prompts prior to a family meeting, and the control arm did not receive prompts. The primary outcome was family perceived involvement in decision-making. Outcomes were measured using a survey. Sixty families participated in the study. The majority of families (87.1% control, 79.3% intervention; P = .334) reported feeling “very included” in decision-making. There was no difference in secondary outcomes, including minimal uptake of the questions by the intervention arm. This has been the first randomized trial evaluating the use of a decision-making tool for families in the ICU. Despite ceiling effects in outcome measures, these results suggest room for future study of the Choosing Wisely 5 questions in the ICU.

865. Social Media Secret Facebook Groups for HIV Pre-Exposure Prophylaxis Awareness among Female Sex Workers in Cameroon

BackgroundAbout 25% of Cameroonian female sex workers (FSW) lived with HIV in 2018. PrEP was introduced in Cameroon in 2019, with minimal uptake as of 2021. The goal of this pilot project was to evaluate the potential of a novel social media intervention to raise Pre-Exposure Prophylaxis (PrEP) awareness and complement HIV prevention strategies among FSW, a key risk population.MethodsFrom October 2020 to April 2021, sixty adult HIV-negative FSW who owned a phone with internet access joined the study; 40 in the intervention arm and 20 in the control arm. The intervention had a Secret Facebook Group (SFG) platform for confidentiality. It included 12 videos on HIV prevention in the local dialect, released over 8 weeks. In-person surveys were administered before and after the intervention, and three months later. Likert scale was used to evaluate the main outcome: PrEP awareness. Data was analyzed using Stata IC/version 14.2.ResultsDemographic characteristics were similar between intervention and control groups for age (29 years, SD7.3), literacy (45% secondary school), parity (1.9, SD1.5), and years as sex worker (7.8, SD5.1). One FSW had heard about PrEP before the intervention. After a brief introduction, 39% (15/38) of FSW in the intervention group and 50% (10/20) in the control group strongly agreed to be interested in taking PrEP (p=0.2). Baseline PrEP knowledge was poor in the intervention group (15/40, 38%) and very poor in the control group (19/20,95%) (p=0.0001). In the second survey, the intervention and control groups’ PrEP knowledge improved (p=0.0001 and p=0.02, respectively). It was more significant in the intervention group, with all FSW reporting good level of knowledge (p=0.0001) (Figure 1). In addition, more FSW in the intervention group (67%,27/40) strongly agreed to be interested in taking PrEP (p=0.01), while numbers remained similar in the control group (55%, 11/20, p=0.8). Three months after the intervention, 31.5% (12/38) of participants reported excellent PrEP knowledge, a significant improvement since the second survey (p=0.02).Figure 1. Self-reported Pre-Exposure Prophylaxis knowledge before and after intervention in the intervention and control groups. ConclusionThe use of a social media HIV prevention tool tailored to FSW in Cameroon improved PrEP awareness with good retention of knowledge. Cross contamination between groups might have hindered the differential impact of the brief intervention. Disclosures All Authors: No reported disclosures

Machine learning-based prediction of invisible intraprostatic prostate cancer lesions on 68Ga-PSMA-11 PET/CT in patients with primary prostate cancer.

68Ga-PSMA PET/CT has high specificity and sensitivity for the detection of both intraprostatic tumor focal lesions and metastasis. However, approximately 10% of primary prostate cancer are invisible on PSMA-PET (exhibit no or minimal uptake). In this work, we investigated whether machine learning-based radiomics models derived from PSMA-PET images could predict invisible intraprostatic lesions on 68Ga-PSMA-11 PET in patients with primary prostate cancer. In this retrospective study, patients with or without prostate cancer who underwent 68Ga-PSMA PET/CT and presented negative on PSMA-PET image at either of two different institutions were included: institution 1 (between 2017 and 2020) for the training set and institution 2 (between 2019 and 2020) for the external test set. Three random forest (RF) models were built using selected features extracted from standard PET images, delayed PET images, and both standard and delayed PET images. Then, subsequent tenfold cross-validation was performed. In the test phase, the three RF models and PSA density (PSAD, cut-off value: 0.15ng/ml/ml) were tested with the external test set. The area under the receiver operating characteristic curve (AUC) was calculated for the models and PSAD. The AUCs of the radiomics model and PSAD were compared. A total of 64 patients (39 with prostate cancer and 25 with benign prostate disease) were in the training set, and 36 (21 with prostate cancer and 15 with benign prostate disease) were in the test set. The average AUCs of the three RF models from tenfold cross-validation were 0.87 (95% CI: 0.72, 1.00), 0.86 (95% CI: 0.63, 1.00), and 0.91 (95% CI: 0.69, 1.00), respectively. In the test set, the AUCs of the three trained RF models and PSAD were 0.903 (95% CI: 0.830, 0.975), 0.856 (95% CI: 0.748, 0.964), 0.925 (95% CI:0.838, 1.00), and 0.662 (95% CI: 0.510, 0.813). The AUCs of the three radiomics models were higher than that of PSAD (0.903, 0.856, and 0.925 vs. 0.662, respectively; P = .007, P = .045, and P = .005, respectively). Random forest models developed by 68Ga-PSMA-11 PET-based radiomics features were proven useful for accurate prediction of invisible intraprostatic lesion on 68Ga-PSMA-11 PET in patients with primary prostate cancer and showed better diagnostic performance compared with PSAD.

Coco Peat as Agricultural Waste Sorbent for Sustainable Diesel-Filter System.

Oil spill incidents are hazardous and have prolonged damage to the marine environment. Management and spill clean-up procedures are practical and rapid, with several shortcomings. Coco peat (CP) and coco fibre (CF) are refined from coconut waste, and their abundance makes them desirable for diesel spillage treatment. Using a filter-based system, the selectivity of coco peat sorbent was tested using CP, CF and peat-fibre mix (CPM). CP exhibited maximal diesel sorption capacity with minimal seawater uptake, thus being selected for further optimisation analysis. The heat treatment considerably improved the sorption capacity and efficiency of diesel absorbed by CP, as supported by FTIR and VPSEM–EDX analysis. Conventional one-factor-at-a-time (OFAT) examined the performance of diesel sorption by CP under varying parameters, namely temperature, time of heating, packing density and diesel concentration. The significant factors were statistically evaluated using response surface methodology (RSM) via Plackett–Burman design (PB) and central composite design (CCD). Three significant (p < 0.05) factors (time, packing density and diesel concentration) were identified by PB and further analysed for interactions among the parameters. CCD predicted efficiency of diesel absorbed at 59.92% (71.90 mL) (initial diesel concentration of 30% v/v) and the experimental model validated the design with 59.17% (71.00 mL) diesel sorbed at the optimised conditions of 14.1 min of heating (200 °C) with packing density of 0.08 g/cm3 and 30% (v/v) of diesel concentration. The performance of CP in RSM (59.17%) was better than that in OFAT (58.33%). The discoveries imply that natural sorbent materials such as CP in oil spill clean-up operations can be advantageous and environmentally feasible. This study also demonstrated the diesel-filter system as a pilot study for the prospective up-scale application of oil spills.

Association of Generic Competition With Price Decreases in Physician-Administered Drugs and Estimated Price Decreases for Biosimilar Competition

Price decreases of biologic and biosimilar products in Medicare Part B have been minimal, even with biosimilar competition. Medicare reimburses clinicians for biologics and biosimilars differently than for brand-name and generic drugs, which has generated greater price reductions. To characterize the nature of price competition among brand-name and generic drugs under Medicare Part B and to estimate the cost savings to the program of subjecting biologic and biosimilar therapies to a similar price competition. This cohort study analyzed all brand-name drugs and their approved generic versions as well as biologics and biosimilars that were reimbursed under Medicare Part B from quarter 1 of 2005 to quarter 2 of 2021. Two separate data sets were created: brand-name and generic drugs as well as biologics and biosimilars data sets. Brand-name products with generic versions that were introduced before 2005 were excluded, and so were vaccines. Number of generic and biosimilar competitors over time. Price change as a percentage of the brand-name drug or biologic price in the quarter before generic or biosimilar competition. Price change was modeled using a linear, fixed-effects time series regression, with the number of generic or biosimilar competitors as the main covariate. Time was expressed as the number of quarters since the first generic or biosimilar competitor entered the market. Savings were estimated by projecting the regression model of brand-name and generic drug competition to observed biologic and biosimilar competition and by applying the estimated price reduction to actual Medicare spending for those products from 2015 to 2019. Of the 988 Healthcare Common Procedure Coding System codes identified, 50 (5.0%) met the inclusion criteria for the brand-name and generic drug data set and 28 (2.8%) met the criteria for the biologic and biosimilar data set. The first generic competitor was associated with reduced drug prices by 17.0%, the second competitor with a 39.5% decrease, the third competitor with a 52.5% decrease, and the fourth and more competitors with a 70.2% decrease (price decline was measured from brand-name drug price before the first generic competitor rather than from price established with fewer competitors). If biologics and biosimilars were subject to the same Medicare reimbursement framework as brand-name and generic drugs, Medicare spending on these products was estimated to have been 26.6% lower ($1.6 billion) from 2015 to 2019. This study found minimal uptake of biosimilars and limited price reductions for biologics and biosimilars under the current Medicare Part B reimbursement policy. Adopting the bundled biosimilar reimbursement structure for biologic and biosimilar therapies may be associated with substantial savings and encourage greater biosimilar market entry.

18F]Fluoromethylcholine PET/CT for CNS lymphoma assessment: a new tool

Background Central nervous system (CNS) lymphomas are a rare subset of lymphoma, which are associated with a poor outcome. The gold standard for CNS imaging is with gadolinium-enhanced magnetic resonance imaging (MRI); however, there are a number of limitations, including some patients with small persistent abnormalities from scarring due to focal haemorrhage or from a previous biopsy, which can be difficult to discern from residual tumour. [18F]Fluoromethylcholine positron emission tomography–computed tomography (FCH-PET/CT) uses an analogue of choline, which due to the upregulation of choline kinase in tumour cells, allows increased uptake of FCH. As there is minimal background grey matter uptake of FCH, FCH-PET/CT can be used in CNS imaging and provide a useful tool for response assessment. Methods This is a cohort study, where we identified 40 patients with a diagnosis of primary or secondary CNS lymphoma between 1st November 2011 and 10th October 2019. Results 26 of the 40 patients (65%) had concordant results. Of the discordant results, 11 out of 14 had partial response (PR) on MRI but showed a metabolic complete response (mCR) on FCH-PET. The overall response rates (ORR) were similar between the two modalities (90% for MRI versus 95% with FCT-PET/CT). Conclusion We conclude that FCH-PET/CT is a reasonable alternative mode of imaging to gadolinium-enhanced MRI brain imaging, providing a new tool for assessment of CNS lymphoma.