Patient metabolic profile defined by liver and muscle 18F-FDG PET avidity is independently associated with overall survival in gastric cancer.

BACKGROUND: PET-CT-based patient metabolic profiling is a novel concept to incorporate patient-specific metabolism into gastric cancer care. METHODS: Staging PET-CTs, demographics, and clinicopathologic variables of gastric cancer patients were obtained from a prospectively maintained institutional database. PET-CT avidity was measured in tumor, liver, spleen, four paired muscles, and two paired fat areas in each patient. The liver to rectus femoris (LRF) ratio was defined as the ratio of SUVmean of liver to the average SUVmean of the bilateral rectus femoris muscles. Kaplan-Meier and Cox-proportional hazards models were used to identify the impact of LRF ratio on OS. RESULTS: Two hundred and one patients with distal gastroesophageal (48%) or gastric (52%) adenocarcinoma were included. Median age was 65 years, and 146 (73%) were male. On univariate analysis, rectus femoris PET-CT avidity and LRF ratio were significantly associated with overall survival (p < 0.05). LRF ratio was significantly higher in males, early-stage cancer, patients with an ECOG 0 or 1 performance status, patients with albumin > 3.5 mg/dL, and those with moderately differentiated tumor histology. In multivariable regression, gastric cancer stage, albumin, and LRF ratio were significant independent predictors of overall survival (LRF ratio HR = 0.73 (0.56-0.96); p = 0.024). Survival curves showed that the prognostic impact of LRF was associated with metastatic gastric cancer (p = 0.009). CONCLUSIONS: Elevated LRF ratio, a patient-specific PET-CT-based metabolic parameter, was independently associated with an improvement in OS in patients with metastatic gastric cancer. With prospective validation, LRF ratio may be a useful, host-specific metabolic parameter for prognostication in gastric cancer.

Electrodeposited MoxSyOz/Ni Tribological Coatings.

Deposition of molybdenum disulfide (MoS2) coatings using physical vapor deposition (PVD) and mechanical burnishing has been widely assessed for solid lubricants in space applications but still suffers from line-of-sight constraints on complex geometries. Here, we highlight one of the first demonstrations of electrodeposited MoxSyOz and MoxSyOz/Ni thin-film coatings from aqueous solutions of ammonium tetrathiomolybdate for solid lubricant applications and their remarkable ability to provide low coefficients of friction and high wear resistance. Characterization of the coating morphology shows amorphous microstructures with a high oxygen content and cracking upon drying. Even so, electrodeposited MoxSyOz can achieve low steady-state coefficients of friction (µ ∼ 0.05-0.06) and wear rates (2.6 × 10-7 mm3/(N m)) approaching those of physical vapor deposited coatings (2.3 × 10-7 mm3/(N m)). Additionally, we show that adding dopants such as nickel increased the wear rate (7.5 × 10-7 mm3/(N m)) and initial coefficient of friction (µi = 0.23) due to compositional modifications such as dramatic sub-stoichiometry (S/Mo ∼ 1) and expression of a NiOx surface layer, although doping did reduce the degree of cracking upon drying.

Engineering CAR-T cells for radiohapten capture in imaging and radioimmunotherapy applications.

Rationale: The in vivo dynamics of CAR-T cells remain incompletely understood. Novel methods are urgently needed to longitudinally monitor transferred cells non-invasively for biodistribution, functionality, proliferation, and persistence in vivo and for improving their cytotoxic potency in case of treatment failure. Methods: Here we engineered CD19 CAR-T cells ("Thor"-cells) to express a membrane-bound scFv, huC825, that binds DOTA-haptens with picomolar affinity suitable for labeling with imaging or therapeutic radionuclides. We assess its versatile utility for serial tracking studies with PET and delivery of α-radionuclides to enhance anti-tumor killing efficacy in sub-optimal adoptive cell transfer in vivo using Thor-cells in lymphoma models. Results: We show that this reporter gene/probe platform enables repeated, sensitive, and specific assessment of the infused Thor-cells in the whole-body using PET/CT imaging with exceptionally high contrast. The uptake on PET correlates with the Thor-cells on a cellular and functional level. Furthermore, we report the ability of Thor-cells to accumulate cytotoxic alpha-emitting radionuclides preferentially at tumor sites, thus increasing therapeutic potency. Conclusion: Thor-cells are a new theranostic agent that may provide crucial information for better and safer clinical protocols of adoptive T cell therapies, as well as accelerated development strategies.

Efficacy of HER2-Targeted Intraperitoneal 225Ac α-Pretargeted Radioimmunotherapy for Small-Volume Ovarian Peritoneal Carcinomatosis.

Epithelial ovarian cancer (EOC) is often asymptomatic and presents clinically in an advanced stage as widespread peritoneal microscopic disease that is generally considered to be surgically incurable. Targeted α-therapy with the α-particle-emitting radionuclide 225Ac (half-life, 9.92 d) is a high-linear-energy-transfer treatment approach effective for small-volume disease and even single cells. Here, we report the use of human epidermal growth factor receptor 2 (HER2) 225Ac-pretargeted radioimmunotherapy (PRIT) to treat a mouse model of human EOC SKOV3 xenografts growing as peritoneal carcinomatosis (PC). Methods: On day 0, 105 SKOV3 cells transduced with a luciferase reporter gene were implanted intraperitoneally in nude mice, and tumor engraftment was verified by bioluminescent imaging (BLI). On day 15, treatment was started using 1 or 2 cycles of 3-step anti-HER2 225Ac-PRIT (37 kBq/cycle as 225Ac-Proteus DOTA), separated by a 1-wk interval. Efficacy and toxicity were monitored for up to 154 d. Results: Untreated PC-tumor-bearing nude mice showed a median survival of 112 d. We used 2 independent measures of response to evaluate the efficacy of 225Ac-PRIT. First, a greater proportion of the treated mice (9/10 1-cycle and 8/10 2-cycle; total, 17/20; 85%) survived long-term compared with controls (9/27, 33%), and significantly prolonged survival was documented (log-rank [Mantel-Cox] P = 0.0042). Second, using BLI, a significant difference in the integrated BLI signal area to 98 d was noted between controls and treated groups (P = 0.0354). Of a total of 8 mice from the 2-cycle treatment group (74 kBq total) that were evaluated by necropsy, kidney radiotoxicity was mild and did not manifest itself clinically (normal serum blood urea nitrogen and creatinine). Dosimetry estimates (relative biological effectiveness-weighted dose, where relative biological effectiveness = 5) per 37 kBq administered for tumors and kidneys were 56.9 and 16.1 Gy, respectively. One-cycle and 2-cycle treatments were equally effective. With immunohistology, mild tubular changes attributable to α-toxicity were observed in both therapeutic groups. Conclusion: Treatment of EOC PC-tumor-bearing mice with anti-HER2 225Ac-PRIT resulted in histologic cures and prolonged survival with minimal toxicity. Targeted α-therapy using the anti-HER2 225Ac-PRIT system is a potential treatment for otherwise incurable EOC.

The use of single-timepoint images to link administered radioiodine activity (MBq) to a prescribed lesion radiation-absorbed dose (cGy): a regression-based prediction interval tool for the management of well-differentiated thyroid cancer patients.

PURPOSE: To introduce a biomarker-based dosimetry method for the rational selection of a treatment activity for patients undergoing radioactive iodine 131I therapy (RAI) for metastatic differentiated thyroid cancer (mDTC) based on single-timepoint imaging of individual lesion uptake by 124I PET. METHODS: Patients referred for RAI therapy of mDTC were enrolled in institutionally approved protocols. A total of 208 mDTC lesions (in 21 patients) with SUVmax > 1 underwent quantitative PET scans at 24, 48, 72, and 120 h post-administration of 222 MBq of theranostic NaI-124I to determine the individual lesion radiation-absorbed dose. Using a general estimating equation, a prediction curve for biomarker development was generated in the form of a best-fit regression line and 95% prediction interval, correlating individual predicted lesion radiation dose metrics, with candidate biomarkers ("predictors") such as SUVmax and activity in microcurie per gram, from a single imaging timepoint. RESULTS: In the 169 lesions (in 15 patients) that received 131I therapy, individual lesion cGy varied over 3 logs with a median of 22,000 cGy, confirming wide heterogeneity of lesion radiation dose. Initial findings from the prediction curve on all 208 lesions confirmed that a 48-h SUVmax was the best predictor of lesion radiation dose and permitted calculation of the 131I activity required to achieve a lesional threshold radiation dose (2000 cGy) within defined confidence intervals. CONCLUSIONS: Based on MIRD lesion-absorbed dose estimates and regression statistics, we report on the feasibility of a new single-timepoint 124I-PET-based dosimetry biomarker for RAI in patients with mDTC. The approach provides clinicians with a tool to select personalized (precision) therapeutic administration of radioactivity (MBq) to achieve a desired target lesion-absorbed dose (cGy) for selected index lesions based on a single 48-h measurement 124I-PET image, provided the selected activity does not exceed the maximum tolerated activity (MTA) of < 2 Gy to blood, as is standard of care at Memorial Sloan Kettering Cancer Center. TRIAL REGISTRATION: NCT04462471, Registered July 8, 2020. NCT03647358, Registered Aug 27, 2018.

Quantitative In Vivo Imaging of the Androgen Receptor Axis Reveals Degree of Prostate Cancer Radiotherapy Response.

Noninvasive biomarkers for androgen receptor (AR) pathway activation are urgently needed to better monitor patient response to prostate cancer therapies. AR is a critical driver and mediator of resistance of prostate cancer but currently available noninvasive prostate cancer biomarkers to monitor AR activity are discordant with downstream AR pathway activity. External beam radiotherapy (EBRT) remains a common treatment for all stages of prostate cancer, and DNA damage induced by EBRT upregulates AR pathway activity to promote therapeutic resistance. [89Zr]11B6-PET is a novel modality targeting prostate-specific protein human kallikrein 2 (hK2), which is a surrogate biomarker for AR activity. Here, we studied whether [89Zr]11B6-PET can accurately assess EBRT-induced AR activity.Genetic and human prostate cancer mouse models received EBRT (2-50 Gy) and treatment response was monitored by [89Zr]11B6-PET/CT. Radiotracer uptake and expression of AR and AR target genes was quantified in resected tissue.EBRT increased AR pathway activity and [89Zr]11B6 uptake in LNCaP-AR and 22RV1 tumors. EBRT increased prostate-specific [89Zr]11B6 uptake in prostate cancer-bearing mice (Hi-Myc x Pb_KLK2) with no significant changes in uptake in healthy (Pb_KLK2) mice, and this correlated with hK2 protein levels. IMPLICATIONS: hK2 expression in prostate cancer tissue is a proxy of EBRT-induced AR activity that can noninvasively be detected using [89Zr]11B6-PET; further clinical evaluation of hK2-PET for monitoring response and development of resistance to EBRT in real time is warranted.

Phase 1 study of intraventricular 131I-omburtamab targeting B7H3 (CD276)-expressing CNS malignancies.

BACKGROUND: The prognosis for metastatic and recurrent tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic targets and modalities is critical. The cell surface glycoprotein B7H3 is expressed on a range of solid tumors with a restricted expression on normal tissues. We hypothesized that compartmental radioimmunotherapy (cRIT) with the anti-B7H3 murine monoclonal antibody omburtamab injected intraventricularly could safely target CNS malignancies. PATIENTS AND METHODS: We conducted a phase I trial of intraventricular 131I-omburtamab using a standard 3 + 3 design. Eligibility criteria included adequate cerebrospinal fluid (CSF) flow, no major organ toxicity, and for patients > dose level 6, availability of autologous stem cells. Patients initially received 74 MBq radioiodinated omburtamab to evaluate dosimetry and biodistribution followed by therapeutic 131I-omburtamab dose-escalated from 370 to 2960 MBq. Patients were monitored clinically and biochemically for toxicity graded using CTCAEv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and serial PET or gamma-camera scans. Patients could receive a second cycle in the absence of grade 3/4 non-hematologic toxicity or progressive disease. RESULTS: Thirty-eight patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma (n = 16) and other B7H3-expressing solid tumors (n = 22). Thirty-five patients received at least 1 cycle of treatment with both dosimetry and therapy doses. Acute toxicities included < grade 4 self-limited headache, vomiting or fever, and biochemical abnormalities. Grade 3/4 thrombocytopenia was the most common hematologic toxicity. Recommended phase 2 dose was 1850 MBq/injection. The median radiation dose to the CSF and blood by sampling was 1.01 and 0.04 mGy/MBq, respectively, showing a consistently high therapeutic advantage for CSF. Major organ exposure was well below maximum tolerated levels. In patients developing antidrug antibodies, blood clearance, and therefore therapeutic index, was significantly increased. In patients receiving cRIT for neuroblastoma, survival was markedly increased (median PFS 7.5 years) compared to historical data. CONCLUSIONS: cRIT with 131I-omburtamab is safe, has favorable dosimetry and may have a therapeutic benefit as adjuvant therapy for B7-H3-expressing leptomeningeal metastases. TRIAL REGISTRATION: clinicaltrials.gov NCT00089245, August 5, 2004.

Preferential Adsorption of Prominent Amino Acids in the Urease Enzyme of Sporosarcina pasteurii on Arid Soil Components: A Periodic DFT Study.

The urease enzyme is commonly used in microbially induced carbonate precipitation (MICP) and enzyme-induced carbonate precipitation (EICP) to heal and strengthen soil. Improving our understanding of the adsorption of the urease enzyme with various soil surfaces can lead to advancements in the MICP and EICP engineering methods as well as other areas of soil science. In this work, we use density functional theory (DFT) to investigate the urease enzyme's binding ability with four common arid soil components: quartz, corundum, albite, and hematite. As the urease enzyme cannot directly be simulated with DFT due to its size, the amino acids comprising at least 5% of the urease enzyme were simulated instead. An adsorption model incorporating the Gibbs free energy was used to determine the existence of amino acid-mineral binding modes. It was found that the nine simulated amino acids bind preferentially to the different soil components. Alanine favors corundum, glycine and threonine favor hematite, and aspartic acid favors albite. It was found that, under the standard environmental conditions considered here, amino acid binding to quartz is unfavorable. In the polymeric form where the side chains would dominate the binding interactions, hematite favors aspartic acid through its R-OH group and corundum favors glutamic acid through its R-Ket group. Overall, our model predicts that the urease enzyme produced by Sporosarcina pasteurii can bind to various oxides found in arid soil through its alanine, glycine, aspartic/glutamic acid, or threonine residues.

Pretargeting: A Path Forward for Radioimmunotherapy.

Pretargeted radioimmunodiagnosis and radioimmunotherapy aim to efficiently combine antitumor antibodies and medicinal radioisotopes for high-contrast imaging and high-therapeutic-index (TI) tumor targeting, respectively. As opposed to conventional radioimmunoconjugates, pretargeted approaches separate the tumor-targeting step from the payload step, thereby amplifying tumor uptake while reducing normal-tissue exposure. Alongside contrast and TI, critical parameters include antibody immunogenicity and specificity, availability of radioisotopes, and ease of use in the clinic. Each of the steps can be optimized separately; as modular systems, they can find broad applications irrespective of tumor target, tumor type, or radioisotopes. Although this versatility presents enormous opportunity, pretargeting is complex and presents unique challenges for clinical translation and optimal use in patients. The purpose of this article is to provide a brief historical perspective on the origins and development of pretargeting strategies in nuclear medicine, emphasizing 2 protein delivery systems that have been extensively evaluated (i.e., biotin-streptavidin and hapten-bispecific monoclonal antibodies), as well as radiohaptens and radioisotopes. We also highlight recent innovations, including pretargeting with bioorthogonal chemistry and novel protein vectors (such as self-assembling and disassembling proteins and Affibody molecules). We caution the reader that this is by no means a comprehensive review of the past 3 decades of pretargeted radioimmunodiagnosis and pretargeted radioimmunotherapy. But we do aim to highlight major developmental milestones and to identify benchmarks for success with regard to TI and toxicity in preclinical models and clinically. We believe this approach will lead to the identification of key obstacles to clinical success, revive interest in the utility of radiotheranostics applications, and guide development of the next generation of pretargeted theranostics.

Using Genomic Selection to Develop Performance-Based Restoration Plant Materials.

Effective native plant materials are critical to restoring the structure and function of extensively modified ecosystems, such as the sagebrush steppe of North America's Intermountain West. The reestablishment of native bunchgrasses, e.g., bluebunch wheatgrass (Pseudoroegneria spicata [Pursh] À. Löve), is the first step for recovery from invasive species and frequent wildfire and towards greater ecosystem resiliency. Effective native plant material exhibits functional traits that confer ecological fitness, phenotypic plasticity that enables adaptation to the local environment, and genetic variation that facilitates rapid evolution to local conditions, i.e., local adaptation. Here we illustrate a multi-disciplinary approach based on genomic selection to develop plant materials that address environmental issues that constrain local populations in altered ecosystems. Based on DNA sequence, genomic selection allows rapid screening of large numbers of seedlings, even for traits expressed only in more mature plants. Plants are genotyped and phenotyped in a training population to develop a genome model for the desired phenotype. Populations with modified phenotypes can be used to identify plant syndromes and test basic hypotheses regarding relationships of traits to adaptation and to one another. The effectiveness of genomic selection in crop and livestock breeding suggests this approach has tremendous potential for improving restoration outcomes for species such as bluebunch wheatgrass.

Prospective evaluation of 18F-FDG positron emission tomography in the preoperative staging of patients with hepatic colorectal metastases.

Background: Despite considerable advances in preoperative imaging, up to one-third of patients operatively explored for hepatic colorectal metastases are unexpectedly found to harbor unresectable intrahepatic or extrahepatic disease. Methods: The current study is a prospective, blinded study comparing utility of [18F]2-fluoro-2-deoxyglucose positron emission tomography (18F-FDG-PET) to computed tomography (CT) and CT arterial portography (CTAP) as preoperative staging. Results: The 125 planned subjects were enrolled. Findings seen on FDG-PET alone changed therapy for 23 of 125 patients (18%). FDG-PET confirmed other radiologic findings in 16 cases (13%), for an overall influence on therapy in 39 cases (31%). FDG-PET was the most sensitive diagnostic imaging test for extrahepatic cancer; it was 80-90% sensitive for extrahepatic cancer and 70-90% specific. For the 28 cases of unresectable disease due to extrahepatic disease, FDG-PET findings solely changed therapies in 16 cases (57%) and influenced therapy in seven other cases (25%). Of the 21 unresectable cases due to extent of intrahepatic disease, FDG-PET did not solely change therapy in any. Overall, FDG-PET had the lowest sensitivity for hepatic sites compared with CT or CTAP. In particular, small (<1 cm) liver tumors were particularly poorly detected by FDG-PET. The area under the receiver operating characteristic (ROC) curve for small tumors was 0.58 and for patients on chemotherapy it was 0.66, a modest improvement over no imaging. Conclusions: FDG-PET is an important test for preoperative staging of patients with hepatic colorectal metastases, affecting treatment decisions in nearly one-third of patients. The high yield is due mainly to detection of extrahepatic disease. It is therefore recommended in patients with extrahepatic lesions suspected to be disseminated cancer or those with high risk for extrahepatic disease. It is not a good test for identification of small tumors in the liver.

A laboratory preparation procedure for studying bioaccumulation of U and its subcellular form in earthworms (Diplocardia spp.).

Uranium (U) is a ubiquitous trace element in soils. With increasing in application of U in nuclear energy and nuclear weapon, a large amount of U was dissipated into the environment including soil and water. Earthworm may be an eco-indicator for U bioaccumulation, transformation and transport across the ecosystem. There have been a variety of methods preformed to assess the bioaccumulation of uranium in small organisms such as earthworms, including uranium speciation, subcellular separation, and total U accumulation. All methods require an initial grinding preparation process that allows for the further fractionation of metals and metalloids in earthworms. The slime like mucus that coats the body of a worm presents a challenge in the disintegration and dissolution of the worm body. In order to analyze U subcellular forms, we developed a reliable and effective procedure to grind the worm body into a uniform fine suspension. We conducted a comparative study of disintegration of worms with 3 grinding techniques (agate mortar, liquid nitrogen freezing then agate mortar, and direct sonication) that would assist U subcellular analyses and bioaccumulation. The essences of this new development was as follows:•A scheme for preparation of earthworm samples for investigation of subcellular U forms in earthworms from U.S. army weapon test range soil with various U forms.•The direct sonication of earthworms was found to be the most proficient process in achieving the best preparation for U subcellular analyses with the high precision.

A laboratory simulation to investigate effects of moistures on U distribution among solid phase components in army range soils.

Uranium is a naturally occurring radioactive trace element found in rocks, soils, and coals. U may contaminate groundwater and soil from nuclear power plant operations, spent fuel reprocessing, high-level waste disposal, ore mining and processing, or manufacturing processes. Yuma Proving Ground in Arizona, USA has been used depleted uranium ballistics for 36 years where U has accumulated in this army testing site. The objective of this study is to develop a laboratory scheme on the effects of soil moisture regiments on the distribution and partitioning of U in army range soil among solid phase components to mimic U biogeochemical processes in the field. Three moisture regiments were saturated paste, field capacity, and wetting-drying cycle which covered major scenarios in fields from the wet summer season to the dry winter season. Uranium in soils with different forms of U (UO2, UO3, uranyl, and schoepite) was fractionated into 8 operationally defined solid components with sequential selective dissolution procedure. The essences of this new development were as following:•A scheme was developed for investigation of U distribution, partitioning and transformation among solid phase components in army weapon test range soils with various U forms under 3 soil moisture regimes.•Soil moisture was one of major environmental factors in controlling biogeochemical processes and fates of U in army weapon test site.

Treatment of Patients with Acute Myeloid Leukemia with the Targeted Alpha-Particle Nanogenerator Actinium-225-Lintuzumab.

PURPOSE: The anti-CD33 antibody lintuzumab has modest activity against acute myeloid leukemia (AML). To increase its potency, lintuzumab was conjugated to actinium-225 (225Ac), a radionuclide yielding 4 α-particles. This first-in-human, phase I trial was conducted to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab. PATIENTS AND METHODS: Eighteen patients (median age, 64 years; range, 45-80) with relapsed or refractory AML received a single infusion of 225Ac-lintuzumab at activities of 18.5 to 148 kBq/kg. RESULTS: The maximum tolerated dose was 111 kBq/kg. Dose-limiting toxicities included myelosuppression lasting > 35 days in one patient receiving 148 kBq/kg and death from sepsis in two patients treated with 111 and 148 kBq/kg. Myelosuppression was the most common toxicity. Significant extramedullary toxicities were limited to transient grade 3 liver function abnormalities. Pharmacokinetics were determined by gamma counting serial whole blood, plasma, and urine samples at energy windows for the 225Ac daughters, francium-221 and bismuth-213. Two-phase elimination kinetics were seen with mean plasma t1/2 - α and t1/2 - ß of 1.9 and 38 hours, respectively. Peripheral blood blasts were eliminated in 10 of 16 evaluable patients (63%) but only at doses of ≥ 37 kBq/kg. Bone marrow blasts were reduced in 10 of 15 evaluable patients (67%), including 3 patients with marrow blasts ≤ 5% and one patient with a morphologic leukemia-free state. CONCLUSIONS: Therapy for AML with the targeted α-particle generator 225Ac-lintuzumab was feasible with an acceptable safety profile. Elimination of circulating blasts or reductions in marrow blasts were observed across all dose levels.

Automated Bone Scan Index to Optimize Prostate Cancer Working Group Radiographic Progression Criteria for Men With Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: Radiographic progression-free survival (rPFS) by Prostate Cancer Working Group (PCWG) criteria is a radiographic endpoint. The automated bone scan index (aBSI) quantifies osseous disease burden on bone scintigraphy as a percentage of total skeletal weight. Using the aBSI, we sought to quantify increase in tumor burden represented by PCWG progression criteria, and to determine the interval increase that best associates with overall survival (OS). PATIENT AND METHODS: Retrospective analysis of trials using androgen receptor axis-targeted drugs for metastatic castration resistant prostate cancer patients (mCRPC). aBSI increase in bone disease was assessed from baseline scan to time-to-progression (per PCWG criteria). Threshold for time to aBSI increase were explored and the association between each time-to-threshold and OS was computed. RESULTS: A total of 169 mCPRC patients had bone scans available for aBSI analysis. Of these, 90 (53%) had progression in bone meeting PCWG criteria. Total aBSI increase in patients meeting PCWG criteria was 1.22 (interquartile range [IQR]: 0.65-2.49), with a median relative increase of 109% (IQR: 40%-377%). Median aBSI at baseline was 3.1 (IQR: 1.3-7.1). The best association between OS and time-to-progression occurred with an absolute increase in aBSI equal to 0.6 (Kendall's tau 0.52). CONCLUSION: An absolute increase of 0.6 or more in aBSI from the first follow-up scan results in the highest association with OS in patients with mCRPC. The rPFS by PCWG, identified progression at nearly twice this tumor burden, suggesting that aBSI may be used to further develop the PCWG criteria without degrading its association with OS.

Enhancing Radioiodine Incorporation in BRAF-Mutant, Radioiodine-Refractory Thyroid Cancers with Vemurafenib and the Anti-ErbB3 Monoclonal Antibody CDX-3379: Results of a Pilot Clinical Trial.

Background: Oncogenic activation of mitogen-activated protein kinase (MAPK) signaling is associated with radioiodine refractory (RAIR) thyroid cancer. Preclinical models suggest that activation of the receptor tyrosine kinase erbB-3 (HER3) mitigates the MAPK pathway inhibition achieved by BRAF inhibitors in BRAFV600E mutant thyroid cancers. We hypothesized that combined inhibition of BRAF and HER3 using vemurafenib and the human monoclonal antibody CDX-3379, respectively, would potently inhibit MAPK activation and restore radioactive iodine (RAI) avidity in patients with BRAF-mutant RAIR thyroid cancer. Methods: Patients with BRAFV600E RAIR thyroid cancer were evaluated by thyrogen-stimulated iodine-124 (124I) positron emission tomography-computed tomography (PET/CT) at baseline and after 5 weeks of treatment with oral vemurafenib 960 mg twice daily alone for 1 week, followed by vemurafenib in combination with 1000 mg of intravenous CDX-3379 every 2 weeks. Patients with adequate 124I uptake on the second PET/CT then received therapeutic radioactive iodine (131I) with vemurafenb+CDX-3379. All therapy was discontinued two days later. Treatment response was monitored by serum thyroglobulin measurements and imaging. The primary endpoints were safety and tolerability of vemurafenib+CDX-3379, as well as the proportion of patients after vemurafenb+CDX-3379 therapy with enhanced RAI incorporation warranting therapeutic 131I. Results: Seven patients were enrolled; six were evaluable for the primary endpoints. No grade 3 or 4 toxicities related to CDX-3379 were observed. Five patients had increased RAI uptake after treatment; in 4 patients this increased uptake warranted therapeutic 131I. At 6 months, 2 patients achieved partial response after 131I and 2 progression of disease. Next-generation sequencing of 5 patients showed that all had co-occurring telomerase reverse transcriptase promoter alterations. A deleterious mutation in the SWItch/Sucrose Non-Fermentable (SWI/SNF) gene ARID2 was discovered in the patient without enhanced RAI avidity after therapy and an RAI-resistant tumor from another patient that was sampled off-study. Conclusions: The endpoints for success were met, providing preliminary evidence of vemurafenib+CDX-3379 safety and efficacy for enhancing RAI uptake. Preclinical data and genomic profiling in this small cohort suggest SWI/SNF gene mutations should be investigated as potential markers of resistance to redifferentiation strategies. Further evaluation of vemurafenib+CDX-3379 as a redifferentiation therapy in a larger trial is warranted (ClinicalTrials.gov: NCT02456701).

Intraperitoneal Pretargeted Radioimmunotherapy for Colorectal Peritoneal Carcinomatosis.

Peritoneal carcinomatosis (PC) is considered incurable, and more effective therapies are needed. Herein we test the hypothesis that GPA33-directed intracompartmental pretargeted radioimmunotherapy (PRIT) can cure colorectal peritoneal carcinomatosis. Nude mice were implanted intraperitoneally with luciferase-transduced GPA33-expressing SW1222 cells for aggressive peritoneal carcinomatosis (e.g., resected tumor mass 0.369 ± 0.246 g; n = 17 on day 29). For GPA33-PRIT, we administered intraperitoneally a high-affinity anti-GPA33/anti-DOTA bispecific antibody (BsAb), followed by clearing agent (intravenous), and lutetium-177 (Lu-177) or yttrium-86 (Y-86) radiolabeled DOTA-radiohapten (intraperitoneal) for beta/gamma-emitter therapy and PET imaging, respectively. The DOTA-radiohaptens were prepared from S-2-(4-aminobenzyl)-1,4,7, 10-tetraazacyclododecane tetraacetic acid chelate (DOTA-Bn). Efficacy and toxicity of single- versus three-cycle therapy were evaluated in mice 26-27 days post-tumor implantation. Single-cycle treatment ([177Lu]LuDOTA-Bn 111 MBq; tumor dose: 4,992 cGy) significantly prolonged median survival (MS) approximately 2-fold to 84.5 days in comparison with controls (P = 0.007). With three-cycle therapy (once weekly, total 333 MBq; tumor dose: 14,975 cGy), 6/8 (75%) survived long-term (MS > 183 days). Furthermore, for these treated long-term survivors, 1 mouse was completely disease free (microscopic "cure") at necropsy; the others showed stabilized disease, which was detectable during PET-CT using [86Y]DOTA-Bn. Treatment controls had MS ranging from 42-52.5 days (P < 0.001) and 19/20 mice succumbed to progressive intraperitoneal disease by 69 days. Multi-cycle GPA33 DOTA-PRIT significantly prolongs survival with reversible myelosuppression and no chronic marrow (929 cGy to blood) or kidney (982 cGy) radiotoxicity, with therapeutic indices of 12 for blood and 12 for kidneys. MTD was not reached.

Biodistribution and Radiation Dosimetry of Intraperitoneally Administered 124I-Omburtamab in Patients with Desmoplastic Small Round Cell Tumors.

The aim of this study was to assess the pharmacokinetics, biodistribution, and radiation dosimetry of 124I-omburtamab administered intraperitoneally in patients with desmoplastic small round cell tumor. Methods: Eligible patients diagnosed with desmoplastic small round cell tumor with peritoneal involvement were enrolled in a phase I trial of intraperitoneal radioimmunotherapy with 131I-omburtamab. After thyroid blockade and before radioimmunotherapy, patients received approximately 74 MBq of 124I-omburtamab intraperitoneally. Five serial PET/CT scans were obtained up to 144 h after injection. Multiple blood samples were obtained up to 120 h after injection. Organ-absorbed doses were calculated with OLINDA/EXM. Results: Thirty-one patients were studied. Blood pharmacokinetics exhibited a biphasic pattern consisting of an initial rising phase with a median half-time (±SD) of 23 ± 15 h and a subsequent falling phase with a median half-time of 56 ± 34 h. Peritoneal distribution was heterogeneous and diffuse in most patients. Self-dose to the peritoneal cavity was 0.58 ± 0.19 mGy/MBq. Systemic distribution and activity in major organs were low. The median absorbed doses were 0.72 ± 0.23 mGy/MBq for liver, 0.48 ± 0.17 mGy/MBq for spleen, and 0.57 ± 0.12 mGy/MBq for kidneys. The mean effective dose was 0.31 ± 0.10 mSv/MBq. Whole-body and peritoneal cavity biologic half-times were 45 ± 9 and 24 ± 5 h, respectively. Conclusion: PET/CT imaging with intraperitoneally administered 124I-omburtamab enables assessment of intraperitoneal distribution and estimation of absorbed dose to peritoneal space and normal organs before therapy.

The Adsorption Characteristics of Uranium(VI) from Aqueous Solution on Leonardite and Leonardite-Derived Humic Acid: A Comparative Study.

The humic substance is a low-cost and effective adsorbent with abundant functional groups in remediating uranium (U) (VI)-contaminated water. In this research study, leonardite together with leonardite-derived humic acid (L-HA) was used to eliminate U(VI) from water under diverse temperatures (298, 308, and 318 K). L-HA showed a higher adsorption volume for U(VI) than leonardite. U adsorption was varied with pH and increased with temperature. The adsorption kinetics of L-HA had a higher determination coefficient (R2) for pseudo-second-order (R2 > 0.993) and Elovich (R2 > 0.987) models, indicating possible chemisorption-assisted adsorption. This was further supported with the activation energies (15.9 and 13.2 kJ/mol for leonardite and L-HA, respectively). Moreover, U(VI) equilibrium adsorption on leonardite was better depicted with the Freundlich model (R2 > 0.970), suggesting heterogeneous U(VI) adsorption onto the leonardite surface. However, U(VI) adsorption onto L-HA followed the Langmuir equation (R2 > 0.971), which implied the dominant role of monolayer adsorption in controlling the adsorption process. Thermodynamic parameters, including standard entropy change (ΔS0 > 0), Gibbs free energy (ΔG0 < 0), and standard enthalpy change (ΔH0 > 0), suggested a spontaneous and endothermal adsorption process. In addition, ionic species negatively affected U(VI) adsorption by leonardite and L-HA.