(University of Chicago Press Journals) Extensive cooperation among biologically unrelated individuals is uniquely human. It would be surprising if this uniqueness were not related to other uniquely human characteristics, yet current theories of human cooperation tend to ignore the human aspects of human behavior. This paper presents a theory of cooperation that draws on social, cultural, and psychological aspects of human uniqueness for which current theories have little or no explanation.

(Universitat Pompeu Fabra - Barcelona) Expansions by groups of humans were common during prehistoric times, after the adoption of agriculture. Among other factors, this is due to population growth of farmers which was greater than of that hunter-gatherers. We can find one example of this during the Neolithic period, when farming was introduced to Europe by migrations from the Middle East.

There aren’t a ton of synonyms for the word “hypocrisy.” I’ve become aware of this problem ever since I began writing about the Tara Reade–Joe Biden situation. I keep gravitating towards phrases such as “despicable hypocrisy,” or “partisan hypocrisy,” or “unconscionable hypocrisy,” but you can only go to the well so often. Really, though, I’m not sure how else to describe the actions of someone like Senator Dianne Feinstein.You might recall that it was Feinstein, the ranking member of the Judiciary Committee, who withheld Christine Blasey Ford's allegation of sexual misconduct against Supreme Court nominee Brett Kavanaugh from the Senate so that it could not be properly vetted, in a last-ditch effort to sink the nomination.Feinstein knew that Ford's credibility was brittle -- the alleged victim could not tell us where or when the attack occurred, hadn’t mentioned Kavanugh’s name to anyone for over 30 years, and offered nothing approaching a contemporaneous witness.At first, Feinstein did not want to provide Ford’s name, or a place or time of the alleged attack, or allow the accused to see any evidence against him, denying him the ability to answer the charges.Henceforth this brand of justice could be referred to as “The Joe Biden Standard,” since it’s exactly the kind of show trial the presumptive Democratic nominee promises college kids via Title IX rules.When finally asked about Reade yesterday, Feinstein responded: “And I don’t know this person at all who has made the allegations. She came out of nowhere. Where has she been all these years? He was vice president.”To put this in perspective, when Ford came forward “out of nowhere,” Feinstein said: “Victims must be able to come forward only when they are ready.”What’s changed?During the Kavanaugh hearings Feinstein noted that “sharing an experience involving sexual assault — particularly when it involves a politically connected man with influence, authority and power — is extraordinarily difficult.”Is Biden not a politically connected man with influence, authority, and power? Feinstein is now arguing the opposite: She is saying we should dismiss Reade’s allegations because she failed to come forward against a powerful man earlier.But to answer Feinstein’s question about what Reade has been “up to” the past 27 years: Well, she’s been telling people that Biden had engaged in sexual misconduct. She relayed her story to her former neighbor, her brother, her former co-worker, and at least two other friends. It is also likely that her mother called Larry King Live asking for advice for her daughter the year of the alleged attack.Yesterday a document uncovered by local journalists in California -- somehow missed by Barack Obama’s crack vetting team -- shows Reade’s ex-husband bolstering her claim in 1996 divorce proceedings: “On several occasions [Reade] related a problem that she was having at work regarding sexual harassment, in U.S. Senator Joe Biden's office.”The reaction to the divorce papers has been extraordinary. Biden defenders argue that because Reade alleged “sexual harassment” -- a catch-all term used in the 1990s when men were getting away with despicable behavior far more often -- it proves her story has changed. Biden, through his deputy campaign manager Kate Bedingfield, alleges that “more and more inconsistencies” come up every day.Even if Reade didn't tell everyone everything that allegedly happened every time she mentioned the incident, that doesn’t definitively prove anything. If it did, none of us would have ever heard the name Christine Blasey Ford.Indeed, at time of Ford’s evolving story, there was a slew of journalists taking deep dives into the unreliability of memory and trauma and complexities of relaying assault allegations. I assume that science hasn’t changed in two years.Let’s also not forget that, despite Ford’s inconsistencies, Biden still argued that Kavanaugh should be presumed guilty. Why shouldn’t he?It is also quite amazing to see Biden’s defenders implicitly contending that Reade is only credibly claiming that she was sexually harassed for nearly 30 years, so her story must be politically motivated.Even if we concede that Reade is a wily Sanders operative or Putin stooge, what political motive could Reade possibly have had back in 1993 -- after working for Biden -- to smear the senator? What motive did she have to repeat that story to her family before Sanders was a candidate or Putin was running Russia?By the way, liberals have never argued that political motivations should be disqualifying. Ford came forward, by her own admission, because she did not believe the man who had allegedly assaulted her in high school should be given a seat on highest court in the land. Reade says she doesn’t want a man who allegedly assaulted her -- when he was in his 50s -- to hold the most powerful office in the world.Feinstein, of course, isn’t the only one to engage in this kind of transparent double standard. When asked about Reade, the idealist Alexandria Ocasio-Cortez, said, “I’m not sure. Frankly, this is a messy moment, and I think we need to acknowledge that -- that it is not clear-cut.”Where was all this hand-wringing and caution over the messiness of sexual-assault claims when nearly every Democrat and all their allies in the press were spreading Julie Swetnick’s alleged “gang rape” piece? Nowhere.AOC, whose position on Biden has evolved, invited Ana Maria Archila, the women who had famously cornered a weak-kneed senator Jeff Flake in an elevator and yelled at him about Kavanaugh, to the 2019 State of the Union address. Archila now says, “I feel very trapped.”I bet.People point out that there are numerous sexual-misconduct allegations leveled at Donald Trump. Indeed. If they haven’t yet, news outlets should scrutinize and investigate the credibility of those allegations, as they did for Biden but not for Kavanaugh. But it’s important to remember that Trump accuser E. Jean Carroll was given immediate and widespread coverage on cable news, while Reade reportedly wasn’t asked to tell her story by any major network -- save Fox News -- until this week.Of course, most Biden defenders are being purposely obtuse about the debate -- Mona Charen’s recent column is an excellent example. The problem isn’t that Biden is being treated unjustly, or that he should be treated unjustly; it’s that he is being treated justly by the same people who treat others unjustly. Democrats have yet to explain why Biden is afforded every benefit of the doubt but not Kavanaugh, and not millions of college students.Public figures such as Biden have every right to demand fair hearings and due process. Voters have every right to judge the credibility of both accuser and accused. Many women are victims. Many women are victims who are powerless to prove it. And some women are frauds. You can’t keep demanding that our political system adjudicate similar incidents under two completely differ set of rules. It’s untenable.

The budget carrier will begin conducting temperature checks via touchless thermometers on June 1. Passengers have to start wearing masks Friday.

(American Geriatrics Society) The COVID-19 pandemic has placed unprecedented pressure on societies worldwide, given the pandemic's rapid, often deadly spread. In health care, the pandemic has raised the pressing question of how society should allocate scarce resources during a crisis. This is the question experts addressed today in a new position statement published by the American Geriatrics Society (AGS) in the Journal of the American Geriatrics Society (DOI: 10.1111/jgs.16537).

(American Association for the Advancement of Science) While an effective vaccine for the SARS-CoV-2 virus is likely many months away, development could be accelerated by conducting controlled human infection (CHI) studies -- which are increasingly being considered by the scientific community due to the urgent need.

(University of Tsukuba) Researchers from the University of Tsukuba discovered that fish schools showed a significant change in behavior with varying school sizes. Using integrated information theory, they showed that a significant change in the interaction between the fish and the overall collective behavior occurred between three- and four-fish schools, including the emergence of leadership within the group. These findings help understand the dynamics of collective behavior.

Teri L. Hernandez
May 1, 2016; 29:82-88
From Research to Practice

Curtis Triplitt
Oct 1, 2006; 19:202-211
Pharmacy Update

Richard O. White
Oct 1, 2010; 23:238-243
Articles

Carlos E. Mendez
Aug 1, 2014; 27:180-188
From Research to Practice

Cynthia Payne
Aug 1, 2001; 14:
Preface

Belinda S. O’Connell
Aug 1, 2001; 14:
Articles

Emmy Suhl
Oct 1, 2006; 19:234-240
Articles

Russell E. Glasgow
Apr 1, 2001; 14:
Feature Articles

As the pandemic ebbed in China, alumni from the region raised more than $2.1 million to send crucial protective gear to New York healthcare workers.

12 June 2019

Research Event

Event participants

Douglas, Legal Director, GCHQ
Zhixiong Huang, Luojia Chair of International Law, Wuhan University
Nemanja Malisevic, Director of Digital Diplomacy, Microsoft
Harriet Moynihan, Associate Fellow, International Law Programme, Chatham House
Chair: Elizabeth Wilmshurst, Distinguished Fellow, International Law Programme, Chatham House

2 December 2019

Hostile cyber operations by one state against another state are increasingly common. This paper analyzes the application of the sovereignty and non-intervention principles in relation to states’ cyber operations in another state below the threshold of the use of force. 

The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A2-mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA2γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses sn-1 specificity, with polyunsaturated fatty acids at the sn-2 position generating polyunsaturated sn-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-LOX) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-LOX oxidation products, 12(S)-HETE-LPC and 12(S)-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA2γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-LOX inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA2γ genetic ablation. Collectively, these results identify previously unknown iPLA2γ-initiated signaling pathways mediated by direct 12-LOX oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions.

Fabry disease is a heritable lipid disorder caused by the low activity of α-galactosidase A and characterized by the systemic accumulation of globotriaosylceramide (Gb3). Recent studies have reported a structural heterogeneity of Gb3 in Fabry disease, including Gb3 isoforms with different fatty acids and Gb3 analogs with modifications on the sphingosine moiety. However, Gb3 assays are often performed only on the selected Gb3 isoforms. To precisely determine the total Gb3 concentration, here we established two methods for determining both Gb3 isoforms and analogs. One was the deacylation method, involving Gb3 treatment with sphingolipid ceramide N-deacylase, followed by an assay of the deacylated products, globotriaosylsphingosine (lyso-Gb3) and its analogs, by ultra-performance LC coupled to tandem MS (UPLC-MS/MS). The other method was a direct assay established in the present study for 37 Gb3 isoforms and analogs/isoforms by UPLC-MS/MS. Gb3s from the organs of symptomatic animals of a Fabry disease mouse model were mainly Gb3 isoforms and two Gb3 analogs, such as Gb3(+18) containing the lyso-Gb3(+18) moiety and Gb3(−2) containing the lyso-Gb3(−2) moiety. The total concentrations and Gb3 analog distributions determined by the two methods were comparable. Gb3(+18) levels were high in the kidneys (24% of total Gb3) and the liver (13%), and we observed Gb3(−2) in the heart (10%) and the kidneys (5%). These results indicate organ-specific expression of Gb3 analogs, insights that may lead to a deeper understanding of the pathophysiology of Fabry disease.

Pathogenic bacteria of the genera Mycobacterium and Corynebacterium cause severe human diseases such as tuberculosis (Mycobacterium tuberculosis) and diphtheria (Corynebacterium diphtheriae). The cells of these species are surrounded by protective cell walls rich in long-chain mycolic acids. These fatty acids are conjugated to the disaccharide trehalose on the cytoplasmic side of the bacterial cell membrane. They are then transported across the membrane to the periplasm where they act as donors for other reactions. We have previously shown that transient acetylation of the glycolipid trehalose monohydroxycorynomycolate (hTMCM) enables its efficient transport to the periplasm in Corynebacterium glutamicum and that acetylation is mediated by the membrane protein TmaT. Here, we show that a putative methyltransferase, encoded at the same genetic locus as TmaT, is also required for optimal hTMCM transport. Deletion of the C. glutamicum gene NCgl2764 (Rv0224c in M. tuberculosis) abolished acetyltrehalose monocorynomycolate (AcTMCM) synthesis, leading to accumulation of hTMCM in the inner membrane and delaying its conversion to trehalose dihydroxycorynomycolate (h2TDCM). Complementation with NCgl2764 normalized turnover of hTMCM to h2TDCM. In contrast, complementation with NCgl2764 derivatives mutated at residues essential for methyltransferase activity failed to rectify the defect, suggesting that NCgl2764/Rv0224c encodes a methyltransferase, designated here as MtrP. Comprehensive analyses of the individual mtrP and tmaT mutants and of a double mutant revealed strikingly similar changes across several lipid classes compared with WT bacteria. These findings indicate that both MtrP and TmaT have nonredundant roles in regulating AcTMCM synthesis, revealing additional complexity in the regulation of trehalose mycolate transport in the Corynebacterineae.

Beatriz Rocha
Apr 1, 2020; 19:574-588
Research

Katrina Meyer
Apr 28, 2020; 0:R120.002034v1-mcp.R120.002034
Review

Elena Lorente
Apr 7, 2020; 0:RA120.002014v1-mcp.RA120.002014
Research

Liye Chen
May 1, 2020; 19:871-883
Research

Yan Zhou Tran
Mar 31, 2020; 0:RA120.002036v1-mcp.RA120.002036
Research

Andreas Linden
Apr 24, 2020; 0:RA120.002028v1-mcp.RA120.002028
Research

Karl A. T. Makepeace
Apr 1, 2020; 19:624-639
Research

Dorte B. Bekker-Jensen
Apr 1, 2020; 19:716-729
Technological Innovation and Resources

Invitation Only Research Event

2 July 2019

29 August 2019

As more space activities develop, there is an increasing requirement for comprehensive space situational awareness (SSA). This paper provides an overview of the current landscape in SSA and space traffic management as well as possible scenarios for EU–US cooperation in this area. 

Invitation Only Research Event

Event participants

Beyza Unal, Senior Research Fellow, International Security Department, Chatham House
Patricia Lewis, Research Director, International Security Department, Chatham House

3 October 2019

Disinformation, as the latest iteration of propaganda suitable for a digitally interconnected world, shows no signs of abating. This paper provides a holistic overview of the current state of play and outlines how EU and US cooperation can mitigate disinformation in the future.

21 January 2020

Discussions of North African integration have evoked ideas of a shared identity and a common destiny in the region. However, recent attempts to build regional blocs in North Africa have been unsuccessful. This paper examines the benefits of a ‘synergistic’ approach to North African cooperation. 

Research Event

Event participants

Osamah Al Rawhani, Deputy Director, Sana’a Center for Strategic Studies
Moderator: Nadim Houry, Executive Director, Arab Reform Initiative

7 April 2020

The currently available therapeutic radiopharmaceutical for high-risk neuroblastoma, ¹³¹I-MIBG, is ineffective at targeting micrometastases due to the low linear energy transfer (LET) properties of high-energy beta particles. In contrast, Auger radiation has high-LET properties with nanometer ranges in tissue, efficiently causing DNA damage when emitted in close proximity to DNA. The aim of this study was to evaluate the cytotoxicity of targeted Auger therapy in pre-clinical models of high-risk neuroblastoma. Methods: Using a radiolabeled poly(ADP-ribose) polymerase (PARP) inhibitor, ¹²⁵I-KX1, we delivered an Auger emitter iodine-125 to PARP-1: a chromatin-binding enzyme overexpressed in neuroblastoma. In vitro cytotoxicity of ¹²⁵I-KX1 was assessed in nineteen neuroblastoma cell lines, followed by in-depth pharmacological analysis in a sensitive and resistant pair of cell lines. Immunofluorescence microscopy was used to characterize ¹²⁵I-KX1-induced DNA damage. Finally, in vitro/in vivo microdosimetry was modeled from experimentally derived pharmacological variables. Results: ¹²⁵I-KX1 was highly cytotoxic in vitro across a panel of neuroblastoma cell lines, directly causing double strand DNA breaks. Based on subcellular dosimetry, ¹²⁵I-KX1 was approximately twice as effective compared to ¹³¹I-KX1, whereas cytoplasmic ¹²⁵I-MIBG demonstrated low biological effectiveness. Despite the ability to deliver focused radiation dose to the cell nuclei, ¹²⁵I-KX1 remained less effective than its alpha-emitting analog ²¹¹At-MM4, and required significantly higher activity for equivalent in vivo efficacy based on tumor microdosimetry. Conclusion: Chromatin-targeted Auger therapy is lethal to high-risk neuroblastoma cells with potential use in micrometastatic disease. This study provides the first evidence for cellular lethality from a PARP-1 targeted Auger emitter, calling for further investigation into targeted Auger therapy.

Objective: To investigate the lesion detection rate of ¹⁸F-DCFPyL-PET/CT, a prostate-specific membrane antigen (PSMA) targeted PET agent, in biochemical relapse prostate cancer patients after primary local therapy. Methods: This is a prospective institutional review board-approved study of 90 patients with documented biochemical recurrence (median PSA 2.5 ng/mL, range 0.21-35.5 ng/mL) with negative conventional imaging after primary local therapies, including radical prostatectomy (n = 38), radiation (n = 27) or combination (n = 25). Patients on androgen deprivation therapy were excluded. Patients underwent whole-body ¹⁸F-DCFPyL-PET/CT (299.9±15.5 MBq) at 2 h p.i. PSMA-PET lesion detection rate was correlated with PSA, PSA kinetics and original primary tumor grade. Results: Seventy patients (77.8%) showed a positive PSMA-PET scan, identifying a total of 287 lesions: 37 prostate bed foci, 208 lymph nodes, and 42 bone/organ distant sites; 11 patients had a negative scan and 9 patients showed indeterminate lesions, which were considered negative in this study. The detection rates were 47.6% (n = 10/21), 50% (n = 5/10), 88.9% (n = 8/9), and 94% (n = 47/50) for PSA >0.2 to <0.5, 0.5 to <1.0, 1 to <2.0, and ≥2.0 ng/mL, respectively. In post-surgical patients, PSA, PSAdt and PSAvel correlated with PET results but the same was not true for post-radiation patients. These parameters also correlated with the extent of disease on PET (intrapelvic vs. extrapelvic). There was no significant difference between the rate of positive scans in patients with higher grade vs lower grade primary tumors (Gleason score ≥4+3 vs <3+4). Tumor recurrence was histology confirmed in 40% (28/70) of patients. On a per-patient basis, positive predictive value was 93.3% (95% CI, 77.6-99.2%) by histopathologic validation, and 96.2% (95% CI, 86.3-99.7%) by the combination of histology and imaging/clinical follow-up. Conclusion: ¹⁸F-DCFPyL-PET/CT imaging offers high detection rates in biochemically recurrent prostate cancer patients; and is positive in about 50% of patients with PSA <0.5 ng/mL, which could substantially impact clinical management. In post-surgical patients, ¹⁸F-DCFPyL-PET/CT correlates with PSA, PSAdt and PSAvel suggesting it may have prognostic value. ¹⁸F-DCFPyL-PET/CT is highly promising for localizing sites of recurrent prostate cancer.

Rationale: Lymphatic tracers can help visualize the lymphatic drainage patterns and sentinel nodes of individual prostate cancer patients. To determine the role of nuclear medicine, in particular the positional guidance of a SPECT/CT-based 3D imaging roadmap, in this process we studied to which extend fluorescence-guidance underestimated the number of target lesions. Methods: SPECT/CT imaging was performed after intraprostatic tracer administration of either ICG-^99mTc-nanocolloid (hybrid tracer group) or ^99mTc-nanocolloid to create a roadmap that depicted all sentinel nodes (SNs). Patients who received ^99mTc-nanocolloid were injected with "free" ICG immediately prior to surgery ("free" ICG group). Before unblinding, fluorescence-guidance was used for intraoperative SN identification. This was followed by extended pelvic lymph node dissection (ePLND). Following unblinding of the SPECT/CT images, the number of missed SN’s were recorded and their resection was pursued when the anatomy allowed. Results: Preoperative SPECT/CT revealed no differences in the SN identification rate between ICG-^99mTc-nanocolloid and ^99mTc-nanocolloid. However, fluorescence-guidance only allowed intraoperative removal of all SNs in 40% of patients in the hybrid tracer group and in 20% of patients in the "free" ICG group. Overall, 75.9% of the intraoperatively resected SNs in the hybrid tracer group and 51.8% of the SNs in the "free" ICG group were removed solely under fluorescence-guidance. During ePLND 22 additional SNs were resected (7 in the hybrid tracer group and 15 in the "free" ICG group). After unblinding 18 remaining SNs were identified (6 in the hybrid group and 12 in the "free" ICG group). In the "free" ICG group, ex vivo evaluation of the excised specimens revealed that 14 SNs removed under ePLND or after unblinding contained radioactivity but no fluorescence. Conclusion: The preoperative imaging roadmap provided by SPECT/CT enhanced the detection of prostate SNs in more ectopic locations in 17 of the 25 patients and the hybrid tracer ICG-^99mTc-nanocolloid was shown to outperform "free" ICG. Overall, fluorescence-guided pelvic nodal surgery underestimated the number of SNs in 60-80% of patients.

Numerous recent works highlight the limited utility of established tumor cell lines in recapitulating the heterogeneity of tumors in patients. More realistic preclinical cancer models are thought to be provided by transplantable, patient-derived tumor xenografts (PDX). Inter- and intra-tumor heterogeneity of PDX, however, present several challenges in developing optimal quantitative pipelines to assess response to therapy. The objective of this work was to develop and optimize image metrics of FDG-PET to assess response to combination docetaxel/carboplatin therapy in a co-clinical trial involving triple negative breast cancer (TNBC) PDX. We characterize the reproducibility of SUV metrics to assess response to therapy and optimize a preclinical PERCIST (µPERCIST) paradigm to complement clinical standards. Considerations in this effort included variability in tumor growth rate and tumor size; solid tumor vs. tumor heterogeneity and necrotic phenotype; and optimal selection of tumor slice versus whole tumor. A test-retest protocol was implemented to optimize the reproducibility of FDG-PET SUV thresholds, SUVpeak metrics, and µPERCIST parameters. In assessing response to therapy, FDG-PET imaging was performed at baseline and +4 days following therapy. The reproducibility, accuracy, variability, and performance of imaging metrics to assess response to therapy were determined. We defined an index—"Quantitative Response Assessment Score (QRAS)"—to integrate parameters of prediction and precision, and thus aid in selecting optimal image metrics of response to therapy. Our data suggests that a threshold value of 25% (SUV25) of SUVmax was highly reproducible (<9% variability). Concordance and reproducibility of µPERCIST were maximized at α=0.7 and β=2.8 and exhibited high correlation to SUV25 measures of tumor uptake. QRAS scores favor SUV25 followed by SUVP14 as optimal metrics of response to therapy. Additional studies are warranted to fully characterize the utility of SUV25 and µPERCIST SUVP14 as image metrics of response to therapy across a wide range of therapeutic regiments and PDX models.

Objectives: Lutetium-177 (¹⁷⁷Lu)-PSMA-617 (LuPSMA) is a radioligand with high affinity for prostate specific membrane antigen (PSMA) enabling targeted beta-irradiation of prostate cancer. We have previously reported favorable activity with low toxicity in a prospective phase II trial involving 30 men with metastatic castrate-resistant prostate cancer (mCRPC). We now report their longer-term outcomes including a 20 patient extension cohort and outcomes of subsequent systemic treatments following completion of trial therapy. Methods: 50 patients with PSMA-avid mCRPC who had progressed after standard therapies received up to 4 cycles of LuPSMA every 6 weeks. Endpoints included PSA response (PCWG2), toxicity (CTCAE v4.03), imaging response, patient-reported health-related quality of life (QoL), progression-free and overall survival. We also describe, as a novel finding, outcomes of men who subsequently progressed and had further systemic therapies, including LuPSMA. Results: 75 men were screened to identify 50 patients eligible for treatment. Adverse prognostic features of the cohort included short median PSA doubling time (2.3 months) and extensive prior treatment including prior docetaxel (84%), cabazitaxel (48%), and abiraterone and/or enzalutamide (90%). The mean administered radioactivity was 7.5 GBq/cycle. PSA decline ≥ 50% was achieved in 32 of 50 patients (64%, 95% CI 50-77%), including 22 patients (44%, 95% CI 30-59%) with ≥ 80% decrease. Of 27 patients with measurable soft tissue disease, 15 (56%) achieved an objective response by RECIST 1.1. The most common toxicities attributed to LuPSMA were self-limiting G1-2 dry mouth (66%), transient G1-2 nausea (48%), G3-4 thrombocytopenia (10%) and G3 anemia (10%). Brief pain inventory severity and interference scores decreased at all time points including at the 3 month follow-up with a decrease of -1.2 (95% CI -0.5 to -1.9, P = 0.001) and 1.0 (95% CI -0.2 to -0.18, P = 0.013), respectively. At a median follow-up of 31.4 months, median OS was 13.3 months (95% CI 10.5-18.7) with a significantly longer survival of 18.4 months (95% CI 13.8-23.8) in patients achieving a PSA decline ≥ 50%. At progression following prior response, further LuPSMA was administered to 15 (30%) patients (median 2 cycles commencing 359 days from enrolment) with PSA decline ≥ 50% in 11 patients (73%). 4 of 21 patients (19%) receiving other systemic therapies upon progression experienced PSA decline ≥ 50%. There were no unexpected adverse events with LuPSMA re-treatment. Conclusion: This expanded 50 patient cohort of men with extensive prior therapy confirms our earlier report of high response rates, low toxicity and improved QoL with LuPSMA radioligand therapy. Upon progression, re-challenge LuPSMA demonstrated higher response rates than other systemic therapies.

Purpose: The aim of this retrospective multicentric study was to develop and evaluate a prognostic FDG PET/CT radiomics signature in early-stage non-small cell lung cancer (NSCLC) patients treated with stereotactic radiotherapy (SBRT). Material and Methods: Patients from 3 different centers (n = 27, 29 and 8) were pooled to constitute the training set, whereas the patients from a fourth center (n = 23) were used as the testing set. The primary endpoint was local control (LC). The primary tumour was semi-automatically delineated in the PET images using the Fuzzy locally adaptive Bayesian algorithm, and manually in the low-dose CT images. A total of 184 IBSI-compliant radiomic features were extracted. Seven clinical and treatment parameters were included. We used ComBat to harmonize radiomic features extracted from the four institutions relying on different PET/CT scanners. In the training set, variables found significant in the univariate analysis were fed into a multivariate regression model and models were built by combining independent prognostic factors. Results: Median follow-up was 21.1 (1.7 – 63.4) and 25.5 (7.7 – 57.8) months in training and testing sets respectively. In univariate analysis, none of the clinical variables, 2 PET and 2 CT features were significantly predictive of LC. The best predictive models in the training set were obtained by combining one feature from PET, namely information correlation 2 (IC2) and one from CT (Flatness), reaching a sensitivity of 100% and a specificity of 96%. Another model combining 2 PET features (IC2 and Strength), reached sensitivity of 100% and specificity of 88%, both with an undefined hazard ratio (HR) (p<0.001). The latter model obtained an accuracy of 0.91 (sensitivity 100%, specificity 81%), with a HR undefined (P = 0.023) in the testing set, however other models relying on CT radiomics features only or the combination of PET and CT features failed to validate in the testing set. Conclusion: We showed that two radiomic features derived from FDG PET were independently associated with LC in patients with NSCLC undergoing SBRT and could be combined in an accurate predictive model. This model could provide local relapse-related information and could be helpful in clinical decision-making.

Objectives: The detection of cancer micrometastasis for early diagnosis and treatment poses a great challenge for conventional imaging techniques. The aim of study is to evaluate the performance of photoacoustic imaging (PAI) in detecting hepatic micrometastases from melanoma in a very early stage and perform tumor resection by intraoperative photoacoustic image-guidance. Methods: In vivo studies were performed by following protocols approved by the Ethical Committee for Animal Research at Xiamen University. First, a B16 melanoma hepatic metastasis mouse model (n = 10) was established to study the development of micrometastases in vivo. Next, the hepatic metastasis mice models were imaged by scalable PAI instrument, ultrasound, 9.4 T high-resolution magnetic resonance imaging (MRI), positron emission tomography/computed tomography (PET/CT), and bioluminescence imaging. Photoacoustic images acquired with optical wavelengths spanning from 680 to 850 nm were spectrally unmixed by using a linear least-squares method to differentiate various components. Differences in the signal-to-background ratios among different modalities were determined with the two-tailed paired t test. The diagnosis results were assessed with histologic examinations. Excised liver samples from patients diagnosed with hepatic cancer were also examined to identify tumor boundary. In vivo metastatic melanoma removal in surgery was precisely guided by the portable PAI system. Results: PAI achieved as small as ~400 µm hepatic melanoma detection at a depth up to 7 mm in vivo, which could early detect small melanoma compared with ultrasound and MRI in mouse models. The signal ratio of tumor-to-liver acquired with PAI in micrometastases at 8 days (4.2 ± 0.2, n = 6) and 14 days (9.2 ± 0.4, n = 5) were significantly higher than those obtained with PET/CT (1.8 ± 0.1, n = 5 and 4.5 ± 0.2, n = 5, P <0.001 for both). Functional PAI provided dynamic oxygen saturation changes during tumor growth. The limit of detection was measured to be approximately 219 cells per microliter in vitro. We successfully performed intraoperative photoacoustic image-guided surgery in vivo using the rapid portable PAI system. Conclusion: Our findings offer a rapid and effective tool to noninvasively detect micrometastases and guide intraoperative resection as a complementary clinical imaging application.

Calculation of radiation dosimetry in targeted nuclear medicine therapies is traditionally resource-intensive requiring multiple post-therapy SPECT acquisitions. An alternative approach is to take advantage of existing pharmacokinetic data from these smaller cohorts to enable dose computation from a single post-treatment scan in a manner that may be applied to a much broader patient population. Methods: In this work, a technical description for simplified dose estimation is presented and applied to assessment of ¹⁷⁷Lu-PSMA-617 therapy (Prostate-Specific Membrane Antigen) for metastatic prostate cancer. By normalizing existing time-activity curves to a single measurement time, it is possible to calculate a mean and range of time-integrated activity values which relate to radiation absorbed dose. To assist with accurate pharmacokinetic modelling of the training cohort, a method for contour-guided image registration was developed. Results: Tissue-specific dose conversion factors for common post-treatment imaging times are reported along with a characterization of added uncertainty in comparison to a traditional serial imaging protocol. Single time point dose factors for tumor were determined to be 11.0, 12.1, 13.6, and 15.2 Gy per MBq/mL at image times of 24, 48, 72, and 96 hours, respectively. For normal tissues, parotid gland factors were 6.7, 9.4, 13.3, and 19.3 Gy per MBq/mL and kidneys were 7.1, 10.3, 15.0, and 22.0 Gy per MBq/mL at those times. Tumor dose estimates were most accurate using delayed scanning at times beyond 72 hours. Dose to healthy tissues is best characterized by scanning patients in the first two days of treatment owing to the larger degree of tracer clearance in this early phase. Conclusion: The work demonstrates a means for efficient dose estimation in ¹⁷⁷Lu-PSMA-617 therapy. By providing methods to simplify and potentially automate radiation dosimetry we hope to accelerate the understanding of radiobiology and development of dose-response models in this unique therapeutic context.

Background: Accurate definition of the extent and severity of left-ventricular assist device (LVAD) infection may facilitate therapeutic decision making and targeted surgical intervention. Here, we explore the value of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for guidance of patient management. Methods: Fifty-seven LVAD-carrying patients received 85 whole-body ¹⁸F-FDG PET/CT scans for the work-up of device infection. Clinical follow-up was obtained over a period of up to two years. Results: PET/CT showed various patterns of infectious involvement of the 4 LVAD components: driveline entry point (77% of cases), subcutaneous driveline path (87%), pump pocket (49%) and outflow tract (58%). Driveline smears revealed staphylococcus or pseudomonas strains as the underlying pathogen in a majority of cases (48 and 34%, respectively). At receiver-operating characteristics analysis, an ¹⁸F-FDG standardized uptake value (SUV) >2.5 was most accurate to identify smear-positive driveline infection. Infection of 3 or all 4 LVAD components showed a trend towards lower survival vs infection of 2 or less components (P = 0.089), while involvement of thoracic lymph nodes was significantly associated with adverse outcome (P = 0.001 for nodal SUV above vs below median). Finally, patients that underwent early surgical revision within 3 months after PET/CT (n = 21) required significantly less inpatient hospital care during follow-up when compared to those receiving delayed surgical revision (n = 11; p<0.05). Conclusion: Whole-body ¹⁸F-FDG PET/CT identifies the extent of LVAD infection and predicts adverse outcome. Initial experience suggests that early image-guided surgical intervention may facilitate a less complicated subsequent course.

Due to improvements in quantitative SPECT/CT, voxel-based dosimetry for radionuclide therapies has aroused growing interest as it promises the visualization of absorbed doses at a voxel level. In this work, SPECT/CT-based voxel-based dosimetry of a 3D printed 2-compartment kidney phantom was performed, and the resulting absorbed dose distributions were examined. Additionally, the potential of the PETPVC partial-volume correction tool was investigated. Methods: Both kidney compartments (70% cortex, 30% medulla) were filled with different activity concentrations and SPECT/CT imaging was performed. The images were reconstructed using varying reconstruction settings (iterations, subsets, and post-filtering). Based on these activity concentration maps, absorbed dose distributions were calculated with pre-calculated ¹⁷⁷Lu voxel S values and an empirical kidney half-life. An additional set of absorbed doses was calculated after applying PETPVC for partial-volume correction of the SPECT reconstructions. Results: SPECT/CT imaging blurs the two discrete sub-organ absorbed dose values into a continuous distribution. While this effect is slightly improved by applying more iterations, it is enhanced by additional post-filtering. By applying PETPVC, the absorbed dose values are separated into 2 peaks. Although this leads to a better agreement between SPECT/CT-based and nominal values, considerable discrepancies remain. In contrast to the calculated nominal absorbed doses of 7.8/1.6 Gy (cortex/medulla), SPECT/CT-based voxel-level dosimetry resulted in mean absorbed doses ranging from 3.0-6.6 Gy (cortex) and 2.7-5.1 Gy (medulla). PETPVC led to improved ranges of 6.1-8.9 Gy (cortex) and 2.1-5.4 Gy (medulla). Conclusion: Our study shows that ¹⁷⁷Lu quantitative SPECT/CT imaging leads to voxel-based dose distributions largely differing from the real organ distribution. SPECT/CT imaging and reconstruction deficiencies might directly translate into unrealistic absorbed dose distributions, thus questioning the reliability of SPECT-based voxel-level dosimetry. Therefore, SPECT/CT reconstructions should be adapted to ensure an accurate quantification of the underlying activity and, therefore, absorbed dose in a volume-of-interest of the expected object size (e.g. organs, organ sub-structures, lesions or voxels). As an example, PETPVC largely improves the match between SPECT/CT-based and nominal dose distributions. In conclusion, the concept of voxel-based dosimetry should be treated with caution. Specifically, it should be kept in mind that the absorbed dose distribution is mainly a convolved version of the underlying SPECT reconstruction.

Triple negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer leading to the worst prognosis. Because current therapeutic approaches lack efficacy, there is a clinically unmet need for effective treatment alternatives. Herein, we demonstrate a promising strategy utilizing a tumor-targeting alkylphosphocholine (NM600) radiolabeled with ¹⁷⁷Lu for targeted radionuclide therapy (TRT) of TNBC. In two murine syngeneic models of TNBC, we confirmed excellent tumor targeting and rapid normal tissue clearance of the PET imaging analog ⁸⁶Y-NM600. Based on longitudinal PET/CT data acquired with ⁸⁶Y-NM600, we estimated the dosimetry of therapeutic ¹⁷⁷Lu-NM600, which showed larger absorbed doses in the tumor compared to normal tissues. Administration of ¹⁷⁷Lu-NM600 resulted in significant tumor growth inhibition and prolonged overall survival in mice bearing syngeneic 4T07 and 4T1 tumors. Complete response was attained in 60% of 4T07 bearing mice, but animals carrying aggressive 4T1 tumor grafts succumbed to metastatic progression. The injected activities used for treatment (9.25 and 18.5 MBq) were well tolerated, and only mild transient cytopenia was noted. Overall, our results suggest that ¹⁷⁷Lu-NM600 TRT has potential for treatment of TNBC and merits further exploration in a clinical setting.

Multiple myeloma (MM) is a plasma cell cancer and represents the second most frequent hematological malignancy. Despite new treatments and protocols including high doses chemotherapy associated with autologous stem cell transplantation, the prognosis of MM patients is still poor. Alpha-radioimmunotherapy (alpha-RIT) represents an attractive treatment strategy due to the high linear energy transfer and short path length of alpha-radiation in tissues, resulting in high tumor cell killing and low toxicity to surrounding tissues. In this study, we investigated the potential of alpha-RIT with ²¹²Pb-Daratumumab (anti-CD38), in both in vitro and in vivo models, as well as an anti-mouse CD38 antibody using in vivo models. Methods: Inhibition of cell proliferation after incubation of RPMI8226 cell line with increasing activities (0.185-3.7 kBq/ml) of ²¹²Pb-isotypic control or ²¹²Pb-Daratumumab was evaluated. Biodistribution was performed in vivo by SPECT-CT imaging and post-mortem. Dose range finding (DRF) and acute toxicity studies were conducted. As Daratumumab does not bind the murine CD38, biodistribution and DRF were also determined using an anti-murine CD38 antibody. To evaluate in vivo efficacy of ²¹²Pb-Daratumumab, mice were engrafted subcutaneously with 5.106 RPMI8226 cells. Mice were treated 13 days post-engraftment with an intravenous injection of ²¹²Pb-Daratumumab or control solutions. Therapeutic efficacy was monitored by tumor volume measurements and overall survival. Results: Significant inhibition of proliferation of the human myeloma RPMI8226 cell line was observed after three days of incubation with ²¹²Pb-Daratumumab compared to ²¹²Pb-Isotypic Control or cold antibodies. Biodistribution studies showed a specific tumoral accumulation of Daratumumab. No toxicity was observed with ²¹²Pb-Daratumumab up to 370 kBq due to the lack of cross-reactivity. Nevertheless, acute toxicity experiments with ²¹²Pb-anti-mCD38 established a toxic activity of 277.5 kBq. To remain within realistically safe treatment activities for efficacy studies, mice were treated with 185 kBq or 277.5 kBq of ²¹²Pb-Daratumumab. Marked tumor growth inhibition compared to controls was observed, with a median survival of 55 days for 277.5 kBq of ²¹²Pb-Daratumumab instead of 11 for PBS control groups. Conclusion: These results showed ²¹²Pb-Daratumumab efficacy on xenografted mice with significant tumor regression and increased survival. This study highlights alpha-RIT potency in MM treatment.