The battle for truth: The BBC's role at 100 22 November 2022 — 6:30PM TO 7:30PM Anonymous (not verified) 13 October 2022 Chatham House and Online

Tim Davie, director general of the BBC, and others discuss how the BBC shapes, and is shaped by, the world today.

This year, the BBC turns 100 and the World Service 90 in a world facing crises of increasing scale and frequency and in an age of disinformation, democratic disruption and a growing assault on truth and free reporting worldwide. What does this mean for Britain’s foremost news provider at home and across the globe?

This conversation considers:

• How does the BBC navigate a drastically changing media landscape?

• What does the BBC represent in the UK and to the world?

• What ‘soft power’ does the BBC have and how does it use it best?

As with all members events, questions from the audience drive the conversation.

Read the transcript. 

I’m often asked if I miss working in the House of Commons. Of course I do; it’s one of the most amazing places in the world and remains the cockpit of our nation.There are obviously days I miss it more than others, usually around the big national moments. Whatever your view of Kim Leadbeater’s private member’s bill—the Terminally Ill Adults (End of Life) Bill—its second reading this month will be one of those big moments.Kim is a friend of mine, and we spoke before she decided to put her bill forward after it topped the private members’ ballot at the start of the new parliament. My advice was to proceed with great care, to remember that this will take over your career in many ways, and to read the report produced earlier this year by the Health and Social Care Committee, which I chaired, on the subject of assisted dying/assisted...

Russia and 9/11: Roads not taken Expert comment NCapeling 9 September 2021

Many Russia watchers recall the fleeting moment 20 years ago when the country could have moved away from a path of confrontation with the US.

On 12 September 2001, Russian president Vladimir Putin was the first foreign leader to call George W. Bush to express his condolences – and to offer him support.

Just the previous year, Putin had said Russia joining NATO was a possibility and it suited Russia to draw parallels between the terrorist attacks on the US and its own ‘anti-terrorist’ campaign in Chechnya at the time.

Even though much of the Russian commentary about 9/11 professed empathy rather than sympathy, in their eyes the US was both a victim – as Russia likes to see itself – and ‘had it coming’ while Russia was blameless.

At that time, many in the West were still tempted by the idea Putin’s Russia might develop in a liberal direction, and Putin himself wanted to be seen as constructive especially after Chechnya. He may also have also assumed that, if Russia joined the international alliance, it would be as a co-leader with the US.

An offer which was never stated

Whether he was sincere in his condolences or not, Putin was of course not offering something for nothing – but then few countries ever do. Although less than one-tenth into his time in control of Russia (so far), Putin was still feeling his way but was not a naive president having already been through the controversial sinking of the Kursk submarine.

His first move was to facilitate access to bases in Central Asia for the US campaign in Afghanistan – vital initially but less so later. Apparently, this offer was against the wishes of many of his senior military commanders – although the extent to which it was in his gift to grant such access is questionable.

The quid pro quo, unstated and only dawning on Washington much later, was for the US to keep out of what Russia saw – and still sees – as its backyard. Putin probably misjudged that the US would have neither the inclination nor the capacity to be in that region for anything other than supply chain purposes. And he hoped America now needed Russia after the humiliations of the 1990s.

Common interests could once have been the basis of a partnership with Russia; but to Moscow that meant a partnership of equals which recognized the Kremlin’s self-declared right to conduct out-of-area operations. But the US took a different view and, with nothing written down and no memorandum ever signed, the ensuing disappointment for Russia was gradual but inexorable.

A purely practical reason for declining the ‘offer’ was that, despite its own illusions, Russia had little to bring to the table which was useful and could be offered on acceptable terms. Subsequent initiatives – from specific joint terrorism initiatives to a ‘grand reset’ – could not narrow differences to the point where the character of the relationship changed.

The Northern Distribution Network for supplying US forces in Afghanistan – Russia’s most practical contribution to the notional common cause – took almost a decade to be established and was plagued by problems which often come with a dependence on Russian goodwill.

The Kremlin also had the pleasure of watching US hubris lead to failure in Iraq. And, although knowing the US intervention in Afghanistan would never end well, even Russia could not have foreseen the scale of the defeat and humiliation of chaotic withdrawal.

US achievements with Russia’s neighbours

When it comes to Russia’s post 9/11 ‘offer’ and subsequent expectations, many of the other newly independent countries might never have achieved what they have over the past 20 years if the US had agreed – tacitly or otherwise – to sit back and accept Moscow’s droit de regard over them.

From the Kremlin’s perspective, these states were Russia’s ‘kith and kin’ but it underestimated US willingness to support smaller states over a ‘great power’ – especially as George H.W. Bush pleaded to those states not to go too far too fast. Albeit uneven, most have benefitted from US support for their own independence as well as practical assistance to strengthen their institutions and diversify external relationships.

The three Baltic states consolidated their democracies while their economies, which severed many ties with Russia early, are flourishing and prosperous in contrast to those still in the Russian orbit. They are not only members of NATO and the European Union (EU) but have on occasion been moral leaders as in the case of Lithuania facing down both Belarus and China.

Ukraine has undergone two revolutions in attempting to follow the paths of the Baltic states that continues today. After many false starts Moldova has undergone a similar change recently but at the ballot box not on the streets, to give itself another shot at the prize of true democracy and international acceptance.

Georgia conducted the most radical governance reforms seen in the region after its own revolution although it has taken a few steps backwards of late. Kazakhstan and Uzbekistan have strengthened their independence since then and adjusted their modus vivendi with Russia to their advantage. Putin would hardly be able to give the same assurances about use of bases there today – and indeed reportedly brushed off a request by Biden to use them in the current withdrawal.

Only a minority of formerly Soviet republics have made no progress whatsoever at the governmental level – Belarus and Turkmenistan for sure, perhaps Azerbaijan and Tajikistan too depending on the criteria.

The roads not taken

America’s failure was not so much rejecting Russia’s offer of partnership but failing to pay sufficient attention to it because Russia was still regarded as weak despite being relatively strong in its immediate neighbourhood.

The question of whether it was worth alienating Russia is a moral one. Refusing to sign the Paris Charter – which recognizes the right of independent states to form their own alliances – would have been a further betrayal of people who have long been subjected to their future being decided by stronger powers around them. But Russia may have chosen a path of confrontation anyway as, for the Kremlin, suzerainty over its former republics is considered an entitlement which comes with being a great power.

Although impossible to conclusively prove, all previous frameworks of Russian assumptions and habits of Russian behaviour indicate Moscow would have pocketed the deal and simply moved on anyway. It certainly seems likely that Russia’s other outrages and offenses over the years – from the murders of Litvinenko and Skripal in the UK to the manipulation of information and elections – would still have occurred even if a shabby deal had been made over the heads of the new states on Russia’s borders.

The atrocity of 9/11 was really an opportunity for Russia, a genuine potential turning point and a chance to create a new relationship with the outside world – but its expectations were unrealistic. Russia blew it with demands at the time that could not be met – and rightly were not met. The US rarely receives credit for withstanding Russian blandishments at a moment when its own aura of strength had been so cruelly and effectively punctured by the most brazen of attacks.

Europe's strategic choices 2021 4 November 2021 TO 5 November 2021 — 8:00AM TO 5:30PM Anonymous (not verified) 21 September 2021 Ritz Carlton Berlin

The 2021 conference will consider how Europe can navigate its political, economic and security challenges, in the context of the lasting effects of the coronavirus pandemic and an increasingly competitive geopolitical environment.

Registration is a two step process and you will receive a link to register on the conference virtually in advance. Please email if you wish to attend in-person.

The Eighth Annual Europe’s Strategic Choices conference, jointly developed and hosted by Chatham House, the Institute for Security Policy at the University of Kiel and the Konrad-Adenauer-Stiftung, aims to understand the complex set of challenges facing Europe in the areas of security, economic competitiveness, trade, technology, and global influence.

Set against the backdrop of a Europe emerging gradually from the COVID-19 pandemic, this annual forum brings together policymakers, and representatives from business, civil society and academia, to explore how European countries can best respond, individually and collectively to their common challenges in an increasingly competitive geopolitical environment.

The conference will be hosted in hybrid format to enable speakers and participants to join in person and allow others to engage virtually via the Conference Plus digital platform. This format ensures we can connect with a geographically diverse audience whilst incorporating important elements of in person engagement in accordance with German Federal government guidelines.

Director’s breakfast briefing: Shifts in European foreign policy since 9/11 14 October 2021 — 8:00AM TO 9:15AM Anonymous (not verified) 4 October 2021 Chatham House

Former MI6 chief, Sir Alex Younger, discusses shifts in European foreign policy since 9/11.

Former MI6 chief Sir Alex Younger, discusses shifts in European foreign policy since 9/11.

The dramatic events surrounding the withdrawal from Afghanistan demonstrates a profound shift in European security priorities since the beginning of the ‘war on terror’. Against the backdrop of the 20th anniversary of 9/11, former MI6 chief, Sir Alex Younger, discusses recent shifts in European foreign policy.

How has the focus on counterterrorism changed over the last two decades particularly in light of new and evolving strategic challenges? Why were many long-term objectives in Afghanistan left unachieved? Has the threat of terrorism changed across Europe? How has cooperation between security and intelligence services across the world changed particularly across the Atlantic? And, 20 years on, is the ‘war on terror’ really over?

This event is only open to Chatham House Partners and Major Corporate Members as well as selected giving circles of Chatham House. If you would like to attend, please RSVP to Linda Bedford at RSVP@chathamhouse.org.

New research on 21st-century conflict 25 April 2022 — 5:00PM TO 6:00PM Anonymous (not verified) 11 April 2022 Online

This International Affairs webinar shares research on US special operations, urban warfare, and digital activism in recent conflicts.

Given the ongoing Russian invasion of Ukraine, and continuing conflicts in Myanmar, Yemen, and other countries, it is important to understand the changing nature of conflict in the 21st century.

In this webinar, authors from the March 2022 issue of International Affairs share research on the transformation of Western special forces, the impact of army size in urban warfare, and the use of social media and online activism in war.

The speakers in this event drew on the following research:

• US Special Forces transformation: post-Fordism and the limits of networked warfare (https://doi.org/10.1093/ia/iiab213)
• Urban insurgency in the twenty-first century: smaller militaries and increased conflict in cities (https://doi.org/10.1093/ia/iiac007)
• Diasporas as cyberwarriors: infopolitics, participatory warfare and the 2020 Karabakh war (https://doi.org/10.1093/ia/iiac015)

International Affairs was started at Chatham House in 1922 to communicate research to members who could not attend in person. Over the past 100 years, it has transformed into a journal that publishes academically rigorous and policy-relevant research. It is published for Chatham House by Oxford University Press. Read the latest issue here.

Methods to shorten [¹⁸F]FDG Patlak PET imaging procedures ranging from 65–90 to 20–30 min after injection, using a population-averaged input function (PIF) scaled to patient-specific image-derived input function (IDIF) values, were recently evaluated. The aim of the present study was to explore the feasibility of ultrashort 10-min [¹⁸F]FDG Patlak imaging at 55–65 min after injection using a PIF combined with direct Patlak reconstructions to provide reliable quantitative accuracy of lung tumor uptake, compared with a full-duration 65-min acquisition using an IDIF. Methods: Patients underwent a 65-min dynamic PET acquisition on a long-axial-field-of-view (LAFOV) Biograph Vision Quadra PET/CT scanner. Subsequently, direct Patlak reconstructions and image-based (with reconstructed dynamic images) Patlak analyses were performed using both the IDIF (time to relative kinetic equilibrium between blood and tissue concentration (t*) = 30 min) and a scaled PIF at 30–60 min after injection. Next, direct Patlak reconstructions were performed on the system console using only the last 10 min of the acquisition, that is, from 55 to 65 min after injection, and a scaled PIF using maximum crystal ring difference settings of both 85 and 322. Tumor lesion and healthy-tissue uptake was quantified and compared between the differently obtained parametric images to assess quantitative accuracy. Results: Good agreement was obtained between direct- and image-based Patlak analyses using the IDIF (t* = 30 min) and scaled PIF at 30–60 min after injection, performed using the different approaches, with no more than 8.8% deviation in tumor influx rate value (K_i) (mean difference ranging from –0.0022 to 0.0018 mL/[min x g]). When direct Patlak reconstruction was performed on the system console, excellent agreement was found between the use of a scaled PIF at 30–60 min after injection versus 55–65 min after injection, with 2.4% deviation in tumor K_i (median difference, –0.0018 mL/[min x g]; range, –0.0047 to 0.0036 mL/[min x g]). For different maximum crystal ring difference settings using the scan time interval of 55–65 min after injection, only a 0.5% difference (median difference, 0.0000 mL/[min x g]; range, –0.0004 to 0.0013 mL/[min x g]) in tumor K_i was found. Conclusion: Ultrashort whole-body [¹⁸F]FDG Patlak imaging is feasible on an LAFOV Biograph Vision Quadra PET/CT system without loss of quantitative accuracy to assess lung tumor uptake compared with a full-duration 65-min acquisition. The ultrashort 10-min direct Patlak reconstruction with PIF allows for its implementation in clinical practice.

Quantification of ¹⁸F-FDG PET images is useful for accurate diagnosis and evaluation of various brain diseases, including brain tumors, epilepsy, dementia, and Parkinson disease. However, accurate quantification of ¹⁸F-FDG PET images requires matched 3-dimensional T₁ MRI scans of the same individuals to provide detailed information on brain anatomy. In this paper, we propose a transfer learning approach to adapt a pretrained deep neural network model from amyloid PET to spatially normalize ¹⁸F-FDG PET images without the need for 3-dimensional MRI. Methods: The proposed method is based on a deep learning model for automatic spatial normalization of ¹⁸F-FDG brain PET images, which was developed by fine-tuning a pretrained model for amyloid PET using only 103 ¹⁸F-FDG PET and MR images. After training, the algorithm was tested on 65 internal and 78 external test sets. All T₁ MR images with a 1-mm isotropic voxel size were processed with FreeSurfer software to provide cortical segmentation maps used to extract a ground-truth regional SUV ratio using cerebellar gray matter as a reference region. These values were compared with those from spatial normalization-based quantification methods using the proposed method and statistical parametric mapping software. Results: The proposed method showed superior spatial normalization compared with statistical parametric mapping, as evidenced by increased normalized mutual information and better size and shape matching in PET images. Quantitative evaluation revealed a consistently higher SUV ratio correlation and intraclass correlation coefficients for the proposed method across various brain regions in both internal and external datasets. The remarkably good correlation and intraclass correlation coefficient values of the proposed method for the external dataset are noteworthy, considering the dataset’s different ethnic distribution and the use of different PET scanners and image reconstruction algorithms. Conclusion: This study successfully applied transfer learning to a deep neural network for ¹⁸F-FDG PET spatial normalization, demonstrating its resource efficiency and improved performance. This highlights the efficacy of transfer learning, which requires a smaller number of datasets than does the original network training, thus increasing the potential for broader use of deep learning–based brain PET spatial normalization techniques for various clinical and research radiotracers.

The peptide hormone ghrelin is produced in cardiomyocytes and acts through the myocardial growth hormone secretagogue receptor (GHSR) to promote cardiomyocyte survival. Administration of ghrelin may have therapeutic effects on post–myocardial infarction (MI) outcomes. Therefore, there is a need to develop molecular imaging probes that can track the dynamics of GHSR in health and disease to better predict the effectiveness of ghrelin-based therapeutics. We designed a high-affinity GHSR ligand labeled with ¹⁸F for imaging by PET and characterized its in vivo properties in a canine model of MI. Methods: We rationally designed and radiolabeled with ¹⁸F a quinazolinone derivative ([¹⁸F]LCE470) with subnanomolar binding affinity to GHSR. We determined the sensitivity and in vivo and ex vivo specificity of [¹⁸F]LCE470 in a canine model of surgically induced MI using PET/MRI, which allowed for anatomic localization of tracer uptake and simultaneous determination of global cardiac function. Uptake of [¹⁸F]LCE470 was determined by time–activity curve and SUV analysis in 3 regions of the left ventricle—area of infarct, territory served by the left circumflex coronary artery, and remote myocardium—over a period of 1.5 y. Changes in cardiac perfusion were tracked by [¹³N]NH₃ PET. Results: The receptor binding affinity of LCE470 was measured at 0.33 nM, the highest known receptor binding affinity for a radiolabeled GHSR ligand. In vivo blocking studies in healthy hounds and ex vivo blocking studies in myocardial tissue showed the specificity of [¹⁸F]LCE470, and sensitivity was demonstrated by a positive correlation between tracer uptake and GHSR abundance. Post-MI changes in [¹⁸F]LCE470 uptake occurred independently of perfusion tracer distributions and changes in global cardiac function. We found that the regional distribution of [¹⁸F]LCE470 within the left ventricle diverged significantly within 1 d after MI and remained that way throughout the 1.5-y duration of the study. Conclusion: [¹⁸F]LCE470 is a high-affinity PET tracer that can detect changes in the regional distribution of myocardial GHSR after MI. In vivo PET molecular imaging of the global dynamics of GHSR may lead to improved GHSR-based therapeutics in the treatment of post-MI remodeling.

Preclinical data have shown that ¹⁶¹Tb-labeled peptides targeting the somatostatin receptor are therapeutically more effective for peptide receptor radionuclide therapy than are their ¹⁷⁷Lu-labeled counterparts. To further substantiate this enhanced therapeutic effect, we performed cellular dosimetry to quantify the absorbed dose to the cell nucleus and compared dose–response curves to evaluate differences in relative biological effectiveness in vitro. Methods: CA20948 cell survival was assessed after treatment with [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTATATE (agonist) and with [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTA-LM3 (antagonist) via a clonogenic assay. Cell binding, internalization, and dissociation assays were performed up to 7 d to acquire time-integrated activity coefficients. Separate S values for each type of particle emission (Auger/internal conversion [IC] electrons and β^– particles) were computed via Monte Carlo simulations, while considering spheric cells. Once the absorbed dose to the cell nucleus was calculated, survival curves were fitted to the appropriate linear or linear-quadratic model and corresponding relative biological effectiveness was evaluated. Results: Although the radiopeptide uptake was independent of the radionuclide, [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 delivered a 3.6 and 3.8 times higher dose to the nucleus, respectively, than their ¹⁷⁷Lu-labeled counterparts on saturated receptor binding. This increased nucleus-absorbed dose was mainly due to the additional emission of IC and not Auger electrons by ¹⁶¹Tb. When activity concentrations were considered, both [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 showed a lower survival fraction than did labeling with ¹⁷⁷Lu. When the absorbed dose to the nucleus was considered, no significant difference could be observed between the dose–response curves for [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTATATE. [¹⁶¹Tb]Tb-DOTA-LM3 showed a linear-quadratic dose response, whereas [¹⁶¹Tb]Tb-DOTATATE showed only a linear dose response within the observed dose range, suggesting additional cell membrane damage by Auger electrons. Conclusion: The IC, rather than Auger, electrons emitted by ¹⁶¹Tb resulted in a higher absorbed dose to the cell nucleus and lower clonogenic survival for [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 than for the ¹⁷⁷Lu-labeled analogs. In contrast, [¹⁶¹Tb]Tb-DOTATATE showed no higher dose response than [¹⁷⁷Lu]Lu-DOTATATE, whereas for [¹⁶¹Tb]Tb-DOTA-LM3 an additional quadratic response was observed. Because of this quadratic response, potentially caused by cell membrane damage, [¹⁶¹Tb]Tb-DOTA-LM3 is a more effective radiopeptide than [¹⁶¹Tb]Tb-DOTATATE for labeling with ¹⁶¹Tb.

Radiolabeled small-molecule DOTA-haptens can be combined with antitumor/anti-DOTA bispecific antibodies (BsAbs) for pretargeted radioimmunotherapy (PRIT). For optimized delivery of the theranostic - and β-emitting isotope ¹⁷⁷Lu with DOTA-based PRIT (DOTA-PRIT), bivalent Gemini (DOTA-Bn-thiourea-PEG4-thiourea-Bn-DOTA, aka (3,6,9,12-tetraoxatetradecane-1,14-diyl)bis(DOTA-benzyl thiourea)) was developed. Methods: Gemini was synthesized by linking 2 S-2-(4-isothiocyanatobenzyl)-DOTA molecules together via a 1,14-diamino-PEG4 linker. [¹⁷⁷Lu]Lu-Gemini was prepared with no-carrier-added ¹⁷⁷LuCl₃ to a molar-specific activity of 123 GBq/μmol and radiochemical purity of more than 99%. The specificity of BsAb-¹⁷⁷Lu-Gemini was verified in vitro. Subsequently, we evaluated biodistribution and whole-body clearance for [¹⁷⁷Lu]Lu-Gemini and, for comparison, our gold-standard monovalent [¹⁷⁷Lu]Lu-S-2-(4-aminobenzyl)-DOTA ([¹⁷⁷Lu]Lu-DOTA-Bn) in naïve (tumor-free) athymic nude mice. For our proof-of-concept system, a 3-step pretargeting approach was performed with an established DOTA-PRIT regimen (anti-GPA33/anti-DOTA IgG-scFv BsAb, a clearing agent, and [¹⁷⁷Lu]Lu-Gemini) in mouse models. Results: Initial in vivo studies showed that [¹⁷⁷Lu]Lu-Gemini behaved similarly to [¹⁷⁷Lu]Lu-DOTA-Bn, with almost identical blood and whole-body clearance kinetics, as well as biodistribution and mouse kidney dosimetry. Pretargeting [¹⁷⁷Lu]Lu-Gemini to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [¹⁷⁷Lu]Lu-Gemini for blood, tumor, liver, spleen, and kidneys of 3.99, 455, 6.93, 5.36, and 14.0 cGy/MBq, respectively. Tumor–to–normal tissue absorbed-dose ratios (i.e., therapeutic indices [TIs]) for the blood and kidneys were 114 and 33, respectively. In addition, we demonstrate that the use of bivalent [¹⁷⁷Lu]Lu-Gemini in DOTA-PRIT leads to improved TIs and augmented [¹⁷⁷Lu]Lu-Gemini tumor uptake and retention in comparison to monovalent [¹⁷⁷Lu]Lu-DOTA-Bn. Finally, we established efficacy in SW1222 tumor-bearing mice, demonstrating that a single injection of anti-GPA33 DOTA-PRIT with 44 MBq (1.2 mCi) of [¹⁷⁷Lu]Lu-Gemini (estimated tumor-absorbed dose, 200 Gy) induced complete responses in 5 of 5 animals and a histologic cure in 2 of 5 (40%) animals. Moreover, a significant increase in survival compared with nontreated controls was noted (maximum tolerated dose not reached). Conclusion: We have developed a bivalent DOTA-radiohapten, [¹⁷⁷Lu]Lu-Gemini, that showed improved radiopharmacology for DOTA-PRIT application. The use of bivalent [¹⁷⁷Lu]Lu-Gemini in DOTA-PRIT, as opposed to monovalent [¹⁷⁷Lu]Lu-DOTA-Bn, allows curative treatments with considerably less administered ¹⁷⁷Lu activity while still achieving high TIs for both the blood (>100) and the kidneys (>30).

Fibroblast activation protein (FAP) is abundantly expressed in the stroma of most human solid tumors. Clinical-stage radiolabeled FAP ligands are increasingly used as tools for the detection of various cancer lesions. To unleash the full therapeutic potential of FAP-targeting agents, ligands need to remain at the tumor site for several days after administration. We recently described the discovery of OncoFAP, a high-affinity small organic ligand of FAP with a rapid accumulation in tumors and low uptake in healthy tissues in cancer patients. Trimerization of OncoFAP provided a derivative (named TriOncoFAP, or OncoFAP-23) with improved FAP affinity. In this work, we evaluated the tissue biodistribution profile and the therapeutic performance of OncoFAP-23 in tumor-bearing mice. Methods: OncoFAP-23 was radiolabeled with the theranostic radionuclide ¹⁷⁷Lu. Preclinical experiments were conducted on mice bearing SK-RC-52.hFAP (BALB/c nude mice) or CT-26.hFAP (BALB/c mice) tumors. ¹⁷⁷Lu-OncoFAP and ¹⁷⁷Lu-FAP-2286 were included in the biodistribution study as controls. Toxicologic evaluation was performed on Wistar rats and CD1 mice by injecting high doses of OncoFAP-23 or its cold-labeled counterpart, respectively. Results: ¹⁷⁷Lu-OncoFAP-23 emerged for its best-in-class biodistribution profile, high and prolonged tumor uptake (i.e., ~16 percentage injected dose/g at 96 h), and low accumulation in healthy organs, which correlates well with its potent single-agent anticancer activity at low levels of administered radioactivity. Combination treatment with the tumor-targeted interleukin 2 (L19-IL2, a clinical-stage immunocytokine) further expands the therapeutic window of ¹⁷⁷Lu-OncoFAP-23 by potentiating its in vivo antitumor activity. Proteomics studies revealed a potent tumor-directed immune response on treatment with the combination. OncoFAP-23 and ^natLu-OncoFAP-23 exhibited a favorable toxicologic profile, without showing any side effects or signs of toxicity. Conclusion: OncoFAP-23 presents enhanced tumor uptake and tumor retention and low accumulation in healthy organs, findings that correspond to a strongly improved in vivo antitumor efficacy. The data presented in this work support the clinical development of ¹⁷⁷Lu-OncoFAP-23 for the treatment of FAP-positive solid tumors.

Our purpose was to prospectively assess the distribution of NETPET scores in well-differentiated (WD) grade 2 and 3 gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and to determine the impact of the NETPET score on clinical management. Methods: This single-arm, institutional ethics review board–approved prospective study included 40 patients with histologically proven WD GEP NETs. ⁶⁸Ga-DOTATATE PET and ¹⁸F-FDG PET were performed within 21 d of each other. NETPET scores were evaluated qualitatively by 2 reviewers, with up to 10 marker lesions selected for each patient. The quantitative parameters that were evaluated included marker lesion SUV_max for each tracer; ¹⁸F-FDG/⁶⁸Ga-DOTATATE SUV_max ratios; functional tumor volume (FTV) and metabolic tumor volume (MTV) on ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET, respectively; and FTV/MTV ratios. The treatment plan before and after ¹⁸F-FDG PET was recorded. Results: There were 22 men and 18 women (mean age, 60.8 y) with grade 2 (n = 24) or grade 3 (n = 16) tumors and a mean Ki-67 index of 16.1%. NETPET scores of P0, P1, P2A, P2B, P3B, P4B, and P5 were documented in 2 (5%), 5 (12.5%), 5 (12.5%) 20 (50%), 2 (5%), 4 (10%), and 2 (5%) patients, respectively. No association was found between the SUV_max of target lesions on ⁶⁸Ga-DOTATATE and the SUV_max of target lesions on ¹⁸F-FDG PET (P = 0.505). ¹⁸F-FDG/⁶⁸Ga-DOTATATE SUV_max ratios were significantly lower for patients with low (P1–P2) primary NETPET scores than for those with high (P3–P5) primary NETPET scores (mean ± SD, 0.20 ± 0.13 and 1.68 ± 1.44, respectively; P < 0.001). MTV on ¹⁸F-FDG PET was significantly lower for low primary NETPET scores than for high ones (mean ± SD, 464 ± 601 cm³ and 66 ± 114 cm³, respectively; P = 0.005). A change in the type of management was observed in 42.5% of patients after ¹⁸F-FDG PET, with the most common being a change from systemic therapy to peptide receptor radionuclide therapy and from debulking surgery to systemic therapy. Conclusion: There was a heterogeneous distribution of NETPET scores in patients with WD grade 2 and 3 GEP NETs, with more than 1 in 5 patients having a high NETPET score and a frequent change in management after ¹⁸F-FDG PET. Quantitative parameters including ¹⁸F-FDG/⁶⁸Ga-DOTATATE SUV_max ratios in target lesions and FTV/MTV ratios can discriminate between patients with high and low NETPET scores.

Our objective is to explore quantitative imaging markers for early prediction of treatment response in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) undergoing [¹⁷⁷Lu]Lu-DOTATATE therapy. By doing so, we aim to enable timely switching to more effective therapies in order to prevent time-resource waste and minimize toxicities. Methods: Patients diagnosed with unresectable or metastatic, progressive, well-differentiated, receptor-positive GEP-NETs who received 4 sessions of [¹⁷⁷Lu]Lu-DOTATATE were retrospectively selected. Using SPECT/CT images taken at the end of treatment sessions, we counted all visible tumors and measured their largest diameters to calculate the tumor burden score (TBS). Up to 4 target lesions were selected and semiautomatically segmented. Target lesion peak counts and spleen peak counts were measured, and normalized peak counts were calculated. Changes in TBS (TBS) and changes in normalized peak count (nPC) throughout treatment sessions in relation to the first treatment session were calculated. Treatment responses were evaluated using third-month CT and were binarized as progressive disease (PD) or non-PD. Results: Twenty-seven patients were included (7 PD, 20 non-PD). Significant differences were observed in TBS_second-first, TBS_third-first, and TBS_fourth-first (where second-first, third-first, and fourth-first denote scan number between the second and first, third and first, and fourth and first [¹⁷⁷Lu]Lu-DOTATATE treatment cycles), respectively) between the PD and non-PD groups (median, 0.043 vs. –0.049, 0.08 vs. –0.116, and 0.109 vs. –0.123 [P = 0.023, P = 0.002, and P < 0.001], respectively). nPC_second-first showed significant group differences (mean, –0.107 vs. –0.282; P = 0.033); nPC_third-first and nPC_fourth-first did not reach statistical significance (mean, –0.122 vs. –0.312 and –0.183 vs. –0.405 [P = 0.117 and 0.067], respectively). At the optimal threshold, TBS_fourth-first exhibited an area under the curve (AUC) of 0.957, achieving 100% sensitivity and 80% specificity. TBS_second-first and TBS_third-first reached AUCs of 0.793 and 0.893, sensitivities of 71.4%, and specificities of 85% and 95%, respectively. nPC_second-first, nPC_third-first, and nPC_fourth-first showed AUCs of 0.764, 0.693, and 0.679; sensitivities of 71.4%, 71.4%, and 100%; and specificities of 75%, 70%, and 35%, respectively. Conclusion: TBS and nPC can predict [¹⁷⁷Lu]Lu-DOTATATE response by the second treatment session.

Unspecific bone uptake (UBU) related to [¹⁸F]PSMA-1007 PET/CT imaging represents a clinical challenge. We aimed to assess whether a combination of clinical, biochemical, and imaging parameters could predict skeletal metastases in patients with [¹⁸F]PSMA-1007 bone focal uptake, aiding in result interpretation. Methods: We retrospectively analyzed [¹⁸F]PSMA-1007 PET/CT performed in hormone-sensitive prostate cancer (PCa) patients at 3 tertiary-level cancer centers. A fourth center was involved in performing an external validation. For each, a volume of interest was drawn using a threshold method to extract SUV_max, SUV_mean, PSMA tumor volume, and total lesion PSMA. The same volume of interest was applied to CT images to calculate the mean Hounsfield units (HU_mean) and maximum Hounsfield units. Clinical and laboratory data were collected from electronic medical records. A composite reference standard, including follow-up histopathology, biochemistry, and imaging data, was used to distinguish between PCa bone metastases and UBU. PET readers with less (n = 2) or more (n = 2) experience, masked to the reference standard, were asked to visually rate a subset of focal bone uptake (n = 178) as PCa metastases or not. Results: In total, 448 bone [¹⁸F]PSMA-1007 focal uptake specimens were identified in 267 PCa patients. Of the 448 uptake samples, 188 (41.9%) corresponded to PCa metastases. Ongoing androgen deprivation therapy at PET/CT (P < 0.001) with determination of SUV_max (P < 0.001) and HU_mean (P < 0.001) independently predicted bone metastases. A composite prediction score, the bone uptake metastatic probability (BUMP) score, achieving an area under the receiver-operating-characteristic curve (AUC) of 0.87, was validated through a 10-fold internal and external validation (n = 89 bone uptake, 51% metastatic; AUC, 0.92). The BUMP score’s AUC was significantly higher than that of HU_mean (AUC, 0.62) and remained high among lesions with HU_mean in the first tertile (AUC, 0.80). A decision-curve analysis showed a higher net benefit with the score. Compared with the visual assessment, the BUMP score provided added value in terms of specificity in less-experienced PET readers (88% vs. 54%, P < 0.001). Conclusion: The BUMP score accurately distinguished UBU from bone metastases in PCa patients with [¹⁸F]PSMA-1007 focal bone uptake at PET imaging, offering additional value compared with the simple assessment of the osteoblastic CT correlate. Its use could help clinicians interpret imaging results, particularly those with less experience, potentially reducing the risk of patient overstaging.

This analysis aimed to identify clinical factors associated with positivity on repeat ⁶⁸Ga-PSMA-11 PET/CT after a negative scan in patients with recurrent prostate cancer (PCa) under observation. Methods: This single-center, retrospective analysis included patients who underwent at least 2 ⁶⁸Ga-PSMA-11 PET/CT scans (PET1 and PET2) at UCLA between October 2016 and June 2021 for recurrent PCa with negative PET1 and no PCa-related treatments between the 2 scans. Using Prostate Cancer Molecular Imaging Standardized Evaluation criteria to define negative and positive scans, the final cohort was divided into PET2-negative (PET2-Neg) and PET2-positive (PET2-Pos). The same PET1 was used twice in the more than 2 PET cases with inclusion criteria fulfilled. Patient characteristics and clinical parameters were compared between the 2 cohorts using Mann–Whitney U test and Fisher exact test. Areas under the curve (AUCs) of the receiver operating characteristic and the Youden index were computed to determine the discrimination ability of statistically significant factors and specific cut points that maximized sensitivity and specificity, respectively. Results: The final analysis included 83 sets of 2 PET/CT scans from 70 patients. Thirty-nine of 83 (47%) sets were PET2-Neg, and 44 of 83 (53%) sets were PET2-Pos. Prostate-specific antigen (PSA) increased from PET1 to PET2 for all 83 (100%) sets of scans. Median PSA at PET1 was 0.4 ng/mL (interquartile range, 0.2–1.0) and at PET2 was 1.6 ng/mL (interquartile range, 0.9–3.8). We found higher serum PSA at PET2 (median, 1.8 vs. 1.1 ng/mL; P = 0.015), absolute PSA difference (median, 1.4 vs. 0.7 ng/mL; P = 0.006), percentage of PSA change (median, +270.4% vs. +150.0%: P = 0.031), and median PSA velocity (0.044 vs. 0.017 ng/mL/wk, P = 0.002) and shorter PSA doubling time (DT; median, 5.1 vs. 8.3 mo; P = 0.006) in the PET2-Pos cohort than in the PET2-Neg cohort. Receiver operating characteristic curves showed cutoffs for PSA at PET2 of 4.80 ng/mL (sensitivity, 34%; specificity, 92%; AUC, 0.66), absolute PSA difference of 0.95 ng/mL (sensitivity, 62%; specificity, 71%; AUC, 0.68), percentage of PSA change of a positive 289.50% (sensitivity, 48%; specificity, 82%; AUC, 0.64), PSA velocity of 0.033 ng/mL/wk (sensitivity, 57%; specificity, 80%; AUC, 0.70), and PSA DT of 7.91 mo (sensitivity, 71%; specificity, 62%; AUC, 0.67). Conclusion: Patients with recurrent PCa under observation after a negative ⁶⁸Ga-PSMA-11 PET/CT scan with markedly elevated serum PSA levels and shorter PSA DT are more likely to have positive findings on repeat ⁶⁸Ga-PSMA-11 PET/CT.

Cancer of unknown primary (CUP) represents a heterogeneous group of metastatic tumors for which standardized diagnostic work-up fails to identify the primary site. We aimed to describe the Peter MacCallum Cancer Centre experience with ¹⁸F-FDG PET/CT in extracervical CUP with respect to detection of a primary site and its impact on management. A secondary aim was to compare overall survival (OS) in patients with and without a detected primary site. Methods: CUP patients treated between 2014 and 2020 were identified from medical oncology clinics and ¹⁸F-FDG PET/CT records. Information collated from electronic medical records included the suspected primary site and treatment details before and after ¹⁸F-FDG PET/CT. Clinicopathologic details and genomic analysis were used to determine the clinically suspected primary site and compared against 2 independent masked reads of ¹⁸F-FDG PET/CT images by nuclear medicine specialists to determine sensitivity, specificity, accuracy, and the rate of detection of the primary site. Results: We identified 147 patients, 65% of whom had undergone molecular profiling. The median age at diagnosis was 61 y (range, 20–84 y), and the median follow-up time was 74 mo (range, 26–83 mo). Eighty-two percent were classified as having an unfavorable CUP subtype as per international guidelines.¹⁸F-FDG PET/CT demonstrated a primary site detection rate of 41%, resulted in a change in management in 22%, and identified previously occult disease sites in 37%. Median OS was 16.8 mo for all patients and 104.7 and 12.1 mo for favorable and unfavorable CUP subtypes, respectively (P < 0.0001). Median OS in CUP patients when using ¹⁸F-FDG PET/CT, clinicopathologic, and genomic information was 19.8 and 8.5 mo when a primary site was detected and not detected, respectively (P = 0.016). Multivariable analysis of survival adjusted for age and sex remained significant for identification of a potential primary site (P < 0.001), a favorable CUP (P < 0.001), and an Eastern Cooperative Oncology Group status of 1 or less (P < 0.001). Conclusion: ¹⁸F-FDG PET/CT plays a complementary role in CUP diagnostic work-up and was able to determine the likely primary site in 41% of cases. OS is improved with primary site identification, demonstrating the value of access to diagnostic ¹⁸F-FDG PET/CT for CUP patients.

Neoadjuvant therapy in patients with locally advanced rectal cancer (LARC) has achieved good pathologic complete response (pCR) rates, potentially eliminating the need for surgical intervention. This study investigated preoperative methods for predicting pCR after neoadjuvant short-course radiotherapy (SCRT) combined with immunochemotherapy. Methods: Treatment-naïve patients with histologically confirmed LARC were enrolled from February 2023 to July 2023. Before surgery, the patients received neoadjuvant SCRT followed by 2 cycles of capecitabine and oxaliplatin plus camrelizumab. ⁶⁸Ga-labeled fibroblast activation protein inhibitor ([⁶⁸Ga]Ga-FAPI-04) PET/MRI, [¹⁸F]FDG PET/CT, and contrast-enhanced MRI were performed before treatment initiation and before surgery in each patient. PET and MRI features and the size and number of lesions were also collected from each scan. Each parameter’s sensitivity, specificity, and diagnostic cutoff were derived via receiver-operating-characteristic curve analysis. Results: Twenty eligible patients (13 men, 7 women; mean age, 60.2 y) were enrolled and completed the entire trial, and all patients had proficient mismatch repair or microsatellite-stable LARC. A postoperative pCR was achieved in 9 patients (45.0%). In the visual evaluation, both [⁶⁸Ga]Ga-FAPI-04 PET/MRI and [¹⁸F]FDG PET/CT were limited to forecasting pCR. Contrast-enhanced MRI had a low sensitivity of 55.56% to predict pCR. In the quantitative evaluation, [⁶⁸Ga]Ga-FAPI-04 change in SUL_peak percentage, where SUL_peak is SUV_peak standardized by lean body mass, had the largest area under the curve (0.929) with high specificity (sensitivity, 77.78%; specificity, 100.0%; cutoff, 63.92%). Conclusion: [⁶⁸Ga]Ga-FAPI-04 PET/MRI is a promising imaging modality for predicting pCR after SCRT combined with immunochemotherapy. The SUL_peak decrease exceeding 63.92% may provide valuable guidance in selecting patients who can forgo surgery after neoadjuvant therapy.

This study evaluates the diagnostic utility of PET/MRI for primary, locoregional, and nodal head and neck squamous cell carcinoma (HNSCC) through systematic review and metaanalysis. Methods: A systematic search was conducted using PubMed and Scopus to identify studies on the diagnostic accuracy of PET/MRI for HNSCC. The search included specific terms and excluded nonhybrid PET/MRI studies, and those with a sample size of fewer than 10 patients were excluded. Results: In total, 15 studies encompassing 638 patients were found addressing the diagnostic test accuracy for PET/MRI within the chosen subject domain. Squamous cell carcinoma of the nasopharynx was the most observed HNSCC subtype (n = 198). The metaanalysis included 12 studies, with pooled sensitivity and specificity values of 93% and 95% per patient for primary disease evaluation, 93% and 96% for locoregional evaluation, and 89% and 98% per lesion for nodal disease detection, respectively. An examination of a subset of studies comparing PET/MRI against PET/CT or MRI alone for evaluating nodal and locoregional HNSCC found that PET/MRI may offer slightly higher accuracy than other modalities. However, this difference was not statistically significant. Conclusion: PET/MRI has excellent potential for identifying primary, locoregional, and nodal HNSCC.

Tumor hypoxia, an integral biomarker to guide radiotherapy, can be imaged with ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) hypoxia PET. One major obstacle to its broader application is the lack of standardized interpretation criteria. We sought to develop and validate practical interpretation criteria and a dedicated training protocol for nuclear medicine physicians to interpret ¹⁸F-FMISO hypoxia PET. Methods: We randomly selected 123 patients with human papillomavirus–positive oropharyngeal cancer enrolled in a phase II trial who underwent 123 ¹⁸F-FDG PET/CT and 134 ¹⁸F-FMISO PET/CT scans. Four independent nuclear medicine physicians with no ¹⁸F-FMISO experience read the scans. Interpretation by a fifth nuclear medicine physician with over 2 decades of ¹⁸F-FMISO experience was the reference standard. Performance was evaluated after initial instruction and subsequent dedicated training. Scans were considered positive for hypoxia by visual assessment if ¹⁸F-FMISO uptake was greater than floor-of-mouth uptake. Additionally, SUV_max was determined to evaluate whether quantitative assessment using tumor-to-background ratios could be helpful to define hypoxia positivity. Results: Visual assessment produced a mean sensitivity and specificity of 77.3% and 80.9%, with fair interreader agreement ( = 0.34), after initial instruction. After dedicated training, mean sensitivity and specificity improved to 97.6% and 86.9%, with almost perfect agreement ( = 0.86). Quantitative assessment with an estimated best SUV_max ratio threshold of more than 1.2 to define hypoxia positivity produced a mean sensitivity and specificity of 56.8% and 95.9%, respectively, with substantial interreader agreement ( = 0.66), after initial instruction. After dedicated training, mean sensitivity improved to 89.6% whereas mean specificity remained high at 95.3%, with near-perfect interreader agreement ( = 0.86). Conclusion: Nuclear medicine physicians without ¹⁸F-FMISO hypoxia PET reading experience demonstrate much improved interreader agreement with dedicated training using specific interpretation criteria.

The tumor marker cancer antigen 15-3 (CA 15-3) is that most commonly used to monitor metastatic breast cancer during active therapy and surveillance for disease recurrence after treatment. The association of CA 15-3 and ¹⁸F-FDG PET/CT findings can be considered complementary, since any significant rise may indicate the presence of disease and imaging is able to map the tumor sites. Although current guidelines do not recommend the routine performance of CA 15-3 in asymptomatic patients being followed up after definitive breast cancer treatment, most oncologists perform serial assessment of the tumor markers as part of routine follow-up of patients. The aim of this study was to evaluate the correlation between CA 15-3 levels and ¹⁸F-FDG PET/CT scan findings in patients with recurrent breast cancer. Methods: This was a cross-sectional study with data collected retrospectively. Patients being evaluated for breast cancer recurrence with ¹⁸F-FDG PET/CT imaging and CA 15-3 level were included. Evaluation of the association between CA 15-3 levels and ¹⁸F-FDG PET/CT scan findings was then done. Results: In total, 154 cases were included in this study; 62 patients had recurrence (positive) on the ¹⁸F-FDG PET/CT scans, whereas 92 patients had normal (negative) findings on follow-up ¹⁸F-FDG PET/CT scans. There was an association between CA 15-3 levels and the presence or absence of recurrence on ¹⁸F-FDG PET/CT scans, with 84.4% (27/32) of patients who had elevated CA 15-3 levels having disease recurrence on ¹⁸F-FDG PET/CT and 84.4% (27/32) of patients who had elevated CA 15-3 levels having disease recurrence on ¹⁸F-FDG PET/CT as well as a correlation with the burden of metastases. Most patients with disease recurrence on ¹⁸F-FDG PET/CT, however, had normal CA 15-3 levels. Conclusion: Higher CA 15-3 levels correlate with breast cancer recurrence on ¹⁸F-FDG PET/CT as well as with burden of metastasis. Notably, CA 15-3 levels within the reference range do not exclude breast cancer disease recurrence since more than half of patients with recurrence had normal CA 15-3 levels. ¹⁸F-FDG PET/CT should therefore be considered in patients with suspected breast cancer recurrence but normal CA 15-3 levels.

Webinar: Turkey’s Challenging Post-COVID 19 Outlook 7 May 2020 — 1:00PM TO 2:00PM Anonymous (not verified) 17 April 2020

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An additional five rhesus macaque monkeys that escaped from a South Carolina research facility last week have been recovered, meaning about a dozen of the rhesus macaque primates remain at large.