Gorbachev's complex legacy is beyond the popular belief Expert comment NCapeling 3 September 2022

The last major figure with a decisive Cold War role, Mikhail Gorbachev was not as bad as Putin’s Russia portrays him, but also not as heroic as the West thinks.

Arguably the worst year of the Cold War since the Cuban Missile Crisis was 1983, with three major incidents which escalated East-West tensions – and any one of them could have led to a full-scale war.

The first was the Korean Airline KAL007 being shot down by an SU15 fighter aircraft for straying into Soviet airspace, killing all 269 passengers and crew. Then came the identification of signals from Soviet satellites as being incoming US intercontinental ballistic missiles – Colonel Stanislav Petrov, going against all protocols, thankfully decided to report them as a false alarm before he could be sure.

The third was perhaps the most dangerous, being the misinterpretation of a live-fire NATO exercise which was believed by some in both East Germany and Russia to be a front for an imminent attack.

All three incidents occurred in the few months following the infamous March 1983 ‘Star Wars’ speech by US president Ronald Reagan, in which he talked about nuclear arms control and laid out the US case for a ballistic missile defence programme.

At that time Mikhail Sergeyevich Gorbachev was the youngest serving member of the USSR Politburo, known to be a favourite of Soviet leader Yuri Andropov, and it is highly likely he had been aware of these close calls and was part of discussions within Kremlin decision-making circles.

A changemaker both inside and outside the USSR

Following the deaths of Andropov in 1984 and his replacement Konstantin Chernenko in 1985, Gorbachev’s appointment as general secretary of the Communist Party saw him immediately begin to change the Soviet Union from within – and also change relationships with the major Western powers, especially the US, Germany, and the UK.

His policies of glasnost (openness) and perestroika (restructuring) were primarily aimed at internal reforms but translated into a major reset of international relations and international security. During his six years as leader, Gorbachev initiated many arms control negotiations which resulted in treaties and increased both the transparency and the confidence between the USSR and the US.

These included the 1986 Stockholm Accord which emanated from the Helsinki Process and allowed for the observation and inspection of large-scale military exercises, the 1985 resumption of the Strategic Arms Reduction Talks which lead to START I, and the 1987 INF Treaty in which the USSR ‘out-yessed’ the US – the most open and transparent disarmament treaty in terms of notification and verification measures ever agreed.

There was also a reciprocal moratorium on nuclear weapons tests starting from 1985 – which laid the groundwork for the 1996 CTBT – the 1991 Chemical Weapons Convention, and the 1990 Conventional Forces in Europe (CFE) Treaty.

The most dramatic moment of all was when Gorbachev and Reagan met at a summit in Reykjavik and came close to deciding to eliminate nuclear weapons – but the initiative failed to reach agreement, mainly because Reagan could not drop his commitment to ballistic missile defences and Gorbachev could not accept the offer of joint development.

Nonetheless, all these nuclear arms control treaties led the way for their descendants which have kept nuclear weapons in check ever since and are still in place in the form of the New START agreement.

But despite these outstanding achievements, Gorbachev had blind spots – such as enabling rather than destroying the USSR bioweapons programme, unlike the US which had dismantled its own bioweapons offensive capability by 1973.

And it is now known that, despite negotiating the Chemical Weapons Convention, Russia withheld information on new chemical weapons agents – Novichoks – which have since been used to lethal effect by Russia in Salisbury and against figures opposing the current regime.

His misguided faith in a Soviet future

Gorbachev was markedly different to his predecessors as secretary general. He was neither as decrepit nor as hardline, and he understood from the outset that the Soviet Union was, by the 1980s, finally dying.

Using the intellectual abilities of Aleksandr Yakovlev, he forced through the reforms which simultaneously captured the imagination of the free world and liberated his countrymen and women.

But although he built solid relationships – even friendships – with the world’s major heads of state and improved the USSR’s human rights, releasing dissidents such as Andrei Sakharov, but many – especially Ukrainian dissidents – continued to languish in camps.

The greatest disappointment in Gorbachev’s legacy was he completely believed the USSR could be reformed and still survive as an entity while others, such as Boris Yeltsin and Ronald Reagan, understood it had to be dismantled.

This shortcoming is especially uncomfortable as today’s Russia continues to insist it has a given right to control other former Soviet states, to the extent it is willing to destroy them if they do not concede.

Culture notes: Will the EU find its voice at last? The World Today mhiggins.drupal 30 January 2023

Russia’s invasion of Ukraine has galvanized the bloc, but doubt remains about how it can capitalize on this moment, writes Catherine Fieschi.

Despite its reticence to believe that Russia would attack Ukraine, once Vladimir Putin’s tanks rolled across the Donbas, the European Union finally grasped the momentous nature of the events unfolding on its eastern flank. The immediate reaction of Europe’s member states was one of unity, resolve and uncharacteristically rapid decision-making, at least on sanctions and energy policy.

That they would need to act in concert across a concatenation of crises that would be either triggered (energy), worsened (inflation) or heightened (geopolitical instability) by Putin’s move was obvious. And so, Europe’s collective narrative of this past year slid into place, and it goes something like this: We gave Russia the benefit of every doubt, including after their invasion of Crimea when we still tried to bring them back to the negotiating table, but Putin has made the fundamental choice of turning away from democracy and the rule of law.

Now, the narrative goes on, we have to treat them as enemies and give ourselves the means to become resilient in the face of aggression as Ukraine is all that stands – both symbolically and geographically – between us and the chaos of a Europe-wide war.

Like any good narrative, it is anchored in previous trials and exploits. Having learnt from its failure to coordinate action during the eurozone crisis and then the migration crisis, Europe was keen to make the most of its resilience in the face of the Covid pandemic in the form of the joint vaccine purchases and a massive recovery plan.

The Russian invasion of Ukraine is an added – albeit dramatic and costly – opportunity to pursue further collective action and discover the next chapter of its shared purpose, as a political and perhaps even a defence alliance.

Europe had long been in need of an arc to follow. In the aftermath of the Second World War, peace and prosperity seemed enough. But the new multipolar world that emerged from the ashes of the Cold War and then 9/11 were more difficult to navigate for a largely commercial and regulatory alliance.

Could the EU, then, ever find its political voice?

David vs Goliath

While Brexit and Covid created rallying points, the shock and tragedy of the invasion delivered everything the EU needed in narrative terms: a David and Goliath story, with the opportunity to feature on Team David in European terms while allying with the United States, and a ‘band of brothers’ element to shore up a union bruised by the defection of a key but troubled member. Above all, the appearance of an arch-villain in the form of Vladimir Putin put Europe back into the familiar and mythical territory of the 1940s and then the Cold War.

When on May 28, 2016, Putin seated himself on the throne of the Byzantine emperors in Mount Athos’ Protaton Church in Greece in a scene truly worthy of Game of Thrones, the writing should have been on the wall. That day he explicitly laid out his aim to appoint himself as the new Eastern emperor who would fight the decadence of the West.

‘Today,’ Putin told the world, ‘we restore the values of patriotism, historical memory and traditional culture.’ Later, he cited Ukraine as the biggest unfinished mission of his years in power. That Europe – and Germany in particular – had taken so long to decipher Putin’s dark designs only adds to the narrative’s epic quality, positioning Europe as a victim of its own good faith and open heart.

Cracks in the narrative

But the narrative is not free from cracks. The Baltic states would argue that they had long warned of Putin’s nefarious intentions; and Poland has always been convinced of the threat posed by its neighbour.

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.

Mutations of p53 protein occur in over half of all cancers, with profound effects on tumor biology. We present the first—to our knowledge—method for noninvasive visualization of p53 in tumor tissue in vivo, using SPECT, in 3 different models of cancer. Methods: Anti-p53 monoclonal antibodies were conjugated to the cell-penetrating transactivator of transcription (TAT) peptide and a metal ion chelator and then radiolabeled with ¹¹¹In to allow SPECT imaging. ¹¹¹In-anti-p53-TAT conjugates were retained longer in cells overexpressing p53-specific than non–p53-specific ¹¹¹In-mIgG (mouse IgG from murine plasma)-TAT controls, but not in null p53 cells. Results: In vivo SPECT imaging showed enhanced uptake of ¹¹¹In-anti-p53-TAT, versus ¹¹¹In-mIgG-TAT, in high-expression p53^R175H and medium-expression wild-type p53 but not in null p53 tumor xenografts. The results were confirmed in mice bearing genetically engineered KPC mouse–derived pancreatic ductal adenocarcinoma tumors. Imaging with ¹¹¹In-anti-p53-TAT was possible in KPC mice bearing spontaneous p53^R172H pancreatic ductal adenocarcinoma tumors. Conclusion: We demonstrate the feasibility of noninvasive in vivo molecular imaging of p53 in tumor tissue using a radiolabeled TAT-modified monoclonal antibody.

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.

To date, the imaging and diagnosis of hepatocellular carcinoma (HCC) rely on CT/MRI, which have well-known limitations. Glypican-3 (GPC3) is a cell surface receptor highly expressed by HCC but not by normal or cirrhotic liver tissue. Here we report initial clinical results of GPC3-targeted PET imaging with [⁶⁸Ga]Ga-DOTA-RYZ-GPC3 (RAYZ-8009), a peptide-based GPC3 ligand in patients with known or suspected HCC. Methods: [⁶⁸Ga]Ga-RAYZ-8009 was obtained after labeling the peptide precursor with ⁶⁸Ga from a ⁶⁸Ge/⁶⁸Ga generator and heating at 90°C for 10 min followed by sterile filtration. After administration of [⁶⁸Ga]Ga-RAYZ-8009, a dynamic or static PET/CT scan was acquired between 45 min and 4 h after administration. Radiotracer uptake was measured by SUVs for the following tissues: suspected or actual HCC or hepatoblastoma lesions, non–tumor-bearing liver, renal cortex, blood pool in the left ventricle, and gastric fundus. Additionally, tumor–to–healthy-liver ratios (TLRs) were calculated. Results: Twenty-four patients (5 patients in the dynamic protocol; 19 patients in the static protocol) were scanned. No adverse events occurred. Two patients had no lesion detected and did not have HCC during follow-up. In total, 50 lesions were detected and analyzed. The mean SUV_max of these lesions was 19.6 (range, 2.7–95.3), and the mean SUV_mean was 10.1 (range, 1.0–49.2) at approximately 60 min after administration. Uptake in non–tumor-bearing liver and blood pool rapidly decreased over time and became negligible 45 min after administration (mean SUV_mean, <1.6), with a continuous decline to 4 h after administration (mean SUV_mean, 1.0). The opposite was observed for HCC lesions, for which SUVs and TLRs continuously increased for up to 4 h after administration. In individual lesion analysis, TLR was the highest between 60 and 120 min after administration. Uptake in the gastric fundus gradually increased for up to 45 min (to an SUV_max of 31.3) and decreased gradually afterward. Conclusion: [⁶⁸Ga]Ga-RAYZ-8009 is safe and allows for high-contrast imaging of GPC3-positive HCC, with rapid clearance from most normal organs. Thereby, [⁶⁸Ga]Ga-RAYZ-8009 is promising for HCC diagnosis and staging. Further research is warranted.

Following early acceptance by urologists, the use of surgical robotic platforms is rapidly spreading to other surgical fields. This empowerment of surgical perception via robotic advances occurs in parallel to developments in intraoperative molecular imaging. Convergence of these efforts creates a logical incentive to advance the decades-old image-guided robotics paradigm. This yields new radioguided surgery strategies set to optimally exploit the symbiosis between the growing clinical translation of robotics and molecular imaging. These strategies intend to advance surgical precision by increasing dexterity and optimizing surgical decision-making. In this state-of-the-art review, topic-related developments in chemistry (tracer development) and engineering (medical device development) are discussed, and future scientific robotic growth markets for molecular imaging are presented.

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