The scale of the current moment is captured by Czernin’s assessment that nuclear medicine is in the middle of a renaissance measurable in both scientific output and financial sustainability. That claim is not mere enthusiasm. Over the past decade, radioligand therapies targeting prostate-specific membrane antigen in prostate cancer and somatostatin receptors in neuroendocrine tumors have delivered survival benefits in pivotal trials, prompting regulatory approvals and triggering substantial industrial investment. The supplement reflects that shift across its entire breadth, covering radionuclide production and supply chains, personalized dosimetry, combination therapies, and the phase 3 trials expected to define the field’s next approved indications.

Yet the supplement is also candid about structural imbalances that could constrain growth. As Czernin observes, science is expanding faster than isotope production capacity, production capacity is expanding faster than dosimetric standardization, and clinical adoption is expanding faster than the trained workforce. In other words, each link in the theranostics chain is lagging behind the one before it, and the weakest links now sit in manufacturing, standardization, and manpower rather than in basic discovery. Industry, he notes, has recognized the opportunity and is funding it accordingly; the remaining burden falls on academic nuclear medicine to keep pace on evidence, personalization, and training.

One of the most technically consequential contributions examines the expanding therapeutic toolbox of emerging isotopes. Cindy Rodriguez, Grace K. Liles, Suzanne E. Lapi, and Jason S. Lewis break down which radionuclides can and cannot be produced at scale today. The distinction matters enormously at the bedside. Alpha-emitting isotopes such as actinium-225 deliver dense, double-strand DNA-breaking radiation over very short path lengths, making them attractive for precise tumor killing, but their global supply remains scarce and production routes are complex. Beta emitters such as lutetium-177 are easier to produce and already anchor approved therapies, while terbium-149, astatine-211, and lead-212 each present distinct chemistry, logistics, and dosimetry challenges that determine whether laboratory promise can ever reach routine clinical use.

Richard Zimmermann’s contribution on the supply chain sharpens that point with a provocative thesis: economics, not science, will decide which radionuclides make it to market. A radionuclide with elegant physics and favorable radiobiology is clinically irrelevant if reactor irradiation capacity, target material availability, generator networks, and reimbursement cannot sustain reliable delivery to hospitals. The supplement’s treatment of this conundrum underscores a reality often obscured by headline trial results: theranostics is as much an industrial logistics problem as a molecular one, and investors, manufacturers, and health systems must align before patients benefit at scale.

Clinical strategy is addressed through two complementary reviews. Yang Wang, Jane McKenzie, and Shahneen Sandhu survey radiopharmaceutical combination therapies in advanced prostate cancer, cataloging trials that pair radioligands with androgen receptor pathway inhibitors, chemotherapy, immunotherapy, and DNA damage response targeting in an effort to overcome monotherapy resistance. Meanwhile, Evan R. Abt, Caius G. Radu, Johannes Czernin, and Christine E. Mona dissect the biology of tumor resistance to radiopharmaceutical therapy itself, examining mechanisms such as heterogeneous target expression, impaired DNA repair pathways, and tumor microenvironmental factors that allow surviving clones to repopulate after treatment. Understanding these mechanisms is the prerequisite for rational combination design rather than empiric trial-and-error.

The phase 3 landscape receives its own detailed mapping from Wolfgang P. Fendler, Michael S. Hofman, David Kersting, Jeremie Calais, and Thomas A. Hope, who chart anticipated future indications across a remarkable slate of trials including PSMAcTION, STAMPEDE2, PSMA-DC, PSMAddition, NETTER-3, ACTION-1, and COMPOSE. These studies extend radioligand therapy into earlier disease stages, combine it with established systemic agents, and test novel targets and isotopes. Their results over the coming years will determine whether theranostics remains a late-line option for advanced disease or becomes embedded earlier in treatment algorithms for prostate cancer, neuroendocrine tumors, and potentially other malignancies.

Personalization is the field’s other great frontier. Richard L. Wahl and Yuni K. Dewaraja examine the evidence for dosimetry-driven personalization of radiopharmaceutical therapies, asking whether patient-specific absorbed dose calculations can and should replace the one-size-fits-all activity prescriptions that dominate current practice. Radiopharmaceutical therapy is unique among cancer treatments in that the therapeutic agent can be imaged directly as it distributes through the body, offering a built-in pharmacokinetic readout. Realizing that advantage requires standardized quantitative imaging, validated dose-response models, and clinical trial designs that test adaptive dosing, all of which remain works in progress despite growing enthusiasm.

Finally, the supplement confronts the human infrastructure problem. Martin Gotthardt, Hossein Jadvar, and David Mankoff argue for a dedicated nuclear oncology subspecialty with tailored training paths, contending that physicians must be fluent simultaneously in radionuclide therapy, molecular imaging, and systemic oncology. Boris Hadaschik and Oliver Sartor examine whether uro-oncologists have embraced nuclear medicine as a true partner in cancer therapy, a question of interdisciplinary trust that will shape referral patterns for years. Caner Civan, Wolfgang P. Fendler, Alina Küper, Lisa Bodei, Wolfgang A. Weber, Louise Emmett, and Ken Herrmann close the volume by taking stock of the field overall and looking ahead to emerging indications. Taken together, the supplement portrays a discipline at an inflection point: scientifically validated, commercially backed, and clinically expanding, but racing to build the isotope supply, dosimetric standards, and specialist workforce its own success now demands. The full supplement is available from The Journal of Nuclear Medicine, with publication support acknowledged from Novartis, Siemens, RayzeBio, and AstraZeneca.

Subject of Research: Current state and future directions of cancer theranostics, including radiopharmaceutical development, dosimetry, clinical trials, and workforce training

Article Title: What’s next for theranostics?

Article References: What’s next for theranostics?. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: theranostics, radiopharmaceuticals, nuclear medicine, radionuclide therapy, dosimetry, prostate cancer, neuroendocrine tumors, phase 3 trials, isotope production, tumor resistance, nuclear oncology, Journal of Nuclear Medicine

The technical heart of this transformation lies in radiopharmaceuticals: molecules engineered to carry a radioactive atom to a specific target inside the body. In diagnostic applications, the radionuclide emits photons that positron emission tomography or single-photon emission computed tomography cameras convert into three-dimensional maps of biological activity. Because these tracers bind to receptors or are taken up by metabolic pathways that behave differently in diseased tissue, they reveal physiology rather than mere anatomy. A PET scan with a glucose analogue such as fluorodeoxyglucose shows where cells are consuming energy; newer tracers bind to prostate-specific membrane antigen or somatostatin receptors, illuminating tumour deposits that conventional imaging may miss entirely. The result is a diagnostic sensitivity that has progressively reshaped oncology, cardiology, and neurology, allowing physicians to stage disease, select therapies, and monitor response with a precision that was unimaginable a generation ago.

What has energised the field most profoundly, however, is the rise of theranostics, a portmanteau of therapy and diagnostics that describes a paired approach to disease. The principle is elegant: the same molecular targeting vector, typically an antibody, peptide, or small molecule, is labelled first with an imaging radionuclide to confirm that a patient’s tumour expresses the target, and then with a therapeutic radionuclide such as lutetium-177 or actinium-225 to deliver cytotoxic radiation directly to those cells. Because the diagnostic step verifies target expression before treatment begins, clinicians can personalise therapy in a way that traditional chemotherapy rarely permits. Beta-emitting radionuclides deposit energy over a few millimetres, while alpha emitters such as actinium-225 release dense, double-strand-breaking radiation over just a few cellular diameters, offering maximal tumour kill with minimal collateral damage to surrounding healthy tissue.

The clinical results emerging from this approach explain why trial activity has surged so dramatically. Patients with advanced, previously treatment-refractory cancers have experienced meaningful responses to radioligand therapy, and regulatory approvals in recent years have validated the strategy across prostate cancer and neuroendocrine tumours. Each success has catalysed further investment: pharmaceutical companies that once viewed nuclear medicine as a niche imaging service now compete to develop targeted radiotherapies, and academic centres have expanded radiopharmacy capacity to meet growing demand. The supply chain for medical isotopes, historically fragile and dependent on a small number of reactors and cyclotrons, has become a strategic concern for health systems worldwide. These industrial and logistical dimensions, as much as the underlying science, will feature prominently in Vienna, where industry exhibition space and educational sessions reflect the field’s new commercial weight.

Artificial intelligence constitutes the second pillar of the congress programme. Nuclear medicine generates extraordinarily data-rich studies: dynamic PET acquisitions produce thousands of volumetric frames, and interpreting them demands both pattern recognition and quantitative rigour. Machine learning models are now being trained to reconstruct images from shorter scan times, reducing radiation dose and improving patient throughput; to segment tumour volumes automatically, replacing laborious manual delineation; and to extract radiomic features that correlate with tumour genotype, grade, and prognosis. Deep learning algorithms have demonstrated the ability to flag subtle findings and prioritise urgent cases, helping physicians read scans faster and more accurately. At EANM’26, sessions will examine not only these technical achievements but also the harder questions of validation, regulatory oversight, and clinical integration, because an algorithm that performs well on retrospective data must still prove itself safe and reliable in the messy reality of routine practice.

Equally significant is the congress’s deliberate expansion beyond oncology. Nuclear cardiology uses single-photon and positron-emitting tracers to assess myocardial perfusion and viability, guiding decisions about revascularisation in coronary artery disease. In neurology, amyloid and tau PET tracers now visualise the hallmark proteinopathies of Alzheimer’s disease, and their role has grown more urgent as disease-modifying therapies require biomolecular confirmation of amyloid pathology before treatment can begin. Tracers targeting inflammation allow clinicians to image infection sites, from prosthetic joint infections to vasculitis, with a sensitivity that complements structural imaging. Paediatric nuclear medicine presents its own distinct challenges, requiring careful dosimetry and child-appropriate protocols, and dedicated sessions will address how the youngest patients can benefit from the field’s advances while minimising radiation exposure. This breadth underscores a central message of the meeting: molecular imaging is not a cancer technology but a whole-of-medicine one.

Valentina Garibotto, Chair of the EANM Scientific Events Council, framed the congress as a moment of collective reflection for a discipline in flux. At a time when nuclear medicine is evolving at an unprecedented pace, she observed, the annual congress has become a key opportunity to pause and define the directions that will shape the field. Her emphasis on translating innovation, evidence, and collaboration into meaningful impact for patients and healthcare systems captures a tension that runs through the entire programme. Radioligand therapies are expensive, logistically demanding, and dependent on isotope supplies that must be produced, transported, and administered within tight time windows dictated by radioactive decay. Ensuring that these advances reach patients equitably, rather than concentrating in wealthy centres, is among the most pressing questions the nuclear medicine community faces, and it is a question that Vienna’s programme treats as central rather than peripheral.

The choice of Vienna itself carries symbolic weight. The European Association of Nuclear Medicine, established in 1985 and headquartered in the Austrian capital, has grown into the largest non-profit medical organisation dedicated to the specialty in Europe. Over four decades it has convened physicians, physicists, chemists, technologists, and other medical societies alongside EU policymakers and industry representatives, working to ensure that patients across the continent can access nuclear medicine services. Hosting the congress at the Austria Center Vienna places the meeting physically close to the association’s institutional home, and the city’s long tradition in physics and medicine provides a fitting backdrop for a field that sits at the intersection of both. Around 10,000 participants moving through the venue’s halls will represent an unusually complete cross-section of a translational pipeline, from isotope production and radiochemistry through preclinical research, clinical trials, and bedside practice.

For the wider scientific public, the significance of EANM’26 extends beyond the specialty itself. Nuclear medicine exemplifies a broader convergence in twenty-first-century healthcare, in which chemistry, physics, computing, and clinical medicine combine to produce therapies tailored to the molecular identity of each patient’s disease. The more than doubling of clinical trials since 2015 signals a field that has crossed from proof of concept into industrial-scale development, and the 50 million annual procedures indicate an installed base of infrastructure and expertise ready to absorb new technologies. The coming decade will likely determine whether theranostics becomes a standard of care across multiple tumour types, whether AI-assisted image interpretation becomes routine, and whether amyloid imaging becomes an everyday tool in dementia care. The conversations in Vienna from October 17 to 21 will help set the agenda for all of these questions, and the answers will shape how medicine diagnoses and treats disease for years to come.

Subject of Research: The EANM'26 congress in Vienna and the rapid growth of nuclear medicine, theranostics, and molecular imaging

Article Title: Vienna to host EANM'26 as nuclear medicine enters a period of rapid transformation

Article References: Vienna to host EANM'26 as nuclear medicine enters a period of rapid transformation. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: nuclear medicine, EANM'26, theranostics, radiopharmaceuticals, molecular imaging, PET, radionuclide therapy, artificial intelligence, Alzheimer's disease, oncology, Vienna, clinical trials

The logic behind the advance rests on radiochemistry that is deceptively simple. Since the mid-1970s, clinicians have labeled white blood cells with gamma emitters such as technetium-99m and indium-111, then reinjected them to locate abscesses and inflammatory lesions. Indium-111, with a physical half-life of about 2.8 days, became the workhorse for this purpose because it persists long enough to follow cells for days. Zirconium-89, with a half-life of 3.3 days, offers a nearly identical temporal window but emits positrons, enabling PET imaging, which delivers substantially higher sensitivity and better spatial and temporal resolution than SPECT. The UAB team exploited 8-hydroxyquinoline, known as oxine, a lipophilic chelator that shuttles zirconium-89 across cell membranes, allowing the radionuclide to become trapped inside the leukocytes rather than merely attached to their surfaces.

The trial enrolled four healthy adult women between 37 and 53 years of age, a deliberate choice grounded in radiation protection logic. Extrapolations from decades of indium-111 oxine dosimetry predicted a higher effective-dose coefficient for females, 1.14 mSv/MBq, than for males, 0.855 mSv/MBq, so studying women represented the more conservative test of safety. There was also a clinical rationale: the team’s longer-term goal is to image neuroinflammation in myalgic encephalomyelitis/chronic fatigue syndrome, a condition that disproportionately affects women. Each participant donated roughly 120 milliliters of blood, from which leukocytes were isolated, incubated with zirconium-89 oxine, washed, and returned intravenously within strict time limits. The mean administered activity was 10.9 plus or minus 2.9 MBq, a modest amount by nuclear medicine standards.

Quality control was rigorous. Every labeled cell preparation had to meet predefined release criteria before reinjection, including radiochemical purity of at least 95 percent, radionuclidic purity of at least 99.5 percent, verified leukocyte viability before and after labeling, sterility, and endotoxin testing. The radiolabeling itself was performed at a licensed commercial radiopharmacy under USP Chapter 797 standards, while the zirconium-89 oxine was produced in the UAB Cyclotron PET Production Facility under USP Chapter 823 guidelines. Only products passing every specification were administered, a framework designed to mirror the established clinical workflow for FDA-approved indium-111 oxine labeling and thereby ease eventual regulatory translation.

Imaging followed a demanding schedule. Each participant underwent whole-body PET/CT at five time points: immediately after injection, then at 4 to 6, 24, 48, and 72 hours. The scans captured a dynamic biological story. Early images showed the labeled cells concentrated in the liver, spleen, heart, and blood pool, as would be expected for cells still circulating. By 24 hours and increasingly at 48 and 72 hours, uptake shifted to the liver, spleen, and red marrow, particularly within the pelvis and iliac crests, reflecting the physiological homing of leukocytes to the organs where they are naturally cleared and stored. The pattern was qualitatively similar to that long documented for indium-111 oxine-labeled leukocytes and consistent with prior mouse and non-human primate studies of zirconium-89 oxine labeling.

The dosimetry numbers carry the study’s headline significance. The highest mean absorbed-dose coefficients appeared in the spleen at 3.52 plus or minus 1.38 mGy/MBq, followed by the liver at 2.1 plus or minus 0.45, the adrenals at 1.62 plus or minus 0.24, the uterus at 1.48 plus or minus 0.98, and the kidneys at 1.36 plus or minus 0.12 mGy/MBq. The mean effective-dose coefficient came out to 0.92 plus or minus 0.06 mSv/MBq, numerically lower than the predicted 1.14 mSv/MBq, a difference that reached statistical significance in an exploratory one-sample t-test with a P value of 0.006. The measured biodistribution also diverged from the assumptions used for prediction: roughly 32 percent of activity localized to the liver, 8 percent to the spleen, and 15 percent to red marrow, rather than the 30-30-34 split assumed from indium-111 data. The authors attribute much of the discrepancy to methodological differences, since PET/CT-based whole-organ dosimetry is inherently more direct than the SPECT-only methods used historically.

Safety results were unambiguous. No adverse events, clinically significant laboratory abnormalities, or pharmacological effects were observed in any participant through 72 hours, and follow-up contact 24 hours after protocol completion turned up nothing further. Vital signs remained stable throughout. One intriguing observation warrants mention: activity concentrations in plasma exceeded those in whole blood, especially at early time points, which the researchers suggest could reflect leukocyte lysis, efflux of the radionuclide from cells, or incomplete buffy coat formation during processing. This phenomenon, they note, deserves closer investigation in subsequent studies.

A key technical concern with any intracellular label is stability. Free zirconium-89 has a well-documented affinity for hydroxyapatite and accumulates in mineralized bone, so progressive cortical bone uptake would signal that the label was leaking from cells. To probe this, the team performed an exploratory skeletal analysis comparing marrow-rich regions of the spine and pelvis with cortical tibial bone. Uptake remained consistently higher in the marrow-rich compartment, while cortical tibial activity stayed low with no progressive accumulation, supporting the interpretation that skeletal signal reflects genuine leukocyte homing to red marrow rather than liberated radionuclide. The authors caution that low-level efflux beyond 72 hours cannot be fully excluded and that longer imaging windows will help settle the question.

The study also showcased a modern dosimetry workflow. Organ regions of interest were generated automatically on CT using an in-house deep learning segmentation tool, then manually refined and propagated across time points. This automation reduces interobserver variability and could make dosimetry scalable across larger, multi-institution cohorts. Time-integrated activity coefficients were computed with Simpson’s rule, and doses were calculated in OLINDA 2.1 using standard adult female phantoms and ICRP 103 tissue weighting factors. Beyond the final 72-hour scan, activity was assumed to decay only physically, a conservative assumption that likely overestimates doses for organs still clearing activity biologically.

Looking ahead, the implications stretch well beyond infection imaging. The same labeling strategy could track CAR T-cells and other cell-based therapies as they home to tumors, offering oncologists a real-time window into treatment delivery. It may prove especially valuable in neurology: animal models of stroke, traumatic brain injury, multiple sclerosis, and Alzheimer’s and Parkinson’s diseases all show leukocyte invasion of the brain, but these events have never been directly visualized in living humans because available PET tracers decay too quickly, while the critical window of immune cell infiltration spans three to four days. Zirconium-89’s half-life fits that window precisely. The research team plans to apply the technique to patients with suspected central nervous system inflammation, including multiple sclerosis and ME/CFS, while working to reduce the blood volume needed for labeling and to improve labeling efficiency. Limitations remain, including the small all-female cohort and the absence of functional testing of labeled cells beyond viability, but the foundation is now laid: for the first time, human dosimetry data confirm that PET imaging of a patient’s own immune cells is both safe and feasible, opening a new chapter in molecular imaging of the immune system.

Subject of Research: First-in-human radiation dosimetry and biodistribution of zirconium-89 oxine-labeled autologous leukocytes imaged with PET/CT

Article Title: First-in-human dosimetry and biodistribution of [89Zr]Zr-oxine-labeled autologous leukocytes using PET/CT

Article References: Gultekin, K., Bartels, J. L., Cardenas, C. E., Kumar, Y., Gimblet, G. R., Jones, C. L., Bankston, C., Jeffers, C. D., White, S. L., Lapi, S. E., Younger, J. W., & McConathy, J. E. (2026). First-in-human dosimetry and biodistribution of [89Zr]Zr-oxine-labeled autologous leukocytes using PET/CT. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08158-w

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08158-w

Keywords: zirconium-89, PET/CT, leukocytes, cell tracking, dosimetry, radiopharmaceuticals, nuclear medicine, oxine, immunimaging, neuroinflammation, CAR T-cells, first-in-human trial

The idea behind the study is theranostics, a portmanteau of therapy and diagnostics that has become one of the most exciting frontiers in oncology. A theranostic agent combines a targeting molecule with a radioactive payload that can either emit gamma rays for imaging or beta particles for destroying tumor cells. Technetium-99m, with its 140 keV gamma emission and short six-hour half-life, is the workhorse of single-photon emission computed tomography and delivers a minimal radiation burden to patients. Rhenium-186 and rhenium-188, by contrast, emit beta particles that can kill cancer cells, making them therapeutic counterparts. Because technetium and rhenium share nearly identical electronic configurations, they form closely related coordination complexes, which is precisely what makes the pair attractive for matched diagnostic and therapeutic agents built from the same ligand.

Hesperidin is an appealing ligand for this purpose. Abundant in citrus fruits, it carries multiple hydroxyl and phenolic groups that can chelate metal ions effectively, and it has already shown cytotoxic effects in various cancer models through modulation of apoptosis and suppression of cell proliferation. Earlier experimental work showed that flavonoids such as quercetin and genistein can be labeled with technetium with radiochemical purities above 90 percent, reinforcing the idea that polyphenolic scaffolds are well suited to radiometal coordination. The research team, led by Taufik Muhammad Fakih and Muchtaridi Muchtaridi, set out to determine computationally whether hesperidin could serve the same dual role for both technetium and rhenium.

The first stage of the investigation relied on density functional theory. The team built three-dimensional models of both metal-hesperidin complexes, optimized their geometries using the B3LYP hybrid functional, and treated the heavy metal centers with the LANL2DZ effective core potential to capture relativistic effects. Frequency calculations confirmed that each optimized structure represented a true energy minimum with no imaginary frequencies. The frontier molecular orbital analysis revealed striking similarity between the two complexes: the HOMO-LUMO energy gap was 0.08848 Hartree for the rhenium complex and 0.08689 Hartree for the technetium complex, indicating nearly identical chemical reactivity. In both cases, the frontier orbitals remained localized on the aromatic rings and oxygen-containing substituents of hesperidin, showing that metal coordination does not disrupt the ligand’s intrinsic electronic distribution or its pharmacophoric structure.

Subtle differences did emerge from the global reactivity descriptors. The technetium complex showed a slightly higher ionization potential, electron affinity, electronegativity, and electrophilicity index, suggesting a marginally stronger tendency to accept electron density. The rhenium complex, meanwhile, exhibited a higher dipole moment of 7.02 Debye compared with 6.52 Debye for technetium, and greater polarizability, hinting at stronger electrostatic interactions in polar environments. A control calculation using the HSEH1PBE functional on the technetium complex produced broadly consistent trends, supporting the internal reliability of the electronic-structure analysis while underscoring that all of these values remain theoretical predictions.

With the electronic groundwork laid, the researchers turned to molecular docking against five breast cancer-related proteins: the estrogen receptor alpha, HER2, AKT1, EGFR, and PIK3CA. After validating the docking protocol by re-docking each receptor’s co-crystallized ligand, with root-mean-square deviations well below 2.0 angstroms for four of the five targets, they ran 100 independent docking simulations per receptor-ligand pair. The results pointed decisively toward kinase targets. Rhenium-hesperidin bound AKT1 with a binding energy of minus 7.49 kcal/mol, corresponding to a micromolar inhibition constant of 3.21 micromolar, the strongest interaction in the entire panel, supported by an extensive hydrogen-bonding network involving residues such as Asn54, Gln59, and Thr211, and hydrophobic contacts with Trp80, Val270, and Leu264. EGFR followed at minus 5.62 kcal/mol, while the hormone receptor ERα and HER2 showed only weak, millimolar-range binding.

The technetium complex told a complementary story. It also favored AKT1, but with a weaker binding energy of minus 5.17 kcal/mol and an inhibition constant of 163.59 micromolar, and its interactions across the panel were generally less potent and less persistent than those of the rhenium analogue. The researchers interpret this asymmetry as functionally meaningful: the stronger, more stable binding of rhenium-hesperidin suits a therapeutic role, while the weaker, more transient engagement of technetium-hesperidin fits the requirements of an imaging agent, which must bind briefly, reveal its location, and clear away.

To test whether these static snapshots would hold up in a dynamic, water-filled environment, the team ran 100-nanosecond molecular dynamics simulations of the two complexes bound to AKT1 and EGFR, using the AMBER99SB-ILDN force field and custom parameters for the metal centers. Both complexes remained stably accommodated in the binding pockets, with acceptable radius of gyration and solvent-accessible surface area profiles. Hydrogen-bond occupancy analysis was particularly revealing: rhenium-hesperidin achieved a total hydrogen-bond occupancy of 407.72 percent against EGFR, far exceeding the 9.11 percent of the native ligand, with persistent contacts at Met793, Lys745, Ser720, and Thr854, residues central to EGFR kinase activity. Technetium-hesperidin also outperformed the native ligand but with lower overall occupancy, again consistent with more reversible binding.

The binding free-energy estimates from MM-PBSA calculations added a final, and deliberately cautious, layer of nuance. For AKT1, the technetium complex produced the most negative mean binding free energy at minus 282.81 kJ/mol, driven by strong van der Waals contributions, compared with minus 220.48 kJ/mol for rhenium. For EGFR, the picture reversed: rhenium-hesperidin averaged minus 47.73 kJ/mol while the technetium complex averaged a slightly positive 20.15 kJ/mol. The authors are careful to stress that these single-trajectory estimates carry large standard deviations, particularly for EGFR, and should be read as comparative trends rather than a definitive ranking. The apparent discrepancy between docking and MM-PBSA reflects the different theoretical foundations of the two methods, one evaluating static poses with empirical scoring and the other incorporating flexibility and solvation from dynamic trajectories.

The study’s limitations are candidly acknowledged: no experimental validation has yet been performed, the PIK3CA docking failed its re-docking criterion, and each molecular dynamics system was simulated only once. Even so, the work lays a credible theoretical foundation for a genuinely elegant concept, a single citrus flavonoid that could carry a gamma-emitting technetium label into the clinic for imaging breast tumors and a beta-emitting rhenium label for therapy, preferentially engaging the AKT1 and EGFR kinases that drive cancer proliferation and survival. Turning that computational promise into a bedside radiopharmaceutical will require radiolabeling experiments, stability and biodistribution studies, and ultimately clinical testing, but the molecular blueprint now exists, and it smells faintly of oranges.

Subject of Research: Computational evaluation of technetium- and rhenium-labeled hesperidin complexes as radiotheranostic agents for breast cancer

Article Title: Theoretical evaluation of technetium-to-rhenium substitution in hesperidin complexes for breast cancer theranostic potential

Article References: Fakih, T. M., Novitasari, D., Syaifudin, M., & Muchtaridi, M. (2026). Theoretical evaluation of technetium-to-rhenium substitution in hesperidin complexes for breast cancer theranostic potential. Heliyon, 12(15), Article e45458. https://doi.org/10.1016/j.heliyon.2026.e45458

Image Credits: AI Generated

DOI: 10.1016/j.heliyon.2026.e45458

Keywords: hesperidin, technetium-99m, rhenium-188, theranostics, breast cancer, molecular docking, molecular dynamics, DFT, AKT1, EGFR, radiopharmaceuticals, flavonoids

The tracer in question is [¹⁸F] AlF-NOTA-Pentixafor, often abbreviated simply as [¹⁸F] Pentixafor. Unlike FDG, which reports on glucose consumption, Pentixafor homes in on CXCR4, a chemokine receptor that acts as a homing beacon for many cancers of the immune system. CXCR4 is overexpressed on the surface of numerous B-cell malignancies, and it plays a genuine biological role in the disease, guiding malignant cells to particular tissue niches and contributing to their survival and dissemination. A tracer that binds CXCR4 therefore does not merely detect a metabolic side effect of cancer; it detects a molecule the cancer actively deploys. This mechanistic distinction is what makes the new study scientifically interesting, because it asks whether a biologically targeted signal can outperform a metabolic one in a tumor type where metabolism is unreliable.

The study was deliberately framed as exploratory. Twenty patients, eleven men and nine women, all with pathologically confirmed gastric MALT lymphoma, underwent both [¹⁸F] FDG PET/CT and [¹⁸F] Pentixafor PET/CT scans. Scanning each patient with both tracers is the strongest design feature of the work, because it allows head-to-head comparison within the same individuals, eliminating the confounding that arises when different cohorts are compared across studies. The researchers then compared how often each tracer detected gastric lesions, and they measured semiquantitative parameters including SUVmax, SUVmean, and the tumor-to-blood pool ratio, or TBR, for both gastric lesions and any disease that had spread beyond the stomach. A statistical test known as the McNemar test, which is specifically designed for paired comparisons of detection rates in the same subjects, was used to assess whether the difference between the two tracers reached significance.

The headline result was numerically striking even if statistically cautious. [¹⁸F] Pentixafor PET/CT was positive in nine of the twenty gastric lesions, a detection rate of forty-five percent, whereas [¹⁸F] FDG PET/CT flagged only four of twenty, or twenty percent. In other words, the CXCR4-targeted tracer found more than twice as many gastric lesions as the standard metabolic tracer. The median SUVmax among Pentixafor-positive gastric lesions was 4.2, with a range running from 1.1 to 7.2, indicating that uptake intensity varied considerably from patient to patient. Yet when the authors subjected this apparent superiority to formal statistical testing, the difference did not reach significance, a finding the team attributes candidly to the small sample size and the non-matched nature of some of the semiquantitative comparisons. This is a crucial nuance: the study does not prove Pentixafor is better, but it provides the kind of preliminary signal that justifies larger, definitive trials.

Perhaps the most intriguing findings came from the subset of patients whose disease had escaped the stomach. Among the five patients with extragastric disease, [¹⁸F] Pentixafor uptake was numerically higher in the lesions outside the stomach than in the gastric lesions themselves, whereas FDG showed no consistent pattern at all. When the researchers pooled lymph-node and pulmonary lesions, the same trend emerged: these sites took up Pentixafor more avidly than FDG. This observation carries real clinical weight, because the management of gastric MALT lymphoma depends heavily on accurate staging. A patient whose disease appears confined to the stomach may be treated with local approaches such as antibiotics targeting Helicobacter pylori infection or radiotherapy, whereas disseminated disease demands systemic therapy. A tracer that reliably illuminates disease beyond the stomach could therefore change treatment decisions in ways that a marginal improvement in gastric detection alone could not.

The researchers also probed which clinical factors predicted a positive Pentixafor scan. The answer was unexpected and, in some respects, sobering. CT-visible gastric wall abnormality was significantly associated with positive Pentixafor PET/CT findings, with a P value below 0.001, making it the only variable that showed a clear statistical relationship. Age, sex, Lugano classification, and the Ki-67 proliferation index, all factors one might reasonably expect to correlate with tracer uptake, showed no significant associations. The association with CT wall abnormalities cuts both ways. On one hand, it suggests that Pentixafor uptake reflects genuine structural disease rather than noise. On the other hand, as the authors themselves note, it implies that the added benefit of the PET signal over CT alone may be limited: if the CT component already shows the abnormality, the radioactive tracer may be confirming rather than discovering it.

The authors are appropriately careful about the limits of their semiquantitative data. All SUV and TBR values are presented as descriptive statistics, and direct comparisons between the two tracers were not performed because the sample was small and the lesion sets were not fully matched. This restraint matters in a field where tracer enthusiasm can sometimes outrun evidence. Pentixafor has generated considerable excitement in nuclear medicine, with studies exploring its use in multiple myeloma, Waldenström macroglobulinemia, and various lymphomas, but each new tumor type demands its own rigorous evaluation. Gastric MALT lymphoma poses particular challenges for any PET tracer: the lesions are often shallow, diffuse, and low in tracer avidity, and physiological uptake in the stomach wall can obscure genuine pathology. A forty-five percent detection rate, while better than twenty percent, still leaves the majority of gastric lesions invisible to the targeted tracer.

Technically, the study also showcases an elegant radiochemistry approach. [¹⁸F] AlF-NOTA-Pentixafor is produced using the aluminum-fluoride labeling method, in which the fluorine-18 radionuclide is chelated to an aluminum ion that binds to the NOTA chelator conjugated to the Pentixafor peptide. This approach avoids the harsh conditions required for direct fluorination of peptides and allows the tracer to be synthesized from the same cyclotron-produced fluorine-18 that already powers FDG production in hospital radiopharmacies. That practical compatibility is not trivial. A tracer that requires exotic isotopes or complex on-site synthesis faces enormous barriers to clinical adoption, whereas one that can be manufactured with existing infrastructure has a realistic path into routine practice. The choice of fluorine-18 also gives the tracer a half-life of about 110 minutes, long enough for distribution and imaging but short enough to limit patient radiation dose.

What should clinicians and patients take away from this work? The honest answer is that it is a promising first step, not a practice-changing result. The study was conducted in accordance with the Declaration of Helsinki, approved by the Ethics Committee of Sichuan Cancer Hospital, and supported by institutional and national nuclear technology research funding, and the authors declare no competing interests. Its conclusions are explicitly framed as preliminary: Pentixafor detected more gastric lesions than FDG, the difference was not statistically significant, and the association with CT wall abnormalities suggests the tracer’s incremental value over conventional imaging remains to be demonstrated. The research team, led by co-first authors Shirong Chen and Xinyang Li and co-corresponding authors Zhuzhong Cheng and Ying Kou, calls for larger studies to define the clinical role of [¹⁸F] Pentixafor PET/CT in this disease.

Still, the broader scientific story is compelling. The study embodies a shift in nuclear medicine from imaging what cancer does, namely consuming glucose, toward imaging what cancer is, namely a cell bearing specific molecular markers. CXCR4 is one of the most heavily studied receptors in tumor biology, and the ability to visualize it noninvasively opens a window on disease biology that metabolic imaging cannot provide. For gastric MALT lymphoma, a cancer that has long evaded reliable molecular imaging, the preliminary numbers from Chengdu suggest that the CXCR4-targeted approach deserves a larger stage. If future studies with adequate statistical power confirm the trends seen here, particularly the apparent advantage in extragastric and nodal disease, then [¹⁸F] Pentixafor could become a genuine complement to FDG in the staging and surveillance of indolent lymphomas, turning a molecular homing receptor into a diagnostic beacon.

Subject of Research: Comparison of FDG and CXCR4-targeted Pentixafor PET/CT tracers for imaging gastric MALT lymphoma

Article Title: A preliminary evaluation of [¹⁸F] FDG and [¹⁸F] AlF-NOTA-Pentixafor PET/CT in gastric MALT lymphoma

Article References: Chen, S., Li, X., Cheng, Z., & Kou, Y. (2026). A preliminary evaluation of [¹⁸F] FDG and [¹⁸F] AlF-NOTA-Pentixafor PET/CT in gastric MALT lymphoma. BMC Medical Imaging. https://doi.org/10.1186/s12880-026-02816-z

Image Credits: AI Generated

DOI: 10.1186/s12880-026-02816-z

Keywords: gastric MALT lymphoma, PET/CT, [¹⁸F] FDG, [¹⁸F] Pentixafor, CXCR4, molecular imaging, SUVmax, tumor-to-blood pool ratio, non-Hodgkin lymphoma, staging, radiopharmaceuticals, BMC Medical Imaging

The study, led by researchers at Peking University Cancer Hospital and Institute in Beijing, enrolled forty-one patients with biopsy-proven neuroendocrine tumors. Every participant underwent both a [68Ga]Ga-DOTA-TATE PET/CT scan and a [18F]AlF-NOTA-JR11 PET/MR examination. JR11, also known as opsomat, is a somatostatin receptor antagonist rather than an agonist, a distinction that matters at the molecular level. Whereas agonist tracers bind preferentially to receptors in an active state and trigger their internalization, antagonists can bind to a larger pool of receptor conformations without activating them, potentially painting a brighter, more complete picture of receptor expression across tumor cells.

The headline result was stark. Across the study population, [18F]AlF-NOTA-JR11 PET/MR depicted 924 lesions in total, compared with 580 lesions detected by [68Ga]Ga-DOTA-TATE PET/CT, a difference the authors reported as highly significant. The advantage was driven overwhelmingly by liver metastases, where the new tracer identified 754 lesions against 405 for the incumbent. Primary tumor detection was similar between the two modalities, with 29 versus 25 primaries found, and there were no significant differences in the detection of lymph node or bone metastases. When the analysis shifted to the patient level, the pattern held: seventy-six percent of patients, thirty-one of the forty-one, had more lesions visualized on the fluorine-18 antagonist scan.

Size matters in these comparisons, and the investigators examined it carefully. The 405 liver metastases seen on both scans were significantly larger, with a median diameter of 14 millimeters, than the 349 lesions seen exclusively on [18F]AlF-NOTA-JR11, whose median diameter was just 6 millimeters. In other words, much of the incremental yield came from tiny sub-centimeter deposits, precisely the kind of small-volume disease that can alter staging, shape decisions about liver-directed therapies, and influence eligibility for peptide receptor radionuclide therapy.

Quantitative imaging metrics told an equally interesting story. Maximum standardized uptake values, the conventional measure of tracer avidity, were actually lower for [18F]AlF-NOTA-JR11 in primary tumors, liver metastases, and bone metastases compared with [68Ga]Ga-DOTA-TATE. That initially counterintuitive finding makes sense once background activity is considered. The fluorine-18 antagonist scan showed significantly lower uptake in normal tissues, and consequently a higher tumor-to-background ratio in primary tumors, lymph node metastases, and liver metastases. A dimmer background against which tumors glow brightly is often more valuable diagnostically than a raw measure of tracer accumulation, because it is contrast, not absolute intensity, that lets a radiologist resolve a lesion from its surroundings.

The chemistry behind the new tracer also carries practical significance. Gallium-68 is produced in a generator, which is convenient but constrains throughput and shelf life, since the isotope decays with a half-life of roughly sixty-eight minutes. Fluorine-18, by contrast, has a half-life of about 110 minutes and can be manufactured in cyclotron facilities with multi-center distribution, mirroring the logistics that made fluorodeoxyglucose the most widely used PET tracer in the world. The aluminum fluoride labeling method used to attach fluorine-18 to the NOTA-chelated peptide is a one-step, aqueous procedure that avoids the harsher conditions required for direct fluorination, making synthesis simpler and more amenable to routine production.

Pairing the tracer with magnetic resonance rather than computed tomography adds a second layer of advantage. MR provides superior soft-tissue contrast, particularly in the liver and abdomen, where diffusion-weighted and hepatobiliary sequences can flag lesions that CT misses. Previous work comparing PET/MR with PET/CT in oncology has shown that the combined modality can change patient management in a meaningful fraction of cases, and neuroendocrine tumors, with their hepatic predilection, stand to benefit most. The Beijing team’s design, in which the superior antagonist tracer is coupled with the superior anatomical imaging platform, deliberately stacks the deck toward maximal lesion conspicuity.

The study builds on a decade of clinical exploration of somatostatin receptor antagonists. Early proof-of-principle work demonstrated that antagonist-based imaging was feasible in humans, and subsequent head-to-head trials of gallium-68-labeled JR11 formulations against agonist tracers showed higher detection rates in metastatic, well-differentiated tumors. A parallel European study comparing a fluorine-18-labeled octreotide antagonist on PET/MR with gallium-68 DOTA-TATE PET/CT reported similar directional findings. What the new study adds is the first clinical comparison of aluminum fluoride-labeled JR11 on PET/MR, consolidating the tracer chemistry, the antagonist pharmacology, and the MR platform into a single evaluation.

Caveats remain before the findings translate into wholesale clinical practice. The cohort of forty-one patients, while adequate for a paired-lesion comparison, is modest, and the study came from a single center with radiopharmaceutical expertise in-house. The researchers did not report changes in patient management attributable to the additional lesions, so the downstream clinical impact of finding more small liver metastases, whether it prolongs survival or simply reshapes surveillance, awaits longitudinal follow-up. The authors also note that one co-author holds a position with a medical imaging company and contributed protocol optimization, although the remaining authors declared no competing interests.

Even so, the evidence positions [18F]AlF-NOTA-JR11 PET/MR as a serious contender to become the next generation of somatostatin receptor imaging. With more than four hundred additional liver lesions visualized across forty-one patients, higher tumor-to-background contrast, and a cyclotron-friendly isotope that could democratize distribution, the combination addresses the two great bottlenecks of current practice: sensitivity for small-volume hepatic disease and the supply chain constraints of gallium-68. For patients with neuroendocrine tumors, whose treatment decisions hinge on a precise map of where their disease has spread, a sharper and more widely available imaging lens could not arrive at a better time.

Subject of Research: Head-to-head comparison of fluorine-18 somatostatin receptor antagonist PET/MR and gallium-68 DOTA-TATE PET/CT for imaging neuroendocrine tumors

Article Title: Head-to-head comparison of [18F]AlF-NOTA-JR11 PET/MR and [68Ga]Ga-DOTA-TATE PET/CT in patients with neuroendocrine tumors

Article References: Head-to-head comparison of [18F]AlF-NOTA-JR11 PET/MR and [68Ga]Ga-DOTA-TATE PET/CT in patients with neuroendocrine tumors. (n.d.). https://doi.org/10.1007/s00259-026-08176-8

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08176-8

Keywords: neuroendocrine tumors, PET/MR, PET/CT, somatostatin receptor antagonist, fluorine-18, gallium-68, DOTA-TATE, liver metastases, molecular imaging, nuclear medicine, tumor-to-background ratio, radiopharmaceuticals

Pancreatic neuroendocrine tumors are an uncommon but stubborn group of malignancies. Unlike the more familiar pancreatic adenocarcinomas, they often express high levels of somatostatin receptors on their surface, a molecular feature that has made them eligible for peptide receptor radionuclide therapy. In this approach, a hormone-like peptide called DOTATATE binds to those receptors and delivers a radioactive payload, lutetium-177, directly into tumor cells. The beta radiation released by lutetium-177 travels only a few millimeters in tissue, damaging DNA and triggering cell death in tumor cells while largely sparing surrounding healthy tissue. Clinical trials have shown meaningful benefit, but responses are rarely complete, and resistance eventually develops in many patients.

Sunitinib, meanwhile, is a multitargeted oral kinase inhibitor that blocks several receptors involved in tumor angiogenesis, including vascular endothelial growth factor receptors and platelet-derived growth factor receptors. By starving tumors of their blood supply and directly inhibiting survival signaling within tumor cells, sunitinib has extended progression-free survival in patients with advanced pancreatic neuroendocrine tumors. Clinicians have observed that combining sunitinib with 177Lu-DOTATATE appears to produce deeper and more lasting responses, but the biological basis of this synergy remained poorly defined.

The new research set out to test a specific hypothesis: that the combination does more than simply add two cytotoxic effects. Immunogenic cell death is a specialized form of cell demise in which dying tumor cells release or expose a characteristic set of signals, often called damage-associated molecular patterns. These include calreticulin translocated to the cell surface, secretion of ATP, release of high-mobility group box 1 protein, and presentation of tumor antigens on major histocompatibility complex molecules. Together, these signals attract and activate dendritic cells, which then carry tumor antigens to lymph nodes and prime cytotoxic T lymphocytes capable of hunting down residual cancer cells throughout the body.

Using preclinical models of pancreatic neuroendocrine tumors, the investigators showed that each therapy alone induced only limited immunogenic signaling. Sunitinib treatment produced vascular changes and some direct tumor cell stress, while 177Lu-DOTATATE delivered DNA-damaging radiation that killed a fraction of receptor-expressing cells. Neither monotherapy reliably provoked the full repertoire of immunogenic death markers. When the two were combined, however, the picture changed dramatically. Tumor cells exposed to both agents displayed significantly increased surface calreticulin, elevated ATP secretion, and heightened release of high-mobility group box 1 protein into the tumor microenvironment.

The mechanistic studies went further. The researchers found that sunitinib pretreatment increased the expression of entosis-related and autophagy pathways in tumor cells, processes that are known to be required for the calreticulin exposure that defines immunogenic cell death. At the same time, radiation from lutetium-177 inflicted the DNA damage and endoplasmic reticulum stress that serve as the danger signals alerting the immune system. In effect, the kinase inhibitor appeared to prepare tumor cells for a form of death that the radiopharmaceutical then converted into an immunological alarm, transforming what would otherwise be a quiet, non-inflammatory demise into a stimulus capable of recruiting dendritic cells and activating T cells.

The immune consequences were visible within the tumors themselves. Combination-treated tumors showed increased infiltration by CD8-positive cytotoxic T lymphocytes, higher ratios of effector T cells to immunosuppressive regulatory T cells, and evidence of dendritic cell activation. Interferon-gamma signatures were upregulated, indicating that T cells within the tumor microenvironment had been functionally engaged rather than merely present. The researchers also documented reductions in myeloid-derived suppressor cells and markers of tumor-associated immunosuppression, suggesting that the combination remodels the tumor microenvironment in a direction that favors immune attack.

Perhaps the most striking evidence came from experiments in which the researchers depleted specific immune cell populations or blocked key signaling pathways. When CD8-positive T cells were removed, the survival advantage and tumor control conferred by the combination largely disappeared, demonstrating that the adaptive immune response was not an incidental byproduct but a required component of the therapeutic synergy. Similarly, blocking the recognition of damage-associated molecular patterns abrogated the dendritic cell activation and downstream T cell priming. These findings establish the combination as a bona fide inducer of a vaccination-like effect arising from within the tumor itself.

The implications for clinical practice are considerable. Immunogenic cell death has become one of the central concepts in the rational design of combinations with immune checkpoint inhibitors, since checkpoint blockade works best when antitumor T cells have already been primed. The new findings provide a mechanistic rationale for testing 177Lu-DOTATATE and sunitinib together with agents such as PD-1 or PD-L1 inhibitors in pancreatic neuroendocrine tumors, a disease in which immunotherapy alone has so far shown limited activity. Ongoing and planned clinical trials may now incorporate biomarkers of immunogenic cell death, such as serum high-mobility group box 1 levels or tumor calreticulin staining, as pharmacodynamic readouts of whether the combination is successfully igniting antitumor immunity in individual patients.

The study also carries broader lessons for nuclear medicine. Radiopharmaceuticals have often been viewed as precision cytotoxic tools whose benefits are confined to their radioactive range. Work of this kind reinforces an emerging view that targeted radionuclide therapy can function as an in situ tumor vaccine, and that pairing it with agents that modulate tumor cell death pathways, vascular biology, or immune checkpoints can convert localized radiation into systemic immunological control. For patients with pancreatic neuroendocrine tumors, whose treatment options narrow sharply after somatostatin analogs, everolimus, sunitinib, and 177Lu-DOTATATE have been exhausted, the prospect of a combination that teaches the immune system to finish what the drugs begin offers a genuinely new therapeutic direction grounded in a mechanism that can now be measured, monitored, and deliberately enhanced.

Subject of Research: Mechanism of synergy between sunitinib and 177Lu-DOTATATE peptide receptor radionuclide therapy via immunogenic cell death in pancreatic neuroendocrine tumors

Article Title: Immunogenic cell death as a mechanism of synergy between sunitinib and 177Lu-DOTATATE peptide receptor radionuclide therapy in pancreatic neuroendocrine tumors

Article References: Essler, M., Veit, N., Müller, A., Marinova, M., & Kreppel, B. (2026). Immunogenic cell death as a mechanism of synergy between sunitinib and 177Lu-DOTATATE peptide receptor radionuclide therapy in pancreatic neuroendocrine tumors. Cell Death Discovery, 12(1), Article 379. https://doi.org/10.1038/s41420-026-03344-z

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03344-z

Keywords: immunogenic cell death, sunitinib, 177Lu-DOTATATE, peptide receptor radionuclide therapy, pancreatic neuroendocrine tumors, calreticulin, damage-associated molecular patterns, dendritic cells, CD8 T cells, tumor microenvironment, radiopharmaceuticals, immunotherapy synergy