The study, published in eClinicalMedicine, brought together 111 adults with chronic disseminated candidiasis from 19 countries, diagnosed between January 2007 and December 2025. The condition, also known as hepatosplenic candidiasis, typically strikes patients with blood cancers such as acute myeloid leukaemia as their white blood cell counts recover after prolonged chemotherapy-induced neutropenia. It produces persistent fever, abdominal pain, cholestasis and characteristic abscesses in the liver and spleen, and it can force delays in cancer treatment that may ultimately matter more than the infection itself.

Almost all patients in the cohort had an underlying haematological malignancy. Acute myeloid leukaemia accounted for 48.6 percent of cases and acute lymphoblastic leukaemia for 24.7 percent, with lymphoma making up a further 15.6 percent. Notably, 24.8 percent of patients developed the infection despite receiving systemic antifungal prophylaxis in the days before diagnosis, so-called breakthrough disease, a figure that underscores the limits of current preventive strategies in the era of widespread mould-active azole prophylaxis.

The researchers applied a sophisticated statistical approach rarely used in this field: marginal structural models with inverse probability of treatment weighting, designed to account for time-varying confounders such as neutropenia and corticosteroid exposure that shift over the course of illness and can distort simple treatment comparisons. After this adjustment, neither the class of first-line antifungal, whether echinocandins, liposomal amphotericin B or azoles, nor the choice between fluconazole and other azoles for long-term oral step-down therapy was significantly associated with treatment response or overall survival.

This is a striking result given that international guidelines currently recommend echinocandins or liposomal amphotericin B as initial therapy, followed by an oral azole. Echinocandins were indeed the most common first-line choice in the cohort, used in 58.6 percent of patients, reflecting alignment with contemporary guidance. But the new data suggest clinicians may have greater flexibility than guidelines imply, particularly for patients with prior azole exposure or resistant organisms, where alternatives to fluconazole have previously rested on thin evidence.

Perhaps the most practice-changing observation concerns treatment duration. The median total course of targeted antifungal therapy was 107 days, substantially shorter than the four to seven months reported in earlier cohorts, and no relapses were documented after treatment was stopped during a median post-discontinuation follow-up of 92 days. Because conventional CT abnormalities can persist for many months after the infection has been controlled, with resolution rates of only 30 to 34 percent at three months in prior studies, the findings support the idea that extending therapy until complete radiological resolution may be unnecessary in selected patients.

Advanced imaging may hold the key to individualising that decision. Positron emission tomography combined with CT was performed in 26.1 percent of patients, and in 12 of them, regression of PET/CT findings was explicitly cited as the reason for stopping antifungal therapy. These patients had markedly longer treatment courses than those without PET-guided decisions, a median of 219 versus 88 days. The results complement the earlier French CANHPARI pilot study, which suggested that PET/CT normalisation at three months may better reflect resolution of active inflammation than conventional imaging, and they point toward PET/CT-guided assessment as a promising tool for distinguishing residual infection from immune reconstitution inflammatory syndrome, the paradoxical worsening that occurs as neutrophils recover.

The study also documented under-recognised manifestations of the disease. Nine patients showed central nervous system involvement, with multifocal punctate or ring-enhancing lesions on neuroimaging and, in some cases, positive cerebrospinal fluid beta-D-glucan testing. Skin and soft tissue involvement occurred in nine patients, six of whom had Candida tropicalis infection, a species known for cutaneous dissemination. The authors suggest that clinicians should consider CNS imaging in patients with neurological symptoms or refractory disease, since cerebral spread may be more common than previously appreciated.

Microbiological findings carried their own geographic and therapeutic signals. Candida albicans accounted for 32.4 percent of identified isolates and C. tropicalis for 24.3 percent, with the latter clustering markedly in Taiwan and Colombia. Fluconazole resistance was found in 11 isolates and was far more frequent in C. tropicalis than in other species, affecting 29.6 percent versus 3.6 percent, and nearly two-thirds of resistant cases occurred in the context of breakthrough infection. Yet resistance did not translate into worse survival, and beta-D-glucan, a fungal cell-wall marker measured at baseline in 35 patients, was positive in 88.6 percent, suggesting it may serve as a useful diagnostic adjunct.

Ultimately, the numbers tell a story about host biology rather than pharmacology. Only 4.5 percent of deaths were attributable to the fungal infection itself, even though all-cause mortality reached 33.3 percent, and patients with breakthrough disease actually survived more often than those without, likely because their underlying cancers were in a more favourable state. The authors caution that their comparative treatment analyses were exploratory and not powered to exclude clinically meaningful differences, and they call for prospective studies incorporating immune biomarkers such as cytokine profiles and Candida-specific T-cell responses alongside PET/CT. But for a disease that has been managed largely by tradition and caution, the message is clear: immune recovery, not drug selection, may be the true engine of cure, and shorter, individually tailored treatment could spare vulnerable patients months of toxicity, cost and delayed cancer therapy.

Subject of Research: Treatment strategies and outcomes of chronic disseminated candidiasis in patients with haematological malignancies in the era of antifungal prophylaxis

Article Title: Treatment and outcome of chronic disseminated candidiasis in the era of antifungal prophylaxis: a retrospective multicentre cohort of 111 patients

Article References: Reinhold, I., Ramirez-Sanchez, I. C., Chen, P.-Y., Chen, Y.-C., Dhariwal, A., Lambourne, J., Agrawal, S., Bastida, M., Gudiol, C., Alfandari, S., Di Pilla, A., Khostelidi, S., Aguilar-Zapata, D., Barac, A., Cipriano, A., Ehrlich, S., Grothe, J., Illarramendi, J., Jennrich, S., … Zager, L. (2026). Treatment and outcome of chronic disseminated candidiasis in the era of antifungal prophylaxis: a retrospective multicentre cohort of 111 patients. eClinicalMedicine, 100, Article 104194. https://doi.org/10.1016/j.eclinm.2026.104194

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104194

Keywords: chronic disseminated candidiasis, hepatosplenic candidiasis, haematological malignancies, antifungal therapy, echinocandins, azoles, Candida tropicalis, fluconazole resistance, PET/CT imaging, immune reconstitution, neutropenia, beta-D-glucan

The central concept behind the research is receptor saturation. Atezolizumab is a monoclonal antibody designed to bind PD-L1, a protein that many tumours deploy on their surfaces to suppress the immune cells that would otherwise attack them. By occupying PD-L1, atezolizumab blocks this molecular camouflage and releases the brakes on the immune system. But the drug can only work where it actually reaches the target in sufficient quantity. If a tumour expresses abundant PD-L1 but has poor blood supply, dense stromal barriers, or unfavourable pharmacokinetics, the antibody may fail to saturate the target even though the patient receives a full therapeutic dose. Conventional testing, which involves staining a biopsy sample for PD-L1 expression, captures only a snapshot of a tiny fragment of the tumour at a single moment in time and says nothing about whether the drug is engaging its target throughout the body.

PET imaging offers a fundamentally different perspective. In the approach examined by the researchers, atezolizumab is labelled with a radioactive tracer, typically the radionuclide zirconium-89, whose decay signature can be detected by the PET scanner. When the labelled antibody is injected into a patient, the scanner produces three-dimensional maps showing exactly where the drug accumulates. If a tumour lights up with signal before treatment, it indicates that PD-L1 is present and accessible to the antibody. If the signal diminishes or disappears after the patient begins therapy with unlabelled atezolizumab, it indicates that the therapeutic antibody has flooded the target sites, occupying them so thoroughly that the labelled tracer can no longer bind. This drop in tracer uptake is the imaging signature of target saturation, the pharmacodynamic state in which the drug is doing its intended molecular job at the tumour site.

The logic of this imaging paradigm rests on a simple competitive principle. Before treatment begins, when no therapeutic antibody is circulating, the radiolabelled atezolizumab analogue can bind freely to PD-L1 molecules on tumour cells, producing strong PET signal. Once a patient starts standard atezolizumab infusions, the circulating therapeutic antibody competes with the tracer for the same binding sites. As the drug concentration rises and saturates available PD-L1, tracer uptake falls. The degree of that fall provides a direct, whole-body measure of how completely the treatment is engaging its target in each tumour lesion. This is often described as an in vivo pharmacodynamic biopsy: instead of sampling one lesion surgically, clinicians can observe drug-target interactions across every detectable tumour deposit simultaneously, including metastases in locations that could never be biopsied safely.

The significance of this capability becomes clear when considering how immunotherapy is currently managed. Patients with non-small cell lung cancer, bladder cancer, and other PD-L1-positive malignancies typically receive atezolizumab or similar agents on fixed schedules, often for months, before standard imaging can reveal whether the tumours are shrinking. Response assessment by CT generally takes weeks to months to show meaningful change, because tumour shrinkage is a delayed downstream consequence of immune activation. Target saturation, by contrast, is an immediate upstream event. If imaging shows that the antibody has fully occupied PD-L1 within days of the first dose, and the tumour still fails to respond over the following months, the problem lies elsewhere: the tumour may have developed alternative immune-evasion mechanisms, the tumour microenvironment may lack infiltrating T cells, or downstream signalling may be blocked. Distinguishing pharmacokinetic failure, where the drug never reached the target, from biological resistance, where the drug engaged the target but the cancer resisted anyway, is exactly the information that saturation imaging is designed to provide.

Past work in this field has demonstrated the technical feasibility of the approach. Radiolabelled versions of atezolizumab and the related antibody pembrolizumab have been used in early-phase clinical trials, showing that PD-L1-specific PET signal can be detected in human tumours, that uptake varies widely between patients, and that heterogeneity exists even among different metastatic lesions within the same individual. These studies revealed something that biopsies had long obscured: a patient whose primary tumour shows strong PD-L1 staining may harbour liver metastases with negligible target expression, and those lesions may behave very differently under treatment. Quantitative measures derived from PET scans, such as standardised uptake values, have been correlated with clinical outcomes in preliminary analyses, hinting that baseline tracer uptake and early changes during therapy could serve as predictive biomarkers in their own right.

Dosing is another area where saturation imaging carries substantial implications. Current atezolizumab regimens were established through trials that sought doses safely exceeding the levels needed for receptor occupancy, but those occupancy estimates were largely derived from circulating drug levels and receptor occupancy measurements on peripheral blood cells, not from direct measurements inside tumours. Tumour penetration is governed by different physics: antibody extravasation through leaky but uneven vasculature, diffusion through the extracellular matrix, binding-site barriers created by dense target expression near blood vessels, and clearance rates that vary with tumour type and location. PET saturation imaging brings these hidden variables into view. A tumour that retains strong tracer uptake even after multiple treatment doses is telling clinicians that the target remains unsaturated, suggesting that dose escalation, altered scheduling, or combination strategies that improve drug delivery might be worth considering for that specific patient.

The study published in the British Journal of Cancer contributes to this evolving evidence base by evaluating PD-L1 PET/CT specifically as a tool to assess tumour saturation during atezolizumab treatment. The broader research programme of which it forms a part reflects a decisive shift in oncology drug development: away from one-size-fits-all dosing and toward imaging-verified pharmacodynamics. Regulatory science has begun to take note. Methods that demonstrate target engagement early in treatment could accelerate clinical trials by providing early surrogate indicators, reducing the sample sizes and follow-up durations needed to establish whether a drug regimen is mechanistically active. They could also support adaptive treatment strategies in routine care, in which imaging results after the first one or two doses inform whether the patient should continue, switch, or intensify therapy long before tumour volume changes would be visible.

Challenges remain before such imaging can enter routine practice. Radiolabelling antibodies with zirconium-89 requires cyclotron facilities, radiochemistry expertise, and regulatory compliance that currently limits availability to specialised centres. The half-life of zirconium-89, roughly 78 hours, suits the slow pharmacokinetics of antibodies, which circulate for days to weeks before reaching peak tumour uptake, but it also means patients must return for scans several days after injection and absorb a meaningful radiation dose. Cost, reimbursement, and the need for standardised scanning protocols and uptake thresholds all stand between promising trial results and clinical adoption. Questions also persist about how best to interpret partial saturation, how tracer signal in the liver and spleen, organs with high background antibody uptake, affects quantification of abdominal lesions, and how the immune response triggered by treatment itself alters target expression over time.

Nevertheless, the trajectory of the field is unmistakable. Molecular imaging of drug-target engagement is converging with immunotherapy at a moment when the limitations of current biomarkers have become painfully evident. PD-L1 immunohistochemistry, tumour mutational burden, and gene-expression signatures each capture only a fragment of the biology that determines whether a patient responds to checkpoint blockade. Saturation imaging promises something those tools cannot: a dynamic, whole-body, patient-specific readout of whether the drug is doing, at the molecular level, what it was designed to do. If validated in larger cohorts, the approach exemplified by this line of research could move immunotherapy closer to the ideal of precision medicine, where the first weeks of treatment generate actionable information rather than a waiting period measured in months. For the many patients whose tumours do not respond to atezolizumab and its peers, that shift could mean less time on ineffective therapy, faster transitions to alternatives, and a clearer mechanistic understanding of why immunotherapy succeeds or fails in each individual.

Subject of Research: PD-L1 PET/CT molecular imaging to assess tumour target saturation during atezolizumab immunotherapy

Article Title: Programmed death ligand 1 (PD-L1) PET/CT imaging to evaluate tumour saturation during atezolizumab treatment

Article References: Hooiveld-Noeken, J. S., van de Donk, P. P., Kist de Ruijter, L., Kok, I. C., van Winkel, C. A. J., Giesen, D., Lub-de Hooge, M. N., Brouwers, A. H., Oosting, S. F., Bensch, F., Smit, L. M., Schröder, C. P., Jalving, M., Elias, S. G., Gietema, J. A., Deurloo, R. J., Williams, S. P., Ungewickell, A., de Groot, D.-J. A., & de Vries, E. G. E. (2026). Programmed death ligand 1 (PD-L1) PET/CT imaging to evaluate tumour saturation during atezolizumab treatment. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03595-8

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03595-8

Keywords: PD-L1, PET/CT imaging, atezolizumab, immunotherapy, checkpoint inhibitors, target saturation, molecular imaging, radiotracer, tumour microenvironment, pharmacodynamics, precision oncology, British Journal of Cancer