The research team, led by Damir Zubac together with Timo Sonntag, Diana Kranjc and Freerk T. Baumann, recruited 19 patients undergoing acute immune checkpoint inhibitor treatment and 21 age-matched healthy controls from the Cologne area. Participants were screened to exclude hypertension, diabetes, chronic lung disease and obesity, and were required to be free of brain, bone or lung metastases. The patients, who had been diagnosed roughly 14 months earlier and had been on immunotherapy for about six months, most commonly had malignant melanoma or breast cancer, with the majority treated with the PD-1 antibodies pembrolizumab or nivolumab. Crucially, the two groups were well matched: there were no significant differences in age, height, body mass, body mass index, resting blood pressure, oxygen saturation or body composition measured by bioelectrical impedance.

Each participant completed two laboratory visits. In the first, they performed a ramp-based cardiopulmonary exercise test on a cycle ergometer to exhaustion, with breath-by-breath measurement of pulmonary gas exchange to determine peak oxygen uptake, peak power output, the gas exchange threshold and the oxygen uptake efficiency slope. In the second session, they completed the Multidimensional Fatigue Inventory questionnaire, a validated 20-item instrument covering general, physical, mental fatigue, reduced activity and reduced motivation, followed by a 30-minute steady-state cycling test at 90 percent of each individual’s gas exchange threshold, during which energy expenditure and gross cycling efficiency were calculated.

The results painted a clear picture of diminished physical capacity in the immunotherapy group. Patients showed significantly lower pulmonary ventilation, oxygen uptake, carbon dioxide production, stroke index and oxygen uptake efficiency slope during maximal testing, all with large effect sizes. Their exercise tests ended roughly four minutes sooner than those of controls, and the peak power output they achieved was dramatically lower, with an effect size of 2.35. Importantly, patients reported the same subjective effort at exhaustion, rating around 19 on the standard scale, meaning they were not simply holding back. The pattern of reduced oxygen pulse alongside only modest differences in maximal heart rate suggests that the limitation lies primarily in the heart’s ability to augment stroke volume and cardiac output during maximal effort, a finding the authors note could hint at early cardiotoxicity, though no direct cardiac diagnostics were performed.

Fatigue, however, was the most dramatic group difference of all. Using age- and sex-standardized cutoffs derived from a representative German community sample, 63 percent of the immunotherapy patients met criteria for clinically relevant chronic fatigue, compared with just 15 percent of the healthy controls. Across all five dimensions of the questionnaire, patients scored substantially worse: general fatigue was elevated by 38 percent, physical fatigue by nearly 40 percent, and mental fatigue, reduced activity and reduced motivation were all similarly increased with moderate to large effect sizes.

Yet when the researchers ran linear regression models asking whether peak oxygen uptake or peak power output, adjusted for age, could predict general fatigue scores, the answer was a consistent no. In healthy controls, the models explained between 8 and 13.5 percent of the variance in fatigue, and in immunotherapy patients only between 4.3 and 5.6 percent, none of it statistically significant. Age, too, failed to predict fatigue, despite the common assumption that aging drives both declining fitness and increasing tiredness. Multicollinearity diagnostics were clean, so the null result was not a statistical artifact of correlated predictors.

A particularly novel observation emerged from the submaximal endurance test. Although every single participant, patient and control alike, managed to complete the full 30 minutes of moderate-intensity cycling at 90 percent of their gas exchange threshold, the patients did so at significantly lower gross efficiency. The average workload was 122 watts for controls versus 88 watts for patients, and the patient group converted metabolic energy into mechanical work measurably less efficiently, with a mean group difference of just over two percentage points. Because similar data in checkpoint inhibitor populations do not otherwise exist, the authors can only hypothesize that impaired mitochondrial coupling in skeletal muscle, a phenomenon previously demonstrated with in vivo phosphorus magnetic resonance spectroscopy in older adults, may underlie the inefficiency. Supporting this idea, recent muscle biopsy work has shown that even a single chemotherapy dose induces mitochondrial dysfunction in breast cancer patients.

The disconnect between how tired patients feel and how their bodies perform on objective testing carries real clinical weight. Structured exercise is recommended as a first-line therapy for cancer-related fatigue, and prior work in immunotherapy-treated patients has shown that exercise interventions can reduce fatigue scores by roughly 8 to 10 points on validated scales. The present findings suggest that a clinically meaningful level of fatigue does not preclude moderate-to-vigorous aerobic exercise: all 19 fatigued patients completed a half hour of cycling under controlled conditions. This supports the feasibility of individualized aerobic exercise prescriptions, calibrated to objective test results rather than to how patients subjectively rate their energy.

The authors are careful to frame the study as exploratory. The cross-sectional design, the modest sample size of 40 analyzed participants, the heterogeneity of cancer diagnoses and prior treatments, and the absence of direct cardiac or mitochondrial measurements all limit how far the conclusions can be pushed. The findings characterize people receiving checkpoint inhibitor therapy rather than proving causal effects of the drugs themselves, and the regression models leave open the question of what actually drives chronic fatigue, with circulating inflammatory cytokines, muscle metabolic changes and neurotransmitter disruption all implicated in the wider literature.

Even so, the study marks a step beyond earlier feasibility and adherence work in this population. It provides the first data on work efficiency in patients under acute checkpoint inhibitor therapy, offers a physiological rationale for prescribing aerobic exercise at the gas exchange threshold, and points future investigators toward more comprehensive, non-invasive assessments of the oxygen transport pathway, such as flow-mediated dilation and vascular occlusion testing, to finally unravel why immunotherapy patients feel so tired even when their exercise capacity tells only part of the story.

Subject of Research: The relationship between self-reported chronic fatigue and objectively measured cardiopulmonary exercise parameters in adult cancer patients receiving immune checkpoint inhibitor therapy

Article Title: Chronic, self‐reported fatigue in adult immunotherapy patients and healthy controls: No association with cardiopulmonary exercise testing parameters

Article References: Zubac, D., Sonntag, T., Kranjc, D., & Baumann, F. T. (2026). Chronic, self‐reported fatigue in adult immunotherapy patients and healthy controls: No association with cardiopulmonary exercise testing parameters. Physiological Reports, 14(17), Article e71090. https://doi.org/10.14814/phy2.71090

Image Credits: AI Generated

DOI: 10.14814/phy2.71090

Keywords: immunotherapy, immune checkpoint inhibitors, chronic fatigue, cancer-related fatigue, cardiopulmonary exercise testing, VO2 peak, cycling efficiency, exercise oncology, cardiorespiratory fitness, MFI-20, mitochondrial dysfunction, supportive care

In OPTIM, patients first receive nivolumab, an immune checkpoint inhibitor that blocks PD-1 signaling and helps reactivate exhausted T cells. Participants who later show progression are not simply discontinued; instead, they enter a randomized phase that assigns one of two subsequent approaches. One arm uses nivolumab-ipilimumab, pairing PD-1 blockade with CTLA-4 inhibition to potentially broaden and intensify antitumor immune responses.

The alternative strategy tests docetaxel, a chemotherapy agent widely used in head and neck cancers. By comparing an immunotherapy intensification route against a conventional cytotoxic option after initial nivolumab failure, the trial aims to identify which sequence is more effective in real-world progression scenarios. This “therapeutic after progression” concept is particularly relevant because many patients initially respond to PD-1 inhibitors only to develop resistance.

Investigators emphasize that sequencing matters: tumors that escape PD-1 blockade may still remain susceptible to immune re-education through combination checkpoint inhibition, or alternatively may respond better to cytotoxic mechanisms that can reduce tumor burden and modify the tumor microenvironment. The study’s randomized design is intended to reduce bias and provide clearer evidence than retrospective treatment comparisons.

Although Phase II trials are not definitive for practice-changing guidance, OPTIM is expected to generate important signals about response rates, progression patterns, and clinical benefit under different post-nivolumab pathways. If the immunotherapy intensification strategy performs well, it could support broader use of combination regimens at progression rather than switching immediately to chemotherapy.

Overall, the trial reflects a growing shift in oncology toward rational sequencing—using biomarkers of clinical behavior, such as progression after first-line immunotherapy, to guide the next line. For patients with advanced head and neck cancer, where options can narrow after relapse, OPTIM offers a structured test of two plausible escape-response strategies.

Subject of Research: Recurrent/metastatic squamous cell carcinoma of the head and neck; sequential immunotherapy after progression

Article Title: OPTIM: a randomized phase II trial of nivolumab followed by nivolumab-ipilimumab or docetaxel at progression in recurrent/metastatic squamous cell carcinoma of the head and neck (OPTIM; AIO-KHT-0117).

Article References: Grünwald, V., Alt, J., Tometten, M. et al. OPTIM: a randomized phase II trial of nivolumab followed by nivolumab-ipilimumab or docetaxel at progression in recurrent/metastatic squamous cell carcinoma of the head and neck (OPTIM; AIO-KHT-0117). Br J Cancer (2026). https://doi.org/10.1038/s41416-026-03558-z

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03558-z

Keywords:

One groundbreaking study introduces a novel PET tracer, ¹⁸F-MeFAMP, engineered to vastly improve early detection and differentiation of tumor responses during immune checkpoint inhibitor (ICI) therapy. Traditional PET scans using the widely adopted ¹⁸F-FDG often struggle to distinguish between true tumor remission and inflammation caused by immune responses, complicating treatment assessment. However, in rigorous preclinical mouse models, ¹⁸F-MeFAMP exhibited superior selectivity by differentiating responders from nonresponders with remarkable clarity. Its notably low uptake in healthy tissues further underscores its potential to enhance early therapeutic decision-making and optimize patient outcomes in immuno-oncology.

Parallel research advances our comprehension of amyloid plaque quantification in Alzheimer’s disease through amyloid PET imaging. Adopting the standardized Centiloid scale, researchers systematically dissected how factors such as sample size and image resolution impact the precision of amyloid burden measurements across diverse tracers and analytic methodologies. Their findings reveal that smaller calibration datasets and decreased image resolution induce modest but significant inaccuracies—particularly pronounced in patients exhibiting elevated amyloid pathology. These insights are critical as PET imaging increasingly informs Alzheimer’s diagnosis, progression monitoring, and therapeutic trials, emphasizing the necessity for robust calibration protocols and high-resolution imaging to ensure consistency in clinical and research settings.

Another compelling frontier captured by these publications is the real-time imaging of the immune system at the molecular level, specifically through tracking cytokines using nuclear medicine technologies. Cytokines orchestrate inflammatory and immune processes, their fleeting and multifaceted signaling dynamics eluding traditional laboratory assays. Emerging PET and SPECT reporter systems now enable visualization of these potent immune messengers in vivo, offering unprecedented windows into the immune microenvironment during health and disease. This capability heralds new opportunities to monitor immune-mediated diseases, assess treatment responses dynamically, and unravel the complexities of immune regulation with high specificity and temporal resolution.

Focusing on prostate cancer, a comprehensive review synthesizes data from nineteen studies evaluating the efficacy of the PET radiotracer ¹⁸F-PSMA-1007 in noninvasive staging. This tracer targets the prostate-specific membrane antigen (PSMA), a cellular marker prevalent on prostate cancer cells, enabling detection of both localized tumors and metastatic spread without the invasiveness of traditional biopsies. The aggregate evidence highlights ¹⁸F-PSMA-1007’s high sensitivity and specificity, establishing it as a robust imaging modality that integrates local, nodal, and distant disease assessment in a single, noninvasive protocol. This innovation holds promise for refining treatment planning, guiding personalized interventions, and potentially improving survival outcomes.

Collectively, these newly presented studies underscore the transformative impact of cutting-edge molecular imaging and theranostic tools in modern medicine. Leveraging radiotracers with exquisite specificity, combined with high-resolution imaging technologies, researchers and clinicians are moving toward a future where diseases can be characterized and managed at a molecular and functional level earlier and more accurately than ever before. This shift not only enhances diagnostic accuracy but also propels the advent of precision medicine—tailoring therapeutic regimens based on individual biological characteristics, minimizing unnecessary treatments, and maximizing efficacy.

The research also spotlights the indispensable role of rigorous quantitative methodologies, standardization, and calibration in molecular imaging. Accurate measurement of biomarkers such as amyloid plaques in neurodegeneration or immune biomarkers in inflammatory diseases relies heavily on consistent imaging parameters and reliable data harmonization. As PET tracer development accelerates and diversified analytic pipelines emerge, establishing consensus protocols and validation standards is paramount to translate these innovations from bench to bedside reliably.

Importantly, the visualization of immune components like cytokines represents a paradigm shift in understanding immune dynamics in vivo. By mapping cytokine distributions and kinetics noninvasively, clinicians can better distinguish pathological immune activation from physiological responses, refining diagnoses in autoimmune diseases, infections, and cancer immunotherapy. This capability may also streamline therapeutic monitoring by indicating real-time immunomodulation effects, enabling rapid treatment adjustments and improving patient prognoses.

In oncology, the introduction of novel tracers such as ¹⁸F-MeFAMP and ¹⁸F-PSMA-1007 exemplifies the intersection of imaging and therapy, where molecular imaging not only detects disease burden but also informs and predicts therapeutic responses. By resolving ambiguity inherent in standard imaging modalities—such as inflammation versus cancer progression—these tracers facilitate more confident clinical decision-making. This precision significantly minimizes overtreatment risks while optimizing therapeutic intensity tailored to biological response, embodying the core ideals of personalized medicine.

Moreover, the comprehensive evaluations detailed in these publications emphasize the necessity for ongoing multidisciplinary collaboration encompassing molecular biologists, radiochemists, nuclear medicine physicians, and computational scientists. Integrating expertise across these domains accelerates the development of innovative tracers, refines imaging protocols, and enhances data interpretation frameworks—essential steps to unlock the full potential of nuclear medicine technologies in clinical practice.

As the field evolves, these advances herald a future in which nuclear medicine stands at the forefront of personalized healthcare, driving earlier diagnoses, smarter therapeutic choices, and improved patient outcomes. The research presented through JNM signals that the integration of precision imaging and theranostics is rapidly advancing, with the promise of revolutionizing disease management paradigms in cancer, neurology, immunology, and beyond.

For ongoing developments and complete access to these pioneering studies and other groundbreaking research in molecular imaging and theranostics, readers are encouraged to visit the Journal of Nuclear Medicine website. Engaging with this vibrant scientific community fosters continual innovation, translating remarkably precise imaging science into everyday clinical excellence worldwide.

Subject of Research:
Molecular imaging, PET tracers, immune response monitoring, amyloid quantification, prostate cancer staging, nuclear medicine theranostics.

Article Title:
New PET Tracer Shows Promise for Early Detection of Immunotherapy Response; Understanding What Affects Accuracy in Amyloid PET Quantification; Imaging the Immune System: Tracking Cytokines with Nuclear Medicine; New PSMA PET Tracer Improves Noninvasive Prostate Cancer Staging.

News Publication Date:
October 24, 2025.

Web References:

• https://doi.org/10.2967/jnumed.125.270466
• https://doi.org/10.2967/jnumed.125.270607
• https://doi.org/10.2967/jnumed.125.270425
• https://doi.org/10.2967/jnumed.125.269818

Keywords:
Molecular imaging, Medical imaging, Positron emission tomography, Immune checkpoint inhibitor, Amyloid PET, Cytokine imaging, PSMA PET, Prostate cancer staging, Theranostics, Precision medicine.