The research team screened nearly 3,700 records and identified 45 studies encompassing 5,283 patients who underwent a broad spectrum of major abdominal procedures, including hepatopancreatobiliary, upper gastrointestinal, colorectal and urological surgery. Of these, 17 studies involving 2,213 patients provided data suitable for quantitative pooling. Using random-effects meta-analysis with Hedges’ small-sample correction and sensitivity analyses across a wide range of plausible correlation values, the researchers calculated standardised mean changes in muscle mass, size and strength at two key intervals: within two weeks of surgery, and between three and six weeks after the operation.

The results were unambiguous. Within two weeks of surgery, skeletal muscle mass or dimensions had declined significantly, with a pooled standardised mean change of 0.34, rising to 0.39 at around one month. By conventional benchmarks these are small-to-moderate effects, but the authors translate them into more tangible terms: a downward shift of roughly 13 percentile points in muscle mass within two weeks, and 15 points by one month. Crucially, the decline appeared regardless of how muscle was measured, whether by computed tomography, ultrasound, bioelectrical impedance analysis or dual-energy X-ray absorptiometry, and it persisted across every surgical specialty examined.

Perhaps the most striking finding is the sheer speed of the process. Of 23 studies that assessed muscle within ten days of surgery, 21 reported measurable declines, and some documented losses within just five days. One study reported a 4.4% drop in total psoas muscle index merely three days after oesophagectomy, while another recorded a 9.16% reduction in the cross-sectional area of the vastus lateralis within five days of open colorectal resection. In critical care medicine, muscle loss of up to 2% per day during the first week of intensive care admission is well documented; the new analysis suggests that major surgery, even in patients who never require intensive care, can trigger a similar accelerated catabolic state.

Muscle function suffers alongside muscle size. Across six studies including 417 patients, handgrip strength fell significantly after surgery, with a pooled standardised mean change of 0.79, an effect the authors describe as indicating clinically relevant perioperative weakness, though they caution that heterogeneity between studies was substantial and the estimate imprecise. Five studies tracked both muscle mass and function simultaneously, and nearly all found parallel declines, suggesting that the loss of tissue seen on scans translates directly into lost strength. Notably, one study of liver transplant recipients found that grip strength returned to baseline within six months, whereas muscle mass took a full year to recover, hinting that function rebounds before structure does.

The clinical consequences of this muscle loss extend far beyond the immediate recovery period. Studies included in the review linked significant perioperative muscle wasting, defined in some analyses as more than a 10% reduction from baseline, with markedly higher rates of postoperative complications, prolonged hospitalisation, anastomotic leakage after oesophagectomy, poorer quality of life and reduced long-term survival. In one pancreatic surgery cohort, restoration of preoperative muscle size within 24 weeks emerged as an independent prognostic factor for survival. Muscle wasting following gastrectomy has likewise been associated with poorer overall survival, indicating that the shadows cast by the surgical catabolic response can stretch for years.

One particularly revealing study examined 457 healthy adult living liver donors, a population with no underlying disease, and found significant muscle wasting within the first postoperative week, with recovery by three months. Because these donors were otherwise well, the finding isolates the effect of surgery itself, though the authors note that hepatic resection and the metabolic demands of liver regeneration may have amplified the loss. All of the studies included in the review were conducted in elective populations, which raises a further concern: patients who undergo emergency abdominal surgery receive no preoperative optimisation and often present with marked inflammation, factors that could predispose them to even greater muscle loss.

Encouragingly, the review identified early signals that the process may be modifiable. Twelve studies tested interventions, seven of them nutritional, including carbohydrate loading, immunonutrition, amino acid supplementation and formulas enriched with the leucine metabolite HMB. Results were mixed but generally modestly positive: perioperative immunonutrition cut muscle wasting at two weeks from 16.9% to 7.04% in one trial, and HMB-enriched supplementation improved both muscle preservation and grip strength one month after liver transplantation. Beyond nutrition, two studies of neuromuscular electrical stimulation showed that stimulating the quadriceps significantly reduced muscle wasting, in one case even implying systemic benefits, while postoperative ghrelin administration reduced loss of erector spinae muscle after oesophagectomy. The evidence base remains limited by small samples and short follow-up, but the direction of effect is promising.

To give the field a common framework, the authors propose a formal concept they call perioperative muscle wasting, or POMW, defined as acute skeletal muscle loss occurring within six weeks of surgery. The threshold is deliberately pragmatic: it aligns with the late postoperative phase, during which patients remain catabolic and functionally impaired, and it coincides with the routine outpatient review that most major surgery patients attend. The authors argue that existing consensus definitions of sarcopenia, developed primarily for older adults by the European and Asian working groups and more recently by the Global Leadership Initiative in Sarcopenia, do not adequately capture the distinctive, rapid, surgery-driven process seen in often younger and fitter patients. A dedicated definition, they contend, would enable standardised measurement, earlier identification and properly powered intervention trials.

The broader message is that muscle health has been a blind spot in perioperative medicine. Enhanced Recovery After Surgery protocols, now standard for most elective major abdominal operations, emphasise early mobilisation and nutrition, yet significant wasting persists even under these regimes. The authors call for routine objective assessment of muscle, whether through CT-derived skeletal muscle index or simple grip strength testing, to be woven into perioperative pathways, alongside targeted multimodal interventions including prehabilitation, even in patients without pre-existing sarcopenia. As surgical and anaesthetic advances allow ever greater numbers of older adults to undergo major operations, the scale of the problem is set to grow. What this analysis makes clear is that the muscle lost in the days after surgery is not an inevitable footnote of recovery but a modifiable, and until now under-recognised, determinant of how well, and how long, patients live afterward.

Subject of Research: Perioperative muscle wasting following major abdominal surgery

Article Title: A Systematic Review and Meta‐Analysis of Perioperative Muscle Wasting Following Major Abdominal Surgery

Article References: Reynolds, A., George, N. M., Papadopoulou, A., & Creagh‐Brown, B. (2026). A Systematic Review and Meta‐Analysis of Perioperative Muscle Wasting Following Major Abdominal Surgery. Journal of Cachexia, Sarcopenia and Muscle, 17(5), Article e70379. https://doi.org/10.1002/jcsm.70379

Image Credits: AI Generated

DOI: 10.1002/jcsm.70379

Keywords: perioperative muscle wasting, sarcopenia, meta-analysis, abdominal surgery, muscle catabolism, handgrip strength, CT imaging, immunonutrition, enhanced recovery, surgical outcomes, Systematic, Review

The biological centerpiece of this framework is metabolic reprogramming, one of the updated Hallmarks of Cancer. Head and neck squamous cell carcinoma cells rely heavily on aerobic glycolysis, the so-called Warburg effect, burning through enormous quantities of glucose and converting it to lactate even in the presence of oxygen. This inefficient ATP generation might seem like a design flaw, but it allows rapid proliferation and creates a continuous drain on the body’s nutrient supply. The lactate released by tumors does not simply disappear; it enters the Cori cycle, forcing the liver to spend energy converting it back into glucose through gluconeogenesis. The result is a futile substrate loop that raises resting energy expenditure and contributes to the hypermetabolic state long observed in cancer patients.

The review emphasizes that the tumor behaves, in the authors’ framing, as a metabolic sink. Glucose, lipids, and amino acids are redirected from skeletal muscle, liver, and adipose tissue toward the growing malignancy. Cytokine-driven activation of proteolytic pathways in muscle triggers the breakdown of contractile proteins and the release of glutamine and other amino acids that can be funneled into tumor metabolism. Meanwhile, tumor-derived factors such as parathyroid hormone-related protein promote lipolysis and the browning of white adipose tissue, converting energy stored in fat into heat rather than usable fuel. These processes, the authors stress, do not directly nourish the tumor; instead, they force the host to mobilize substrates in a losing attempt to maintain homeostasis, producing thermogenic inefficiency and accelerating energy wasting.

Chronic systemic inflammation amplifies this catabolic storm. Elevated circulating levels of interleukin-6, tumor necrosis factor-alpha, and interleukin-1 beta are commonly found in head and neck cancer patients and correlate with weight loss, sarcopenia, and poorer clinical outcomes. Interleukin-6 has been strongly linked to loss of body mass and adipose tissue depletion, while tumor necrosis factor-alpha enhances ubiquitin-proteasome-mediated protein degradation and impairs glucose transport in peripheral tissues. Within skeletal muscle, activation of the myostatin/SMAD signaling pathway suppresses protein synthesis and accelerates atrophy. Together, these mechanisms create a self-perpetuating loop in which inflammation sustains catabolism, tissue wasting further fuels inflammatory signaling, and the patient’s metabolic reserve erodes progressively, often before any anticancer therapy has begun.

This model explains a clinical observation that has long puzzled oncologists: many patients lose weight and muscle mass early in the disease course, even when their oral intake appears adequate, and caloric supplementation alone frequently fails to prevent muscle loss or cachexia. The internationally accepted GLIM criteria for diagnosing malnutrition already recognize inflammation as a key etiologic driver, requiring at least one phenotypic criterion such as weight loss or reduced muscle mass alongside an etiologic criterion such as reduced intake or disease-related inflammation. The new review goes further, arguing that in head and neck cancer the inflammatory and metabolic components dominate, and that nutritional impairment should be viewed as a dynamic, tumor-driven process rather than a simple caloric deficit.

Translating this biology into measurable clinical tools is where the review makes its most distinctive contribution. Sarcopenia, the progressive loss of skeletal muscle, is one of the most clinically relevant manifestations of cancer-related metabolic derangement. Because patients with head and neck cancer rarely undergo routine abdominal imaging, cross-sectional muscle assessment at the level of the third cervical vertebra has emerged as a validated surrogate for whole-body muscle mass. The resulting C3 skeletal muscle index can identify muscle depletion that body mass index misses entirely, and it carries prognostic weight: sarcopenia has been consistently associated with poorer overall survival, increased treatment-related toxicity, and reduced quality of life, making it a robust biomarker rather than a mere byproduct of treatment intolerance.

On the metabolic side, functional imaging offers a window into the tumor’s glycolytic appetite. Total lesion glycolysis, derived from 18F-FDG PET scans, integrates tumor volume with metabolic activity to reflect the overall glucose consumption of the malignancy. High values have been associated with aggressive tumor biology, greater inflammatory burden, and adverse oncologic outcomes. Crucially, recent prospective data in locally advanced head and neck squamous cell carcinoma showed that higher tumor metabolic activity measured by total lesion glycolysis was significantly associated with reduced skeletal muscle mass at the third cervical vertebra, elevated inflammatory markers, and impaired nutritional status at the start of treatment. This provides clinical validation of the biological model: tumor-driven hypermetabolism and inflammation translate into measurable deterioration of body composition and nutritional reserve.

The authors are careful to acknowledge the limitations of the current evidence base. The studies linking PET-derived metabolic parameters with nutritional impairment remain limited in number and observational in design, and external validation in larger prospective cohorts is still needed. Methodological heterogeneity in PET acquisition protocols, lesion segmentation strategies, and cutoff values complicates comparisons across studies, and standardized imaging protocols and universally accepted thresholds for C3-based muscle assessment have not yet been fully established. Metabolic imaging biomarkers should therefore be considered complementary tools alongside conventional nutritional and body composition assessment rather than stand-alone diagnostic markers. In practice, the review advocates a multimodal approach combining clinical nutritional evaluation, C3-derived muscle assessment when available, inexpensive and widely accessible inflammatory markers such as C-reactive protein and the neutrophil-to-lymphocyte ratio, and metabolic imaging parameters in patients already undergoing PET imaging.

The therapeutic implications are perhaps the most consequential part of the framework. If malnutrition is an immune-metabolic syndrome, then early nutritional intervention should aim not merely to increase calories but to modulate systemic inflammation and preserve functional body composition. Current European Society for Clinical Nutrition and Metabolism guidelines support early nutritional intervention as a cornerstone of multidisciplinary care in head and neck oncology, and intervention appears most effective during the pre-cachectic or early cachectic phases, when metabolic alterations remain potentially reversible. Immunonutrition enriched with arginine, omega-3 fatty acids, and nucleotides has shown promising effects, including improvement of the CD4/CD8 T-cell balance and accelerated postoperative recovery, but the evidence remains heterogeneous, and the authors caution that adequately powered randomized trials are needed before routine use beyond current guideline indications can be recommended.

Patients with locally advanced disease, high tumor metabolic burden, marked systemic inflammation, and early muscle depletion are especially vulnerable, as are those with advanced age, HPV-negative tumors, extensive smoking histories, dysphagia, or treatment with concurrent chemoradiotherapy. For these individuals, the review argues, nutritional management should prioritize preservation of lean body mass over weight maintenance alone, with adequate protein and energy provision embedded in integrated supportive care that includes pain control and oncologic treatment planning. Nutritional support alone is unlikely to fully reverse the underlying immune-metabolic alterations, but early recognition of high-risk features could shift the paradigm from reactive nutritional rescue to proactive metabolic management. By uniting tumor metabolism, systemic inflammation, and imaging-based body composition into a single conceptual framework, the Naples team offers oncologists a way to identify vulnerable patients before cachexia takes hold, and a biological rationale for treating the tumor’s metabolic sabotage, not just the patient’s empty plate, as the true target of nutritional care in head and neck cancer.

Subject of Research: Tumor-driven immune-metabolic mechanisms of cancer-related malnutrition in head and neck squamous cell carcinoma

Article Title: Beyond reduced intake: tumor metabolism and immune dysregulation drive cancer-related malnutrition in head and neck squamous cell carcinoma (HNSCC)

Article References: Zurlo, V., Piccirillo, A., Marciano, M. L., Pontone, M., Rampetta, F. R., Perri, E., & Perri, F. (2026). Beyond reduced intake: tumor metabolism and immune dysregulation drive cancer-related malnutrition in head and neck squamous cell carcinoma (HNSCC). Supportive Care in Cancer, 34(10), Article 1056. https://doi.org/10.1007/s00520-026-11115-w

Image Credits: AI Generated

DOI: 10.1007/s00520-026-11115-w

Keywords: head and neck cancer, cancer-related malnutrition, sarcopenia, tumor metabolism, Warburg effect, systemic inflammation, immunonutrition, total lesion glycolysis, C3 skeletal muscle index, cachexia, PET imaging, nutritional intervention

The logic behind the index is deceptively simple. C-reactive protein, an acute-phase protein produced by the liver, rises rapidly in response to systemic inflammation and is one of the most widely used markers of inflammatory activity in clinical practice. Ferritin, the intracellular iron-storage protein, is also an acute-phase reactant, and in severe COVID-19 it can reach extraordinary concentrations, partly reflecting macrophage activation and the cytokine-driven disarray that characterizes critical disease. Albumin, by contrast, falls during inflammation and malnutrition, a phenomenon known as transient capillary leak combined with suppressed hepatic synthesis and, in prolonged illness, genuine protein-energy depletion. By placing the two inflammatory markers in the numerator and the nutritional marker in the denominator, the HNI is intended to capture, in a single value, the simultaneous burden of inflammation and the erosion of nutritional reserve.

The study itself was an observational cross-sectional analysis of 60 patients with confirmed COVID-19, stratified into three groups according to the level of care they required: outpatients treated without hospital admission, patients managed on general wards, and patients admitted to the intensive care unit. The researchers measured a broad panel of laboratory parameters, including standard inflammatory markers, a set of cytokines, and β2-microglobulin, a small protein component of the major histocompatibility complex class I molecule that is shed into the serum during heightened immune cell turnover. The retrospective design relied on stored serum samples collected during routine clinical practice, and the protocol received ethics approval from the Sakarya University Faculty of Medicine Health Sciences Scientific Research Ethics Committee, with the informed consent requirement waived because only archived specimens were used.

The central finding was a clear gradient across the three care levels. Intensive care patients exhibited significantly higher concentrations of inflammatory markers, cytokines, β2-microglobulin, and the HNI itself compared with ward patients and outpatients. This pattern is consistent with the established understanding of severe COVID-19 as a state of escalating immune activation, in which circulating interleukin-6, interleukin-10, and tumor necrosis factor-alpha rise in parallel with acute-phase proteins, and in which rapid lymphocyte turnover releases β2-microglobulin into the circulation. The fact that a composite index derived from three routine laboratory tests tracked this gradient as faithfully as the more specialized cytokine assays is the study’s most practically interesting observation.

The correlation analysis sharpened that picture considerably. HNI showed a very strong correlation with ferritin, with a correlation coefficient of 0.945, a figure so high that it raises an immediate statistical question: when a variable is part of the formula that defines an index, the two will inevitably move together, a phenomenon known as mathematical coupling. The authors themselves flag this concern explicitly, noting that the strong association between HNI and ferritin should be interpreted cautiously precisely because ferritin sits in the numerator of the index. Beyond ferritin, HNI showed moderate correlations with the measured cytokines, suggesting that the index does carry information about the broader inflammatory milieu rather than merely echoing a single component of its own formula.

Diagnostic performance was assessed using receiver operating characteristic analysis, a standard technique for evaluating how well a continuous marker discriminates between two groups, in this case presumably severe and non-severe disease. The area under the curve for HNI reached 0.953, a value that, on its face, would indicate near-perfect discrimination. An AUC of 1.0 represents flawless classification and 0.5 represents performance no better than chance, so 0.953 would place HNI among the most accurate severity markers reported for COVID-19. Yet the authors are careful to temper enthusiasm, emphasizing that this finding should be interpreted cautiously given the small sample size of 60 patients and the potential for mathematical coupling between the index and its constituent measurements.

That caution is well founded and reflects a broader lesson in biomarker research. Composite indices derived from routine laboratory values have proliferated during and after the pandemic, ranging from the neutrophil-to-lymphocyte ratio to more elaborate immunonutritional scores combining multiple cell counts and serum proteins. Their appeal is obvious: they are cheap, they require no specialized assays, and they can be calculated from blood tests already ordered for clinical reasons. Their peril is equally obvious: combining correlated variables can inflate apparent performance, small samples can produce optimistic estimates that shrink dramatically on validation, and the arithmetic of an index can create associations that do not exist in any single underlying measurement. The authors of the present study appear acutely aware of these pitfalls, describing HNI as an exploratory marker rather than a validated clinical tool.

Perhaps the most intellectually honest element of the paper is its conclusion about what HNI actually represents. Rather than claiming the index as an independent biomarker with novel predictive power, the authors conclude that it appears to reflect the combined burden of inflammation and nutritional status, and that its clinical utility beyond the individual parameters from which it is built remains uncertain. This framing matters. A composite index earns its place in clinical practice only if it adds information that its components do not already provide, either by improving risk stratification, by simplifying decision-making, or by capturing an interaction between inflammation and nutrition that neither dimension reveals alone. Whether HNI meets any of those tests cannot be determined from a 60-patient cross-sectional study; it requires validation in larger, ideally prospective cohorts with outcomes such as mortality, mechanical ventilation, and length of stay as endpoints.

The inclusion of β2-microglobulin in the analysis adds a distinctive dimension to the work. As a component of MHC class I molecules expressed on nearly all nucleated cells, β2-microglobulin is released during increased cellular turnover and immune activation, and elevated serum levels have been reported in severe infections, in autoimmune disease, and in conditions involving lymphocyte proliferation. Its significant elevation in the intensive care group of this COVID-19 cohort aligns with the picture of profound immune activation in critical disease, and its correlation with the composite index suggests that HNI, despite its simple formula, moves in step with markers of deep immunological disturbance. Whether β2-microglobulin itself offers prognostic value beyond established markers remains a question for larger studies, but its presence here underscores the study’s attempt to connect a bedside index to the underlying biology of the cytokine-driven inflammatory response.

The study, led by Gülsüm Kaya of Yalova University with colleagues including corresponding author Cengiz Karacaer of Sakarya University, was conducted without external funding and published as open access research on 29 September 2026. Its contribution is best understood as a carefully hedged proof of concept: evidence that a single arithmetic combination of C-reactive protein, ferritin, and albumin can track the severity gradient of COVID-19 and correlate with both cytokine levels and β2-microglobulin, offered with explicit acknowledgment of the mathematical and statistical caveats that such composite measures demand. For clinicians, the message is that routine laboratory data already contain much of the severity signal that specialized assays reveal, but that no new index should be adopted into practice until it has demonstrated, in adequately powered validation studies, that it adds genuine value beyond the numbers already on the chart. For researchers, the work provides a template for how composite biomarkers should be evaluated: with correlation analyses that acknowledge coupling, with ROC analyses interpreted in light of sample size, and with conclusions that distinguish what an index measures from what it independently predicts.

Subject of Research: A combined inflammatory and nutritional biomarker index for assessing COVID-19 severity

Article Title: Hyperinflammatory nutritional index as an exploratory combined inflammatory and nutritional marker: associations with cytokines and β2-microglobulin in COVID-19

Article References: Kaya, G., Karacaer, C., Sunu, C., Ergenç, H., & Öğütlü, A. (2026). Hyperinflammatory nutritional index as an exploratory combined inflammatory and nutritional marker: associations with cytokines and β2-microglobulin in COVID-19. BMC Infectious Diseases, 26(1), Article 1738. https://doi.org/10.1186/s12879-026-14525-7

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14525-7

Keywords: COVID-19, hyperinflammatory nutritional index, C-reactive protein, ferritin, albumin, cytokines, β2-microglobulin, inflammation, nutritional status, biomarkers, disease severity, immunonutrition