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Background: Non-islet cell tumor hypoglycemia is increasingly reported with gastrointestinal stromal tumors (GIST), but population-level estimates of its clinical impact are limited. We evaluated associations between hypoglycemia and inpatient outcomes among GIST hospitalizations. Methods: We conducted a retrospective cross-sectional study of the National Inpatient Sample (NIS) 2018–2020. Adult GIST discharges were identified by ICD-10-CM codes and stratified by hypoglycemia. Primary outcomes were in-hospital mortality and resource utilization—length of stay (LOS) and total hospital charge. Secondary outcomes included malnutrition, sepsis, ascites, peritonitis, bowel perforation, intestinal obstruction, gastrointestinal bleeding, and iron deficiency anemia. Analyses used survey-weighted logistic regression for binary outcomes and generalized linear models for continuous outcomes. A propensity score-matched sensitivity analysis balanced sepsis and malnutrition. Results: Among 61,725 GIST hospitalizations, 0.72% had hypoglycemia. Mortality was 12.6% with hypoglycemia vs. 3.1% without; adjusted odds of death were higher (aOR 4.16, 95% CI 2.06–8.37; p < 0.001). Hypoglycemia was also associated with malnutrition (aOR 5.63, 3.37–9.40), sepsis (aOR 4.00, 2.24–7.14), ascites (aOR 3.43, 1.63–7.19), and peritonitis (aOR 2.91, 1.17–7.22). LOS was 4.61 days longer on average (not significant; p = 0.185), and total hospital charge was $5218 higher (β = 19,116.8; p = 0.95). In the matched cohort, the mortality association attenuated but persisted (aOR 1.38, 1.27–1.49; p < 0.001); peritonitis remained significant (aOR 1.10, 1.04–1.17), intestinal obstruction (aOR 4.91, 3.44–7.05) and iron deficiency anemia (aOR 3.54, 1.62–7.74) became significant, while ascites and gastrointestinal bleeding were not significant. Conclusions: Hypoglycemia in GIST, although uncommon, marks a higher-risk inpatient trajectory with increased mortality and several complications; these signals largely persist after balancing severity proxies. Resource-use differences were directionally higher but not statistically significant. Recognition of hypoglycemia may aid risk stratification and inpatient management in GIST. Full article

The paraneoplastic syndrome referred in the literature as non-islet-cell tumor hypoglycemia (NICTH) and extra-pancreatic tumor hypoglycemia (EPTH) was first reported almost a century ago, and the role of cancer-secreted IGF-II in causing this blood glucose-lowering condition has been widely established. The landscape emerging in the last few decades, based on molecular and cellular findings, supports a broader role for IGF-II in cancer biology beyond its involvement in the paraneoplastic syndrome. In particular, a few key findings are constantly observed during tumorigenesis, (a) a relative and absolute increase in fetal insulin receptor isoform (IR^A) content, with (b) an increase in IGF-II high-molecular weight cancer-variants (big-IGF-II), and (c) a stage-progressive increase in the IGF-II autocrine signal in the cancer cell, mostly during the transition from benign to malignant growth. An increasing and still under-exploited combinatorial pattern of the IGF-II signal in cancer is shaping up in the literature with respect to its transducing receptorial system and effector intracellular network. Interestingly, while surgical and clinical reports have traditionally restricted IGF-II secretion to a small number of solid malignancies displaying paraneoplastic hypoglycemia, a retrospective literature analysis, along with publicly available expression data from patient-derived cancer cell lines conveyed in the present perspective, clearly suggests that IGF-II expression in cancer is a much more common event, especially in overt malignancy. These findings strengthen the view that (1) IGF-II expression/secretion in solid tumor-derived cancer cell lines and tissues is a broader and more common event compared to the reported IGF-II association to paraneoplastic hypoglycemia, and (2) IGF-II associates to the commonly observed autocrine loops in cancer cells while IGF-I cancer-promoting effects may be linked to its paracrine effects in the tumor microenvironment. Based on these evidence-centered considerations, making the autocrine IGF-II loop a hallmark for malignant cancer growth, we here propose the functional name of IGF-II secreting tumors (IGF-IIsT) to overcome the view that IGF-II secretion and pro-tumorigenic actions affect only a clinical sub-group of rare tumors with associated hypoglycemic symptoms. The proposed scenario provides an updated logical frame towards biologically sound therapeutic strategies and personalized therapeutic interventions for currently unaccounted IGF-II-producing cancers. Full article

Hypoglycemia in patients without diabetes is a diagnostic challenge for the endocrinologist. Sometimes it is related to rare causes such as Doege–Potter Syndrome (DPS). DPS is caused by an abnormal insulin-like grow factor 2(IGF-2) that retains part of the E domain during the production process, resulting in a longer peptide called “big-IGF-2”. We present a case report of DPS with emphasis on the diagnosis and especially on the difficulties in interpreting the biochemical findings. An elderly patient with an intrathoracic neoplasm and hypoglycemia underwent various tests: insulin autoantibodies and fasting test were both negative. She had low values of IGF-1 and normal values of IGF-2 that apparently excludes a diagnosis of DPS. The evaluation of the IGF-2/IGF-1 ratio is the most important test because a ratio >10 is widely considered to be indicative of non-islet cell tumor hypoglycemia (NICTH). Glucose infusion and steroid therapy were used to control the hypoglycemia, but the definitive treatment was surgery, which almost immediately reversed the hypoglycemia. The differential diagnosis of hypoglycemia should include rare causes such as DPS, and the IGF-2/IGF-1 ratio is a useful tool. Full article