(1) Background: Neutropenic enterocolitis (NEC) is a life-threatening complication following chemotherapy with high mortality rates. Early diagnosis is crucial to improve outcomes. We designed a large prospective study employing bedside ultrasonography (US) as a novel approach to allow early diagnosis and prompt treatment to reduce mortality. (2) Methods: NEC was defined as US or computed tomography (CT)-proven bowel wall thickness ≥ 4 mm at the onset of at least one of the following symptoms: fever and/or abdominal pain and/or diarrhea during neutropenia. From 2007 to 2018, 1754 consecutive patients underwent baseline bedside US that was invariably repeated within 12 h from the onset of symptom(s) suggestive of NEC. (3) Results: Overall, 117 episodes of NEC were observed, and overall mortality was 9.4%. Bowel wall thickening was invariably absent in the negative control group. Abdominal pain associated with one or more symptoms correlated with the highest relative risk (17.33), sensitivity (89.7%), specificity (100%), and accuracy (96.2%) for diagnosis. The combination of abdominal pain and fever at onset significantly correlated with worse survival (p < 0.0001, OR 13.85). BWT (p = 0.046), type of therapy (p = 0.049) and blood culture positivity (p = 0.003) correlated with worse survival. (4) Conclusions: Bedside ultrasound is a non-invasive and radiation free imaging technique for early diagnosis of NEC and its prompt treatment significantly reduced mortality.
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