Imaging-guided prognostic score-based approach to assess the benefits of combotherapy versus monotherapy with immune checkpoint inhibitors in metastatic MSI-H colorectal cancer patients.

BACKGROUND: This retrospective study determined survival responses to immune checkpoint inhibitors (ICIs), comparing mono- (mono) and combo-immunotherapy (combo) in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) by analyzing quantitative imaging data and clinical factors. METHODS: One hundred fifty patients were included from two centers and divided into training (n = 105) and validation (n = 45) cohorts. Radiologists manually annotated chest-abdomen-pelvis computed tomography and calculated tumor burden. Progression-free survival (PFS) was assessed, and variables were selected through Recursive Feature Elimination. Cutoff values were determined using maximally selected rank statistics to binarize features, forming a risk score with hazard ratio-derived weights. RESULTS: In total, 2258 lesions were annotated with excellent reproducibility. Key variables in the training cohort included: total tumor volume (cutoff: 73 cm3), lesion count (cutoff: 20), age (cutoff: 60) and the presence of peritoneal carcinomatosis. Their respective weights were 1.13, 0.96, 0.91, and 0.38, resulting in a risk score cutoff of 1.36. Low-score patients showed similar overall survival and PFS regardless of treatment, while those with a high-score had significantly worse survivals with mono vs combo (P = 0.004 and P = 0.0001). In the validation set, low-score patients exhibited no significant difference in overall survival and PFS with mono or combo. However, patients with a high-score had worse PFS with mono (P = 0.046). CONCLUSIONS: A score based on total tumor volume, lesion count, the presence of peritoneal carcinomatosis, and age can guide MSI-H mCRC treatment decisions, allowing oncologists to identify suitable candidates for mono and combo ICI therapies.

Targeted and non-targeted liver biopsies carry the same risk of complication.

OBJECTIVES: To reappraise the rate of and risk factors for complications of targeted and non-targeted US-guided liver biopsy in a large series. METHODS: We analyzed 2405 liver biopsies performed in 2137 patients (58% males, mean age 54 ± 15 years old) between January 2010 and December 2015. Biopsies were performed for focal liver lesions characterization (targeted) or chronic liver disease assessment (non-targeted). Clinical, laboratory, and technical data were recorded. For targeted biopsies, we also recorded the largest diameter, location, enhancement pattern, and pathology. Advert events were divided into marked symptoms and complications. Those requiring specific treatment (embolization or surgery) were considered as severe. RESULTS: A total of 1283 (53%) targeted and 1122 (47%) non-targeted biopsies were performed. Marked symptoms occurred after 134 biopsies (5.6%) (95 (7.4%) targeted and 39 (3.5%) non-targeted, p < 0.001), the most common being pain (109/134). Complications occurred after 38 biopsies (1.6%) (24 (1.9%) targeted and 14 (1.2%) non-targeted, p = 0.253) and were severe in 13 patients. In univariate analysis, prothrombin time (p = 0.006), serum creatinine level (p < 0.001), largest lesion diameter (p < 0.001), and tumor pathology (p = 0.040) were associated with the occurrence of complications but not platelet count or lesion enhancement pattern. In multivariate analysis, only the largest lesion diameter was retained (OR 1.014 [1.002-1.026], p = 0.018). CONCLUSION: The rate of advert events after US-guided liver biopsy was low, with no difference between targeted and non-targeted biopsies. When focusing on targeted biopsies, the largest lesion diameter but not enhancement pattern appeared as the main risk factor. KEY POINTS: • Targeted and non-targeted liver biopsies are associated with the same observed risk of complication. • Arterial phase hyperenhanced tumors on contrast-enhanced CT or MRI are not associated with a higher risk of complication when compared with non-hyperenhanced ones. • A high serum creatinine level is associated with a higher risk of complication and should motivate strict post-biopsy surveillance.

Possible involvement of calpain-like activity in normal processing of cellular prion protein.

Time-lapse imaging analysis was previously used to show that spontaneous proteolysis of PrP(C), which is fluorescence-labeled at both NH(2)- and COOH-termini, occurred in mouse neuroblastoma neuro2a (N2a) cells susceptible to PrP(Sc). We demonstrated that, unlike other protease inhibitors, a calpain inhibitor, calpastatin, drastically inhibited endoproteolysis of PrP(C), as observed with time-lapse imaging in living cells, suggesting calpain-like activity. Calpastatin also inhibited cleavage of endogenous PrP(C), and unprocessed molecules and the double-labeled PrP(C) accumulated around the perinuclear region. The molecular weight of PrP(C) fragments generated by spontaneous proteolysis was identical to those produced when PrP(C) synthesized in vitro was exposed to exogenous calpain. These results suggest that a calpain-like activity mediates normal processing of PrP(C) in N2a cells.