Inhibition of insulin-like growth factor-1 receptor enhances eribulin-induced DNA damage in colorectal cancer.

Microtubule targeting agents (MTAs) such as taxanes are broadly used for the treatment of patients with cancer. Although MTAs are not effective for treatment of colorectal cancer (CRC), preclinical studies suggest that a subset of patients with CRC, especially those with cancers harboring the BRAF mutation, could benefit from such agents. However, two MTAs, eribulin (Eri) and vinorelbine, have shown limited clinical efficacy. Here, we report that insulin-like growth factor 1 receptor (IGF-1R) signaling is involved in Eri resistance. Using CRC cell lines, we showed that Eri induces activation and subsequent translocation of IGF-1R to the nucleus. When the activation and/or nuclear translocation of IGF-1R was inhibited, Eri induced DNA damage and enhanced G2 /M arrest. In a xenograft model using the Eri-resistant SW480 cell line, the combination of Eri and the IGF-1R inhibitor linsitinib suppressed tumor growth more efficiently than either single agent. Thus, our results indicated that combination dosing with Eri and an IGF-1R inhibitor could overcome Eri resistance and offer a therapeutic opportunity in CRC.

The effect of deep convolutional neural networks on radiologists' performance in the detection of hip fractures on digital pelvic radiographs.

PURPOSE: The purpose of our study is to develop deep convolutional neural network (DCNN) for detecting hip fractures using CT and MRI as a gold standard, and to evaluate the diagnostic performance of 7 readers with and without DCNN. METHODS: The study population consisted of 327 patients who underwent pelvic CT or MRI and were diagnosed with proximal femoral fractures. All radiographs were manually checked and annotated by radiologists referring to CT and MRI for selecting ROI. At first, a DCNN with the GoogLeNet model was trained by 302 cases. The remaining 25 cases and 25 control subjects were used for the observer performance study and for the testing of DCNN. Seven readers took part in this study. A continuous rating scale was used to record each observer's confidence level. Subsequently, each observer interpreted with the DCNN outputs and rated them again. The area under the curve (AUC) was used to compare the fracture detection. RESULTS: The average AUC of the 7 readers was 0.832. The AUC of DCNN alone was 0.905. The average AUC of the 7 readers with DCNN outputs was 0.876. The AUC of readers with DCNN output were higher than those without(p < 0.05). The AUC of the 2 experienced readers with DCNN output exceeded the AUC of DCNN alone. CONCLUSION: For detecting the hip fractures on radiographs, DCNN developed using CT and MRI as a gold standard by radiologists improved the diagnostic performance including the experienced readers.

Eribulin as a first-line treatment for soft tissue sarcoma patients with contraindications for doxorubicin.

Doxorubicin is a first-line therapy for patients with unresectable advanced soft tissue sarcoma (STS). However, because of cardiotoxicities, it is not used for patients with cardiac problems. Eribulin has exhibited efficacy for advanced STS in second- or later-line treatments. In the present study, we retrospectively analyzed the efficacy and safety of first-line eribulin therapy for patients with advanced STS unable to receive doxorubicin. Six of 28 patients who received eribulin as any line treatment received eribulin as a first-line treatment. The reasons for avoiding doxorubicin were as follows: cardiac problems for four patients and advanced age for two. Median progression-free survival (PFS) of the patients who received eribulin as first-line and, second or later-line therapy were 9.7 months (95% CI: 1.0-not reached) and 3.9 months (95% CI: 2.7-5.9), which were not significantly different. The reasons for discontinuation of eribulin were disease progression and adverse events (2 fatigue and 1 neuropathy) for three patients each. No treatment-related cardiotoxicity was observed. The findings of this study indicated that eribulin exhibits meaningful efficacy for the patients with contraindications for doxorubicin as a first-line treatment without cardiac adverse events. However, appropriate safety management is necessary because older patients are typically among those intolerable of doxorubicin.