Carrier-free nano-prodrugs for minimally invasive cancer therapy.

An anticancer nanodrug with few side effects that does not require the use of a nanocarrier, polyethylene glycol, or other additives has been developed. We have fabricated nano-prodrugs (NPDs) composed only of homodimeric prodrugs of the anticancer agent SN-38, which contains a disulfide bond. The prodrugs are stable against hydrolysis but selectively release SN-38 when the disulfide bond is cleaved by glutathione, which is present in high concentrations in cancer cells. The best-performing NPDs showed good dispersion stability in nanoparticle form, and animal experiments revealed that they possess much higher antitumor activity than irinotecan, a clinically applied prodrug of SN-38. This performance was achieved by improving tumor accumulation due to the size effect and targeted drug release mechanism. The present study provides an insight into the development of non-invasive NPDs with high pharmacological activity, and also offers new possibilities for designing prodrug molecules that can release drugs in response to various kinds of triggers.

Correlation between Efficacy and Cardiovascular Adverse Events in Patients with Advanced Solid Cancer Who Received VEGF Pathway Inhibitors: Hypertension within the First Eight Weeks is Associated with Favorable Outcomes of Patients Treated with VEGF Pathway Inhibitors.

Objective Many vascular endothelial growth factor (VEGF) pathway inhibitors are used in the treatment of patients with various advanced cancers; however, treatments induce cardiovascular adverse events (CVAEs), such as hypertension, heart failure, arrhythmia, arterial or venous embolism, and hemorrhage. Some studies have suggested a correlation between efficacy and CVAEs; however, further evidence is required. This study evaluated real-world data concerning the frequency and degree of CVAEs and possible associations between CVAEs and efficacy in such patients. Methods and Patients We analyzed CVAEs observed in 294 patients with advanced cancer who were treated with ramucirumab, regorafenib, pazopanib, sunitinib, or sorafenib. Results CVAEs of any grade and proteinuria within 8 weeks after the initiation of VEGF pathway inhibitors (early) or during the treatment period (total period) were observed in 72%-85% and 77%-92% of the patients, respectively. The progression-free survival (PFS) of patients with a CVAE of grade ≥1 in the early period was favorable compared with the PFS of those who had no CVAE (median, 4.9 vs. 3.5 months, P = 0.016, log-rank test). Furthermore, the PFS of patients with a CVAE grade ≥3 in the early period was favorable compared to that of those with CVAEs of grades 0-2. Taken together, a higher degree of CVAE was correlated with favorable patient outcomes. Conclusion This study revealed the frequency and degree of CVAEs in patients with solid cancers who received VEGF pathway inhibitors in a real-world setting and added evidence regarding the correlation between CVAEs and efficacy of VEGF pathway inhibitors.

Genome-wide DNA methylation status is a predictor of the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer: Translational research of the EPIC trial.

PURPOSE: The genome-wide DNA methylation status (GWMS) predicts of therapeutic response to anti-epidermal growth factor receptor (EGFR) antibodies in treating metastatic colorectal cancer. We verified the significance of GWMS as a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer. METHODS: Clinical data were obtained from a prospective trial database, and a genome-wide DNA methylation analysis was performed. GWMS was classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC). The patients were divided into subgroups according to the treatment arm (cetuximab plus irinotecan or irinotecan alone) and GWMS, and the clinical outcomes were compared between the subgroups. RESULTS: Of the 112 patients, 58 (51.8%) were in the cetuximab plus irinotecan arm, and 54 (48.2%) were in the irinotecan arm; 47 (42.0%) were in the HMCC, and 65 (58.0%) were in the LMCC group regarding GWMS. Compared with the LMCC group, the progression-free survival (PFS) was significantly shortened in the HMCC group in the cetuximab plus irinotecan arm (median 1.4 vs. 4.1 months, p = 0.001, hazard ratio = 2.56), whereas no significant differences were observed in the irinotecan arm. A multivariate analysis showed that GWMS was an independent predictor of PFS and overall survival (OS) in the cetuximab plus irinotecan arm (p = 0.002, p = 0.005, respectively), whereas GWMS did not contribute to either PFS or OS in the irinotecan arm. CONCLUSIONS: GWMS was a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer.

Nivolumab-induced Thrombotic Thrombocytopenic Purpura in Patients with Gastric Tube Cancer.

Recently, immune checkpoint inhibitors (ICIs) have been used to treat several cancer types. ICIs have been reported to cause a wide variety of immune-related adverse events, including endocrine, neurologic, gastrointestinal, and cutaneous disorders. Thrombotic thrombocytopenic purpura (TTP) is an autoimmune hematologic disorder characterized by the presence of autoantibodies against a disintegrin and metalloprotease with thrombospondin-1, member 13. Several previous cases of TTP were thought to have been caused by ICI treatment. We herein report a rare case of TTP that developed after long-term treatment with an ICI (nivolumab) for gastric tube cancer.

Chylous Ascites Associated with Advanced Pancreatic Cancer That Improved with Appropriate Treatment: A Case Report.

Chylous ascites is a rare form of ascites with high triglyceride content arising from the thoracoabdominal lymph nodes in the peritoneal cavity due to various benign or malignant etiologies, including pancreatic cancer. During cancer chemotherapy, the accumulation of ascites can lead to the deterioration of the patient's general condition, making chemotherapy administration difficult, and resulting in a poor prognosis. We encountered a rare case of chylous ascites complicated by advanced pancreatic cancer. The patient presented with a discrepancy between the shrinkage of the pancreatic cancer and the accumulation of ascites. Therefore, we were able to promptly diagnose chylous ascites by performing biochemical tests. The patient was treated with octreotide, reportedly effective in treating chylous ascites, which rapidly improved the chylous ascites and general condition of the patient, allowing the patient to continue chemotherapy for pancreatic cancer. Therefore, physicians should consider the possibility of chylous ascites when clinically unexplained ascites are observed in patients with advanced cancer. The investigation and treatment of chylous ascites should be initiated as soon as possible.