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Purpose: To investigate the efficacy and safety of A0001 (brilliant blue G250) for visualization of the internal limiting membrane (ILM) during and after vitrectomy., Methods: Patients (n = 31) requiring ILM peeling during vitrectomy were enrolled in this clinical trial. After injection of A0001 (range: 0.0625 to 0. 125 mg), the staining grade and the peeling ease of the ILM were evaluated in five steps (levels 0 to 4). The safety of A0001 was investigated for 7 days after surgery., Results: From the evaluation of a primary endpoint by the Independent Data Monitoring Committee (IDMC) and a secondary endpoint by each surgeon, A0001 was effective in all cases at three or more levels ( ≥ level 2 was defined as effective) for evaluation of the grade of visualization and operating ease. Adverse events occurring in two or more cases included elevated intraocular pressure, eye pain, eye discharges, and retinal bleeding. One serious adverse event was a case of unclosed macular hole after vitrectomy, but the patient recovered after reoperation., Conclusions: A0001 was effective and safe for visualization of the ILM during vitrectomy, and there was an improvement in ease of operation.

Objective: Sorafenib is an oral multi-kinase inhibitor of Raf-1, VEGF and PDGF receptors and others, resulting in tumor regression and anti-angiogenesis. We studied serum pancreatic enzyme increase associated with sorafenib treatment., Patients and Methods: In a phase II study of Japanese patients with metastatic renal cell carcinoma, a total of 131 patients received sorafenib 400 mg twice per day. Serum levels of lipase and amylase were measured on day 7 and every 3-4 weeks thereafter during treatment period. When grade 3 or 4 enzyme abnormalities were observed, ultrasound or computed tomography scan was performed to detect pancreatitis., Results: The incidence of all-grades lipase and amylase increases were 55. 7% and 38. 2%, respectively, while those of grade 3 or 4 were 30. 5% and 5. 3%, respectively. The majority of these events were observed in the first 3 weeks of sorafenib treatment. Grade 3 or 4 lipase increase was detected in 32 patients (24. 4%)on day 7 measurement. These abnormal elevations spontaneously resolved in all patients. Regarding grade 3 lipase increase, the median time to recovery to grade 2 and 1 were 7 and 14 days, respectively. Three patients required interruption of the treatment. No patient showed any clinical manifestation or abnormal imaging finding suggesting pancreatitis., Conclusion: Pancreatic enzyme increases observed frequently under sorafenib treatment were transient and asymptomatic. They were not related to symptomatic pancreatitis.

A 72-year-old man was diagnosed with right renal cell carcinoma (RCC) with multiple brain and lung metastases (cT3aN0M1). He underwent γ-knife treatment for brain metastases, palliative right renal artery embolization for primary RCC, and interferon- alpha treatment for residual lung metastases. Although the interferon-alpha treatment was effective, it was discontinued because of side effects. He received sorafenib (800 mg/daily) therapy for 2 months. Suddenly, he developed left cardiac failure, and he died 6 days later through a rapid clinical course that included circulatory failure, abnormal glucose tolerance, disseminated intravascular coagulation, and multiple organ failure. A pathological examination could not explain the cause of death. It is important to carefully observe metastatic RCC patients receiving a tyrosine kinase inhibitor, especially sorafenib, because critical side effects may appear.

Unlabelled: Some clinical studies confirmed the efficacy and safety of sorafenib in advanced hepatocellular carcinoma(HCC), for which the standard initial dose is 400 mg twice daily. However, it is unclear whether this dosage is tolerable for patients with a low body surface area(BSA). We retrospectively analyzed the difference in efficacy and safety of sorafenib between patients with low BSA and high BSA., Method: From July 2009 to June 2010, 64 patients with Child-Pugh grade A cirrhosis receiving sorafenib at 4 institutions were enrolled, and divided into two groups(BSA<1. 6m2 and ≥1. 6m2)., Results: In BSA<1. 6m2 and BSA≥1. 6m2 groups, grade 3-4 adverse events were observed in 64. 3% and 55. 3% of patients, respectively, and subsequent discontinuation was 38. 5% and 24. 2%, respectively indicating poor compliance in the former group. The disease control rate was 33. 3% and 37. 8%, the median time-to-radiological progression(TTRP)was 2. 1 months and 3. 6 months(p=0. 003), and median survival time was 6. 6 months and 11. 2 months in low BSA and high BSA groups(p=0. 10), respectively. Multi-variate analysis showed that poor prognostic factors for TTRP were ECOG performance status of ≥1 and BSA<1. 6m2., Conclusion: Standard dosage seems intolerable for patients with low BSA, and results in poor prognosis.

We report here the experience of the treatment with sorafenib for advanced hepatocellular carcinoma (HCC) in our department. Forty patients received the therapy of sorafenib until April 2011. Twenty seven unresectable advanced HCC, 7 lung metastasis, 6 bone metastasis, 3 abdominal lymph node metastasis, and 2 peritoneal dissemination were included. The median duration of sorafenib treatment was 197 days. Grade 3 adverse event occurred in 9 patients (22.5%), and grade 4 adverse event occurred in 1 patient (3%). The response rate and disease control rate were 5% and 55%, respectively (CR 2, PR 0, SD 20, PD 9). The median overall survival was 15.2 months, and median recurrence-free survival was 3.7 months. These results suggested that a prevention of adverse events would lead to a continued treatment with sorafenib, and could expect to have a prolonged survival in patients with advanced HCC.

A 60-year-old man with liver cirrhosis caused by hepatitis C, who was receiving warfarin anticoagulation following acute myocardial infarction, was diagnosed with advanced hepatocellular carcinoma and multiple lung metastases, and began treatment with sorafenib 200 mg daily. From the treatment's start to 14 and 63 days later, sorafenib was increased to 400 mg and 600 mg, respectively. After increasing the quantity to 600 mg, he had an increase in PT-INR values and experienced a lower-extremity hemorrhage. For the patient with liver cirrhosis, who is receiving warfarin, PT-INR values might be elevated during the early period of sorafenib treatment dosage as for the increase in quantity. Therefore, when increasing dosage, a frequent measurement of PT-INR and a careful follow-up for PT-INR is necessary.

We analyzed the treatment outcome and effect of sorafenib in advanced hepatocellular carcinoma. Nine patients were received the therapy of sorafenib between June 2009 and October 2009. The overall incidence of treatment-related adverse events was 87.5%. Grade 3 drug-related adverse events included a hand-foot skin reaction (two patients) and fatigue (one patient). Grade 2 hypertension (three patients), grade 1 diarrhea (two patients) and anorexia (four patients) occurred at this study. The response rate was 0% (CR/PR 0, SD 2, PD 6) and median overall survival length was 101 days. Now there are two patients undergoing the therapy of sorafenib. Effect of sorafenib in advanced hepatocellular carcinoma was not good in this study, and drug-related adverse events had a high rate. However, the continuous treatment was possible with dose modified chemotherapy.

Unlabelled: We evaluated the effect of sorafenib and intermittent hepatic arterial infusion chemotherapy (HAIC) using cisplatin for unresectable advanced hepatocellular carcinoma (HCC)., Methods: 5 patients (4 male/1 female, median age: 73.0 years) with unresectable advanced HCC including portal vein tumor thrombus were treated with soraenib (400 mg/body, day 1-28) and cisplatin (20 mg/m2 HAIC, day 1, 8, 15). We assess efficacy and safety after 1 course of this therapy., Results: Grade 3 adverse events occurred in 2 patients (1 serum bilirubin and aspartate aminotransferase (AST) elevation, 1 serum bilirubin elevation and hepatic encephalopathy). Grade 2 adverse events occurred in 4 patients (1 hypertension and nertropenia, 1 hypertension and thrombocytopenia, 1 hypertension and serum amylase elevation, and 1 abdominal pain). Grade 3 adverse events were improved by suspending this therapy, and completion of this therapy was achieved in all patients. After one course of this therapy, the clinical response was rated as 1 partial response (PR), 3-stable disease (SD), and 1 progressive disease (PD)., Conclusion: Sorafenib and intermittent HAIC using cisplatin for unresectable advanced HCC was expected to be safe and effective treatment.

Sorafenib(Nexavar)is a multikinase inhibitor, with disruptive activity at intracellular C-RAF, B-RAF and mutant BRAF receptors, and extracellular C-KIT, FLT-3, VEGFR-2, VEGFR-3 and PDGFRb receptors. In the phase III study, as compared with placebo, treatment with sorafenib significantly prolonged progression free survival(PFS)in patients with advanced renal cell carcinoma in whom previous therapy has failed. Diarrhea, rash, fatigue, hand-foot skin reactions, and hypertension were the most common adverse events associated with sorafenib. As sorafenib was associated with similar rates of clinically manageable side effects in elderly patients as compared to younger patients, response rates to sorafenib in elderly patients were comparable to those of younger patients. Sorafenib was approved multinationally for the treatment of advanced and/or metastatic renal cell carcinoma. Sorafenib and sunitinib are reference standards of care for the treatment of advanced renal cell carcinoma and are recommended by current clinical guidelines. For the future, research of biomarker, adverse drug reaction, and combined regimens are needed to maximize the effects of molecular-targeted drugs.

Although medical treatment for advanced renal cell carcinoma has included cytokine therapies such as interferon and interleukin-2, the treatment system has been revolutionized with the emergence of molecular target medicine. A vascular endothelial growth factor and its receptor for the target molecule are the mainstream, but the efficacy of inhibitors of an alternate pathway has been established. It seems that even newer molecular target medicine will be introduced in the future, but the optimal medicine based on the individual condition must be provided in renal cell carcinoma cases.