Cisplatin, a first-generation platinum derivative, is one of the most widely used anticancer agents and can treat a broad spectrum of malignancies. Cisplatin-induced nephrotoxicity is a major dose-limiting side effect resulting from damage to the proximal tubules of the kidney. This nephrotoxicity can be prevented by lowering the concentration of cisplatin and shortening the period of cisplatin exposure to the proximal tubules. In clinical practice, high-volume hydration(>3 L intravenous isotonic saline), forced diuresis(mannitol and/or furosemide), and magnesium supplementation have been generally used to lower the risk of cisplatin-induced nephrotoxicity. Short hydration(short-term, low-volume hydration with oral fluid intake)has recently been undertaken among patients with reserved renal function and good performance status, especially in outpatient settings. Carboplatin is a second-generation platinum-based agent that is almost completely excreted from the kidneys following its administration. Its pharmacokinetics can be predicted based on the glomerular filtration rate(GFR). The area under the blood concentration-time curve(AUC), an indicator of drug exposure volume in the body, is closely correlated with hematotoxicity and antitumor effect. It is now a widespread practice to set carboplatin doses based on the GFR after establishing a target AUC. This article describes the characteristics of these 2 platinum-based drugs, focusing on the recommendations based on the recently published guidelines regarding nephropathy in patients undergoing cancer drug therapy.

In recent years, among patients treated with anticancer chemotherapy, the rate of chronic kidney disease has been increasing. Nephropathy is a major potential adverse event in cancer drug therapy. Anticancer chemotherapy, particularly in patients with comorbid chronic kidney disease, requires sufficient examination of the balance between the potential therapeutic benefit and the risk of decreased renal function. The overwhelming diversity of drugs used to treat cancer involves equally diverse nephropathy pathologies and dose adjustments. There is no established method for assessing renal function during cancer drug therapy. Although serum creatinine levels and eGFR are used to assess renal function in real-world clinical settings, they are generally recognized to be somewhat problematic, and there is currently no established method for assessing renal function before and after cancer drug therapy. When assessing renal function for adjusting anticancer drug doses, the Japanese eGFR is recommended. However, if the patient requires an adjustment of the anticancer drug dose, the renal functional assessment method that have used at the clinical trial have a high likelihood of being safe. In addition, despite the importance of the early diagnosis of acute kidney injury(AKI), currently, we cannot strongly recommend biomarker-based assessment for the early diagnosis of anticancer drug-induced AKI.

Immune checkpoint inhibitors, including the anti-CTLA-4 antibody ipilimumab, the anti-PD-1 antibodies nivolumab and pembrolizumab, and the anti-PD-L1 antibody atezolizumab had produced long-lasting tumor responses in several malignancies. Immune-related Adverse Events(irAEs)which are different from adverse events of conventional chemotherapy and molecular targeted therapy, occur as a consequence of impaired self-tolerance from loss of T-cell inhibition. The main irAEs of immune checkpoint inhibitors include dermatological, gastrointestinal, pulmonary, hepatic, endocrine, renal toxicities. Every organ system can be potentially involved, but nivolumab, pembrolizumab and atezolizumab have a different toxicity profile with fewer high grade events compared with ipilimumab. In this article, we provide an approach to appropriate management for each class of irAEs.

We retrospectively evaluated the efficacy and toxicity of low-dose estramustine phosphate (EMP) monotherapy in patients with castration-resistant prostate cancer (CRPC). We administered EMP at 140 or 280 mg/day to 89 patients between January 2003 and December 2012. None of the patients were receiving concomitant dexamethasone and none had ever been treated with docetaxel. Fifty-three patients (59.6%) experienced a decline in prostate-specific antigen (PSA) levels, including 20 (22.5%) with a decline of more than 50%. The median time to PSA progression was 90 days. PSA-progression-free survival was significantly longer in patients treated with EMP 140 mg compared with patients treated with EMP 280 mg, and there was no significant difference in the incidence of adverse events between the two groups. The most frequent toxicities were nausea and anorexia. Two patients had grade 3 adverse events of pulmonary embolism and liver dysfunction. EMP treatment was discontinued in nine patients (10.1%) because of side effects (nausea and anorexia in 7, liver dysfunction and lacunar infarction in 1). Low-dose EMP monotherapy is well tolerated and can effectively reduce PSA levels.

Nyugan-jun is a manual that was used at Hanaoka's school, Shunrinken, describing two oral medicines and three ointments routinely administered after breast cancer surgery. Nyugan-jun Furoku is also a manual that was used at the school, depicting a variety of diseases of the breast, and oral concoctions to be administered. The earliest manuscript of both manuals was transcribed in February 1812. A manuscript of Ben-nyugansho narabini Chiho Soko, written by Ryozo Chiba in 1811, includes descriptions of an oral medicine and four ointments routinely given after breast cancer surgery. Although Choeito was only a common oral concoction in Nyugan-jun and Chiba's manuscript, the latter bears an original trace of Nyugan-jun. This indicates that Nyugan-jun and Nyugan-jun Furoku were completed by the end of February 1812, and their completion dates were not before August 1811.

Recently, the importance of a team approach to multidisciplinary medical treatment and care has been recognized. Patient satisfaction must be the purpose of the team approach. With advances in Western scientific methodology, the biological approach to breast cancer has been established. However, psychological, ethical, economic, and social approaches are also required. Key points of the team approach are considered to be the quality of communication between the patients and physicians and among medical staff. We believe that “caring for people who are ill” leads to a good team approach, resulting in patient satisfaction. Additionally, treatment and care should not only occur in a hospital as patients live in society. Multidisciplinary care must be extended from hospitals to the society at large.

A 69-year-old woman underwent proximal gastrectomy with distal pancreatectomy and splenectomy for a gastrointestinal stromal tumor of the stomach.Adjuvant imatinib was administered for a year.Two years after resection of the tumor, liver metastasis in S8 was detected.Therefore, imatinib was re-administered at 300mg/day.After a year of re-administration, the patient suffered muscle cramps in the hands, and therefore imatinib was administered with intervals, such as 4 weeks administration and 4 weeks rest.Re -administration of imatinib was effective and her liver metastasis decreased in size.It was not detected with CT after 1 year and 4 months and remained in complete response(CR)for 3 years and 8 months.After she suffered a brain infarction, imatinib administration was stopped for 4 months.Consequently, the liver metastasis was detectable in S8 again.This clinical course suggested that low-dose and interval administration of imatinib is effective in the treat- ment of GIST.

Nedaplatin(NDP)is a platinum derivative anticancer drug.An NDP dose of 100mg/m2 every 4 weeks is recommended in non-elderly Japanese patient because a higher dose may lead to myelosuppression, such as thrombocytopenia.In a pharmacokinetic analysis, thrombocytopenia was significantly correlated with renal function.However, the correct dose in patients with impaired renal function remains unclear.To evaluate the usefulness of dose reduction in patients with renal dysfunction, we conducted a retrospective study.This study included Japanese solid cancer patients who received NDP monotherapy in Nagoya University Hospital between April 2011 and March 2014. Eighty three patients were evaluated and divided into 2 groups based on renal function: a creatinine clearance(Ccr; mL/min)≥60 group and a Ccr<60 group.The frequency of B Grade 3 thrombocytopenia and neutropenia was significantly higher in the Ccr<60 group than that in the Ccr≥60 group (3.4% vs 32.0%; p=0.001 and 6.8% vs 32.0%; p=0.005, respectively).In the Ccr<60 group, the frequency of BGrade 3 thrombocytopenia and neutropenia was lower in the reduced dose group than that in standard dose(100mg/m2)group (41.7% vs 23.1%; p=0.410 and 41.7% vs 23.1%; p=0.410, respectively).A multiple logistic regression analysis revealed that NDP dose and serum creatinine were risk factors for the incidence of BGrade 3 thrombocytopenia and neutropenia.These results suggest that NDP dose should be reduced to achieve safe drug treatment in patients with Ccr<60.

We report the case of a patient who had renal cell carcinoma with high everolimus blood concentrations and hyperglycemia due to everolimus-induced hepatic dysfunction. A 74-year-old man who underwent right nephrectomy for renal cell carcinoma was administered everolimus for multiple lung metastases. Everolimus caused grade 3 hepatic dysfunction and hyperglycemia; hence, high blood levels of everolimus were observed. Although the patient was re-administrated everolimus after recovering from hepatic dysfunction, hepatic function test values worsened again. Everolimus was discontinued before its blood concentration increased, and the patient was switched to axitinib treatment. Therefore, the measurement of everolimus blood level is considered useful for the management of adverse events in renal cell carcinoma.

The adolescent and young adult(AYA)generation is defined as population aged 15 through 39years and is widely used by many organizations and associations. Female fertility preservation consists of oocyte freezing, embryo freezing, ovarian tissue freezing and transplantation, and ovarian protection by the GnRH agonist in anticancer agents. In particular, owing to the characteristics of fertility preservation for cancer patients in the AYA generation, a longer frozen storage period is possible. Special consideration for the devised and informed consent protocol for adolescent patients and psychological support are needed when patients gets older. At the same time, a safer and more effective technology could be developed during the storage period.

Drug resistance is a critical problem inhibiting the effective use of targeted molecular cancer therapies. Investigators have revealed a variety of resistance mechanisms, including alterations in drug targets, activation of pro-survival pathways, and the ineffective induction of cell death. The key alterations driving this resistance are likely condition-dependent, and a detailed analysis would be required to characterize these diverse alterations under a variety of conditions in order to facilitate practical precision medicine for treating individual cancer patients. We have been investigating the molecular mechanisms of anti-cancer drug resistance, and analyzed our original resistant cells against anti-mitotic kinase inhibitors. This study suggests that novel mechanisms reduce cytokinetic dysregulation caused by those inhibitors, and anti-apoptotic activities are associated with resistant phenotypes. These observations suggest that the activation of various bypass mechanisms may allow cancer cells to avoid the selective antiproliferative effect of molecularly targeted drugs, and such bypass activation mechanism would thus be a critical target for designing combination chemotherapy to overcome non-genetic drug resistance.

Receptor tyrosine kinases (RTKs) are known to be key regulators of cancer cell proliferation, migration, invasion and metastatic spread. Ligand-binding to the extracellular domain triggers canonical activation of the intracellular tyrosine kinase domain. In contrast, it has become evident that RTKs are also regulated by non-canonical tyrosine kinase-independent mechanisms via phosphorylation of their serine/threonine residues. In this review, I mainly introduce our recent findings on the non-canonical regulation of epidermal growth factor receptor (EGFR), ErbB2 and erythropoietin-producing hepatocellular receptor A2 (EphA2), and discuss the roles of non-canonical activation of RTKs in cancer progression and resistance to targeted cancer agents. Further characterization of non-canonical regulation will contribute to the development of new target cancer therapies.

Aberrant activation of Wnt/β-catenin canonical signaling is observed in multiple malignant tumors, and is recognized as an attractive therapeutic target for molecular targeted drugs. This signaling pathway is also involved in maintaining pluripotency in adult stem cells. Therefore, lowering potential stem cell toxicity is a key factor for the development of a Wnt/β-catenin signaling inhibitor. Here, we show Wnt/β-catenin pathway inhibitors with low toxicity, identified through phenotype-based screening using zebrafish embryos. Artificial activation of the Wnt/β-catenin pathway in fertilized eggs, which are often considered the "ultimate stem cells", results in an "eyeless" phenotype in zebrafish embryos. Screening for compounds that rescue this "eyeless" phenotype and have no effects on normal embryogenesis could help us identify Wnt/β-catenin pathway inhibitors with minimal stem cell toxicities, at least at a concentration that suppresses aberrant signaling. Chemical suppressors of the "eyeless" phenotype include novel and known compounds with different modes of action. Some of these compounds diminish the activation of crosstalk between other signaling pathways and the Wnt/β-catenin pathway. These inhibitors reduced tumor growth in ApcMin/+ mice and did not show apparent toxicities. Thus, our screening for chemical suppressors of the "eyeless" phenotype allowed us to successfully identify inhibitors for the Wnt/β-catenin pathway with low toxicity.

The emergence of drug resistance is a major obstacle to the successful pharmacological treatment of cancer. Tumor heterogeneity is one of the key factors underlying drug resistance. Cancer cell heterogeneity in tumors is caused by genetic mutation and by the existence of cancer stem cells (CSCs). CSCs are defined as a subpopulation of highly tumorigenic cancer cells with self-renewal activity. It has been reported that various types of cancer involve CSCs, and that CSCs are generally resistant to anticancer drugs. Therefore, CSC-targeting agents could allow for more effective pharmacological treatment of cancer. Using a comprehensive gene expression study and functional genomic approach, we are trying to identify CSC-specific survival factors, as well as candidate compounds that interfere with CSC-selective survival signaling. These CSC-targeting drugs could be promising new therapeutic agents which would suppress the emergence of drug-resistant cells and enhance the effect of antitumor agents.

Eye disorders are one of the characteristic adverse events associated with S-1 chemotherapy. In this retrospective study, we investigated the frequency and outcome of eye disorders associated with S-1 chemotherapy in gastric cancer patients. This retrospective study included 75 advanced gastric cancer patients who received S-1 monotherapy between January 2014 and December 2015. We retrospectively evaluated the frequency, Grade, and treatment of eye disorders. Eye disorders were observed in 16 patients(21%). The median time of onset was 3(range, 1-8)months. Grade 2 watering eyes, eye discharge, and conjunctivitis were reported in 14, 8, and 4 patients, respectively. Artificial tears, fluorometholone eye-drops, and both of these treatments were used in 7, 1, and 8 patients, respectively. Ophthalmologic examination was performed for 3 patients. No delay or reduction of S-1 therapy was required for the eye disorders. Eye disorders associated with S-1 therapy in gastric cancer patients did not affect treatment if managed properly using eye drops.

The prognosis of hepatocellular carcinoma(HCC)with main portal vein(MPV)and/or the inferior vena cava(IVC)tumor thrombi is dismal. The management of HCC with severe tumor thrombus is complicated. In this study, we report a case of HCC with tumor thrombi in the MPV and IVC that was successfullytreated via liver resection and perioperative hepatic arterial infusion chemotherapy(HAI). A 68-year-old man was referred to our institution to treat huge HCC lesion in the right lobe of the liver. Abdominal computed tomography(CT)revealed a tumor(12 cm in diameter)in the right hepatic lobe and tumor thrombi in the MPV and IVC. The patient was initiallytreated with HAI(cisplatin 100mg/body). After 3 courses of HAI, the tumor was dramaticallyreduced in size, and the thrombus in the IVC had disappeared; however, the thrombus in the MPV remained. Therefore, we performed right hepatectomy, wedge resection of the IVC, combined resection of the MPV, and portal vein reconstruction. The histopathological findings of the resected specimen revealed that viable cancer cells were observed onlyin an 8×8mm lesion. Subsequently, HAI was performed as adjuvant therapy for 3 courses. The patient died of other causes 2 years 3 months after surgery. There was no sign of recurrence at the time of death. This case suggested that perioperative HAI and liver resection mayrepresent an effective treatment strategyfor HCC with severe tumor thrombus.

We reported a case of hilar cholangiocellularcarcinoma with complete obstruction of the portal vein. The patient, who was a 65-year-old woman, suffered from fever and general fatigue as a result of acute cholangitis after insertion of a tube stent into the right bile duct. The main tumor was present on the right side of S1 and spread to both sides of the bile duct. S1 lobe was swollen and diffuse intrahepatic invasion was noted in the right lobe and S1. The portal vein was completely obstructed at the porta hepatis with a coronary vein-left renal vein shunt. We immediately administered a high-dose hepatic arterialinfusion( 5-FU 1 g×3 days: one day off 1 g×3 days)(HDHAI)to the right hepatic artery using a transient catheter insertion method. After 2 courses of HDHAI, the intrahepatic invasion decreased. However, after 4 courses of HDHAI(2 on the right side and 2 on the left side), the invasion on the left side of the IVC had increased. We then chose radiation therapy. Subsequently, transient cystic changes were observed; however, 4 months after radiation, the invasion on the left side of the IVC had regrown into the cardia. The patient suffered from vomiting as a result of the narrowing of the esophagus. We chose HDHAI and dilation of the esophagus using a balloon. Finally, the invasion on the left side of the IVC and S1 swelling decreased, and she could eat again. Thirteen months later, she remains an outpatient. We recommend HDHAI and radiation therapy to hilar cholangiocellularcarcinoma even if the portal vein is completely obstructed.

A 74-year-old man was diagnosed with hepatocellular carcinoma(HCC; S4/8)and underwent anterior segment resection of the liver in 2015. He was hospitalized with a wound infection 2 months after surgery. On the 8th hospital day he complained of respiratory discomfort. A CT showed multiple lung metastases and a ground-glass appearance in both lungs. We diagnosed interstitial pneumonia with metastatic lung tumors. Steroid therapy was performed for the interstitial pneumo- nia(prednisolone 1,000mg/day×3 days), and sorafenib therapy was initiated for the metastatic lung cancer(starting from 200mg/day to 800mg/day). The prednisolone improved his symptoms. The lung metastatic tumors shrunk by the 36th hospital day after the CT. However, he developed difficulty in breathing again on the 58th hospital day, and again showed a ground-glass appearance in both lungs by CT. We thought it was drug-induced interstitial pneumonia and we discontinued oral sorafenib. He underwent steroid pulse therapy, but his symptoms did not improve and he died.

We analyzed 26 cases of unresectable or recurrent gastric cancer treated with oxaliplatin(OX)combination therapy between September 2014 and January 2016. The number of unresectable gastric cancer cases was 14 and there were 12 recurrent cases. The number of patients receiving S-1 plus OX(SOX), SOX plus trastuzumab(Tmab), capecitabine(Cape)plus OX(CapeOX), and CapeOX plus Tmab was 17, 1, 6, and 2, respectively. The starting dose of OX was 130mg/m2 in 12 patients and 100mg/m2 in 14. The median follow-up duration from the first treatment was 6 months(1-14). The median number of treatment cycles was 5(1-19). Dose reductions occurred in 14 cases, and treatment delay occurred in 13 cases. Grade 3 adverse events occurred in 2 cases(8%); thrombocytopenia and stomatitis occurred in 1 case. The response rate was 23%, the disease control rate was 69%, and the median relapse-free survival time was 4 months(1-14). OX combination therapy for unresectable or recurrent gastric cancer was feasible in terms of safety and might be effective for disease control.

We report a 43-year-old TSC man with repeated hemorrhage of bilateral renal AML. He was diagnosed with TSC based on the findings of facial angiofibroma, mental retardation and epilepsy in childhood. In 2011, he experienced three times in AML-associated hemorrhage from the left kidney and received selective transarterial embolotherapy (TAE). In 2013, he also experienced AML-associated hemorrhage from the right kidney and received selective TAE. To control his AML, treatments with Everolimus was started and well tolerated. So far, his renal AML remarkably shrunk without retroperitoneal hemorrhage for 24 months, while he had some episode of side effect.