A 73-year-old woman diagnosed with unresectable pancreatic cancer received weekly gemcitabine(GEM)plus albuminbound paclitaxel(nab-PTX)therapy. Four months after nab-PTX therapy was initiated, she presented with a rapidly decreasing vision in her left eye at an ophthalmology clinic. On admission, her visual acuity was decreased, and optical coherence tomography(OCT)revealed a cystoid macular edema(CME)only in her left eye. She discontinued the nab-PTX therapy immediately. Her visual acuity improved on follow-up 6 months later. The CME finding on OCT was reduced but not completely resolved. CME is a rare adverse event induced by nab-PTX therapy, with only 14 cases reported since 2008. In most of the reported cases, the patients had breast cancer, and this is the first reported case of CME in a patient with pancreatic cancer. The time to CME onset from starting nab-PTX therapy was reported to range from3 to 30months, but the predilection time has not been clarified. Many reports indicated that symptoms improved in a short period after discontinuation of nab-PTX therapy, but effective treatment was not established, except discontinuation of nab-PTX therapy. In daily medical treatment, the incongruity of the ophthalmologic domain should be confirmed for early detection of CME.

A 65-year-old man was diagnosed with leptomeningeal carcinomatosis based on the findings of cerebrospinal fluid cytology and magnetic resonance imaging(MRI).Treatment with erlotinib and bevacizumab was initiated, and partial improvement in consciousness and MRI findings were obtained.However, it was difficult to continue the treatment because of elevation in levels of liver enzymes and melena.We switched the treatment to afatinib monotherapy, and his consciousness improved immediately.Progression -free survival and overall survival from the initiation of the treatment with afatinib were 7 and 9.4 months, respectively. This clinical course suggests activity of afatinib for central nervous system lesions of EGFRmutated lung cancer.

A 74-year-old woman, who developed advanced colon cancer with focal recurrence, received two courses of a low dose of nivolumab. Five days after the second course she noticed bilateral ptosis. Her symptoms rapidly progressed to generalized manifestations including limb and neck weakness, dyspnea, and myalgia within the following two weeks. Neurological and laboratory findings supported the diagnosis of myasthenia gravis and myositis induced by nivolumab. The combination immunotherapy including oral prednisolone, intravenous immunoglobulin and plasma exchange with noninvasive positive-pressure ventilation successfully avoid tracheal intubation. Nivolumab, one of the immune checkpoint inhibitors, is the anti-programmed cell death-1 (PD-1) protein monoclonal antibody, which is effective for various cancers. Since the immune checkpoint inhibitors are going to be used widely, it is important to recognize the specific subtype of myasthenia gravis for neurologists.

A man in his 30s who presented with an enlarged right testicle was diagnosed with a germ cell tumor via orchiectomy. Adjuvant chemotherapy with cisplatin, etoposide and bleomycin(BEP)was initiated. He developed a headache 8 days later, followed by neurological deficits 10 days later. Magnetic resonance imaging(MRI)and magnetic resonance venography(MRV)showed thrombotic occlusion at the superior sagittal sinus. Anticoagulant therapy with heparin was initiated. However, a generalized epileptic seizure occurred 11 days later, and an antiepileptic drug therapy was initiated. The headache and neurological deficits gradually improved, and MRI findings showed that the superior sagittal sinus had re-canalized. The main cause of the sinus thrombosis in this patient was considered dehydration and cisplatin-induced hypercoagulability. Five courses of BEP therapy were carried out with care to avoid dehydration. The patient has remained free of testicular tumor recurrence, metastasis, and cerebral sinus thrombosis for 2 years. Cisplatin-based chemotherapy is an established risk factor for venous thromboembolism(VTE), and cerebral sinus thrombosis is a rare but dangerous complication. Therefore, cerebral sinus thrombosis should be considered when patients with testicular cancer who undergo cisplatin-based chemotherapy start to develop neurological symptoms. Clinicians should be aware of this treatable complication.

In the malignant tumors in women, uterine cervical cancer, endometrial cancer, ovarian cancer, and breast cancer are representative diseases. The cancer treatment is classified roughly into an operation, medical treatment, and radiation therapy and has an extremely big influence on ovarian function. With the improvement in survival of cancer patients, the importance of the health care for the cancer survivors increases. It is necessary to prevent the onset of the osteoporotic fractures to maintain QOL. This paper describes the action that the malignant tumors of the women affect bone metabolism mainly from the viewpoint of ovarian function.

Because generic medicines reduce the financialburden on patients and medicalinsurance providers, they have become increasingly popular. However, there are only a few reports that have analyzed the efficacy and safety of generic medicines, especially in terms of their characteristics and side effects. Gemcitabine is an antineoplastic drug that is frequently used with good results in the treatment of lung cancer, pancreatic cancer, breast cancer, ovarian cancer, and malignant lymphoma. However, its fat solubility is high, and several adverse events, such as myelosuppression, are known to develop during its use. We investigated the efficacy, characteristics, and the incidence of adverse events for the generic versions of gemcitabine. We found differences between the generic versions in terms of the characteristics and preparation time; however, the incidence of adverse events was not significantly different, suggesting that the generic versions could be a reasonable substitute.

Since the rate of elderly patients in cancer death is continuously increasing, elderly pa- tients are not special, but ordinary population in daily clinical settings. Geriatric assessment (GA) is recommended to evaluate elderly patients when they undergo anticancer chemother- apy. Geriatric 8 (G8) is an excellent screening tool to evaluate physical and mental function of elderly patients. By such screening tools, elderly patients are divided into 3 categories; "fit": standard regimen for non-elderly patients are applicable, "vulnerable": some modified regi- men should be needed since moderate dysfunction due to aging is recognized, "frail": best supportive care rather than standard therapy should be considered. Thus, individualization of anticancer therapy seems to be most important point for elderly patients.

"Japanese clinical practice guidelines for the management of kidney disease in cancer survivors"have been published. This guideline recommended several managements for nephrotoxicity of other agents than platinum such as the urinary alkylation during methotrexate administration, suspending of anti-angiogenetic agent for the grade 2 or more proteinuria, dose modification of bisphosphonate based on the renal function. Understanding the background of these recommendations will contribute for safe cancer chemotherapy.

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.

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.

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.