Peripheral neuropathy is a common adverse effect of paclitaxel and oxaliplatin treatment. The major dose-limiting side effect of these drugs is peripheral sensory neuropathy. The symptoms of paclitaxel-induced neuropathy are mostly sensory and peripheral in nature, consisting of mechanical allodynia/hyperalgesia, tingling, and numbness. Oxaliplatin-induced neurotoxicity manifests as rapid-onset neuropathic symptoms that are exacerbated by cold exposure and as chronic neuropathy that develops after several treatment cycles. Although many basic and clinical researchers have studied anticancer drug-induced peripheral neuropathy, the mechanism is not well understood. In this review, we focus on (1) analysis of transient receptor potential vanilloid 1 (TRPV1) channel expression in the rat dorsal root ganglion (DRG) after paclitaxel treatment and (2) analysis of transient receptor potential ankyrin 1 (TRPA1) channel in the DRG after oxaliplatin treatment. This review describes that (1) paclitaxel-induced neuropathic pain may be the result of up-regulation of TRPV1 in small- and medium-diameter DRG neurons. In addition, paclitaxel treatment increases the release of substance P, but not calcitonin gene-related peptide, in the superficial layers of the spinal dorsal horn. (2) TRPA1 expression via activation of p38 mitogen-activated protein kinase in small-diameter DRG neurons, at least in part, contributes to the development of oxaliplatin-induced acute cold hyperalgesia. We suggest that TRPV1 or TRPA1 antagonists may be potential therapeutic lead compounds for treating anticancer drug-induced peripheral neuropathy.

To compare pro re nata (PRN) intravitreal injections of aflibercept (IVA) and ranibizumab (IVR) in patients with treatment naïve age-related macular degeneration (AMD).

An 86-year-old woman underwent a cholecystectomy for gallbladder cancer. Seven months later, an abdominal CT scan showed multiple liver and lymph node metastases. Treatment with S-1 was started at a dose of 100 mg/day, but was changed to alternate-day administration because of diarrhea. Metastatic lesions showed a complete response after 7 months of chemotherapy. S-1 alternate-day therapy could be maintained without any severe adverse events. This method can be managed safely and with certainty in an elderly patient and it has demonstrated efficacy in the treatment of recurrent gallbladder cancer.

S-1 (tegafur/gimeracil/oteracil potassium) is an effective oral anticancer drug for treatment of a wide spectrum of cancers. However, it may incur serious adverse effects through factors such as interactions with other drugs, renal dysfunction, or an insufficient washout period. In view of this, pharmacists should play an increasingly significant role in managing the medication history of patients treated with S-1. As there seems to be no standardized management tool for patients receiving S-1, we conducted a retrospective study to evaluate medication history management methods, which are commonly available in community pharmacies as well as hospitals. We identified 128 outpatients who were prescribed S-1 for the first time at the National Cancer Center Hospital from July to December of 2011. These patients were divided into in-hospital (n=48) and out-of-hospital (n=80) groups. The percentage of patients, who dropped out during the first course of S-1 treatment, was 16.7% for the in-hospital group, and 10% for the out-of-hospital group. Examining renal dysfunction, non-elderly patients with low creatinine clearance (Ccr) were found. These results suggest that there is the possibility of side effect occurrence in both the in-hospital and out-of-hospital prescription groups. Community pharmacists should check prescriptions with particular attention to the Ccr. It is necessary to develop mechanisms for cooperation between hospital and community pharmacists, with clear role sharing between them, allowing the community pharmacists to exercise medication history management for patients prescribed S-1 to the same degree as hospital pharmacists based on available information including laboratory test values.

Advancements in cancer chemotherapy and the introduction of Japanese traditional medicine"Kampo"have been successful in improving the prognosis of malignant tumors. Many Kampo drugs have been used in the treatment of adverse effects. We investigated the safety and efficacy of Hangeshashinto in the prevention and treatment of chemotherapy-induced oral mucositis in patients with gastric and colorectal cancer. Hangeshashinto was shown to reduce the risk of development of mucositis. We also investigated the efficacy of Goshajinkigan in the prevention of chemotherapy-induced neurotoxicity. Goshajinkigan appears to have a promising effect in delaying the onset of neurotoxicity of gradeB2 without reducing the efficacy of treatment. Kampo drugs such as Rikkunshito, Jyuzentaihoto, and Hochuekkito have also been used successfully in the prevention and treatment of chemotherapy-induced adverse effects. It is very important to know the efficacy and safety of Kampo drugs for alleviating the adverse effects of anticancer drugs in patients undergoing cancer treatment with chemotherapy.

Patients with cancer exhibit various symptoms induced by cancer itself and its therapy leadingto fatigue; however, their vital energy can be restored by administration of Kampo, which is a traditional Japanese herbal medicine. Restoration and maintenance of mental and physical energy are important for successful cancer treatment. For this purpose, appropriate use of Kampo formulas, such as"Ho-zai", formulas to vitalize fatigued patients (eg, Hochu-ekki-to, Juzen-taiho-to, Ninjin-yoeito), "Hojin-zai", formulas to restore energy (eg, Gosha-jinki-gan), and"Kuoketsu-zai ", formulas to resolve stagnant blood flow (eg, Keishi-bukuryo-gan, Tokaku-joki-to, Toki-shakuyaku-san) are administered in combination. Consequently, basic autonomic functions, such as appetite, sleep, defecation, and urination normalize and the nutritional and mental conditions are restored. These favorable changes in the patients' condition allow completion of the standard cancer therapy course, resultingin an improved outcome of cancer therapy and successful treatment. Kampo therapy can be administered as the final treatment option for patients with last-stage cancer who do not have any other effective therapy options. If patients with cancer are administered Kampo formulas, their vital energy is restored, and they develop a will to fight the cancer. As a result, communication becomes easier.

Although the efficacy of adjuvant chemotherapy with oxaliplatin for colorectal cancer patients has been established, the tolerability of this regimen is rarely reported in Japan. The aim of this study was to clarify the tolerability of adjuvant oxaliplatin-based regimen for Japanese patients with colorectal cancer.

A 61-year-old man underwent a curative operation for advanced esophageal cancer (CT-pT3N2M0, pStage Ⅲ), which had been downstaged with docetaxel, CDDP, 5-FU (DCF) neoadjuvant chemotherapy. Five months after the operation, we diagnosed the patient with recurrence of esophageal cancer with para-aortic lymph node (PALN) metastasis. Systemic chemotherapy was initiated using a regimen of weekly paclitaxel (PTX) administration. After 2 courses, abdominal computed tomography examination indicated regression of the PALN swelling. Eighteen months have passed since the curative operation, and the patient has been doing well with no signs of recurrence. In summary, we successfully treated a case of lymph node metastases from esophageal cancer with weekly PTX chemotherapy.

A 67-year-old woman underwent total mastectomy, postoperative radiation therapy, and adjuvant hormonal therapy more than 9 years 4 months previously. There were no symptoms of recurrence for 3.5 years after completing adjuvant hormonal therapy. A hard mass appeared on the front chest wall and was diagnosed as recurrence of breast cancer histopathologically. A computed tomography (CT) scan revealed multiple metastases in the left side of the chest wall, in the left Level Ⅱ axillary lymph nodes, and in the left lung. The patient was prescribed high-dose tremifene (HD-TOR 120 mg/day). After less than 4 months, she presented with general fatigue and yellow skin, and was admitted with grade 4 hyperbilirubinemia and grade 3 hepatic dysfunction (AST and ALT). CT and magnetic resonance imaging (MRI) showed no abnormal findings in the liver or biliary tract. Drug-induced liver injury (DILI) caused by HD-TOR was suspected and this therapy was discontinued. The liver dysfunction showed a tendency to improve with conservative treatment and the patient was discharged on the 10th day of illness. She had almost recovered after 5.5 months. A liver biopsy, a drug-lymphocyte stimulation test, and other detailed examinations were not performed, but we judged this case to be one of liver failure caused by HD-TOR-induced DILI.

By remarkable progress of chemotherapy for pancreatic cancer, we sometimes achieve resection of initially unresectable pancreatic cancer after chemotherapy. Otherwise, the safety and feasibility of radical pancreatic resection after chemotherapy is not still clear. In this report, we evaluated the safety and feasibility of conversion surgery for initially unresectable pancreatic cancer in our center.

Neovascular glaucoma is a serious complication associated with retinal ischemic changes, which increase the production of vascular endothelial growth factor. Vascular endothelial growth factor has been implicated as a key molecule in the development of newly formed vessels and neovascular glaucoma. Intravitreal injection of bevacizumab, a full-length humanized anti-vascular endothelial growth factor monoclonal antibody, leads to a dramatic regression of the new iris and iridocorneal angle vessels on slitlamp examination. However, anterior segment angiography reveals that bevacizumab does not cause a regression of the neovascular vessels themselves but reduces vascular permeability while newly formed vessels are still present in the iris and iridocorneal angle. This review focuses on the pathology and diagnosis of neovascula glaucoma and the effect of intravitreal bevacizumab on the iris and iridocorneal angle neovascularization.

Cetuximab was approved in Japan as the only clinically available molecular targeted drug for the treatment of head and neck cancer. Hypomagnesemia associated with cetuximab is considered one of the most serious adverse events. However, the factors influencing the development of hypomagnesemia are not clear, although the drug was previously approved for the treatment of patients with colorectal cancer. Thus, we studied the factors involved in the development of hypomagnesemia in patients receiving cetuximab therapy for head and neck cancer. Patients' background data and laboratory values before starting cetuximab therapy did not affect the development of hypomagnesemia. Among patients who had never been treated with cisplatin (NT group), 36.4% developed hypomagnesemia. In contrast, all patients who had previously been treated with cisplatin (T group) developed hypomagnesemia (p=0.034). Magnesium is reabsorbed by transient receptor potential subfamily melastatin 6 (TRPM6) in the distal convoluted tubule. The expression level of TRPM6 is controlled by the epidermal growth factor (EGF) pathway. Cetuximab is an EGF receptor inhibitor and reduces the expression of TRPM6. Additionally, recent studies have shown that the expression of TRPM6 is reduced by cisplatin. Therefore, we considered that the serum magnesium level was cumulatively reduced by cetuximab and cisplatin. In conclusion, the T group was more likely to develop hypomagnesemia than the NT group, and therefore the serum magnesium level in the T group requires careful monitoring so that magnesium supplementation can be provided to patients when the level decreases.

In recent years, the incidence of eye disorders due to antineoplastic agents such as S-1 has increased. Eye disorders including visual field defect, visual field impairment, optic neuritis, and visual acuity reduction have been reported as serious adverse effects of oxaliplatin, an agent that is frequently used as a standard therapy for colorectal cancer. However, specific details about these conditions, such as the timing relative to oxaliplatin administration and frequencies at which they appear, remain to be clarified; therefore, we conducted a retrospective analysis of patients with eye disorders due to oxaliplatin in order to obtain evidence that would be useful in routine medical practice. Of the 55 patients who were treated with oxaliplatin in this analysis 10 (18.2%) presented with eye disorders, including blepharoptosis (5 patients, 9.1%), visual field impairment (2 patients, 3.6%), visual acuity reduction (2 patients, 3.6%), eye pain (1 patient, 1.8%), congestion (1 patient, 1.8%), watering eyes (1 patient, 1.8%), and blurred vision (1 patient, 1.8%). These symptoms appeared during the early period of treatment, such as after the first or the second dose. We found that all patients had mild symptoms (Grade 1 or 2), and most improved spontaneously. Thus, eye disorders due to oxaliplatin affect Japanese patients somewhat frequently, although the symptoms are reversible and are mild in most cases. Detailed studies that include data from a larger number of facilities should be conducted in the future.

Hyponatremia is one of the electrolyte abnormalities frequently encountered in cancer therapy. Cisplatin is a well-known drug which can raise various adverse events, including hyponatremia. A male with advanced oropharyngeal cancer is presented in the present report, who was treated with radiotherapy with concurrent administration of cisplatin and who underwent a total of three episodes of severe hyponatremia in the course of therapy. The first two attacks of hyponatremia following cisplatin administration were accompanied by dehydration and excessive urination, and the patient recovered in one week with rehydration and salt supplementation. Excessive loss of salt in urine confirmed that these events were caused by renal salt wasting syndrome after cisplatin administration. On the other hand, the third attack was due to the syndrome of inappropriate antidiuretic hormone secretion after surgery for a bone fracture. Estimation of the extracellular fluid volume and salt intake/output balance is always believed to be necessary for the diagnosis and proper management of severe hyponatremia after chemotherapy-based treatment with cisplatin.

A 52-year-old woman was admitted to our hospital with right upper quadrant pain with gallbladder wall thickening and multiple liver tumors. Endoscopic ultrasound-guided biopsy revealed small cell carcinomas of both the gallbladder and liver. After 10 cycles of chemotherapy with etoposide and cisplatin, marked shrinkage of the tumors was evident on computed tomography. The patient subsequently underwent hepatectomy and resection of the extrahepatic bile duct and gallbladder with curative intent. Although no viable tumor cells were found in the resected specimens, we confirmed phagocytosis of tumor cells killed by chemotherapy in the resected liver specimen. Therefore, we suspected that the patient had primary small cell carcinoma of the liver that had been successfully treated. This is a rare case of primary small cell carcinoma of the liver that showed pathological complete response to chemotherapy with etoposide and cisplatin.

Drug delivery techniques to tumor cells have attracted considerable attention. For instance, folic acid (FA) as a tumor-targeting ligand is widely used because of overexpression of folate receptor-α (FR-α) in various kinds of epithelial tumor cells. On the other hand, methyl-β-cyclodextrin (M-β-CyD) is acknowledged to induce cell death through the extraction of cholesterol from lipid rafts. It was recently reported that intraperitoneal administration of M-β-CyD exerted antitumor activity in human tumor xenografted athymic nude mice. However, the cytotoxic activity of M-β-CyD is known to lack tumor cell selectivity. Therefore in the present study, in an attempt to confer tumor cell selectivity to M-β-CyD, we newly synthesized folate-appended M-β-CyD (FA-M-β-CyD) and evaluated its potential as a novel antitumor agent. FA-M-β-CyD showed potent antitumor activity in various FR-α-positive cells such as KB cells, Ihara cells, and M213 cells but not in FR-α-negative cells, A549 cells. FA-M-β-CyD induced the formation of autophagic vacuoles in KB cells. In addition, the antitumor activity of FA-M-β-CyD, but not M-β-CyD, was inhibited by addition of the autophagy inhibitors chloroquine and bafilomycin A1 in KB cells. A single intravenous injection of FA-M-β-CyD drastically inhibited tumor growth and significantly improved survival rate in Colon-26 cells-allografted or M213 cells-xenografted mice. In conclusion, FA-M-β-CyD has potential as a novel tumor-selective anticancer agent due to FR-α-mediated cellular uptake. The present results provide useful information for the design and development of novel antitumor drug carriers and antitumor drugs based on CyDs.

The recently discovered high mannose (HM)-binding lectin family in lower organisms such as bacteria, cyanobacteria, and marine algae represents a novel class of anti-viral or anti-tumor compounds. This lectin family shows unique carbohydrate binding properties with exclusive high specificity for HM glycans with core trisaccharide comprising Manα(1-3)Manα(1-6)Man at the D2 arm. At low nanomolar levels, these lectins exhibit potent antiviral activity against HIV and influenza viruses through the recognition of HM glycans on virus spike glycoproteins. In addition, some of these lectins, such as bacterial PFL, show cytotoxicity for various cancer cells at low micromolar levels. Cell surface molecules to which PFL bound were identified as integrin alpha 2 and epidermal growth factor receptor (EGFR) by peptide mass finger printing with MALDI-TOF MS. Upon PFL binding, these molecules were rapidly internalized to cytoplasm. EGFR was time dependently degraded in the presence of PFL, and this process was largely responsible for autophagy. Furthermore, PFL sensitizes cancer cells to the EGFR kinase inhibitor, gefitinib. In vivo experiments showed that intratumoral injection of PFL significantly inhibited the growth of tumors in nude mice. PFL-mediated down regulation of integrin/EGFR ultimately contributed to the inhibition of tumor growth both in vitro and in vivo. Thus, the novel anti-cancer mechanism of PFL suggests that this lectin is potentially useful as an anti-cancer drug or as an adjuvant for other drugs. This class of proteins will likely have beneficial impact as a tool for biochemical and biomedical research because of its unique carbohydrate specificity and various biological activities.