We report a 59-year-old male patient with metastatic small cell carcinoma of the bladder treated with systemic chemotherapy including an amrubicin. The patient was referred to our hospital complaining of macrohematuria. A cytoscopy revealed a non-papillary, broad-based tumor extending from the right to the posterior wall of the bladder. A computed tomography showed bilateral hydronephrosis caused by the bladder tumor and multiple metastases to the para-aortic and common iliac lymph nodes. The histopathological findings following a transurethral resection of the bladder tumor revealed a T2N3M1, LYM, stage IV small cell carcinoma. We administered two courses of systemic chemotherapy consisting of cisplatin (CDDP) plus an etoposide (VP-16), a first-line treatment usually administered to patients with small cell carcinoma of the lung. We then administered second-line chemotherapy consisting of CDDP plus an irinotecan. When the first and second-line therapies failed to halt progression of the disease, we decided to use amrubicin as the third-line therapy concomitant with radiotherapy for local control. Although the NSE (neuron-specific enolase) value decreased, the patient died 11 months after the initial examination. To our knowledge, this is the first case in which small cell carcinoma of the bladder was treated with amrubicin.

A 64-year-old man with recurrent multiple myeloma (BJP-κ type) was treated with 15 mg of lenalidomide (LEN) and dexamethasone. He developed Quincke's edema on his eyelid on day 4. Since the edema improved after withdrawal of LEN, the drug was subsequently re-administered at a decreased dose. However, the edema developed again on day 4. After withdrawal of LEN, the drug was administered again with gradually dose escalation, while confirming the absence of eyelid edema. Although edema did not develop, eosinophils and basophils were increased, and the CRP level was elevated. During the third course of LEN administration, his chest CT showed bilateral ground-glass opacity, and LEN-induced hypersensitivity pneumonitis was diagnosed. The pneumonitis resolved after LEN withdrawal and prednisolone administration. These observations suggested that Quincke's edema, eosinophilia and basophilia, CRP elevation, and hypersensitivity pneumonitis might occur due to the immunological effects of LEN, which is classified as an immunomodulatory drug.

Hypomagnesemia is one side effect in patients receiving cisplatin. However, there are few reports of cisplatin-induced hypomagnesemia in Japan. We retrospectively investigated the incidence of hypomagnesemia and nephrotoxicity in patients undergoing radiation therapy who were treated with cisplatin alone (dosage: 40 mg/m2, administration interval: 1 week) for cervical cancer. Thirty-two patients undergoing radiation therapy who received cisplatin alone for cervical cancer between January 2012 and May 2016 at Aichi Medical University Hospital were included. We measured patients' serum magnesium and creatinine levels on the day before cisplatin was administered. We utilized the RIFLE criteria (categorized into "risk", "injury", "failure", "loss", and "end-stage kidney disease") to define levels of cisplatin-induced nephrotoxicity, and classified cisplatin-induced nephrotoxicity into "risk" or "injury". Eighteen patients (56.3%) had cisplatin-induced hypomagnesemia, the majority of which occurred after the 4th treatment cycle. The number of patients with moderate renal dysfunction classified as "risk" in the hypomagnesemia group was not significantly higher than in the non-hypomagnesemia group (hypomagnesemia group=27.8%, non-hypomagnesemia group=7.1%; p=0.20). This survey sheds light on the incidence rates of cisplatin-induced hypomagnesemia in patients receiving cisplatin alone. We recommend monitoring the serum magnesium levels during cisplatin administration to prevent hypomagnesemia.

Purpose: To investigate the current status of corneal and conjunctival disorders due to antitumor drugs in Japan. Methods: Questionnaires on corneal and conjunctival disorders due to antitumor drugs were sent to members of the Japan Cornea Society, and data on patients' background, clinical findings, treatment and prognosis of cases between January 2009 and December 2011 were collected and analyzed. Results: Out of all 221 cases from 66 facilities, TS-1Ⓡ had been administered in 210 cases (95.0%). Corneal findings were noted in 192 cases (86.9%), including 161cases (72.9%) of superficial punctate keratopathy, 55 cases (24.9%) of epithelial crack line, 38 cases (17.2%) of sheet-like epithelial abnormality, and 15 cases (6.8%) of corneal erosion. Conjunctival and ciliary findings were observed in 49 cases (22.2%). Lacrimal obstruction and constriction were found in 81cases (36.7%). Logistic regression analyses revealed the discontinuation and switching of antitumor drugs as the significant factor of good prognosis of clinical signs and visual acuity in cases with TS-1Ⓡ administration. Conclusions: Although corneal and conjunctival disorders due to antitumor drugs, especially TS-1Ⓡ, are important adverse effects, the only effective treatment at this time is the discontinuation and switching of antitumor drugs. Future prospective studies are needed to elucidate pathogenesis, aiming to the prediction and prevention of the occurrence.

Multi-drug administration is problematic in elderly patients, and the situation is further complicated in those with cancer, owing to a high possibility of side effects and augmentation due to interactions between concomitant or previous drugs the patients are receiving and the anti-cancer drugs administered. Analysis of the factors that influence the likelihood of cancer chemotherapy multi-drug administration in the elderly showed that age alone was a fundamental risk factor for multi-drug administration, comorbidities, and drug interactions. In addition, the risks of drug interaction with chemotherapy were approximately 5.8 fold for drugs administered to treat hypertension, and approximately 10.3 fold for cardiovascular agents. Because of increased cancer morbidity, it is important to reduce the risks associated with the treatment.

Dexrazoxane(DXZ)is a drug used for treating extravasation(EV)of anthracycline antitumor antibiotics based on 2 of its mechanisms of action through Topo II. In Japan, it has been used in approximately 150 patients as of January 2016, but there is no detailed report. Three DXZ treatments were carried out for 2 cases in our facilities. One case involved a patient's right forearm while 2 cases occurred involved the left and right forearms of each of the patients, and both were Grade 2(CTCAE v4.0). The EV healed in all cases, and surgical procedures were not needed. Moreover, chemotherapy was performed without extending the treatment period. One year 8 months after administration there was no recurrence in both cases, and skin disorders did not develop. In our hospital, DXZ is managed based on the regimen as well as the anticancer agents, and administration within 6 hours from extravasation was made possible by the cooperation of pharmaceutical wholesalers. Nurses and pharmacists who engage in chemotherapy are encouraged to participate in the study sessions of the hospital, it has been the effort to learn the day-to-day knowledge and technology. DXZ is effective in treating the EV of anthracycline antitumor antibiotics and may be well tolerated. To properly use DXZ by integrating these cases, it is necessary to verify its effectiveness and safety.

Peritoneal metastasis of gastric cancer remains a refractory disease, and the standard treatment strategy is still unclear. Intraperitoneally administered paclitaxel(PTX)remains in the intraperitoneal(IP)cavity for a long time and directly infiltrates peritoneal metastatic nodules, thereby producing antitumor effects. We designed an IP chemotherapy regimen of S-1 combined with weekly intravenous(IV)and IP PTXadministration. In our phase I study, the recommended dose of IP PTXwas determined to be 20mg/m2. In our phase II study for patients with P1(macroscopic peritoneal metastasis-positive)or CY1 (cytology-positive)gastric cancer, the 1-year overall survival(OS)rate was 78%and the median survival time(MST)was 23.6 months. In another phase II study of patients with P1 gastric cancer, the 1-year OS rate was 77%and the MST was 17.1 months. A phase III PHOENIX-GC trial comparing IP chemotherapy to S-1 plus cisplatin has recently been completed. Phase II studies of the IP administration of docetaxel have also shown favorable results. Recently, the results of several clinical studies investigating the effects of S-1 combined with weekly IV and IP PTXadministration for peritoneal metastasis of pancreatic cancer have been published.

To determine factors affecting physical activity in outpatients with gastrointestinal cancer.

After the year 2000, the treatment of cancer remarkably changed, including the development of outpatient cancer chemotherapy. Meanwhile, we have encountered many clinical problems related to cancer patient pharmacy services. To resolve these problems, I have tried to establish the individualized and optimal cancer pharmacotherapy utilizing the findings of basic research. In this review, three topics of my research will be introduced. 1) In 2005, information regarding the genetic polymorphism of UGT1A1*28 was described in the package insert of the drug irinotecan in the United States. At that time, however, there was little similar information for Japanese patients. Through clinical research, we demonstrated that UGT1A1*6 was a significant factor for neutropenia, as induced by irinotecan. 2) Tyrosine kinase inhibitors are mainly used at a fixed dose, but wide interpatient variability has been observed relative to their pharmacokinetics and/or pharmacodynamics. To overcome these variations, clinical and basic pharmacological research on erlotinib, sorafenib and sunitinib was carried out. Especially, in sunitinib therapy, we demonstrated that the breast cancer resistant protein in the intestine functions as a limiting factor for oral absorption, and that therapeutic drug monitoring could be helpful for avoiding severe toxicities, resulting in prolonged progression-free survival. 3) We quantitatively assessed side effect management by pharmacist intervention for outpatient chemotherapy. We calculated the improvement ratio between before and after pharmacist intervention, and found that 135 suggestions (50.8%) led to significant improvements, indicating that pharmacist intervention could be useful for attenuating the side effects of cancer chemotherapies.

We treated 19 cancer patients with cancer types other than melanoma and lung cancer with immune checkpoint inhibitors, between June 2015 and April 2016. We administered nivolumab at 2-3mg/kg bw every 2-3 weeks. One patient received 14 doses, 5 received 6 doses, 3 received 5 doses, 3 received 4 doses, and 3 received 3 doses. Three remarkably effective responses were seen in cases of pancreatic cancer, esophageal cancer, and brain malignant lymphoma. In every effective case, dendritic cell therapy was administered prior to nivolumab.

A 57-year-old woman had been diagnosed with sigmoid colon cancer at surgery for ovarian cancer, and underwent simultaneous radical resection. Because of the pathological diagnosis of sigmoid cancer with ovarian metastasis, adjuvant chemotherapy was scheduled, with Leucovorin(LV)25 mg. This was immediately followed with 5-fluorouracil(5-FU)500 mg, via a 2-hour systemic intravenous infusion daily for 5 consecutive days, with courses repeated at 5 weeks, followed by maintenance once every 1 or 2 weeks for 2 years. There had been no evidence of recurrence for 10 years after surgery; however, peritoneal recurrence and a thyroid tumor were found using computed tomography(CT)at the 10-yearsur veillance. Chemotherapy with mFOLFOX6+bevacizumab was initiated because the peritoneal recurrence was determined to be unresectable and because of the metastasis to the thyroid. Chemotherapy was maintained, except for oxaliplatin(L-OHP)due to toxicity, with shrinkage of the peritoneal tumor; however, it was difficult to maintain the chemotherapy due to toxicity. Eleven months after initiation of chemotherapy, lung and bone metastases were detected, and she subsequently died.

Treatment for ovarian cancer with bevacizumab(Bmab)has been covered by public medical insurance in Japan since November 2013. It is recommended that the use of Bmab is limited to the first treatment for FIGO stage III or IV ovarian cancer. The OCEAN trial for platinum sensitivity in relapsed patients and the AURELIA trial for platinum-resistance in relapsed patients were performed, and both significantly improved progression-free survival.

The REGARD and RAINBOW trials showed that ramucirumab(RAM)alone and RAM plus paclitaxel(PTX) were effective therapies for advanced gastric cancer patients previously treated with chemotherapy. In this retrospective study, we evaluated the safety and efficacy of RAM alone and PTX plus RAM in such patients.

We present a 36-year-old woman who had been taking oral dasatinib for 3 years for the treatment of chronic myelogenous leukemia (CML). Although adverse events such as thrombocytopenia and pleural effusion developed, she showed a major molecular response (MMR) 22 months after the initiation of oral dasatinib administration, and the therapy was thus continued. Approximately 34 months after oral dasatinib initiation, she developed severe exertional dyspnea and had to be urgently hospitalized. There was no apparent pleural effusion increase, and neither imaging nor blood test results suggested pneumonia or other infections. Pulmonary arterial hypertension (PAH) was suspected on the basis of transthoracic echocardiography. PAH was then confirmed by right heart catheterization. Though dasatinib was discontinued on the day of hospitalization, pulmonary hypertension and heart failure progressed, and she did not respond to catecholamines or PDE5 (phosphodiesterase type 5) inhibitors. On the 4(th) hospital day, she experienced cardiopulmonary arrest and died 1 week later. Cases with PAH due to oral administration of dasatinib have been reported previously. However, cases showing the rapid progression documented in our patient are rare and we advocate that PAH be considered a potential adverse event associated with dasatinib therapy.

Hyponatremia is one of the common electrolyte disorders associated with cisplatin (CDDP) administration. We report here two cases of hyponatremia associated with CDDP. Case 1 : A 75-year-old man with urothelial carcinoma of bladder (cT3N1M0) underwent neoadjuvant chemotherapy with CDDP and gemcitabine. He lost consciousness on the eighth day after the chemotherapy. Blood tests showed severe hyponatremia (Na 113 mEq/l), low plasma osmolality and high level of plasma vasopressin. Urine tests showed low osmolality. These findings were consistent with the syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH). His consciousness level was improved after saline infusion and fluid restriction. Case 2 : A 54-year-old man with penile cancer (cT3N2M0) underwent neoadjuvant chemotherapy with CDDP, paclitaxel and fluorouracil. He lost consciousness on the seventh day after the chemotherapy. Blood tests showed hyponatremia(Na 121 mEq/l) with renal dysfunction. We concluded that the hyponatremia is due to the renal salt wasting syndrome (RSWS) based on renal dysfunction and high urinary sodium excretion. His consciousness level was improved after saline infusion. Although it is difficult to distinguish between SIADH and RSWS, correct evaluation is necessary for appropriate management of hyponatremia after CDDP administration.

There are almost no reports about drug excretion management during colorectal cancer chemotherapy. Anticancer chemotherapeutic drugs excreted in urine and feces may exert toxic effects and promote teratogenesis, mutagenesis, and carcinogenesis. To assess the knowledge of patients about drug excretion, a questionnaire survey was performed among 45 patients receiving chemotherapy for colorectal cancer in our hospital; among them, 36 patients completed the survey. Most of the patients did not know about the excretion and toxic effects of anticancer drugs. The results indicate that patients should be instructed on the management ofexcretion during chemotherapy to minimize toxic exposure. We believe that unnecessary exposure of patients and their families to anticancer drugs should be minimized. This study highlights the importance of issuing guidelines regarding excretion management during cancer chemotherapy.

In Japan, cardiovascular diseases are frequent complications in cancer patients owing to the rapidly aging population and changes in the overall lifestyle. In addition, cancer itself including advanced cancer, and certain therapies used to treat it, often cause further cardiovascular complications. Moreover, although the recently developed molecularly targeted cancer drugs have improved patient prognosis, unexpected cardiovascular side effects, especially cardiotoxicity, have become an important limitation of cancer therapy. Recent molecularly targeted therapies for cancer may result in a variety of cardiovascular side effects, such as cardiac dysfunction, hypertension, and thromboembolism. As such, cardiologists should fully understand these molecularly targeted therapies and the potential pathogenic mechanisms at molecular levels. To protect cancer patients from cardiotoxicity, further basic and clinical research on the pathogenesis and mechanisms of cardiotoxicity of the molecularly targeted cancer drugs is of paramount importance. Furthermore, in-depth research in these areas could potentially result in new insights about onco-cardiology and cardiovascular medicine.