The advent of anaplastic lymphoma kinase(ALK)inhibitors has revolutionized treatment of ALK fusion gene-positive nonsmall cell lung cancer(NSCLC). Nevertheless, it has become clear that cases refractory and resistant to ALK inhibitors occur at a certain incidence, and how to treat such cases is a current issue. Following crizotinib and alectinib, ceritinib(Zykadia® capsules)is the third ALK inhibitor approved in Japan, and it is expected to be useful for patients who have developed crizotinib resistance. However, ceritinib has been pointed out to have a high incidence of gastrointestinal adverse events that impact patients' quality of life. Accordingly, in this paper, we report the clinical results and incidence of gastrointestinal adverse reactions with ceritinib in treatment of ALK-positive NSCLC patients. We also present management methods of the adverse events.

We report a case of a rupture of the common carotid artery caused by the medication of lenvatinib. The patient, 70-yearold female, was referred to our hospital by unresectable papillary thyroid cancer infiltrated the left common carotid artery. Externalbeam radiotherapy and radioiodine therapy were undergone after totalthyroidectomy. After 1 year 7 months from operation, she admitted our hospital due to left shoulder pain and dysphagia caused by the growing left cervical tumor. The medication of lenvatinib was decided after the careful informed consent. Computed tomography on the eighth day of lenvatinib medication showed the existence of air infiltration into the tumor surrounded left common carotid artery. So, a discontinuance of lenvatinib medication was decided immediately. But, on the ninth day, a rupture of the left common carotid artery occurred and on the tenth day, she died. Lenvatinib medication for the patient with the tumor surrounded artery should be decided carefully.

Non-occlusive mesenteric ischemia(NOMI)causes intestinal necrosis due to irreversible ischemia of the intestinal tract despite the absence of organic obstruction in the mesenteric blood vessels. The disease has extremely poor prognosis. We encountered 2 cases of NOMI hypothesized to have developed after chemotherapy; thus, we report these cases considering the available literature. Case 1: A7 9-year-old man. The patient complained of abdominal pain during the first week after introducing docetaxel for local recurrence of prostate cancer. Abdominal computed tomography(CT)revealed mesenteric ischemia and intestinal emphysema. The patient was diagnosed with NOMI, and an emergency operation was performed. Upon laparotomy, the small intestine; ascending, transverse, and descending colon; recto sigmoid; and gall bladder appeared mottled necrotic. As such, all these were excised. He was admitted back to the hospital 3 weeks after surgery due to pneumonia. Case 2: A7 4-year-old man. Combination chemotherapy of docetaxel, cisplatin, and 5-FU was given for oropharyngeal cancer. After 1 week, fever and abdominal pain were noted. Abdominal contrast CT examination was performed, and mesenteric ischemia was confirmed as NOMI. Emergency surgery was performed on the same day. The entire ileum was discolored with mottling, and it was determined to be necrotic. Thus, it was excised. Postoperative course is good, and the patient was followed up after discharge from the hospital. Before NOMI onset in both cases, docetaxel was used to treat myelosuppression. Considering the patient conditions, the association between NOMI onset and docetaxel was suspected. In general, mesenteric ischemia after administration of anticancer drugs is rare, and only a few cases have been reported.

　Anticancer drug-induced stomatitis develops in 30% to 40% of cancer patients undergoing chemotherapy. However, medications for this condition are not commercially available in Japan. The "hospital formulation" is a customized medicine which hospital pharmacists prepare when doctors cannot carry out the medical therapy most suitable for a patient using commercial medicines. However, as the duties of pharmacists increase, use of the "hospital fomulation" decreases. Therefore, development of "hospital fomulations" based on individual evidence has a limit. Irsogladine maleate (IM) is a drug with gastric mucosal protective properties. IM increases intracellular cAMP levels in the gastric mucosa and activates communication between cells. It has been reported that the oral administration of IM reduces the incidence of 5-FU-based chemotherapy-induced stomatitis. However, there have been no reports on the effect of the direct use of IM in treating stomatitis. Therefore, we studied the development of an IM oral spray for stomatitis treatment, and obtained evidence of a direct effect in an animal experiment using a stomatitis model. Next, rebamipide mouthwash was administered to patients who had stomatitis caused by cancer chemotherapy. The total scores were classified into Grades 0 to 4 and evaluated as a stomatitis evaluation score (SES). When comparing SES and changes in the stomatitis area in patients, gradual reductions in the extent of stomatitis were observed, even during the period when SES did not change. Having patients fill in an observation chart was effective for grasping changes in symptoms in outpatients.

To investigate the safety and efficacy of cisplatin(CDDP)treatment after carboplatin(CBDCA)hypersensitivity reactions (CHSR)in gynecologic malignancies, we retrospectively reviewed the clinical records of 544 patients who underwent paclitaxel and CBDCA therapy(TC therapy). CHSR was observed in 18 patients. Eight patients were administered weekly paclitaxel and CDDP therapy(wTP therapy)continuously, to confirm that there was no CDDP hypersensitivity followingintravenous administration of 10 mgCDDP. At the onset of CHSR, the patients had received a median of 9 TC therapy cycles, and the median number of CBDCA administrations was 14. The frequency of CHSR was significantly higher in patients who received 7 cycles or more of TC therapy and CBDCA administration(p<0.0001). The median number of wTP therapy administrations was 8. Although CDDP hypersensitivity reactions were observed in 2 patients, their symptoms were mild(Grade 2, CTCAE v4.0). Of the 6 patients who received wTP therapy and had evaluable disease sites, 1, 2, 2 and 1 patients showed CR, PR, SD, and PD, respectively. The median progression-free survival in these 6 patients was 9.5 months. For patients with the platinum- sensitive disease who have CHSR, CDDP could improve their prognosis.

Recent progress in cancer chemotherapy has improved the long-term outcome for cancer patients. Under such circumstances, it is increasingly of clinical importance to manage the cardiovascular complications, which are related to both cancer itself and adverse effects of cancer therapies. Among the most concerning as cardiovascular complications of cancer therapies is chemotherapy-induced cardiotoxicity or chemotherapy-related cardiac dysfunction(CTRCD). CTRCD has been intuitively classified according to the extent of structural abnormalities and degree of reversibility; type 1 is irreversible and dose-dependent with structural abnormalities, and type 2 is reversible after cessation of treatment and dose-independent without structural abnormalities. An example of drugs causing type 1 and 2 CTRCD is anthracyclines and trastuzumab, respectively, although both drugs are likely to induce cardiotoxicity through a combined action. In addition, there is growing awareness that CTRCD is also caused by anti-VEGF inhibitors and tyrosine kinase inhibitors(TKIs), particularly in patients with cardiovascular comorbidities and risk factors. Interdisciplinary collaboration between oncology and cardiology specialists will contribute to the solution of unmet needs to elucidate epidemiologic and pathophysiologic aspects of CTRCD and to establish diagnostic strategies with risk prediction and evidence-based therapeutic strategies against CTRCD in cancer patients and cancer survivors.

In Japan, cardiovascular diseases are frequent complications in cancer patients owing to the rapidly aging population and changes in the overall lifestyle. In addition, new anticancer therapies have substantially improved the prognosis of cancer patients. Cardiotoxicity, also referred to as cancer treatment-related cardiac dysfunction, has become an important cause of morbidity and mortality in cancer patients. Cardiotoxicity may consist of hypertension, arrhythmia, thromboembolism, coronary artery disease, valvular disease, and left ventricular dysfunction which may progress to heart failure. Close interactions between cardiologists and oncologists are required for the optimal care of many cancer patients. Although cardiologists are expected to assist and advise the oncologist by providing diagnostic and prognostic information regarding developing cardiotoxicity, little is known about the cardiovascular pathogenic mechanisms associated with cancer treatment. Onco-cardiology is a medical subspecialty that focuses on the diagnosis and treatment of cardiotoxicity in cancer patients. This review describes the concept of onco-cardiology, and focuses on the management of cardiotoxicity that may arise during or after cancer therapy from the standpoint of cardiology. We also discuss noninvasive diagnostic options to identify and characterize cardiotoxicity.

Cancer and cardiovascular disease are 2 major disease of the Japanese cause of death. Both patients with cancer complicated with cardiovascular disease and patients with cancer developing cardiovascular disorder during cancer therapyare increasing recently. Because aging is the onset risk factor, as for these, it is predicted that the patients with both cancer and cardiovascular disease increase more and more by the arrival of the aging society. Recently, the new research field called cardiooncology( or onco-cardiology)has been established, and the cooperation of medical oncologist and cardiologist becomes indispensable.

 In general, the intraventricular administration of cytotoxic antitumor drugs provides a high drug concentration in the cerebrospinal fluid with a reduced risk of systemic adverse reactions. Methotrexate (MTX) high-dose therapy requires close monitoring when performed in combination with trimethoprim-sulfamethoxazole (ST) therapy and proton pump inhibitor (PPI) and nonsteroidal anti-inflammatory drug administration for excretion delay and toxicity enhancement. While the frequency of systemic side effects is thought to be low with intrathecal administration, such effects do rarely but occasionally occur. We must consider drug interactions with combination therapy as a potential factor inducing such effects. We examined the patients who received MTX intrathecal administration at Fukuoka University Hospital from January 2013 to December 2014 with respect to the onset of side effects and combination therapy. MTX intrathecal administration was performed a total of 79 times in 27 patients. In five of these 27 patients, MTX intrathecal administration was performed twice a week, and hematotoxicity and non-hematotoxicity developed in two patients in whom ST was also administered. On the other hand, even if ST and/or PPI was administered, no side effects were observed in the patients administered levofolinate.

(Purpose) We investigated the outcome of selective organ preservation in invasive bladder cancer using chemoradiation therapy. (Patients and method) We examined locally invasive bladder cancer in 60 patients (51 men, 9 women; mean age at treatment 66.1 years) who underwent chemoradiation therapy for bladder preservation in the Department of Urology at Sumitomo Hospital between 2000 and 2015. The clinical stage was T1, T2, T3 and T4 in 4, 24, 17, 4 patients. Our protocol includes transurethral resection of the bladder tumor (TURBT) and 46 Gy radiation (2 Gy/fraction) to the bladder with concurrent cisplatin chemotherapy (20 mg/body/day, 10 days, intravenously). The initial evaluation included urine cytology and transurethral bladder biopsy. If patients developed superficial residual or recurrent cancer, they were treated with TURBT and/or intravesical Bacillus Calmette-Guerin (BCG), while patients with invasive residual or recurrent cancer were advised to undergo a salvage cystectomy. The mean follow-up was 55 months. (Results) The first assessment after the chemoradiation therapy showed that the complete remission rate for evaluable cases was 72% (38/53) and bladder preservation was achieved in 56 patients (93%). The 1-, 3-, and 5-year overall survival rate was 95, 86, and 78%, respectively. The 1-, 3-, and 5-year cancer-specific survival rate was 97, 90, and 85%, respectively. The 5-year patient survival rate with an intact bladder was 68%. Hydronephrosis and cisplatin dose (<200 mg) were independent adverse factors of overall survival in a Cox model (HR 4.5 and 4.1, respectively). (Conclusions) Chemoradiation therapy for invasive bladder cancer can achieve similar survival rate to those in patients treated with radical cystectomy, and enable the majority of patients to preserve the bladder.

A 70-year-old man presented with right renal cell carcinoma with inferior vena caval tumor thrombus into the right atrium. CT Scan presented local invasion and lymph node metastasis. We estimated inoperative case, so he was started sunitinib. After 5 month he had general fatigue and admitted to our hospital. He diagnosed serious adverse events of fulminant hepatitis and left ventricular systolic dysfunction and discontinued sunitnib. After drug discontinuance reduction of tumor and tumor thrombus were detected. 7-months later, we showed the increase of tumor and the improvement of the left ventricular systolic dysfunction. We performed right renal nephrectomy and it passes now in 14 months after surgery, but doses not show a recurrence, metastasis.

Recent developments in cancer immunotherapy are remarkable. Many reports have described the clinical effects of immune checkpoint inhibitors (ICIs), supporting their utility as a promising therapy that will achieve prominent effects even in patients resistant to cytotoxic anticancer drugs or gene-targeting therapy. ICIs may also prolong overall survival. We analyzed 10 cases of advanced lung cancer targeted with nivolumab, which is one of ICIs in our hospital and reviewed the literature regarding ICIs. We retrospectively analyzed 10 cases that consisted of 6 males and 4 females, which comprised 7 adenocarcinomas, 2 squamous cell carcinomas and one pleomorphic carcinoma. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase mutations were negative in all the adenocarcinoma cases. The 10 analyzed cases included 9 inoperable cases and 1 postoperative recurrent case, 8 second-line cases, a third-line case, and a fourth-line case. The average frequency of administrations of nivolumab was 7.4 times. The survival rate was calculated by using the Kaplan-Meier method. The clinical responses to nivolumab were partial response in 2 cases, stable disease in 4 cases, and progressive disease in 4 cases. In the 10 cases, the response rate and disease control rate were 20% and 60%, respectively. The median progression-free survival time and median survival time were 115 days and 126 days, respectively. We observed 2 cases of dermatitis and one each of pyrexia, general fatigue and drug-induced pneumonia as adverse events (AEs). One of these AEs was severe (Stevens-Johnson syndrome grade 4) but could be treated by steroid pulse therapy, steroid ointment and instillation. Among the 10 examined cases of advanced lung cancer treated with ICIs at our hospital, ICIs proved effective in 2 cases. However, we also experienced a case with Stevens-Johnson syndrome grade 4 as a severe AE. These findings suggest that while ICIs may be effective in treating patients, candidates for ICIs must be carefully selected and cautiously observed.

A 77-year-old man with castration-resistant prostate cancer (CRPC) received abiraterone acetate in October 2014. He visited our outpatient clinic because of general malaise and anorexia 27 days after starting abiraterone acetate. The lab test showed hepatic dysfunction (aspartate transaminase, AST 440 U/l, alanine transaminase, ALT 420 U/l) and the elevation of liver enzymes continued on the next day even after stopping abiraterone acetate. Three days later, he was hospitalized due to severe elevation of liver enzymes (AST 1,171 U/l, ALT 1,487 U/l) , and the decreased prothrombin activity (60.5%). The result of the lab test were negative for viral and autoimmune hepatitis. Three days after admission, he entered hepatic coma (grade III) and prothrombin activity decreased (23.2%) , compatible with fulminant hepatitis. Plasma exchange and steroid pulse therapy were started the next day, but he died 39 days after starting abiraterone acetate. In addition, the result of drug-induced lymphocyte stimulation test performed 3 days before his death was possibly positive.

Pulmonary artery hypertension (PAH) has been reported to be a severe adverse event associated with dasatinib therapy. Among the 76 chronic myeloid patients who were treated with dasatinib at our hospital, six patients showed high estimated pulmonary arterial systolic pressure, as observed by echocardiography. PAH was confirmed using right heart catheterization in three (3.9%) patients with increased mean pulmonary artery pressure (mPAP). In one patient, although mPAP was higher than the normal range, it did not fulfill the criteria of pulmonary hypertension. After the discontinuation of dasatinib, BNP and dyspnea were improved in five patients. Therefore, it should be noted that dasatinib can cause PAH at higher rates than those reported previously, and if PAH is confirmed or suspected during dasatinib therapy, then dasatinib should be immediately discontinued.

A Stage IV lung adenocarcinoma was diagnosed in the left upper lobe of an 81-year-old man 2.5 years ago. Following another form of chemotherapy, he then received docetaxel as fourth-line therapy. After 21 days of therapy, although his white blood cell count recovered, his platelet count decreased to 20,000/mL and continued to decrease. Subsequently, he was closely monitored without therapy, and eventually, his platelet count returned within the normal range after 112 days. Blood biochemistry and bone marrow paracentesis findings suggested the presence of paraneoplastic syndrome, idiopathic thrombocytopenic purpura, and drug-induced immune thrombocytopenia. It was difficult to distinguish between the presence of myelosuppression, carcinoma with bone marrow invasion, and paraneoplastic syndrome. This is believed to have resulted from a docetaxel-induced immune thrombocytopenia because, although the platelet count decreased after docetaxel chemotherapy, it eventually returned to normal levels without therapy.

Body surface area(BSA)is a parameter frequently used to calculate the chemotherapy dosage. Several different equations for predicting BSA have been developed. We examined the formula suggested for BSA calculation for 62 chemotherapy drugs where the recommended dosage was based on patient BSA. We found that the description of the formula to be used for BSA calculation was not provided in the package inserts or in the drug interview forms in the majority of cases; the BSA formula was mentioned in the guide for appropriate use of medication in only 8 of 62 chemotherapy drugs. Furthermore, we observed that the choice of formula used to calculate patient BSA caused differences in the dosage of drugs administered to patients undergoing certain oral anti-cancer drug therapies. The results ofour study indicate that clinical oncologists should pay careful attention to the formula used to calculate BSA.