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.

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.

 Two types of cell death, necrosis and apoptosis, are defined in terms of cell death morphological features. We have been studying the mechanisms by which cell death processes are switched during the treatment of mouse tumor FM3A with anticancer, 5-fluoro-2'-deoxyuridine (FUdR): it induces original clone F28-7 to necrosis, but its sub-clone F28-7-A to apoptosis. We identified several such switch regulators of cell death: heat shock protein 90 (HSP90), lamin-B1, cytokeratin-19, and activating transcription factor 3 (ATF3), by using transcriptomic, proteomic analyses and siRNA screening. For example, the inhibition of HSP90 by its inhibitor geldanamycin in F28-7 caused a shift from necrosis to apoptosis. We also observed that the knockdown of lamin-B1, cytokeratin-19, or ATF3 expression in F28-7 resulted in a shift from necrosis to apoptosis. Recently, we used microRNA (miRNA, miR) microarray analyses to investigate the miRNA expression profiles in these sister cells. The miR-351 and miR-743a were expressed at higher levels in F28-7-A than in F28-7. Higher expression of miR-351 or miR-743a in F28-7, induced by transfecting the miR mimics, resulted in a switch of cell death mode: necrosis to apoptosis. Furthermore, transfection of an miR-351 inhibitor into F28-7-A resulted in morphological changes, and mode of cell death from apoptosis to necrosis. These findings suggest that the identified cell death regulators may have key roles in switching cell death mode. Possible mechanisms involving cell death regulators in the switch of necrosis or apoptosis are discussed. We propose a novel anticancer strategy targeting the switch regulators of necrosis or apoptosis.

Chemotherapy-related adverse events can deteriorate the quality of life, as well as chemotherapy tolerance, for patients with gastric cancer. Nutritional support may prevent chemotherapy-related adverse events.

Interstitial lung disease (ILD) is a common side effect of the mechanistic target of rapamycin inhibitor everolimus. Most cases of everolimus-induced ILD are mild and reversible. As per guidelines, even if Common Terminology Criteria for Adverse Events grade 1 or 2 everolimus-induced ILD occurs, either continuation of everolimus without dose reduction or readministration at a low dose is possible. However, the pathophysiology of everolimus-induced ILD is unknown. We present a case of everolimus-induced ILD with spontaneous remission during treatment in a patient with metastatic renal cell carcinoma. At autopsy, there was no evidence of remodeling or chronic inflammation in the lungs. Cryptogenic interstitual pneumonia and broncholitis obliterans with organizing pneumonia can be suspected as a pattern of mild everolimus-induced ILD. This case report provides evidence that everolimus-induced ILD is reversible fromthe pathological perspective.

Immune checkpoint-blocking antibodies may induce specific side effects known as immune-relatedad verse events.

With the aim of evaluating the safety and efficacy of filgrastim biosimilar 1(Filgrastim BS syringe for Inj. "MOCHIDA"and "F"), we conducted a drug use results survey of this product for its indications, including mobilization of hematopoietic stem cells into peripheral blood and chemotherapy-induced neutropenia. Of the 518 cases enrolled between August 2013 and July 2015, 495 were selected to be subjects of our safety and efficacy evaluations. 37 cases (7.47%)experienced side effects, which were mainly lower back pain(19, 3.84%), fever(8, 1.62%)and bone pain(3, 0.61%). As for serious side effects, interstitial pneumonia was reported in 2 cases, but this disorder has already been ecognized as being associated with the use of filgrastim originator, and there were no reports of unknown side effects calling for immediate attention. In addition, we investigated hypersensitivity reactions(such as nettle rash and anaphylactic shock)and diminished drug effects, both of which are considered to be attributable to immunogenicity, and found that non-serious nettle rash was reported in 2 cases. However, there have been no reports of anaphylactic shock or diminished drug effects. The efficacy rate based on physicians' clinical observations was 97.98%. This study confirmed that there are no problems with the clinical use of filgrastim biosimilar 1.

6-Mercaptopurine (6-MP) is one of the main components for the treatment of childhood acute lymphoblastic leukemia (ALL). However, many patients require a dose reduction of 6-MP due to its severe toxicities. NUDT15 variants are one of the factors that cause 6-MP intolerability in Asians. In each patient with heterozygous variants of NUDT15, 6-MP intolerability differs. Therefore, we hypothesized that the combination of NUDT15 genotype with ABCC4 genotype, which is associated with 6-MP efflux, might enable to accurately predict 6-MP intolerability. We analyzed the association between 6-MP-related events and the genotypes of NUDT15 and ABCC4. All patients with both NUDT15 rs116855232 heterozygous variants and ABCC4 rs3765534 variants suffered from severe leukopenia and required 6-MP dose reduction to less than 35 mg/m2/day. In conclusion, genotyping NUDT15 and ABCC4 facilitates the prediction of 6-MP intolerability. The results of this study will improve personalized medicines in Japanese patients with childhood ALL.

The 208 trial showed that lenvatinib has a significant antitumor effect on unresectable anaplastic thyroid cancer(ATC). Herein, we present a retrospective review of data from 7 patients with unresectable ATC who received lenvatinib in our hospital between May 2015 and October 2016. Two patients were men and 5 were women. The median age was 78(range, 72-85)years, and 1 patient had Stage IV A disease, 1 had Stage IV B, and 5 had Stage IV C at diagnosis, respectively. Three patients experienced a partial response and 1 patient experienced stable disease. The response rate was 43%, and the disease control rate was 57%. The median progression-free survival(PFS)was 4.1(range, 1.1-12.2)months. Grade 3 and Grade 4 gastrointestinal hemorrhage were observed in 2patients and Grade 3 anorexia was observed in 1 patient. Further clinical research seems to be needed to establish a treatment strategy involving lenvatinib for ATC.

In addition to chemotherapy for advanced renal cell carcinoma(RCC), molecular targeted drugs such as tyrosine kinase inhibitors(TKI)and mTOR inhibitors have been clinically introduced, and they have contributed to improved progression free survival(PFS)and overall survival(OS). However, complete response over a long period are rarely obtained with these drugs, and there are many cases of recurrence and progression. The anti-PD-1 antibody nivolumab, an immune checkpoint inhibitor, has approved for the indication of "Unresectable or metastatic RCC" in Japan, based on the phase III study results for advanced RCC with previous TKI treatment. The nivolumab response indicates the possibility of a sustained treatment effect for a long period of time, but also suggests the tendency to take time to develop the effect. Regarding safety, immune-related adverse events(irAEs)with a profile that may be different from those of conventional drugs, and in addition to fully understanding these features, we need to be familiar with how to manage irAEs.