Cytotoxic T-lymphocyte associated antigen 4(CTLA-4), programmed death 1(PD-1), and programmed death-ligand 1 (PD-L1)are referred to as immune-checkpoints. CTLA-4 is located on the surface of activated T-cells, therefore inhibiting binding of CD28 to B7 molecule on antigen presenting cells. The CTLA-4 pathway predominantly acts in lymph nodes. PD-1 is majorly expressed on T-cells. The PD-1 pathway is involved with tumor microenvironment. Immune-checkpoint inhibitors (ICIs)are monoclonal antibodies to these molecules and are promising novel agents for malignant tumor treatment. ICIs promote T-cell-mediated cytotoxicity directed at cancer cell antigens. Approximately 20-30% of patients with advanced cancer were found to be responders of ICIs. However, various adverse events have been reported as immune-related adverse events(irAEs). IrAEs include dermatological, gastrointestinal, hepatic, neurological, and endocrine disorders. In the endocrine system, irAEs in the pituitary glands, thyroid glands, pancreas, and adrenal glands have been reported. Since rapidly progressive fatal endocrine systems failure may provoke during ICI therapy, precise diagnosis and prompt treatment as well as close follow-up is critical. We propose routine monitoring of endocrine functions and related symptoms(ie. worsened fatigue, hyperglycemia, hypoglycemia, hypotension, and hyponatremia), as well as other laboratory tests during ICI therapy. We herein discuss possible mechanisms of endocrine irAEs with ICIs, and highlight diagnostic approaches, treatments, and future prospects of endocrine irAEs during ICI therapy.

Immune checkpoint inhibitors(ICIs)have shown efficacy in many clinical trials and have an important role in the treatment for advanced cancers.Many physicians recently have chances to use ICIs across tumor types.ICIs are associated with a unique set of toxic effects, which are defined as immune-related adverse events(irAEs).Drug -induced pneumonitis is considered to be one of important irAEs.Pneumonitis as irAE has been not so frequently observed, and all Grade in 0~10%and Grade 3 or 4 in 0~3% of patients receiving ICIs.However severe or life-threatening pneumonitis was observed in some cases, so that pneumonitis caused by ICIs has been clinically important.The incidence of pneumonitis caused by ICIs for Japanese patients is similar to previous reports.Symptoms of pneumonitis by ICIs are considered to be dyspnea and cough.Some patients are diagnosed as asymptomatic pneumonitis with abnormal radiographic findings.Cryptogenic organizing pneumonia(COP) pattern has been reported to be most frequently observed in radiographic patterns of pneumonitis caused by ICIs(43~65%). Since some cases shows pneumonitis with different radiographic pattern from other drug-induced pneumonitis, blood test and bronchoscopy may be useful for diagnosis.It has been recommended to treat patients with ICIs-related pneumonitis according to severity of pneumonitis.In most patients, pneumonitis is improved with corticosteroids and withdrawal of ICIs, though a few patients with severe pneumonitis may need immunosuppressants.It has been recommended for medical oncologists to consult and cooperate with pulmonologists for diagnosis and treatment of ICIs-related interstitial lung disease(ILD). The mechanism of pneumonitis induced by ICIs may differ from those of other drug-induced pneumonitis.Therefore, medical oncologists should be careful for ICIs-related pneumonitis as a new disease category in the treatment of ICIs.

A 52-year-old man with chronic myelogenous leukemia (CML) received dasatinib after the failure of imatinib and nilotinib therapy. Two years after the initiation of dasatinib, he developed shortness of breath that gradually worsened. Chest X-ray and computed tomography scan showed pulmonary infiltrative shadows and bilateral pleural effusion. We performed a transbronchial lung biopsy and diagnosed organizing pneumonia caused by dasatinib treatment. Corticosteroid therapy was initiated after the discontinuation of dasatinib and all his symptoms were significantly improved. Because of the exacerbation of CML, the patient was treated with imatinib and then nilotinib; however, these drugs failed to decrease the leukemic cells. Re - administration of dasatinib in combination with corticosteroid therapy successfully controlled CML without recurrence of organizing pneumonia.

There are many reports that describe the effectiveness of aromatase inhibitors as endocrine therapy after breast cancer surgery. However, there are few detailed evaluations of patient adherence to anastrozole(ANA)therapy. Here, we evaluated the adherence to ANA therapy in postoperative patients with primary breast cancer.

A safety evaluation of chemotherapy is performed by CTCAE. It is the evaluation by health care workers, and distress evaluation by patient himself is not included in it. Therefore, a health care worker underestimates patients' distress. This study was carried out to identify the patients' characteristics underlying differences between safety evaluation and distress evaluation. The patients who met the criteria were 72 in number. They were divided into 2 groups. Group A(17 patients)included patients who demonstrated difference between safety evaluation and distress evaluation. Group B(55 patients)included patient who did not show difference between safety evaluation and distress evaluation. The patients who visited a hospital were evaluated for QOL, depression screening, CTCAE(safety evaluation), and PRO-CTCAE(distress evaluation). A meaningful difference was observed between depression screening, QOL-ACD(physical status, psychological status, face scale, and total), and the number of items of side effect by PRO-CTCAE through a univariate analysis. A meaningful difference was observed for QOL-ACD(physical)in logistic regression analysis(odds ratio=1.47, p=0.013). It is suggested that having physical distress reflected by the QOL evaluation before chemotherapy results in the difference between safety evaluation and distress evaluation.

Several cases of hormone receptor-positive HER2-negative advanced and recurrent breast cancer treated with fulvestrant (FUL)were retrospectively investigated to assess the efficacy and safety of the treatment. FUL was administered to a total of 41 patients-33 with recurrent and 8 with Stage IV cancer-from January 2012 to September 2016. The median number of lines that used FUL was 3, the median time to treatment failure(TTF)was 7 months, the overall response rate(RR)was 19.5%, and the clinical benefit rate(CBR)was 53.6%. Our result was similar to those of the FIRST and the FALCON studies, which showed a decrease in RR after the fourth-line. With regard to RR, FUL seemed to provide better results at Cthird-lines of treatment. While a shorter TTF was seen in the cases with liver metastases, a longer TTF was seen in the cases with soft tissue metastases. Therefore, it may be helpful to consider the site of metastasis when predicting the effects of FUL.

　Intravenously administered obligate anaerobic bacteria, such as bifidobacteria, grow specifically in tumor tissues. This specificity is attributed to the following: (1) Vascular walls in tumor tissues have nanometer- to micrometer-wide cracks, which allow the bacteria to pass through; (2) the intratumoral environment is hypoxic, due to poor vascularization, and therefore bifidobacteria can survive and proliferate in this anaerobic environment; (3) bifidobacteria cannot survive in well-oxygenated normal tissues. Moreover, unlike gram-negative bacteria, the gram-positive bifidobacteria do not produce endotoxins; therefore, there is no risk of endotoxin shock associated with their intravenous administration. Recently, the utility of bifidobacteria for specific drug delivery to tumor tissues has been highlighted. We have established a novel anti-cancer drug-delivery system using Bifidobacterium longum for the specific release of anti-tumor antibodies (e.g., antibody-drug complexes or single-chain antibodies) to targeted tumor tissues. Here, we introduce the results of our investigation.

　Use of the microelectrode array (MEA) system to record spontaneous neuron activity from networks of cultured neurons has potential as a good risk evaluation method for drug-induced seizure events. Spontaneous electrical activity in neural networks consists of action potential spikes and organized patterns of action potential bursts. In both potentiated rodent primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons, an epileptogenic response pattern manifests as a synchronized burst from spatially separated neurons. Here, we delineate how to perform MEA experiments using cultured neurons, and how to analyze the MEA data to detect drug-induced seizurogenic abnormalities. Usually, a drug's effects, as shown by MEA data, include changes in spike frequency, inter-spike intervals (ISI), burst frequency, burst duration, spikes in a burst, etc. Subsequently, seizurogenic events are evidenced by changes in synchronized burst phenotypes from spatially separated multiple channels in an MEA probe, such as a change in the cross correlation of the spike events from all channels in an MEA probe, or a change in histogram from the sum of ISI for all channels in a probe, etc. We attempted to depict an epileptogenic marker using a histogram of the sum of spikes for all channels in an MEA probe. Verification of these metrics for drug induced abnormalities is ongoing in various collaboration organizations, including the Consortium for Safety Assessment using Human iPS Cells (CSAHi), iPS Non-clinical Experiments for the Nervous System (iNCENS). Collaboration networks for the utilization of iPSC-derived cells during drug development are also summarized here.

　Cancer chemotherapy-induced stomatitis may spread throughout a patient's entire oral cavity and decrease the patient's QOL. The therapy for stomatitis at Iwate Medical University Hospital (IMUH) includes dental treatment before chemotherapy, in addition to oral rinses or cryotherapy as a preventative measure. However, in our survey of doctors and nurses, the responses of patients "satisfied" with the present approach for stomatitis treatment reached only 5.1%. Therefore, we attempted treatment using an indomethacin spray, prepared as a hospital preparation, with pre-approval of the ethics committee and based on a previous report of its positive effect on patients at another hospital. We observed that the indomethacin spray succeeded in decreasing chemotherapy-induced oral pain, and its effect was maintained for 2 h in patients at IMUH. The ratio of female patients who rated indomethacin spray as good was higher than that of males. Comments from some patients included a complaint that the nozzle of the injection tip was too short; thus we increased the length of the nozzle from 2 to 7 cm. At present, indomethacin spray is being used to treat stomatitis patients at IMUH. Indeed, the indomethacin spray has been used since October 2011. It was used on 34 patients in 2016. In this review, we describe the collaboration between IMUH and the basic application of studies in our university laboratory.

Clinical N2-stageⅢA non-small cell lung cancer(NSCLC) is known to be quite heterogeneous. Many clinical trials proved the effect of postoperative adjuvant chemotherapy for locally advanced NSCLC, which is recommended as grade C1 by Clinical Guideline for Lung Cancer, however, induction treatment for clinical N2-stageⅢA remains still controversial. We showed retrospective data of concurrent chemoradiotherapy using S-1 and cisplatin followed by surgery, which may provide a better prognosis for locally advanced NSCLC patients. In addition, we summarized the findings of prospective clinical trials for treatment of clinical N2-stageⅢA NSCLC patients.

　Nucleic acid therapy is expected to be a next generation medicine. We recently developed a multifunctional envelope-type nano device (MEND) for use as a novel delivery system. The modification of polyethylene glycol (PEG), i.e., PEGylation, is useful for achieving the delivery of MENDs to tumors via an enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits the cellular uptake and endosomal escape of MEND, which results in significant loss of action, and therefore lost effectiveness, of the cargo therapeutic. For successful nucleic acid delivery in cancer treatment, the crucial problem associated with the use of PEG, known as the "PEG dilemma", must be solved. In this review, we describe the development and application of MEND in overcoming the PEG dilemma based on manipulating both the pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release using a cleavable PEG lipid, a pH-sensitive fusogenic peptide, and a pH-sensitive cationic lipid. We also developed dual-ligand liposomes with a controlled diameter of around 300 nm, then modified these with a specific ligand and a cell penetrating peptide designed to target the neovasculature of tumors. Dual-ligand liposomes could induce an anti-tumor effect in drug resistant tumors by delivering drugs to tumor blood vessels, rather than to the cancer cells themselves. Here, we review our recent efforts to develop a novel liposomal drug delivery system (DDS) by manipulating pharmacokinetics and intracellular trafficking for drug therapy and nucleic acid medicine.

It was reported that focusing on palliative care for patients with cancer improved their anxiety and depression and prolonged their survival. Similarly, the pharmacist intervention for cancer patients suggested the improvement in anxiety and depression; but, such improvement has not yet been demonstrated by focusing on pharmacist attitudes and behaviors of which the patients were the primary beneficiaries. Therefore, we evaluated the significance of pharmacist intervention focusing on improvement of adverse events and cancer pain. We randomized patients to pharmacist intervention group or no intervention group and evaluated whether the pharmacist intervention improved patients' anxiety and depression. Patients receiving new chemotherapy in the outpatient chemotherapy room were invited to enroll in this study between July 2015 and February 2017. The patients were assessed for their quality of life using the Structured Clinical Interview for ACD and for anxiety and depression using the Structured Clinical Interview for HAD at baseline and again at the 4th chemotherapy. The difference between the baseline and 4th chemotherapy scores was calculated and compared between the pharmacist intervention and no intervention groups. HAD depression subscale and HAD scale scores decreased in the pharmacist intervention group compared to the no intervention group,(-1 versus 0.5, p=0.024)and(-3 versus 0.5, p=0.011)respectively. We demonstrated that the pharmacist intervention focused on improvement of adverse event and cancer pain decreased cancer patients' anxiety and depression.

Chemotherapeutic agents(cytotoxic anticancer drugs)have played a central role as cancer drug therapy for a long time. Since the 2000s, molecular targeted drugs have been developed as therapeutic methods that match the standards specifically for cancer cells, and in solid cancers epidermal growth factor receptor(EGFR)and vascular endothelial growth factor(VEGF) have been approved mainly for drugs targeted. The combination therapy of molecular targeted drugs and radiotherapy has been developed to solve the problem of many adverse events of chemo-radiotherapy. However, cetuximab-combined radiotherapy, which is a typical combination therapy, is not a treatment with few adverse events, centered on acute dermatitis and mucositis, it is important to properly select cases. Similarly, it is necessary to pay attention to specific gastrointestinal obstruction in combination treatment of angiogenesis inhibitor and radiotherapy. In recent years, immune checkpoint inhibitors also have been focused on many cancers and attract attention. To achieve further efficacy, combination therapy with radiotherapy are testing.

Concurrent cisplatin based chemoradiotherapy(CRT)is the standard of care for patients with locoregionally advanced squamous cell carcinoma of the head and neck(LA-SCCHN). Based on the Bonner trial showing the superiority of cetuximab plus radiotherapy to radiotherapy alone, cetuximab based bioradiotherapy(BRT)is considered as an alternative for patients with LA-SCCHN. However, the non-inferiority of BRT compared to CRT has not yet been demonstrated. Furthermore, severe mucositis and dermatitis induced by BRT cannot be neglected. Therefore, the patient's general status and comorbidity should be considered before BRT. Supportive care and patient education are also necessary to safely complete the treatment. Several phase III trials are ongoing to evaluate BRT and CRT for human papillomavirus(HPV)positive oropharyngeal carcinoma. Novel biomarkers are needed for identifying patients most likely to benefit from BRT.

Systemic chemotherapy based on 5-fluorouracil(5-FU)is a standard treatment for unresectable or recurrent colon cancers. Here, we report a case of hyperammonemia induced by chemotherapy using 5-FU for metastatic colon cancer. An 84-yearold male patient with past histories of liver cirrhosis related to hepatitis C virus and renal dysfunction underwent an operation for the rectosigmoid colon cancer 8 years ago. Three years after that operation, a local recurrence of the colon cancer was diagnosed, and chemotherapy using sLV5FU2 was initiated. The recurrence lesion reduced markedly by this chemotherapy, which was ceased 2 years ago. Two years after the cessation the recurrent tumor had been enlarged, and the chemotherapy using the same drugs at the same dose was performed. On the treatment day 3, he was emergently transported to our hospital due to the disturbance of consciousness. Since laboratory tests showed the high concentration of plasma ammonia and the progressed renal dysfunction with no other definite cause of obnubilation, he was diagnosed as the hyperammonemia induced by 5-FU. He was treated by administrating the branched-chain amino acids solutions combined with fluid therapy, which quickly recovered him from the encephalopathy. He is followed up without any chemotherapy because of his high age. When a patient treated with the chemotherapy using 5-FU is sent with the disturbance of consciousness, we should take hyperammonemia into consideration, especially when he or she has the hepatic or renal dysfunction.

We report the case of a 61-year-old man who experienced severe adverse effects of capecitabine because of dihydropyrimidine dehydrogenase (DPD) deficiency. In 2016, he visited our hospital for adenocarcinoma of the gastroesophageal junction and was prescribed neoadjuvant chemotherapy with capecitabine, cisplatin, and trastuzumab. On day 14 of chemotherapy, he developed severe diarrhea, canker sores, enterocolitis, febrile neutropenia, and thrombocytopenia. He was then urgently hospitalized, and anticancer treatment was stopped. We administered antibiotics and G-CSF, and he gradually recovered. However, he complained of severe bloody stools due to hemorrhagic enteritis;hence, we performed a bowel resection. The level of DPD protein, which metabolizes 5-fluorouracil (FU), was very low (2.83U/mg). Therefore, he was diagnosed with DPD deficiency, based on DPD protein or urinary pyrimidine levels, which caused serious adverse effects of capecitabine. It is a rare condition, and 5-FU administration should be avoided in DPD deficiency cases.

Lacrimation is among the typical adverse drug reactions associated with S-1 treatment. However, lacrimation frequencies differ between reports, and a clear consensus regarding reaction times, risk factors, and symptomatic treatment for lacrimation is lacking. We retrospectively investigated the reaction times, risk factors, and outcomes of symptomatic treatment for lacrimation in 202 patients treated with S-1. The median estimated creatinine clearance noted upon initiation of cancer treatment was 75.8mL/min. The median of the relative treatment intensity was 87.1%, while the incidence of lacrimation was 26.7%. The median cumulative dose of S-1 before the onset of lacrimation was 23,520 mg in all patients, and 5,050 mg in those who developed lacrimation. Of the patients who developed lacrimation, 40.7% developed this symptom within 2 months after starting S-1 treatment. There were no apparent risk factors. The most frequently employed symptomatic treatment was a physiological saline ophthalmic solution provided as a hospital preparation. After treatment with this ophthalmic solution, 29.4% of the affected patients showed improvement and 70.6% showed no change; none however, experienced worsening of symptoms. These results suggest that clinicians should assess the presence of lacrimation after starting treatment with S-1. Symptomatic treatment with an ophthalmic solution that does not have a tear retention capacity may be useful in patients who have developed lacrimation.