Safety measures against occupational exposure to anticancer drugs are practiced in line with guidelines; however, countermeasures against exposure for families in pediatric areas have not yet been considered. We investigated the recognition and practice of anticancer drug exposure measures for children and families by nurses working in pediatric cancer hospitals(15 facilities in total). The results suggest that the current situation of anticancer drug exposure measures, including family guidance, are not practiced adequately.

Oral molecular-targeted agents are used clinically for the treatment of various types of cancer. However, even when treatment is started at the dosage indicated in the medical package insert, we have experienced many cases in which treatment had to be stopped early owing to the occurrence of serious side effects or an insufficient therapeutic effect. In recent years, a wide range of studies has been conducted on the therapeutic drug monitoring (TDM) of oral molecular-targeted therapeutic agents to prevent serious side effects and maximize the therapeutic effect. In Japan, the TDM of imatinib has been covered by insurance since 2012, and the TDM of sunitinib has been covered since 2018. In contrast, tyrosine kinase inhibitors may have severe side effects, but their TDM is not covered by medical insurance. We aimed to identify a safe, highly effective chemotherapy regimen based on scientific evidence gathered from Japanese patients. We examined the relationship between the plasma concentration of drugs and clinical findings, such as side effects and treatment effects, at our hospital. In this symposium review, we introduce our results based on the treatment of patients with renal cell carcinoma.

Cancer chemotherapy has progressed remarkably with conventional and molecular-targeted anticancer drugs as well as immune checkpoint inhibitors. However, adverse drug reaction (ADR) management remains a challenge in cancer chemotherapy. Therefore, improving the quality of medical care through clinical pharmacology research is warranted. Intravenous injection of bendamustine in patients with follicular or mantle cell lymphoma frequently causes venous irritation. Because the underlying mechanisms are not clear, we investigated the factors responsible for bendamustine-induced venous irritation. Based on the results of our analysis, we altered the administration regimen and observed that the incidence of venous irritation, which manifested in a concentration-dependent manner following conventional approaches, significantly decreased when following the modified regimen. Guidelines on the management of chemotherapy-induced nausea and vomiting recommend aprepitant, a selective neurokinin-1 (NK-1) receptor antagonist, 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, and dexamethasone as prophylactic antiemetics. Pretreatment with high-dose chemotherapy before hematopoietic stem cell transplantation has extremely high emetogenic potential. This can be countered by using aprepitant in combination with conventional antiemetics. However, the safety and efficacy of such combinations are unexplored. Upon evaluation, we observed improved antiemetic effects without an increase in ADRs. At this symposium, I highlight the significance of clinical pharmacology research for promoting individualized cancer chemotherapy.

An 84-year-old woman developed blepharoptosis, diplopia, weakness of extremities, and dysphagia with elevation of serum CK levels after treatment with nivolumab against renal cell carcinoma. 3 Hz repetitive stimulation showed waning in the trapezius muscle, leading to the diagnosis of myasthenia gravis. Laboratory examination showed that anti-acetylcholine receptor antibody was negative. We performed IVIg and steroid therapy. However, her symptoms did not improve, and she died of respiratory failure, although serum CK levels ameliorated to the normal range. The results of autopsy showed atrophy of muscle fibers and massive infiltration of inflammatory cells in the endomysium of the iliopsoas muscle and diaphragm, indicating occurrence of myositis. Immunohistochemical analysis showed that CD8-positive T cells mainly infiltrates in the endomysium with a small number of CD4-potive T cells. Here, we report an autopsy case of nivolumab-induced myasthenia gravis and myositis.

Lenvatinib is an oral multikinase inhibitor that targets VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT. The preclinical studies of lenvatinib for hepatocellular carcinoma (HCC) suggest that lenvatinib exerts the potent antitumor effect on the basis of the inhibitory actions on VEGF and FGF-induced tumor angiogenesis and on FGF-induced tumor cell growth. Phase I and II trials were conducted in Japan and Korea evaluating the maximal tolerated dose, efficacy, and safety of lenvatinib for HCC patients and have produced promising results. Considering the relationship between body weight, AUC and dose in HCC patients, the recommended starting dose was determined to be 8 mg/day for patients weighing lower than 60 kg and 12 mg/day for patients of 60 kg and higher. A phase III REFLECT study have demonstrated that the non-inferiority of lenvatinib to sorafenib in overall survival was confirmed and that lenvatinib was significantly superior to sorafenib in the analysis of progression-free survival and response rate. Based on these results, lenvatinib has been approved for the treatment of patients with unresectable HCC in Japan, US, EU and others this year. Clinical studies of lenvatinib combination therapy with transarterial chemoembolization (TACE) and with immune checkpoint inhibitors are currently on-going. Because of the potent antitumor effect, lenvatinib may change treatment strategy for HCC patients in the future.

Lymphomatosis cerebri (LC) is a variant of primary central nervous system lymphoma, which demonstrates diffuse white matter infiltrates without showing definite enhanced mass lesions on MR scans. We present a case of seventy-one year-old immunocompetent male who manifested with progressive truncal ataxia and drowsiness. The MRI exhibited diffuse white matter lesions from brainstem to cerebral hemispheres with minimum enhanced lesions at the first presentation. Because the diagnosis of LC was suspected, we performed a brain biopsy from the enhanced lesion near the right thalamus, which revealed diffuse large B cell lymphoma. After he underwent methylprednisolone pulse therapy and methotrexate chemotherapy, he obtained remission. Making a diagnosis of LC is often difficult because image findings resemble those of inflammatory or autoimmune diseases. LC is an important differential diagnosis to be considered in patients presenting with diffuse white matter disease. Performing a brain biopsy at the early phase is essential for the correct diagnosis and the favorable prognosis.

Compared to other types of breast cancers, triple-negative breast cancer(TNBC)has poor prognosis. However, much work has been done towards establishing an effective therapeutic strategy. Vinorelbine(VNB)is an effective therapeutic agent for TNBC, however, the mechanism for its efficacy remains to be elucidated. We found that MX-1, a TNBC cell line, exhibits apoptosis and polyploidy upon VNB treatment. Neither apoptosis nor polyploidy were observed in other types of breast cancer cells upon VNB treatment. Furthermore, inhibitors of respiration, protein synthesis, and DNA synthesis suppressed apoptosis and polyploidy induced by VNB in MX-1 cells. Among microtubule toxins, clinically effective paclitaxel(PTX)and VNB had a greater effect than colchicine and nocodazole on polyploidy induction in MX-1 cells. These results suggest that VNB induces apoptosis in some types of TNBCs through the induction of polyploidy, which is, at least in part, the likely mechanism of its clinical efficacy.

This case involved a 28-year-old female with rectal cancer in the inner pelvis. Two courses of SOX plus Cmab therapy, and 4 courses of FOLFOX-Cmab therapy were administered as preoperative chemotherapies, which resulted in a reduction in the major lesion. Subsequently, laparoscopic low anterior resection and dissection of the bilateral lymph nodes were performed. After the surgery, adjuvant chemotherapy with FOLFOX was administered. Afterwards, the patient developed severe anal pain and visited us for treatment. The severe anal pain continued even after FOLFOX treatment and increased with defecation. A side effect of oxaliplatin was suspected, and sLV5FU chemotherapy was administered. As a result, the anal pain disappeared. Thus, the pain was considered to be induced by oxaliplatin. While peripheral neuropathy is a widely known side effect of oxaliplatin, this case was considered to be unique because anal pain occurs very rarely with oxaliplatin treatment.

Prophylaxis using pegfilgrastim is recommended to prevent cabazitaxel-induced neutropenia. We observed GradeB3 neutropenia in a patient after administration of cabazitaxel, despite prophylaxis using pegfilgrastim. To identify the risk factors associated with GradeB3 neutropenia, we retrospectively investigated the records of 10 patients who received prophylaxis with pegfilgrastim after administration of cabazitaxel. They were divided into GradeB3 neutropenia and non-GradeB3 neutropenia groups, and we compared the background data and laboratory values between the 2 groups. A univariate analysis revealed that hypoalbuminemia was significantly observed in patients with cabazitaxel-induced GradeB3 neutropenia. The incidence of GradeB3 neutropenia was significantly high in patients with serum albumin levels<3.6 g/dL. Cabazitaxel has a high rate of protein binding; moreover, serum albumin levels<3.6 g/dL might be associated with high concentrations of unbound cabazitaxel, and thus an increase in the incidence of GradeB3 neutropenia. Therefore, hypoalbuminemia at the time of administration of cabazitaxel may be a risk factor related to the development of GradeB3 neutropenia.

Ramucirumab, an antiangiogenic agent, often causes proteinuria as a characteristic adverse effect. We retro- spectively evaluated proteinuria and clarified the significance of the protein/creatinine ratio by using single urine samples from patients with advanced gastric cancer who were treated with ramucirumab.

Nivolumab, an anti-programmed cell death 1 antibody, has been approved for the treatment of unresectable advanced non-small-cell lung cancer (NSCLC). Although immune-related adverse events (irAEs) such as dermatologic, digestive, endocrine, hepatic, and pulmonary toxicities are known to occur upon administration of immune checkpoint inhibitors, case reports of polymyalgia rheumatica (PMR) associated with nivolumab use are rare. We report a case of an NSCLC patient who developed PMR during treatment with nivolumab and received corticosteroids. A 74-year-old man without a history of autoimmune diseases received nivolumab at a dosage of 3 mg/kg once every 2 weeks for the treatment of stage IIIB squamous cell carcinoma. After 12 cycles of nivolumab treatment, he developed grade 3 muscle pain and arthralgia, requiring hospitalization and discontinuation of nivolumab. A bone scintigraphy revealed no bone metastasis. Serological tests showed that although creatine phosphokinase did not increase, C-reactive protein and the erythrocyte sedimentation rate were both high. Tests for the rheumatoid factor, anti-cyclic citrullinated peptide antibody, and anti-nuclear antibody were negative. In addition to the serological findings, joint ultrasonography data and clinical symptoms were evaluated, leading to the diagnosis of PMR. Oral prednisolone 20 mg/d was started to treat the PMR without giant-cell arteritis. The patient's symptoms improved within 5 d of the initiation of treatment. Prednisolone was tapered to 5 mg/d without recurrence of PMR. Although grade 3 or 4 irAEs (except in type 1 diabetes) are generally treated with high-dose corticosteroids, grade 3 PMR associated with nivolumab use may be treatable with low-dose corticosteroids.

A 54-year-old woman with unresectable multiple liver-limited metastases of rectal cancer was treated with cisplatin-based transcatheter arterial chemoembolization(TACE). Before initiating TACE, we performed abdominoperineal resection for advanced rectal cancer, resection of the bilateral ovaries for metastasis, liver resection for metastasis, and oxaliplatin/irinote- can/anti-EGFR chemotherapy for the unresectable liver metastases. For the liver-limited metastases that did not respond to systemic chemotherapy, we successfully controlled the disease in 26 months with TACE every 4 or 5months. A combination of 50mg cisplatin and 4 mL lipiodol was injected into the liver through the left or middle hepatic artery with a microcatheter via the femoral artery. The hepatic arteries were mildly embolized with Embosphere. Immediately after TACE, non-contrastenhanced CT was performed to confirm the distribution of the cisplatin powder and embolization. Tumor response was assessed by enhanced CT 3 months after the treatment. We report a case of liver metastasis of colorectal cancer successfully controlled with cisplatin-based TACE over 2 years.

Although nivolumab was previously reported to cause immune-related interstitial lung diseases (ILD), the detailed characteristics of ILD in gastric cancer are not fully understood. We herein present a rare case of a 66-year-old male with advanced gastric cancer who experienced acute-onset high-grade fever and dyspnea and diagnosed with early-onset ILD during the first cycle of nivolumab. Computed tomography revealed patchy infiltrative shadows and ground-glass opacities. No pathological bacteria were detected in the sputum or the bronchoalveolar lavage, and serous antigens for virus and beta-D-glucan were below the detection limit. These findings were consistent with nivolumab-induced organizing pneumonia. The steroid pulse therapy was effective for ILD, and the patient had complete radiological response, although he relapsed twice during the steroid tapering period.

A 61-year-old man with squamous cell lung cancer was admitted to our hospital because of consciousness disturbance after treated with pembrolizumab. Cerebrospinal fluid examination revealed increased protein level (209.2 mg/dl) and lymphocytic pleocytosis(79/μl). He was diagnosed as a meningoencephalitis probably caused by an immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs), and was successfully treated with 1,000 mg methylprednisolone intravenously for 3 days twice and the consequent oral 1 mg/kg prednisolone. As ICIs, which activate the immune systems, are becoming important choices of the treatments against malignancies, we should keep the possibility of irAE in mind and, when needed, start the treatment as soon as possible.

We report a case of successful control of advanced duodenal cancer with paclitaxel chemotherapy. A woman in her 70s with epigastralgia was diagnosed with hemorrhagic duodenal ulcer upon upper gastrointestinal endoscopy. A type 3 tumor was found in the duodenal bulb upon upper gastrointestinal endoscopy and biopsy at our hospital. By contrast CT, we found wall hypertrophy of the duodenal bulb, lymph node metastasis, and liver metastasis and started chemotherapy. Four courses of SOX therapy were first administered. The wall hypertrophy of the duodenal bulb worsened, and new lesions appeared in the liver, so we diagnosed progressive disease. Next, 4 courses of wPTX therapy were administered. The wall hypertrophy of the duodenal bulb improved, and all liver metastatic lesions shrunk and became obscure. The reduction rate was 75%, so we diagnosed partial response. Accumulation in the primary tumor was observed on PET-CT, and the lymph node and liver metastases disappeared, so we considered radical curative resection. The patient underwent subtotal stomach preserving pancreatoduodenectomy, D2 lymph node dissection, reconstruction of the digestive tract by the modified CHILD method, partial hepatectomy, and Brawn's anastomosis. No cancer cells were found in the hepatectomized area. Paclitaxel chemotherapy may be useful for advanced duodenal cancer.

A 60-year-old woman was admitted for abdominal distention, abdominal pain, and anorexia. Abdominal CT showed a 30×20 cm mass with contrast effect. gastrointestinal stromal tumor(GIST) of the omentum or the mesenterium was suspected. Peritoneal nodules were also recognized. We performed palliative surgery. The tumor was considered to have originatedfrom the greater omentum andinvolvedthe marginal artery of the transverse colon. We performedpartial excision of the transverse colon andresection of the tumor. Immunohistochemically, the tumor cells were c-kit(+), CD34(+), S100(-), andDOG1(-), with 1 fission image for 50 fields of view with high magnification. The patient was diagnosed with high-risk GIST originating from the greater omentum. The patient was started on imatinib administration on the 37th day but died on the 109th day.

S-1 plus cisplatin(CDDP)has been a key regimen for advanced gastric cancer treatment. However, CDDP confers dose-limiting nephrotoxicity, requires a hospital stay for conventional massive hydration, and reduces patients' quality of life. We evaluated the nephrotoxicity of CDDP combination chemotherapy in an outpatient setting with short hydration for gastric cancer and investigated the feasibility of the short hydration method.

A 24-year-old male patient with T-cell acute lymphoblastic leukemia was diagnosed with severe hypertriglyceridemia after the sixth administration of L-asparaginase during remission-induction therapy of the Japan Adult Leukemia Study Group (JALSG) -ALL 202-U protocol. Lipoprotein analysis revealed type IV hyperlipidemia, which is associated with a relatively low risk for pancreatitis. Hypertriglyceridemia immediately resolved after discontinuing L-asparaginase and beginning a lipid-restricted diet. The patient did not develop any severe complications of hypertriglyceridemia (e.g., pancreatitis and thrombosis) ; therefore, L-asparaginase could be readministered according to the treatment protocol. Four adult patients with L-asparaginase-induced severe hypertriglyceridemia have been reported to date; however, none of the reports indicated that L-asparaginase had been readministered. Thus, this is the first report of a patient receiving such readministeration. In order to evaluate the safety of continuing L-asparaginase, it is considered necessary to accumulate similar readministration cases.