Leptomeningeal metastasis(LM)is a rare complication in patients with breast cancer. We report 3 cases of LMs in patients with breast cancer who were treated with intrathecal methotrexate via an Ommaya reservoir. In 2 patients, a significant neurological improvement was observed, whereas in 1 patient there was no response. The overall survivals for the patients who experienced improvements were 22 and 9 months. Although we have no evidence for the efficacy of intrathecal chemotherapy for LMs in patients with breast cancer, its effects for some patients could be promising, after reservoir management and drug selection establishment.

A 66-year-old man underwent nephrectomy for right renal cell carcinoma (cT3bNOMl (PUL)). Thereafter, he was treated with sunitinib for lung metastasis as the first-line therapy for 5 months and then axitinib as the second-line therapy for 2 months. Because lung metastasis progressed despite molecular targeted therapies, nivolumab was used as the third-line treatment. Three months later, he complained of painful stiffness in hands and wrist joints symmetrically. He was diagnosed as having rheumatoid arthritis. Treatment with nivolumab was discontinued and prednisolone and methotrexate were started. Although the painful stiffness in joints was improved l month later, synovitis remained partially 6 months after starting treatment of disease with anti-rheumatic drugs. Therefore, treatment for rheumatoid arthritis was continued. On the other hand, because the lung lesion had progressed 2 months after discontining nivolumab, everolimus was used as the fourth-line therapy.

A 66-year-old man had undergone multiple treatments for metastatic renal cell carcinoma, including 11 cycles of nivolumab, which was discontinued because of disease progression. About three weeks after discontinuing nivolumab, he reported suffering from worsening of dyspnea. Pulse oximetry showed no desaturation. His cardiovascular and pulmonary functions were normal. His dyspnea slowly worsened with no underlying diagnosis. Two months after symptoms developed, he was diagnosed with isolated adrenocorticotropic hormone deficiency. His dyspnea disappeared soon after receiving hydrocortisone. Nivolumab-induced isolated adrenocorticotropic hormone deficiency may not present with typical symptoms, and can occur even after discontinuing nivolumab. Cortisol levels should be routinely monitored in patients who receive nivolumab.

Resistance to the breakpoint cluster region-abelson (BCR-ABL) tyrosine kinase inhibitor (TKI), imatinib, poses a major problem in the treatment of chronic myeloid leukemia (CML). Imatinib resistance often results from a secondary mutation in BCR-ABL1. However, the basis of this BCR-ABL1-independent resistance in the absence of such mutation remains to be elucidated. The aim of the present study is to identify the mechanism of imatinib resistance in CML. To gain insight into BCR-ABL1-independent imatinib resistance mechanisms, we performed an array-based comparative genomic hybridization. We identified various resistance-related genes, focusing on the receptor tyrosine kinase MET. Treatment with an MET inhibitor resensitized K562/IR cells to BCR-ABL TKIs. A treatment combining imatinib and a MET inhibitor in K562/IR cells inhibited extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) activation, but did not affect AKT activation. Moreover, the combination of MET inhibitor and imatinib suppressed tumor growth in vivo. These results indicate that the activation of MET/ERK and MET/JNK are potential mechanisms of BCR-ABL TKI resistance. Our findings provide new and important information concerning the mechanisms of imatinib resistance in CML, and reveal new proteins potentially involved in BCR-ABL TKI resistance.

Adjuvant aromatase inhibitor therapy for hormone receptor-positive breast cancer in postmenopausal women, and gonadotropin-releasing hormone agonist for prostate cancer in men, are associated with bone loss, leading to the increment of fracture risks. Assessment of bone status, improvement of life style such as diet and exercise, and osteoporosis treatments are essential to keep good bone health in cancer treatment-induced bone loss.

We report the case of a 72-year-old female who underwent laparoscopic total gastrectomy for gastric cancer. The pathological diagnosis was pT3, N1, M0, pStage II B. She received adjuvant chemotherapy with the TS-1®combination OD tablet, beginning 48 days after gastrectomy. The first course was stopped at day 7 because of neutropenia. The dose was decreased, a second course was started, and the patient completed her second course without neutropenia. After completion of the second course, we discovered that she had taken generic drugs(NKS-1®combination OD tablet)during the second course. She was enrolled in a clinical trial in which the administration of generic drugs was not permitted, as per the protocol. Beginning with the third course, we once again treated her with TS-1, and we observed a return of neutropenia in every subsequent course. We decreased the dose of TS-1 and changed the administration schedule each time. She exhibited no neutropenia only when using the generic S-1 formulation. It is possible that the anti-tumor effect of the generic S-1 formulation, and its associated adverse events, are not identical to the innovator formulation.

The patient was a 66-year-old male. Following surgery for pulmonary adenocarcinoma in the upper right lobe and adjuvant chemotherapy, the patient relapsed. We carried out treatment using the immune checkpoint inhibitor pembrolizumab (KEYTRUDA®)for high expression of PD-L1. Following the first administration, severe drug eruption occurred and despite temporary improvement seen by intravenous infusion of steroids in combination with oral administration and external use thereof, it relapsed in the early stages and toxic epidermal necrosis developed. Skin problems were improved by multidisciplinary treatments such as gammaglobulin therapy, systemic steroid administration, and broad-spectrum antibiotics. There were no reports oftoxic epidermal necrosis occurring during pembrolizumab administration for lung cancer. This case went through a unique course in which the disease relapsed into a more severe condition at an early stage following temporary remission.

Hypersensitivity reactions(HSRs)are adverse events that are potentially caused by all anticancer agents. HSRs are unpredictable and can occur at any time, and prompt intervention is needed when symptoms occur. The types of symptoms and their degrees vary with the anticancer agent used and the number of chemotherapy cycles. Here, we evaluated the degree of HSRs and their frequencies in the outpatient chemotherapy center of Gunma University Hospital. Among 55,046 patients, 141 (0.26%)cases of HSRs and 70(0.13%)cases of infusion reactions were identified. Oxaliplatin and docetaxel conferred higher incidences of HRSs, whereas infliximab and rituximab conferred higher incidences of infusion reactions. The most common symptoms were skin reactions. HSRs to oxaliplatin were observed after a median of 7 cycles of chemotherapy, and the number of the patients developing HSRs was the highest during the second cycle of chemotherapy. The incidences of HSRs and the profiles of the anticancer drugs exhibiting higher frequencies of HSRs were similar to those in previous reports. The present study provides valuable information about appropriate management for HSRs depending on the anticancer agents used.

A 51-year-old man with chronic myeloid leukemia undergoing treatment with dasatinib received colonoscopy for a positive fecal occult blood test. Colonoscopy revealed more than 100 erythematous, multilobulated polyps with mucoid discharge. Endoscopic mucosal resection was performed for diagnosis, and the histological analysis of polyps showed hyperplastic glands and proliferative smooth muscle cells. Our findings suggested that the polyposis was caused by inflammation triggered due to the adverse effects associated with dasatinib. The patient discontinued dasatinib;the follow-up colonoscopy performed four months later revealed significantly improved polypoid lesions in the colon. The erythematous heads of the polyps and mucoid discharge disappeared. The cessation of dasatinib seemed to contribute to the improvement of inflammatory reactive polyposis;therefore, we inferred that the polyposis was caused by dasatinib in the present case.

From January 2016 through December 2017, 18 patients received paclitaxel plus ramucirumab combination therapy and 1 patient received ramucirumab monotherapy. Thus, a total of 19 patients were analyzed in terms of both therapeutic effect and adverse events. The response evaluation of the targeted lesion was as follows; CR: 0, PR: 1, SD: 16, PD: 2. The median of overall survival and progression-free survival of the combination therapy was 9.9 months and 4.2 months, respectively. Although more than half of the patients were enforced after tertiary therapy in our department, the therapeutic effect of paclitaxel plus ramucirumab combination therapy was considerably satisfactory. Neutropenia as an adverse event was observed in 13(68.4%)out of 19 patients, and 8 patients(42.1%)had neutropenia greater than Grade 3. Non -hematologic toxicity was observed in 17 cases(89.5%), and anorexia, nausea, diarrhea, dysgeusia, peripheral neuropathy, hair loss, and fatigue were determined to be either Grade 1 or 2. Alternatively, 1 patient developed Grade 3 interstitial pneumonia, and 3 patients(15.8%)had complicated Grade 3 high blood pressure. Only 2 patients who had severe adverse events, one was interstitial pneumonia and the other was high blood pressure, discontinued paclitaxel plus ramucirumab combination therapy.

Skin reactions to nivolumab are typical immune-related adverse events. We investigated the relation between patient background and test values before nivolumab administration and skin reactions. From February 2016 to February 2017, we evaluated the clinical outcomes of 21 patients who were administered nivolumab. Patients were divided into 2 groups: 3 cases of skin reactions to nivolumab(skin reaction group)and 18 cases without skin reactions to nivolumab(non-skin reaction group). In the skin reaction group, the numbers of eosinophils and basophils before nivolumab administration were significantly higher than those in the non-skin reaction group(p=0.0015 and p=0.0075, respectively). It was suggested that the numbers of eosinophils or basophils before nivolumab administration might be associated with the appearance of skin reactions.

Febrile neutropenia is a serious adverse drugreaction to cancer chemotherapy. Prophylactic administration of granulocyte colony-stimulatingfactor (G-CSF)is recommended in patients who require cancer chemotherapy associated with a risk of febrile neutropenia or intense treatment. However, we had patients who developed fever after prophylactic administration of G-CSF. This study investigated the risk factors of fever after prophylactic administration of G-CSF. The subjects were patients who underwent preoperative chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for esophageal cancer and prophylactic administration of G-CSF. Medical charts were retrospectively reviewed for age, sex, date of G-CSF administration, presence or absence of fever after G-CSF administration, Multinational Association for Supportive Care in Cancer(MASCC) risk index score at the time of G-CSF administration, and blood counts at the time of G-CSF administration. The MASCC risk index score(21[17-21]vs 20[19-21])and neutrophil count at the time of G-CSF administration were significantly higher in the non-fever group than in the fever group. Neither factor was an independent risk factor in the multivariate analysis. However, we considered that evaluation at the time of G-CSF administration is useful for early symptomatic treatment of febrile neutropenia.

Cancer chemotherapy has a high frequency of side effects, and patients often experience adverse health effects. This review focuses on risk factors and supportive care for the prevention of chemotherapy side effects. 1) Drug-induced interstitial lung disease (DILD) is one of the serious adverse events associated with chemotherapy, and this retrospective study investigated the risk of DILD in Japanese patients with lung cancer. Among the 459 patients who received lung cancer chemotherapy from April 2007 to March 2013, 33 (7.2%) developed chemotherapy-associated DILD. Preexisting interstitial lung disease was a risk factor for DILD [odds ratio (OR)=5.38; 95% confidence interval (CI)=2.47-11.73]. Early death was observed in 10 of the 33 patients who developed DILD. Epidermal growth factor receptor-tyrosine kinase inhibitor use (OR=9.26; 95%CI=1.05-81.96) and two or more prior chemotherapy regimens (OR=6.95; 95%CI=1.14-42.35) were identified as poor prognostic factors. 2) The incidence of pemetrexed-induced rash is high. The aim of this retrospective study was to evaluate the efficacy of corticosteroids for pemetrexed-induced rash. Rash developed in 26.9% of patients who received pemetrexed between April 2009 and March 2014. Supplementation with dexamethasone (≥1.5 mg) on days 2 and 3 significantly reduced the incidence of rash compared with no supplementary corticosteroids (39.4% vs. 17.8%, p<0.05). Increasing the corticosteroid dose had no additional effect on pemetrexed-induced rash development. These results suggest that supplementary corticosteroids may prevent pemetrexed-induced rash, and low-dose corticosteroids are sufficient for such prevention.

A 59-year-old man who had postoperative recurrence of lung adenosquamous cell carcinoma was administered nivolumab as 3rd-line chemotherapy. Although nivolumab was considered effective, bleeding from a metastatic lesion at the jejunum was recognized by double-balloon enteroscopy, and partial resection was performed. Although the re-administration of nivolumab was planned, the patient died of acute respiratory failure 6 days postoperatively.

A man in his 50s with small cell lung cancer received amrubicin as the fourth-line therapy from August 201X-1. Serum phosphorus levels before treatment were normal at 2.9mg/dL, but grade 2 hypophosphatemia(2.1mg/dL)was observed at the beginning of the 2nd course. He underwent laryngoplasty after the 4th course. Retreatment was initiated in June 201X due to disease progression. After reinitiating treatment, the disease developed to grade 3 hypophosphatemia. As we identi- fied lower levels(1.1mg/dL)at the start of the 10th course, a pharmacist proposed oral phosphate therapy to the attending physician, which we administered. After then, the levels improved to 2.2mg/dL; thus, oral phosphate therapy was interrupted. However, because of a decline in serum phosphorus levels to grade 3, we administered the therapy again, and observed favorable improvement. For hypophosphatemia in this case, general reasons in clinical practice were not applicable; thus, amrubicin is considered to be a most possible cause.

We report a case of nephrotic syndrome induced by ramucirumab for metastatic rectal cancer. A 48-year old woman who had received FOLFIRI plus ramucirumab for rectal cancer with liver, lung, and bone metastases presented to our hospital with edema and increased body weight. Laboratory studies showed hypoalbuminemia and severe proteinuria, and the patient was diagnosed with nephrotic syndrome. After administration of an angiotensin II receptor blocker and thiazide diuretic, her symptoms disappeared and serum albumin level normalized. To the best of our knowledge, this is the first detailed report of nephrotic syndrome related to ramucirumab. This case serves to emphasize that the possibility of nephrotic syndrome should be considered during anti-vascular endothelial growth factor therapy.

When a medical provider(medical personnel)becomes a medical receiver(patient), does the consciousness about chemotherapy change ? If yes, what is the main reason ? In this study, we conducted a questionnaire on the consciousness of doctors and pharmacologists engaged in chemotherapy for gastric and/or colorectal cancer. The number of questionnaires collected was 83 and 92 for gastric and colorectal cancer, respectively. In adjuvant chemotherapy, 5%and 4%do not want to receive any chemotherapy for gastric and colorectal cancer if they are patients. The main reasons are binding hours, side effects, and no wish for life extension. About 11%and 9%change their consciousness regarding chemotherapy according to whether they are care providers or receivers. The main reasons are medical perspective and their sense of duty. In chemotherapy for advanced cancer, 6% and 5% of gastric and colorectal cancer patients, do not want to receive any chemotherapy. The main reasons are low expectations for being cured, binding hours, and no wish for life extension. Further, 21%and 14%wish to have limited chemotherapy. As regards consciousness on chemotherapy, 26% and 18% reported changes according to whether they are providers or receivers. The main reasons are medical perspective and their sense of duty. As for the purpose of chemotherapy for advanced gastric and colorectal cancer, 96% and 43% answered prolonging life and relief, respectively. The proportion of persons who answered complete cure is statistically higher in colorectal(32%)than in gastric cancer(18%). The most common answer for an adverse event they want to avoid if they are patients is peripheral neuropathy. These results clearly demonstrate that a considerable proportion of medical personnel hold a negative attitude against or are reluctant to receiving chemotherapy, especially for advanced gastric and colorectal cancer. It is of great importance to make use of these results in clinical practice.

 Various neuropeptides play an essential role in the nutrient sensing mechanism and related homeostasis. Nesfatin-1 is a newly identified neuropeptide having anorectic activity, and nesfatin-1-containing neurons are widely distributed in the brain, including the hypothalamus and brain stem. Our previous study showed that dehydration-induced anorectic effects are mediated via the central nesfatin-1 pathway in rats. Our recent studies have also shown that peripheral anorectic peptides (cholecystokinin-8, glucagon-like peptide-1, and leptin) and an antineoplastic agent (cisplatin) caused inhibition of feeding via the central nesfatin-1 pathway in rats. Nesfatin-1-containing neurons in the central nervous system, in particular the hypothalamus and the brain stem, may mediate peripheral nutrient signals and regulate feeding behavior.

Upon administration of irinotecan(CPT-11), cholinergic symptoms, such as perspiration and abdominal pain, may develop. These symptoms are reported to increase with higher doses of CPT-11. However, to date, in Japan, factors influencing cholinergic symptoms, such as dosage of CPT-11, regular medications, and laboratory values indicating liver function, have not been studied. Therefore, to assess such factors, we conducted a retrospective investigation. Cholinergic symptoms occurred in 74(40.4%)of 183 patients. Moreover, of these 74 patients, cholinergic symptoms occurred in 45 patients(60.8%)in the first course, and sweating was the most common symptom in these patients. According to binomial logistic regression analysis, the most significant factor affecting cholinergic symptom expression was a single dose(per body surface area)(odds ratio: 1.03, 95% confidence interval: 1.02-1.05, p<0.01), and the cut-off value in the receiver operating characteristic curve was 137mg/m2. By detecting cholinergic symptoms at an early stage after the administration of a single dose of CPT-11, the discontinuation of therapy administration can be avoided, and cholinergic symptoms can be alleviated.