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.

We examined the outcome of treatment with first-line chemotherapy with bevacizumab(Bmab)formetastatic colorectal cancer in our hospital to clarify the outcome for RAS mutant patients.

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.

An ethoxycarbonyl 1-ethyl hemiacetal ester of levofloxacin (LVFX-EHE) avoids insoluble chelate formation with metal-containing drugs in the intestinal tract and is rapidly hydrolyzed to the parent drug. Furthermore, the minimum inhibitory concentration confirms that LVFX-EHE is less likely to cause pseudomembranous colitis because of less susceptibility to normal intestinal bacteria flora. Pemetrexed dimedoxomil, the prodrug of pemetrexed, was synthesized via reaction with medoxomil bromide after modification of L-glutamate with the tert-butyloxycarbonyl protecting group (BOC), followed by hydrolysis of the BOC moiety with trifluoroacetic acid (TFA) in CH2Cl2 at a temperature of 0°C for 2 h. A serum pemetrexed concentration of >2 μg/mL was observed after oral administration of pemetrexed dimedoxomil at a dose of 60 mg/kg to rats.

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.

A 73-year-old woman diagnosed with unresectable pancreatic cancer received weekly gemcitabine(GEM)plus albuminbound paclitaxel(nab-PTX)therapy. Four months after nab-PTX therapy was initiated, she presented with a rapidly decreasing vision in her left eye at an ophthalmology clinic. On admission, her visual acuity was decreased, and optical coherence tomography(OCT)revealed a cystoid macular edema(CME)only in her left eye. She discontinued the nab-PTX therapy immediately. Her visual acuity improved on follow-up 6 months later. The CME finding on OCT was reduced but not completely resolved. CME is a rare adverse event induced by nab-PTX therapy, with only 14 cases reported since 2008. In most of the reported cases, the patients had breast cancer, and this is the first reported case of CME in a patient with pancreatic cancer. The time to CME onset from starting nab-PTX therapy was reported to range from3 to 30months, but the predilection time has not been clarified. Many reports indicated that symptoms improved in a short period after discontinuation of nab-PTX therapy, but effective treatment was not established, except discontinuation of nab-PTX therapy. In daily medical treatment, the incongruity of the ophthalmologic domain should be confirmed for early detection of CME.

A 65-year-old man was diagnosed with leptomeningeal carcinomatosis based on the findings of cerebrospinal fluid cytology and magnetic resonance imaging(MRI).Treatment with erlotinib and bevacizumab was initiated, and partial improvement in consciousness and MRI findings were obtained.However, it was difficult to continue the treatment because of elevation in levels of liver enzymes and melena.We switched the treatment to afatinib monotherapy, and his consciousness improved immediately.Progression -free survival and overall survival from the initiation of the treatment with afatinib were 7 and 9.4 months, respectively. This clinical course suggests activity of afatinib for central nervous system lesions of EGFRmutated lung cancer.

A 74-year-old woman, who developed advanced colon cancer with focal recurrence, received two courses of a low dose of nivolumab. Five days after the second course she noticed bilateral ptosis. Her symptoms rapidly progressed to generalized manifestations including limb and neck weakness, dyspnea, and myalgia within the following two weeks. Neurological and laboratory findings supported the diagnosis of myasthenia gravis and myositis induced by nivolumab. The combination immunotherapy including oral prednisolone, intravenous immunoglobulin and plasma exchange with noninvasive positive-pressure ventilation successfully avoid tracheal intubation. Nivolumab, one of the immune checkpoint inhibitors, is the anti-programmed cell death-1 (PD-1) protein monoclonal antibody, which is effective for various cancers. Since the immune checkpoint inhibitors are going to be used widely, it is important to recognize the specific subtype of myasthenia gravis for neurologists.

A man in his 30s who presented with an enlarged right testicle was diagnosed with a germ cell tumor via orchiectomy. Adjuvant chemotherapy with cisplatin, etoposide and bleomycin(BEP)was initiated. He developed a headache 8 days later, followed by neurological deficits 10 days later. Magnetic resonance imaging(MRI)and magnetic resonance venography(MRV)showed thrombotic occlusion at the superior sagittal sinus. Anticoagulant therapy with heparin was initiated. However, a generalized epileptic seizure occurred 11 days later, and an antiepileptic drug therapy was initiated. The headache and neurological deficits gradually improved, and MRI findings showed that the superior sagittal sinus had re-canalized. The main cause of the sinus thrombosis in this patient was considered dehydration and cisplatin-induced hypercoagulability. Five courses of BEP therapy were carried out with care to avoid dehydration. The patient has remained free of testicular tumor recurrence, metastasis, and cerebral sinus thrombosis for 2 years. Cisplatin-based chemotherapy is an established risk factor for venous thromboembolism(VTE), and cerebral sinus thrombosis is a rare but dangerous complication. Therefore, cerebral sinus thrombosis should be considered when patients with testicular cancer who undergo cisplatin-based chemotherapy start to develop neurological symptoms. Clinicians should be aware of this treatable complication.

In the malignant tumors in women, uterine cervical cancer, endometrial cancer, ovarian cancer, and breast cancer are representative diseases. The cancer treatment is classified roughly into an operation, medical treatment, and radiation therapy and has an extremely big influence on ovarian function. With the improvement in survival of cancer patients, the importance of the health care for the cancer survivors increases. It is necessary to prevent the onset of the osteoporotic fractures to maintain QOL. This paper describes the action that the malignant tumors of the women affect bone metabolism mainly from the viewpoint of ovarian function.

Because generic medicines reduce the financialburden on patients and medicalinsurance providers, they have become increasingly popular. However, there are only a few reports that have analyzed the efficacy and safety of generic medicines, especially in terms of their characteristics and side effects. Gemcitabine is an antineoplastic drug that is frequently used with good results in the treatment of lung cancer, pancreatic cancer, breast cancer, ovarian cancer, and malignant lymphoma. However, its fat solubility is high, and several adverse events, such as myelosuppression, are known to develop during its use. We investigated the efficacy, characteristics, and the incidence of adverse events for the generic versions of gemcitabine. We found differences between the generic versions in terms of the characteristics and preparation time; however, the incidence of adverse events was not significantly different, suggesting that the generic versions could be a reasonable substitute.

Since the rate of elderly patients in cancer death is continuously increasing, elderly pa- tients are not special, but ordinary population in daily clinical settings. Geriatric assessment (GA) is recommended to evaluate elderly patients when they undergo anticancer chemother- apy. Geriatric 8 (G8) is an excellent screening tool to evaluate physical and mental function of elderly patients. By such screening tools, elderly patients are divided into 3 categories; "fit": standard regimen for non-elderly patients are applicable, "vulnerable": some modified regi- men should be needed since moderate dysfunction due to aging is recognized, "frail": best supportive care rather than standard therapy should be considered. Thus, individualization of anticancer therapy seems to be most important point for elderly patients.

Immunosuppressive therapy after solid organ transplantation is known to be a risk factor for the development of myelodysplastic syndromes (MDS). Herein, we report 2 patients, both of whom developed low-risk MDS after solid organ transplantation and were successfully treated with azacitidine (AZA). The 1st case was a 74-year-old man who had received liver transplantation. The initial immunosuppressive therapy consisted of cyclosporine and prednisolone. Nine years after transplantation, he was diagnosed as having MDS (RCMD). The 2nd case was a 47-year-old woman who had received cadaveric renal transplantation. The initial immunosuppressive therapy was comprised of cyclosporine, azathioprine, and prednisolone. Twenty-seven years after transplantation, she developed MDS (RA). Both patients received 75 mg/m2 AZA once daily for five consecutive days on a 28-day cycle. After 2 courses of therapy, both patients achieved hematological improvement (IWG 2006 criteria) without severe (grade 3/4) non-hematological adverse events. Moreover, AZA did not affect the status of organ transplantation in terms of engraftment and function of the graft. In conclusion, AZA would be a safe and effective agent for patients with MDS after solid organ transplantation. However, long-term follow-up is needed to confirm the safety and efficacy of AZA for patients undergoing solid organ transplantations.

"Japanese clinical practice guidelines for the management of kidney disease in cancer survivors"have been published. This guideline recommended several managements for nephrotoxicity of other agents than platinum such as the urinary alkylation during methotrexate administration, suspending of anti-angiogenetic agent for the grade 2 or more proteinuria, dose modification of bisphosphonate based on the renal function. Understanding the background of these recommendations will contribute for safe cancer chemotherapy.