Sorafenib is a tyrosine kinase inhibitor (TKI) of the vascular endothelial growth factor receptor (VEGFR) used for advanced renal cell carcinoma. Treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal cell carcinoma. However, in spite of its therapeutic efficacy, sorafenib causes a wide range of adverse events. Cardiovascular adverse events have been observed when sorafenib was used with targeted agents. Although these adverse events like hypertension, reduced left ventricular ejection fraction, cardiac ischemia or infarction were manageable with standard medical therapies in most cases, some had a poor clinical outcome. We report three cases of acute myocardial infarction associated with sorafenib in patients with metastatic renal cell carcinoma.

Advances in molecular and cellular biochemistry, such as the development of targeted cancer therapy, have dramatically improved the prognosis of cancer patients. Emerging data have suggested that bevacizumab treatment may act by controlling the cancer microenvironment. Many reports have examined the interaction of cancer cells with the tumor microenvironment, and cancer-associated fibroblasts (CAFs) are thought to play a central role in this process. We speculated that the cancer microenvironment and in particular, CAFs, strongly influence the development of esophageal cancer. We have analyzed the signaling pathways of molecular targets. However, inhibition of a single signaling pathway is insufficient to treat cancer effectively. Photoimmunotherapy is a molecular-targeted specific cancer therapy using near-infrared radiation, which was introduced by Mitsunaga et al. in 2011. We are using its specific method of killing cells to target CAFs. We will report the results of its effect on cancer cells in the future.

In this study, we report the rare case of an elderly woman who developed thrombophlebitis after being treated with tamoxifen for breast cancer. She visited our department with a lump in her left breast. She underwent core needle biopsy, and she was diagnosed with breast cancer (invasive ductal carcinoma, ER- and PgR-positive, HER2-negative). We chose hormonal therapy because surgical treatment was deemed too invasive considering her general status. She was administered tamoxifen (20 mg/day) instead of an aromatase inhibitor in consideration of her osteoporosis. Six months after initiating tamoxifen therapy, she exhibited swelling in her left leg. Computed tomography and ultrasound revealed thrombophlebitis in her left femoral vein. She stopped taking tamoxifen and started warfarin potassium as thrombolytic therapy, after which thrombophlebitis was relieved. Advanced age may be a risk factor for thrombophlebitis associated with tamoxifen treatment; therefore, precautions should be taken accordingly.

Case 1: An 86-year-old man was diagnosed with large cell or squamous cell lung cancer of clinical Stage II A.He was administered nanoparticle albumin-bound paclitaxel(nab-PTX)as fourth-line chemotherapy after monochemotherapy with docetaxel, vinorelbine, and S-1.The patient continues to show complete remission at the 15 courses of nab-PTX.Case 2: A 79-year-old man underwent partial resection of the right lower lung, and the pathological diagnosis was large cell lung cancer of pStage I A.However, recurrence in the right lung and multiple lymph node metastases were identified 3 years after the surgery.He was administered nab-PTX as second-line chemotherapy after vinorelbine monotherapy, and he has shown complete remission for a year.Weekly intravenous nab-PTX may be useful in elderly patients with non-small-cell lung cancer.

Studies of neurological dysfunction have revealed the neuroprotective effect of several cationic drugs, suggesting their usefulness in the treatment of neurological diseases. In the brain and retina, blood-tissue barriers such as blood-brain barrier (BBB) and blood-retinal barrier (BRB) are formed to restrict nonspecific solute transport between the circulating blood and neural tissues. Therefore study of cationic drug transport at these barriers is essential to achieve systemic delivery of neuroprotective agents into the neural tissues. In the retina, severe diseases such as diabetic retinopathy and macular degeneration can cause neurological dysfunction that dramatically affects patients' QOL. The BRB is formed by retinal capillary endothelial cells (inner BRB) and retinal pigment epithelial cells (outer BRB). Blood-to-retina transport of cationic drugs was investigated at the inner BRB, which is known to nourish two thirds of the retina. Blood-to-retinal transport of verapamil suggested that the barrier function of the BRB differs from that of the BBB. Moreover, carrier-mediated transport of verapamil and pyrilamine revealed the involvement of novel organic cation transporters at the inner BRB. The identified transport systems for cationic drugs are sensitive to several cationic neuroprotective and anti-angiogenic agents such as clonidine and propranolol, and the involvement of novel transporters was also suggested in their blood-to-retina transport across the inner BRB.

With improvement of survival owing to the recent implementation of new anti-myeloma (MM) agents, bone management will become more important for maintaining the quality of life (QoL) of patients. Bisphosphonates are currently the standard of care for MM-related bone disease. Zoledronic acid is recommended for newly diagnosed MM patients receiving front-line anti-MM treatment regardless of existing detectable bone lesions. Intriguingly, an overall survival benefit has been observed with zoledronic acid in patients on anti-MM treatment with documented bone disease at baseline. Denosumab, a human monoclonal antibody against RANKL, has been demonstrated to reduce bone-related events in patients with MM as effectively as zoledronic acid. Hypocalcemia is generally accepted as occurring more frequently and more severely with denosumab than with zoledronic acid, especially in patients with renal insufficiency. Bisphosphonates but not denosumab deposit in bone with a long half-life, which may make a difference in long-term efficacy as well as adverse effects. Clinical benefits of long-term anti-resorptive therapies after achieving a good response should be clarified, in order to avoid the emergence of severe complications. Impacts of new agents in combination with these anti-resorptive agents on bone metabolism have yet to be studied.

We report a suspected photosensitive reaction induced by weekly paclitaxel (PTX) in a patient with breast cancer. The patient was a 72-year-old woman with right breast cancer (T2N1M0, Stage II B). She received 80 mg/m² PTX weekly as neoadjuvant chemotherapy. After the 5 courses of weekly PTX, she began to develop skin lesions with itchy sensations on the areas of her body that had been exposed to sunlight. The symptoms persisted after the 6 courses of weekly PTX, and topical steroid and antihistamine treatments were initiated. The skin lesions resolved once the patient avoided sunlight and used sunscreen. Ultimately, she received 12 courses of PTX. We need to recognize the appearance of a photosensitive reaction following weekly PTX for breast cancer.

Weight loss during chemotherapy is a result of malnutrition and metabolism abnormality. A few reports have focused on the treatment and prevention of weight and appetite loss in patients with advanced cancer. We evaluated the relationship between weight and appetite loss during chemotherapy by studying the meal intake of patients. In addition, we also investigated whether anorexia is associated with the level of 8-hydroxy-2' -deoxyguanosine (8-OHdG), an oxidation stress marker. The weight loss rate in patients who lack energy intake was significantly higher than that in patients with adequate energy intake. Moreover, the pre-chemotherapy total energy intake, measured according to the hospital meal consumption of patients, was lower among those with than among those without anorexia. The 8-OHdG levels in the patients with anorexia were significantly higher. In conclusion, nutritional management is important for patients even before chemotherapy is started. The 8-OHdG level can be used as an index to evaluate appetite.

To examine the effect of S-1 adjuvant chemotherapy on muscle volume after curative gastrectomy in gastric cancer patients.

Efficacy of cancer pharmacotherapy depends upon drug exposure to the body and responsiveness of the tumor to the drug treatment. Drug exposure is determined by pharmacokinetics and dose, whereas responsiveness is intrinsically variable by tumor heterogeneity. Molecular targeting drugs are used as promising therapy for cancers, and most of them are coupled with particular diagnostics which can predict responders and non-responders before treatment. On the other hand, lower drug exposure to the body can lead to insufficient efficacy. A number of important evidences have been published recently on exposure-response relationships for molecular targeting drugs including monoclonal antibodies and small molecules. In this chapter, two examples are presented; anti-HER2 antibody and tyrosine kinase inhibitor. Patients with the lowest trough concentrations of trastuzumab in cycle 1 showed shorter overall survival in metastatic gastric cancer study. Efficacy of imatinib in chronic myelogenous leukemia depended on plasma concentration of imatinib, and therapeutic drug monitoring (TDM) of imatinib is expected to improve the therapeutic outcome in CML.

Tumor angiogenesis contributes to the development of tumor progression. Several vascular endothelial growth factor(VEGF)-targeted agents, administered either as single agents or in combination with chemotherapy, have been shown to benefit patients with advanced-stage malignancies. In particular, bevacizumab is a humanized monoclonal antibody that specifically targets VEGF, inhibiting angiogenesis, thereby impeding tumor growth and survival. It is also possible that combined VEGF and the epidermal growth factor (EGFR) pathway blockade could further enhance antitumor efficacy and help prevent resistance to therapy. Preclinical and clinical studies have shown new various molecular targets and the functional characteristics of tumor angiogenesis, which may provide strategies for improving the therapeutic benefit.

Poly(ADP-ribose) polymerases(PARP) synthesize the ADP-ribose polymers onto proteins and play a role in DNA repair. PARP inhibitors block the repair of single-strand breaks, which in turn gives rise to double-strand breaks during DNA replication. Thus, PARP inhibitors elicit synthetic lethality in cancer with BRCA1/2 loss-of-function mutations that hamper homologous recombination repair of double-strand breaks. Olaparib, the first-in-class PARP inhibitor, was approved for treatment of BRCA-mutated ovarian cancer in Europe and the United States in 2014. Other PARP inhibitors under clinical trials include rucaparib, niraparib, veliparib, and the "PARP-trapping" BMN-673. BRCA1/2 sequencing is an FDA-approved companion diagnostics, which predicts the cancer vulnerability to PARP inhibition. Together, synthetic lethal PARP inhibition is a novel promising strategy for cancer intervention even in cases without prominent driver oncogenes.

Apoptosis and autophagy usually function to eliminate damaged cells and damaged proteins, respectively. Dysfunction of these events induces oncogenesis and cancer development. Therefore, small compounds that activate apoptosis and autophagy are good candidates for anti-cancer chemotherapeutics to combat cancers. This review focuses on recent advances in apoptosis/autophagy and their relationship with tumorigenesis.

Target-based screening and cell-based screening are major approaches to identify anticancer drug candidates. Cell-based screening often contributes to the discovery of first-in-class drugs, but identification of the cellular targets of obtained compounds is a time-consuming step. To overcome this problem, affinity purification with small-molecule probes, which is a classic, but still the most common approach, has become more sophisticated and diversified. In addition, recent advances in omics studies and imaging analyses have allowed us to profile the biological effects of small molecules globally and quantitatively. Consequently, new therapeutic targets/drug leads involved in cancer cell cycle, transcription and redox regulation have been discovered.

A 67-year-old woman was diagnosed with chronic lymphocytic leukemia (CLL) in October 2001. In August 2004, she received chemotherapy consisting of fludarabine and cyclophosphamide (FC therapy). After three cycles of FC therapy, the number of tumor cells was markedly decreased. However, anemia progressed. She was diagnosed with pure red cell aplasia (PRCA) by bone marrow examination and was successfully treated with cyclosporin A (CsA). In October 2008, anemia progressed with the exacerbation of CLL and she received three cycles of fludarabine therapy. Although the number of tumor cells diminished, the anemia did not improve. She was diagnosed with PRCA recurrence and was again successfully treated with CsA. PRCA is a rare complication in patients with CLL and has been attributed to T cell-mediated mechanisms. Six cases with PRCA that developed after fludarabine therapy for CLL have already been reported. Fludarabine therapy may be toxic to Treg, resulting in the loss of self-tolerance. It is important to consider the possibility of PRCA in patients with progressive anemia after fludarabine therapy for CLL.

Chemotherapy-induced oral mucositis (CIOM) is a severe adverse event resulting from cancer chemotherapy. Toxic free radicals and pro-inflammatory cytokines produced by anticancer drugs have been reported to be associated with CIOM. Rebamipide has been shown to increase gastric endogenous prostaglandin E2 and I2, to promote gastric epithelial mucin, and to behave as an oxygen free-radical scavenger in addition to other anti-inflammatory actions. We developed a gargle solution of rebamipide, adding ultrahydrogel for mucosal protection and to maintain rebamipide on the oral mucosa. A 300 mL rebamipide gargle solution combines 600 mg rebamipide, 3 g high molecular-weight polyethylene oxide, 1.2 g carrageenan, pineapple flavoring, and water. The efficacy of the rebamipide gargle was evaluated in 175 patients with CIOM from November 2009 to December 2012, each instructed to use the rebamipide gargle 5-6 times daily. The severity of CIOM was assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). Their CTCAE scores (3/2/1/0) changed from n=13/64/98/0 to 0/10/103/62, respectively, after initiation of the rebamipide gargle (p<0.01; paired t-test). The median duration to best response was 14 days (range: 1-49). CTCAE scores decreased in 132 patients (75.4%), including 62 (35.4%) who achieved grade 0. There were no unexpected safety events. Rebamipide gargle was well tolerated and demonstrated to have significant therapeutic efficacy against CIOM.

Severe stomatitis caused by chemotherapy and radiotherapy is accompanied by severe pain and results in a poor quality of life. We used a spray preparation of indomethacin (IM; 0.25% IM dissolved in phosphate buffer, pH 7.4), a nonsteroidal anti-inflammatory drug (NSAID) to control the pain associated with stomatitis at the University of Tsukuba Hospital. This review specifically aimed to collect information on the use of the IM spray preparation, from our previous studies, to facilitate its proper use in a hospital setting. On studying the stability of the IM spray preparation, we concluded that the preparation should be kept in the refrigerator for daily use, and that it can be stored for at least 2 months at 4°C, and for 24 months at -20°C. To evaluate the efficacy of the IM spray preparation, we retrospectively surveyed its analgesic effects. Using the 10-grade Visual Analogue Scale in 23 patients, we found that pain associated with stomatitis was reduced from 10 to 4.7 after application of the spray. In conclusion, our study results on the stability and efficacy of the IM spray preparation have led to the proper use of the spray in cancer patients with stomatitis caused by chemotherapy and radiotherapy.