Diarrhea is a side effect of a 5-fluorouracil (5-FU) anti-cancer drug-induced intestinal mucosal disorder, which sometimes becomes more severe. Blood diamine oxidase (DAO; EC1. 4. 3. 6) activity is reported to be significantly correlated with activity in the small intestinal mucosal tissue, and to be a reliable indicator of small intestinal mucosal integrity and maturity. Here, we investigated whether blood DAO activity can be a biomarker for the gastrointestinal (GI) mucosal disorder caused by 5-FU anti-cancer drugs, both in rats and humans. From results of the rat study, the degree of jejunal mucosal disorder caused by the 5-FU anti-cancer drug was well correlated with a decrease in blood DAO activity. Clinically, 12 out of 28 patients (43%) administered 5-FU anti-cancer drug suffered from diarrhea. The plasma DAO activity within one week of the onset of diarrhea significantly decreased compared with that before the administration. Furthermore, before drug administration, plasma DAO activity in patients suffering from diarrhea was higher than those in patients without diarrhea. Although DAO activity differs by the individual, it is a useful biomarker for estimating the degree of intestinal mucosal disorder, and possibly for estimating manifestations of diarrhea induced by 5-FU anti-cancer drug administration.

After the introduction of imatinib, the outcome for patients with advanced gastro-intestinal stromal tumor (GIST) was vastly improved. However, resistance to imatinib has become a new problem. The cause of resistance to imatinib is the low sensitivity of gene mutations in the KIT gene or PDGFRα, or an acquisition of additional mutations, and a low plasma level of imatinib. Sunitinib is the first drug that showed an effectiveness for treating GIST refractory to imatinib. New molecular target drugs for overcoming imatinib resistance are being developed now.

The use of injectable generic antineoplastic agents has been increasing. Few studies have compared the quality and adverse reactions of generic and branded antineoplastic agents; and therefore, generic agents have not gained wide acceptance. Paclitaxel injections, which are used for treating solid cancers, are being marketed by some companies in Japan. The degree of hypersensitive reactions to these drugs may vary because of the differences in chemical properties of the polyoxyethylene castor oil that is used as a solvent in the paclitaxel preparations. Therefore, we investigated the incidence of pulmonary edema occurring as a hypersensitive reaction in rats administered branded and generic paclitaxel injections. Moreover, we compared the chemical properties of these preparations. We found that the pH of branded and generic paclitaxel preparations diluted with saline was different. This difference in pH may be attributed to a difference in chemical properties from the additive. We observed no significant differences in pulmonary vascular permeability, arterial partial pressure of oxygen, or leakage of protein in the pulmonary alveolus, between paclitaxel preparations administered to rats. These results suggest that both paclitaxel preparations induced pulmonary edema of a similar level in rats, irrespective of the differences in their chemical properties.

A survey on chemotherapy-induced nausea, vomiting and food intake was conducted on 126 outpatients receiving chemotherapy during a days from February 1 to February 12, 2010 in our hospital. Responses were obtained from 66 outpatients. In the acute phase, 11%of the patients developed nausea. In the late phase, 35%patients developed nausea. The development of nausea was significantly increased in the late phase, compared to the acute phase(p=0. 0008). Though nobody developed vomiting in the acute phase, 3% of the patients developed vomiting in the late phase. For food intake, in the acute phase, nobody showed a"reduced amount of diet", and 12% showed"not eating". In the late phase, 26% of the patients showed"reduced amount of food", and 8%"not eating". Food intake was significantly decreased in the late phase, compared in acute phase(p=0. 0001). Currently, in our hospital, steroids and/or 5-HT3 antagonists are given for antiemetic therapy, but the effect is not enough. We should add other antiemetics, which act in the late phase.

Ehime Priority Hospitals of Cancer Care Network(Ehime Cancer Kyoten Hospitals)regularly have meetings to discus the current problems in cancer care in Ehime Prefecture. We established three subcommittees:"Registration of Cancer Incident," "Critical Paths for the Management of Patients with Cancer,"and"Palliative Care for Patients with Advanced Cancer"to exchange our opinions. We recently set up a new subcommittee related to the physical and spiritual care of patients undergoing chemotherapy treatment,"A Subcommittee dealing with Cancer Chemotherapy and its Management"."This subcommittee has tried to identify current problems with chemotherapy for outpatients in each institution through questionnaire and analysis. As a result of this survey, it was found that Ehime Priority Hospitals have total of seventy-three beds for outpatients undergoing chemotherapy, and that they performed chemotherapy 19, 671 times in 2008. A total of eight oncology physicians and sixteen oncology nurses were engaged in performing chemotherapy in this system. The questions patients most frequently asked during chemotherapy concerned the management of therapy-related complications, dealing with problems at night and during holidays after chemotherapy, and financial problems related to the costs of treatment. In this study we found three issues that need to be managed in Ehime Priority Hospitals. First, for the nursing of outpatients undergoing chemotherapy, more staff engaged in different types of care is required. Second, a new system to deal with emergencies at night and during holidays after chemotherapy is necessary, because Ehime Priority Hospitals use the same system to deal with chemotherapy patients as for other patients. Third, cooperation between pharmacies and out-clinics is important for patient compliance during chemotherapy, especially for the administration of oral anti-tumor agents. Ehime Priority Hospitals of Cancer Care Network is trying to improve each institution while dealing with these problems.

A 76-year-old woman received chemotherapy with gemcitabine and cisplatin (GC therapy) for local advanced bladder cancer. She suffered from dyspnea on day 19 during the first course of GC therapy. Both chest X-ray and computed tomography (CT) images revealed diffuse bilateral interstitial infiltrates. She was diagnosed as having drug-induced interstitial pneumonia. We identified gemcitabine as the causative agent based on the results of examinations (CT, X-ray, KL-6 level, drug lymphocyte stimulation test (DLST)). After three months of steroid therapy, her interstitial pneumonia was completely resolved on CT scans. Although gemcitabine-induced interstitial pneumonia is a rare adverse event, it should be considered a severe complication because delayed diagnosis and treatment can lead to a fatal outcome. Thus, early detection of drug-induced interstitial pneumonia is extremely important during GC therapy.

In Japan, XELOX (capecitabine plus oxaliplatin) was approved for the treatment of advanced/recurrent colorectal cancer in September 2009. However, patients treated with XELOX sometimes experience intense, sporadic venous pain during administration of oxaliplatin through peripheral vein. To investigate the etiology and management of this event, we measured the titratable acidity, osmotic pressure, and pH of 5% dextrose in water (D5W) containing oxaliplatin with or without dexamethasone. The dexamethasone-containing solution was then tested for its efficacy in venous pain relief. D5W containing oxaliplatin had a pH of approximately 4. 8, whereas the titratable acidity and osmotic pressure were 0. 1 mEq/L and 300-320 mOsm/L, respectively, suggesting that the venous pain was partly attributable to the pH.When 1. 65-6. 6 mg of dexamethasone was added to this solution, the pH of the resulting solution was increased to 6. 5-7. 6. Moreover, pain was relieved in patients administered oxaliplatin with dexamethasone in D5W. When adjusted for pH by the addition of 1. 65-3. 3 mg of dexamethasone, oxaliplatin in D5W is associated with less venous pain without decreasing oxaliplatin content although it is not generally recommended to dissolve oxaliplatin in a basic solution since it is unstable under alkaline conditions.

A standard therapeutic regimen of a 5-HT₃ receptor antagonist antiemetic agent+dexamethasone was administered as antiemetic therapy for 29 patients who received chemotherapy for colorectal cancer in the Department of Surgery at Gunma Saiseikai Maebashi Hospital, from January to March 2010. For 13 patients with delayed nausea, the therapy was changed to an aprepitant regimen (aprepitant+5-HT₃ receptor antagonist antiemetic agent+dexamethasone)to evaluate the preventive effect of aprepitant on acute and delayed nausea and vomiting. This aprepitant regimen produced a significant improvement in the primary endpoint, based on a complete response (CR) of no vomiting and no rescue treatment throughout the administration period, and in the secondary endpoint of CR in the delayed phase, with no delayed nausea. In addition, a tendency for improvement was found in other secondary endpoints: complete protection (CP) based on no vomiting, no rescue treatment, and no significant nausea throughout the observation period; no vomiting; and no significant nausea. These findings suggest that using aprepitant as an antiemetic therapy during chemotherapy for colorectal cancer may be effective for patients with nausea and vomiting that are intractable to standard therapeutic regimens.

The clinical utility of anticancer drugs is seriously limited by the development of adverse effects and acquisition of resistance to these drugs by tumor cells. The mechanism underlying the toxicity of anticancer drugs is still not fully understood. To elucidate the mechanisms underlying the toxicity of anticancer drugs in greater detail, we performed a screen for determinants of sensitivity to adriamycin, an anthracycline antitumor antibiotic, using budding yeast as a model eukaryote. We found that overexpression of Akl1, a protein kinase of uncertain function, confers resistance to adriamycin. We investigated the function of Akl1 in adriamycin resistance and found that downregulation of the internalization step in endocytosis by Akl1 might be closely involved in the mechanism of adriamycin resistance. In human cells, overexpression of AAK1 and a human homologue of Akl1, also decreased adriamycin toxicity, suggesting that downregulation of endocytosis via phosphorylaiotn might be involved in the acquisition of adriamycin resistance not only in yeast cells but also in human cells. Further detailed investigation of the relationship between the endocytosis pathway and adriamycin toxicity might contribute further information for the improvement of chemotherapy with adriamycin.

Recently, the safety and effectiveness of bortezomib for patients with multiple myeloma and renal failure has been reported. In this study, we retrospectively analyzed the 8 myeloma patients with renal failure who have received bortezomib in our hospital.One patient had already required constant hemodialysis before bortezomib.Bortezomib treatment was performed for 229 days, during which time it was injected 30 times.The other 2 patients with chronic renal failure also showed no further renal impairment due to bortezomib.In the remaining 5 patients, serum creatinine levels decreased through 2 cycles(total: 8 injection)of bortezomib treatment.Two patients were complicated with herpes zoster, and 2 patients were complicated with neuropathy in grade 3.We showed the safety and efficacy of bortezomib in Japanese patients with multiple myeloma complicated with renal failure.We should positively consider the therapeutic choice of bortezomib for the refractory myeloma with renal failure.

The aim of this study was to retrospectively assess if arterial hypertension induced during treatment with bevacizumab was associated with the clinical outcome in advanced, recurrent colorectal cancer patients treated with first-line bevacizumab.

Bevacizumab (BV) is widely used for patients with metastatic colorectal cancer. We investigated the efficacy and safety of chemotherapy combined with BV for metastatic colorectal cancer. From July 2007 to October 2008, 59 patients were treated by chemotherapy with BV in our hospital. Of the 47 patients who received BV in first-line therapy, 3 cases (6%) with complete response (CR), 25 cases(53%) with partial response (PR), and 17 cases (36%) with stable disease (SD) were observed. The overall response rate and tumor control rate were 60% and 96%, respectively. The median progression-free survival (PFS) was 11. 9 months, and median overall survival (OS) was 23. 6 months. There were 12 patients treated first with BV in second-line therapy. Of the 12 patients, 1 case (8%) with CR, 3 cases (25%) with PR, and 4 (33%) with SD were observed. The overall response rate and tumor control rate were 33% and 67%, respectively. The median PFS was 6.0 months and median OS was not reached. With regard to the grade 3 to 4 adverse events by NCI-CTCAE ver3.0, neutropenia was observed in more than half of the patients (56%), but a few of patients had gastrointestinal toxicities, peripheral neuropathy and infections in non-hematologic toxicities. BV-associated adverse events were hypertension, proteinuria, venous thrombosis, wound healing complication, gastrointestinal perforation and bleeding, each of which were few and not serious. Six of the patients experienced PD after first-line therapy treated with BV continuously in second-line therapy. Four of six were surviving without disease progression at the last follow-up, which suggests the effectiveness of continuation of BV. Our study showed the efficacy and safety of BV for metastatic colorectal cancer.

Various cancer treatments can cause gonadal dysfunction and bone loss. Especially, endocrine therapies for breast cancer or prostate cancer carry a significant risk of cancer treatment-induced bone loss (CTIBL) . LHRH agonist- or chemotherapy-induced premature menopause in premenopausal breast cancer patients, aromatase inhibitor in postmenopausal breast cancer patients, and LHRH agonist with or without anti-androgen in prostate cancer patients may cause bone loss of 5% or more within several years. Oral or intravenous bisphosphonates are effective for prevention of CTIBL, and RANKL antibody (denosumab) is also effective. During treatment, physicians should follow bone mineral density and avoid QOL impairment due to osoteoporosis.

We report a case of sclerosing cholangitis caused by oral chemotherapy with S-1. A 79-year-old woman with a history of hypertension presented with epigastric discomfort. Upper gastrointestinal endoscopy revealed advanced gastric cancer in the gastric antrum and abdominal computed tomography showed multiple lymph node metastasis. The patient underwent chemotherapy with S-1. Since 2 months later, blood chemistry analysis showed liver dysfunction and hyperbilirubinemia, and chemotherapy was discontinued. Endoscopic retrograde cholangiopancreatography revealed stenosis of the bile duct at the hepatic hilum. There was no evidence of tumor in the liver. We diagnosed chemotherapy-induced sclerosing cholangitis (CISC) caused by S-1. Although treatment with ursodeoxycholic acid and corticosteroids was temporarily effective, she eventually died of CISC and gastric cancer. To the best of our knowledge, this is the first case report of CISC caused by S-1. We present this rare condition with a review of the literature.

Anti-cancer drugs have relatively low effective rates and high frequencies of adverse reactions, occasionally leading to cessation of their treatments. Use of pharmacogenomic (PGx) information could be able to select the patients with high-response and less-adverse reactions, resulting in increase of patients' QOL and proper use of drugs. We have been collaborating with National Cancer Center for PGx analysis of anti-cancer drugs including irinotecan and gemcitabine in Japanese cancer patients. Irinotecan, now used for treatments of many cancers, is metabolically activated to SN-38 and then inactivated to SN-38 glucuronide by a UDP-glucuronosyltransferase UGT1A1. In the UGT1A1 gene, two representative genetic polymorphisms, *28 and *6, were detected at 0.138 and 0.167, respectively in 177 Japanese cancer patients. When the patients were homozygotes of *28 or *6, or compound heterozygotes of them, statistically significant decreases were observed in the SN-38 glucuronidation activity and increases in the rate of severe neutropenia, compared to those in the patients without *28 or *6. Our results and papers were cited in the Japanese package inserts of irinotecan. Gemcitabine was inactivated by cytidine deaminase (CDA) into 2'-2'-difluorodeoxyuridine. A CDA polymorphism 208G>A (Ala70Thr) was detected at 0.037 frequency in 256 Japanese cancer patients and associated with reduced gemcitabine clearance as well as increased frequency of severe neutropenia. In the 4 patients suffered from very severe bone marrow toxicities, 3 patients were homozygous CDA*3, suggesting that this polymorphism is exquisite for predicting severe adverse reactions by gemcitabine in Japanese.

A 74-year-old man, who had mantle cell lymphoma treated with several anticancer drugs including rituximab, was admitted to our hospital because of gait disturbance and progressive paralysis of the right lower limb. T2-weighted MR image showed multiple high intensity lesions in the left parietal lobe. Suspected of being cerebral invasion of lymphoma, high-dose methotrexate was begun, but the patient died of sepsis without neurological improvement. At autopsy, it was proven that neurological symptoms had been caused by progressive multifocal leukoencephalopathy (PML). PML should be considered as a possible complication of heavily treated lymphoma.