Impact of a surgical safety checklist on surgical site infections, antimicrobial resistance, antimicrobial consumption, costs and mortality.

BACKGROUND: In 2010, following the recommendations of the World Health Organization (WHO), our hospital implemented a surgical safety programme centred around a surgical safety checklist. AIM: The aim of this study was to compare indicators of surgical site infection, antimicrobial consumption, antimicrobial resistance, costs and in-hospital mortality before (January 2006 to July 2010) and after (August 2010 to December 2014) implementation of the programme. METHODS: A case-control study was carried out matching patients with surgical site infection (SSI) to surgical patients without infection to examine the impact of the intervention. FINDINGS: Use of the surgical checklist was associated with a significant reduction in SSI. When comparing the two time periods, we also identified a reduction in infections due to micro-organisms in the ESKAPE group (from 90.7% to 73.9%, P<0.001), a reduction of SSI in patients with contaminated, infected and potentially contaminated wounds, and for those in whom perioperative antimicrobial prophylaxis was discontinued in less than 48 hours. Overall, there was a reduction in antimicrobial resistance, though there was increased resistance to carbapenems for, to glycopeptides for Enterococcus faecium, and to clindamycin for Staphylococcus aureus. We also detected increased antimicrobial consumption of second- and third-generation cephalosporins and clindamycin. We observed a reduction in hospital deaths from 6.4% to 3.2% (P=0.001), but we did not observe any reduction in costs. CONCLUSIONS: Implementation of a surgical checklist was an independent predictor of SSI reduction, and was also associated with a decrease in antimicrobial resistance and reduced in-hospital mortality.

Stent-supported angioplasty of a residual coronary artery dissection following replacement of the ascending aorta for acute type A aortic dissection. A report of a successful case.

A 54-year-old-man suddenly experienced severe back pain while eating. On admission to our hospital, contrast-enhanced computed tomography revealed an acute type A aortic dissection, and emergency surgical repair was performed the same day. Through median sternotomy, graft replacement of the ascending aorta, including removal of the site of the intimal tear, was carried out under deep hypothermia and retrograde cerebral perfusion. Although the postoperative course was satisfactory, the patient suddenly complained of sever chest pain on postoperative day 23; the ECG trace showed anomalous alterations. Emergency coronary angiography revealed the presence of a wide coronary artery dissection from the entry of the left anterior descending aorta (LAD) to the re-entry of the left circumflex artery (LCX). Multiple stents were implanted in the LAD and LCX. After stenting, the chest symptoms remitted and the ECG trace was normal. The patient was discharged from our hospital on postoperative day 42.

[Management of remaining coronary artery dissection after the replacement of the ascending aorta in acute type A aortic dissection].

The authors report a case study of a 54-year-old male admitted to our hospital with severe chest pain and ST depression in II, III and aVf lead on the electrocardiogram. The chest X-ray showed an enlarged superior mediastinum. An enhanced computed tomography (CT) was performed and confirmed the diagnosis of acute type A aortic dissection. The patient underwent emergency surgical repair with the replacement of the ascending aorta. The patient recovered without complication until the fifteenth postoperative day, when another severe chest pain appeared. Emergency coronary angiography revealed a remaining dissection in both the left anterior descending artery (LAD) and the left circumflex artery (LCx). Implantation of Elite stents to the LAD and the LCx was performed. The patient recovered uneventfully after this operation. Remaining coronary artery dissection after the replacement of the ascending aorta is very rare. In this case coronary intervention with Elite stents was effective.

Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain.

BACKGROUND: Pathologic changes in the Alzheimer disease (AD) brain occur in a hierarchical neuroanatomical pattern affecting cortical, subcortical, and limbic regions. OBJECTIVE: To define the time course of pathologic and biochemical changes-amyloid deposition, amyloid beta-peptide (Abeta) accumulation, neurofibrillary tangle (NFT) formation, synaptic loss, and gliosis-within the temporal association cortex of AD cases of varying disease duration, relative to control brains. METHODS: Stereologic assessments of amyloid burden and tangle density as well as ELISA-based measurements of Abeta, synaptophysin, and glial fibrillary acidic protein (GFAP) were performed in the superior temporal sulcus from a cohort of 83 AD and 26 nondemented control brains. RESULTS: Relative to control cases, AD brains were characterized by accumulation of NFT and amyloid plaques, increase of tris- and formic acid-extractable Abeta species, reduced levels of synaptophysin, and elevated levels of GFAP. In AD cases, the duration of dementia correlated with the degree of tangle formation, gliosis, and synaptic loss but not with any Abeta measures. Accumulation of Abeta, measured both neuropathologically and biochemically, was markedly increased in AD brains independent of disease duration, even in cases of short duration. CONCLUSIONS: These data support distinct processes in the initiation and progression of AD pathology within the temporal cortex: Deposition of Abeta reaches a "ceiling" early in the disease process, whereas NFT formation, synaptic loss, and gliosis continue throughout the course of the illness.

[Surgical management of acute type A aortic dissection with a complaint of disturbance of consciousness; report of a case].

A 50-year-old female was admitted to our hospital with a chief complaint of disturbance of consciousness (DOC). Left-sided hemiparalysis was noted on examination and cerebral infarction was diagnosed with total occlusion of the right common carotid artery revealed by cerebral angiography. Pharmacological thrombolysis (urokinase 720,000 U) was performed. Dissection of the right common carotid artery was noted after successful thrombolytic therapy. Enhanced chest computed tomography (CT) showed the acute type A aortic dissection involving the cerebral artery. Ascending aortic replacement was performed 4 days after the thrombolytic therapy to avoid brain edema and hemorrhagic infarction during cardiopulmonary bypass. The postoperative course was uneventful. In the case of acute type A aortic dissection with DOC, proper indication and optimal timing of the operation may help to improve patient survival.

[A successful surgical case of chronic DeBakey IIIb dissecting aortic aneurysm associated with right-sided aortic arch].

A case of chronic DeBakey IIIb dissecting aneurysm associated with right-sided aortic arch and aberrant left subclavian artery is reported. A 51-year-old man was admitted to our institute for surgical treatment of chronic dissecting aortic aneurysm which occurred 3 years ago. A right posterolateral thoracotomy was made through the 4th intercostal space. Closure of entry was performed under temporary hypothermic circulatory arrest and then, this was followed by plication of false lumen under hypothermic CPB. Post-operative clinical course was uneventful and an intra-venous digital subtraction angiography demonstrated that false lumen in the thorax was completely closed. The patient was discharged from the hospital on 21th POD. Dissecting aortic aneurysm associated with right-sided aortic arch is extremely rare. In operative case, pertinent selection of operative methods considering anatomical diversity is required.

Mechanism of the radiosensitization induced by vinorelbine in human non-small cell lung cancer cells.

Vinorelbine (Navelbine, KW-2307), a semisynthetic vinca alkaloid, is a potent inhibitor of mitotic microtubule polymerization. The aims of this study were to demonstrate radiosensitization produced by vinorelbine in human non-small cell lung cancer (NSCLC) PC-9 cells and to elucidate the cellular mechanism of radiosensitization. A clonogenic assay demonstrated that PC-9 cells were sensitized to radiation by vinorelbine with a maximal sensitizer enhancement ratio at a 10% cell survival level of 1.35 after 24-h exposure to vinorelbine at 20 nM. After 24-h exposure to vinorelbine at 20 nM, the approximately 67% of the cells that had accumulated in the G2/M-phase were cultured in the absence of vinorelbine and then irradiated at a dose of 8 Gy. Flow cytometric analyses showed prolonged G2/M accumulation concomitant with continuous polyploidization, and induction of apoptosis was observed in the cells subjected to the combination of vinorelbine-pretreatment and radiation. Polyploidization and induction of apoptosis were confirmed by morphological examination and a DNA fragmentation assay, respectively. We concluded that vinorelbine at a minimally toxic concentration moderately sensitizes human NSCLC cells to radiation by causing accumulation of cells in the G2/M-phase of the cell cycle. Prolonged G2/M accumulation concomitant with continuous polyploidization and increased susceptibility to induction of apoptosis may be associated with the cellular mechanism of radiosensitization produced by vinorelbine.

Mechanisms of action of the novel sulfonamide anticancer agent E7070 on cell cycle progression in human non-small cell lung cancer cells.

E7070 is a novel sulfonamide antitumor agent that exhibits potent antitumor activity in vitro and in vivo. This compound affects cell cycle progression in human tumor cells. To elucidate the mechanisms by which E7070 inhibits tumor cell growth, we established and characterized an E7070-resistant subline, A549/ER, from a human non-small cell lung cancer cell line A549. Flow cytometric analyses demonstrated an increase in G0/G1 and a decrease in S phase populations in cells treated with E7070 at 20 or 100 microg/ml for 24 h. Longer exposure to E7070, i.e. 48 and 72 h, increased the G2/M phase fraction in A549 cells. These inhibitory actions of E7070 on cell cycle progression were not observed in A549/ER cells. E7070 inhibited the phosphorylation of pRb, decreased expressions of cyclin A, B1, CDK2, and CDC2 proteins, and suppressed CDK2 catalytic activity with the induction of p53 and p21 proteins in A549 cells but not in A549/ER cells. Taken together, these results suggest that E7070 exerts its antitumor effects by disturbing the cell cycle at multiple points, including both the G1/S and the G2/M transition, in human lung cancer cells.

Enhancement of in vivo antitumor activity of a novel antimitotic 1-phenylpropenone derivative, AM-132, by tumor necrosis factor-alpha or interleukin-6.

TK5048 and its derivatives, AM-132, AM-138, and AM-97, are recently developed antimitotic (AM) compounds. These 1-phenylpropenone derivatives induce cell cycle arrest at the G2 / M phase of the cell cycle. TK5048 inhibited tubulin polymerization in human lung cancer PC-14 cells in a concentration-dependent manner. In a polymerization assay using bovine brain tubulin, AM-132 and AM-138 were quite strong, AM-97 was moderately strong, and TK5048 was a relatively weak inhibitor of tubulin polymerization. A murine leukemia cell line resistant to a sulfonamide antimitotic agent, E7010, which binds to colchicine-binding sites on tubulin, was cross-resistant to the in vitro growth-inhibitory effect of AM compounds. Inhibition of tubulin polymerization is therefore one of the mechanisms of action of these AM compounds against tumor cells. To profile the antitumor effect of AM compounds, the in vivo antitumor effect of AM-132 was evaluated against cytokine-secreting Lewis lung carcinoma (LLC). Tumor-bearing mice were treated with intravenous AM-132 using three different treatment schedules. LLC tumors expressing tumor necrosis factor-alpha (TNF-alpha), granulocyte macrophage colony-stimulating factor (GM-CSF), or interleukin (IL)-6 were very sensitive to AM-132. In particular, LLC tumors expressing IL-6 were markedly reduced by AM-132 treatment, and showed coloring of the tumor surface and unusual hemorrhagic necrosis. These results suggest a combined effect of AM-132 and cytokines on the blood supply to tumors.

In vitro synergistic interactions between the cisplatin analogue nedaplatin and the DNA topoisomerase I inhibitor irinotecan and the mechanism of this interaction.

Among the numerous clinical regimens used in combination chemotherapy, synergy is particularly marked in combinations containing cisplatin (CDDP). However, the clinical use of CDDP is sometimes limited due to its nephrotoxicity. Nedaplatin (NDP) is a second-generation platinum complex with reduced nephrotoxicity that may substitute for CDDP or even surpass it for use in combination with other drugs. We investigated the effects of combinations of NDP and other anticancer drugs on the growth of human small cell lung cancer cells (SBC-3) and non-small cell lung cancer cells (PC-14) using a three-dimensional analysis model. Among the combinations tested, the combination of NDP and irinotecan (CPT-11) showed the most marked synergistic interaction, and the synergism has also been observed against PC-14 cells. With regard to treatment schedule, a remarkable synergistic interaction was produced by concurrent exposure to NDP and CPT-11. On the other hand, sequential exposure to the two drugs led only to additivity. To analyze the interaction between the drugs, the effect of NDP on the 7-ethyl-1-hydroxy-CPT (the active form of CPT-11)-induced inhibitory effect on DNA topoisomerase I was examined. The topoisomerase I-inhibitory effect of 7-ethyl-1-hydroxy-CPT was enhanced 10-fold in the presence of NDP at microgram/milliliter concentrations. These biochemical interactions might be responsible for the synergistic interaction between NDP and CPT-11. These results suggest that the combination of NDP with CPT-11 may be clinically useful for the chemotherapy of lung cancer.

Mechanism of action of aragusterol a (YTA0040), a potent anti-tumor marine steroid targeting the G(1) phase of the cell cycle.

Aragusterol A (YTA0040), isolated from the Okinawan marine sponge of the genus Xestospongia, is a potent anti-tumor marine steroid that possesses a unique structural component. This compound showed broad-spectrum anti-proliferative activity against a panel of 14 human cancer cell lines (IC(50) = 0.01-1.6 microM). P-glycoprotein-mediated, multidrug-resistant cells showed cross-resistance to YTA0040 cells, whereas cisplatin-resistant non-small-cell lung-cancer (NSCLC) sublines showed a collateral sensitivity to YTA0040. In transplantable murine tumor models, YTA0040 displayed a broad spectrum and high degree of anti-tumor activity when administered i.p. or p.o. (life span T/C = 135-234%). In P388 murine leukemia cells, YTA0040 caused dose- and time-dependent suppression of nucleic acid and protein synthesis, with protein synthesis being more potently and rapidly inhibited than nucleic acid synthesis. Flow-cytometric analysis revealed that YTA0040 blocked the entry of human NSCLC-derived A549 cells into S phase, leading to arrest in the G(1) phase of the cell cycle. Western blot analysis demonstrated that YTA0040 caused a dose-dependent decrease in the levels of expression of hyperphosphorylated pRb and cyclin A in A549 cells. The level of p53 protein expression was decreased by YTA0040 treatment. A higher concentration of YTA0040 down-regulated the levels of expression of CDK2, CDK4, cyclin D1 and cyclin E. These findings indicated that YTA0040 arrested human NSCLC cells in late G(1) phase of the cell cycle through inhibition of pRb phosphorylation. Inhibition of pRb phosphorylation by YTA0040 resulted from down-regulation of levels of expression of the CDKs and cyclins involved in the G(1)/S transition and not from induction of p53 and/or the CDK inhibitor p21.

[Three approaches to surgical treatment of traumatic disruption of the thoracic aorta].

Traumatic disruption of the thoracic aorta is said to occur most often near the aortic isthmus because of the mechanisms of aortic injury. Between November 1990 and August 1999, we encountered eight cases of surgical treatment for traumatic injury of the thoracic aorta combined with multi-system injury. In some cases, the injury was located near the aortic isthmus; in such cases, we selected surgical options that made use of three different approaches, namely, media sternotomy, posterolateral left thoracotomy, and anteroaxillal thoracotomy. Each approach has advantages and disadvantages. In selecting an appropriate approach, it is not only necessary to consider the various features of the approach itself, but it is also necessary to consider other factors, such as the assisting apparatus in use, the effects of other injuries sustained by perioperative positioning, safety measures against accidental bleeding during surgery, deployment of the operative field, and potential complications after surgery.

[Estimation of adverse drug reactions by the evaluation scores of subjective symptoms (complaints) and background of patients. IV. Drug eruptions].

OBJECTIVES: The purpose of this study is to develop, implement, and assess an estimation procedure for preventing adverse drug reaction by subjective symptoms (complaints) of patients. This time, we focused and studied on drug eruptions. METHODS: We have built a database for CARPIS (Case Reports of Adverse Drug Reaction and Poisoning Information System) since 1987, and the case reports of adverse drug reactions accumulated in the CARPIS database to be total about 20,000. We studied 1473 cases of drug eruptions cumulated in CARPIS database. The evaluation scores were created based on the subjective symptoms and backgrounds of the patients. We estimated 1473 cases using this evaluation scores. RESULTS: We could estimate 1455 cases (98.8%) in 1473 cases to be drug eruptions using this evaluation scores. The validity of this evaluation scores were sensitivity = 98.8%, specificity = 91.0% and predictive value of positive test = 99.4%. The positive likelihood ratio was 11.0 and negative likelihood ratio was 0.01. CONCLUSIONS: This study confirmed the validity of our evaluation scores. We reported the evaluation scores about drug-induced liver diseases, drug-induced extra-pyramidal symptoms and drug-induced leukopenia before. In order to apply these evaluation scores to the clinical practice, we prepared an evaluation form for subjective symptoms and backgrounds of the patients with adverse drug reactions.

Ectopic p16(ink4) expression enhances CPT-11-induced apoptosis through increased delay in S-phase progression in human non-small-cell-lung-cancer cells.

A tumor-suppressor gene, p16(INK4), which is deleted or mutated in tumors, regulates cell-cycle progression through a G(1)-S restriction point by inhibiting CDK4(CDK6)/cyclin-D-mediated phosphorylation of pRb. We have found that ectopic p16(INK4) expression increased cellular sensitivity of human non-small-cell-lung-cancer (NSCLC) A549 cells to a selective growth-inhibitory effect induced by the topoisomerase-I inhibitor 11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin (CPT-11) in vitro. In this study, we observed enhanced apoptosis characterized by DNA fragmentation in A549 cells transfected with p16(INK4) cDNA (A549/p16-1) and treated with CPT-11. This apoptosis was suppressed by the inhibitor of interleukin-1beta-converting enzyme (ICE/caspase-1) or ICE-like proteases, Z-Asp-CH2-DCB, as determined by DNA fragmentation and proteolytic cleavage of poly(ADP-ribose) polymerase, a natural substrate for CPP32/caspase-3. In A549/p16-1 cells, cytosolic peptidase activities that cleaved Z-DEVD-7-amino-4-trifluoromethylcoumarin increased during CPT-11-induced apoptosis and were suppressed by a highly specific caspase-3 and caspase-3-like inhibitor, Z-DEVD-fluoromethylketone. These findings indicate that p16(INK) is positively involved in the activation pathway of the caspase-3 induced by CPT-11. The increased delay in S-phase progression and subsequent induction of apoptosis were observed in CPT-11-treated A549/p16-1 cells on the basis of DNA histograms. Specific down-regulation of the cyclin-A protein level in A549/p16-1 cells was observed after CPT-11-treatment, whereas cyclin B, cdk2, and cdc2 protein levels were unaffected. These results suggest that ectopic p16(INK4) expression inappropriately decreases cyclin A and thereby terminates CPT-11-induced G(2)/M accumulation, which is followed by increased apoptosis in p16(INK4)-expressing A549 cells.

Molecular determinants of UCN-01-induced growth inhibition in human lung cancer cells.

UCN-01 (7-hydroxystaurosporine) inhibits the growth of various malignant cell lines in vitro and in vivo. In this study, a human small cell lung carcinoma subline resistant to UCN-01, SBC-3/UCN, was established and characterized. SBC-3/UCN cells showed 8-fold greater resistance to the UCN-01-induced growth-inhibitory effect than the parent cells, SBC-3. No UCN-01-induced G1 accumulation in SBC-3 cells was observed in SBC-3/UCN cells and decreased expression of phosphorylated RB protein was found in SBC-3 cells. Neither basal expression nor induction of p21(Cip1) by UCN-01 treatment was detected in the SBC-3/UCN cell line. An inhibitory effect of UCN-01 on CDK2 activity, which is mediated by p21(Cip1)/CDK2 complex formation upon UCN-01 treatment, was observed in SBC-3 but not in SBC-3/UCN cells. SBC-3/UCN showed higher CDK6 activity than SBC-3 cells. UCN-01 did not inhibit the CDK4 and CDK6 activities in both cells. We screened the cell cycle regulatory molecules associated with G(1)/S progression and found a remarked decrease in interferon regulatory factor 1 (IRF-1), which is known to cooperate with p53 in p21(Cip1) induction. Our results suggest that p21(Cip1) regulation via the IRF-1-associated pathway may represent a major determinant of UCN-01-induced growth inhibition in human lung cancer cells.

Primary cultures of neuronal and non-neuronal rat brain cells secrete similar proportions of amyloid beta peptides ending at A beta40 and A beta42.

To determine the types of brain cells responsible for the production of amyloid beta peptides (A beta), as well as their carboxyl-terminal properties, we studied the secretion of A beta in rat neuronal, astrocytic, microglial and meningeal primary cell cultures. All four types of cells produced A beta, among which neurons secreted approximately 4 times more A beta than other cell types. The percentage of A beta42 ending at position 42 as a fraction of total A beta was similar between different cell types, ranging from 10 to 15%. These results suggest that neurons might be the most potent source for A beta production in the brain, although other non-neuronal type cells could also contribute to this process.

Effect of a chimeric anti-ganglioside GM2 antibody on ganglioside GM2-expressing human solid tumors in vivo.

Ganglioside GM2 is expressed on the surface of neuroblastoma and glioblastoma cells, and may also be detected on lung cancer cells. We reported previously that anti-ganglioside GM2 antibody exhibited strong in vitro anti-tumor activity against adriamycin-resistant cancer cells, which overexpressed ganglioside GM2. In the present study, we examined the in vivo anti-tumor effect of the chimeric anti-ganglioside GM2 antibody, KM966, against human lung and breast carcinoma cells, SBC-3 and MCF-7, and respective adriamycin-resistant clones, SBC-3/ADM and AdrR MCF-7 in BALB/c nu/nu mice. Ratios of tumor volume (T/C) between KM966-treated group and control group were 0.01 for SBC-3, 0.00 for SBC-3/ADM, 0.85 for MCF-7 and 0.34 for AdrR MCF-7 cells, respectively. Nude mice, which were pretreated with anti-asialo GM1 antibody to remove natural killer cells, were transplanted with 4 x 10(7) of SBC-3 and SBC-3/ADM subcutaneously. Seven days later, when tumors had grown to a diameter of over 8 mm, mice began to receive intravenous treatment of 120 microgram/mouse KM966 daily. Fourteen daily treatments induced regression to less than 4-mm diameter in 4/5 SBC-3 tumors and 5/5 of SBC-3/ADM tumors. All SBC-3/ADM tumors disappeared completely, suggesting that KM966 exerts a strong in vivo anti-tumor effect on ganglioside GM2-expressing cancer cells. In KM966-treated mice, the surface of the tumor cells stained positive with anti-human IgG. In addition, numerous leukocytes had infiltrated into the tumor mass. Antibody-dependent cell-mediated cytotoxicity (ADCC) of KM966 against tumor cells was examined in vitro by (51)Cr-release assay and revealed that KM966 induces ADCC activity against ganglioside GM2-expressing tumors. Our results suggest that immunotherapy using KM966 may be useful for the treatment of ganglioside GM2-expressing solid tumors.

Drug resistance in lung cancer.

The major problem in lung cancer chemotherapy is the emergence of inherent and acquired drug resistance of the cancer cells. Establishment of drug-resistant sublines and comparative investigations of such cell lines with their parental cells to determine their molecular, biologic, and biochemical properties are important research strategies. Genetic changes in tumor cells may induce changes in their biochemical properties and chemosensitivity. Many mechanisms that render tumor cells resistant have been identified, and they have provided new molecular targets for surrogate markers to predict chemosensitivity. The new categories of anticancer drugs, such as topoisomerase I inhibitors and taxanes, and non-cytotoxic new drugs, have been introduced clinically. It is important to define the molecular determinants of resistance to these drugs. The development of an appropriate model for overcoming drug resistance is one of the important issues that should be solved before carrying out further clinical trials.

Enhancement of cisplatin sensitivity in high mobility group 2 cDNA-transfected human lung cancer cells.

To elucidate the role of high mobility group 2 protein (HMG2) in cis-diamminedichloroplatinum (II) (cisplatin, CDDP) sensitivity, we constructed a human HMG2-transfected human non-small cell lung cancer cell line, PC-14/HMG2. The HMG2 mRNA expression level was approximately twice those of parental PC-14 and mock-transfected PC-14/CMV. Gel mobility shift assay revealed a CDDP-treated DNA-protein complex in the nuclear extract of PC-14/HMG2, which was not found in the extracts of PC-14 and PC-14/CMV. This complex formation was subject to competition by CDDP-treated non-specific salmon sperm DNA, indicating that ectopic HMG2 recognizes CDDP-damaged DNA. PC-14/HMG2 showed more than 3-fold higher sensitivity to CDDP than PC-14 and PC-14/CMV. The intracellular platinum content of PC-14/HMG2 after exposure to 300 microM CDDP was 1.1 and 1.5 times that of PC-14 and PC-14/CMV, respectively. Cellular glutathione levels were not different in these cell lines. Repair of DNA interstrand cross-links determined by alkaline elution assay was decreased in PC-14/HMG2. These results suggest that HMG2 may enhance the CDDP sensitivity of cells by inhibiting repair of the DNA lesion induced by CDDP.