Resolvin D1 suppresses inflammation-associated tumorigenesis in the colon by inhibiting IL-6-induced mitotic spindle abnormality.

While failure in resolution of inflammation is considered to increase the risk of tumorigenesis, there is paucity of experimental as well as clinical evidence supporting this association. Resolvin D1 (RvD1) is a representative pro-resolving lipid mediator that is endogenously generated from docosahexaenoic acid for the resolution of inflammation. Here, we report a decreased level of RvD1 in the blood from colorectal cancer patients and mice having inflammation-induced colon cancer, suggesting plasma RvD1 as a potential biomarker for monitoring colorectal cancer. Administration of RvD1 attenuated dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM) plus DSS-induced colorectal carcinogenesis by suppressing the production of interleukin-6 (IL-6) and IL-6-mediated chromosomal instability. The protective effect of RvD1 against chromosomal instability is associated with downregulation of IL-6-induced Cyclin D1 expression, which appears to be mediated by blocking the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) axis. RvD1 inhibited the STAT3 signaling pathway by interfering with the binding of IL-6 to its receptor (IL-6R), suggesting the novel function of RvD1 as a putative IL-6R antagonist. Together, our findings suggest that RvD1-mediated blockade of IL-6 signal transmission may contribute to inhibition of chromosomal instability and tumorigenesis.

Comparison of Clinical and Echocardiographic Characteristics between Cardiac Myxomas and Masses Mimicking Myxoma.

BACKGROUND AND OBJECTIVES: Cardiac myxoma is the most frequent benign cardiac tumor that can result in cardiac and systemic symptoms. We investigated clinical and echocardiographic characteristics of patients with cardiac masses suggesting myxoma. METHODS: We investigated 265 consecutive patients with an echocardiographic diagnosis of cardiac myxomas in 4 teaching hospitals in Korea. RESULTS: The mean age was 61±16 years and 169 patients (63.8%) were female. The most frequent referral reason for echocardiography was an evaluation of cardiac symptoms (43.4%). Tumors were incidentally detected in 82 patients (30.9%). Left atrium (LA) was the most frequently involved site (84.5%) and 19 patients (7.2%) had non-atrial tumors. The mean tumor size was 38.7×26.0 mm (range, 4-96 mm). Of 186 patients (70.2%) who had pathological diagnosis, 174 (93.5%) were confirmed with myxoma, 8 (4.3%) with other tumors and 4 (2.2%) with thrombi. Compared to myxoma, smaller size (20.4×12.6 mm vs. 41.4×27.6 mm, p<0.01) and non-LA location (87.5% vs. 10.5%, p<0.001) were associated with non-myxoma tumors, and more frequent atrial fibrillation (AF, 75.0% vs. 7.0%, p<0.001) and larger LA diameter (55.0±14.6 mm vs. 41.3±7.7 mm, p=0.001) were related to thrombi. CONCLUSIONS: Of 265 patients with an echocardiographic diagnosis with cardiac myxomas, 174 (65.7%) were surgically confirmed with myxomas. Compared with cardiac myxoma, other tumors were smaller and more frequently found in non-atrial sites. Thrombi were associated with AF and larger LA diameter.

Surgical Outcomes of Subtotal Parathyroidectomy for Renal Hyperparathyroidism.

OBJECTIVES: The aim of this study was to evaluate the effectiveness of subtotal parathyroidectomy for patients with renal hyperparathyroidism. METHODS: We studied 25 patients with renal hyperparathyroidism who underwent subtotal parathyroidectomy from October 2002 to October 2017. We analyzed serum intact parathyroid hormone (iPTH), calcium, and inorganic phosphorus levels before and at multiple time points following surgery, and evaluated the surgical outcomes and complications. RESULTS: Of the 25 patients, 13 (52%) were male and 12 (48%) were female, and the mean age was 53.4±9.3 years. The mean duration of dialysis before parathyroidectomy was 156.8±79.5 months. Mean preoperative serum iPTH and calcium levels were 1,199.0±571.3 pg/mL and 10.5±1.0 mg/dL, respectively. At 6 months postoperatively, the mean iPTH and calcium levels decreased to 49.2±47.6 pg/mL (P<0.01) and 8.0±1.0 mg/dL (P<0.01), respectively. Recurrent hyperparathyroidism occurred in two patients: one subsequently underwent kidney transplantation and the other continued hemodialysis and maintained normal calcium levels. One patient developed postoperative permanent hypoparathyroidism. CONCLUSION: Subtotal parathyroidectomy is a safe and effective surgical treatment for renal hyperparathyroidism.

Structural and Biophysical Analyses of Human N-Myc Downstream-Regulated Gene 3 (NDRG3) Protein.

The N-Myc downstream-regulated gene (NDRG) family belongs to the α/ß-hydrolase fold and is known to exert various physiologic functions in cell proliferation, differentiation, and hypoxia-induced cancer metabolism. In particular, NDRG3 is closely related to proliferation and migration of prostate cancer cells, and recent studies reported its implication in lactate-triggered hypoxia responses or tumorigenesis. However, the underlying mechanism for the functions of NDRG3 remains unclear. Here, we report the crystal structure of human NDRG3 at 2.2 Å resolution, with six molecules in an asymmetric unit. While NDRG3 adopts the α/ß-hydrolase fold, complete substitution of the canonical catalytic triad residues to non-reactive residues and steric hindrance around the pseudo-active site seem to disable the α/ß-hydrolase activity. While NDRG3 shares a high similarity to NDRG2 in terms of amino acid sequence and structure, NDRG3 exhibited remarkable structural differences in a flexible loop corresponding to helix α6 of NDRG2 that is responsible for tumor suppression. Thus, this flexible loop region seems to play a distinct role in oncogenic progression induced by NDRG3. Collectively, our studies could provide structural and biophysical insights into the molecular characteristics of NDRG3.

Structural Analyses on the Deamidation of N-Terminal Asn in the Human N-Degron Pathway.

The N-degron pathway is a proteolytic system in which a single N-terminal amino acid acts as a determinant of protein degradation. Especially, degradation signaling of N-terminal asparagine (Nt-Asn) in eukaryotes is initiated from its deamidation by N-terminal asparagine amidohydrolase 1 (NTAN1) into aspartate. Here, we have elucidated structural principles of deamidation by human NTAN1. NTAN1 adopts the characteristic scaffold of CNF1/YfiH-like cysteine hydrolases that features an α-ß-ß sandwich structure and a catalytic triad comprising Cys, His, and Ser. In vitro deamidation assays using model peptide substrates with varying lengths and sequences showed that NTAN1 prefers hydrophobic residues at the second-position. The structures of NTAN1-peptide complexes further revealed that the recognition of Nt-Asn is sufficiently organized to produce high specificity, and the side chain of the second-position residue is accommodated in a hydrophobic pocket adjacent to the active site of NTAN1. Collectively, our structural and biochemical analyses of the substrate specificity of NTAN1 contribute to understanding the structural basis of all three amidases in the eukaryotic N-degron pathway.

Structural and Functional Analyses of Human ChaC2 in Glutathione Metabolism.

Glutathione (GSH) degradation plays an essential role in GSH homeostasis, which regulates cell survival, especially in cancer cells. Among human GSH degradation enzymes, the ChaC2 enzyme acts on GSH to form 5-l-oxoproline and Cys-Gly specifically in the cytosol. Here, we report the crystal structures of ChaC2 in two different conformations and compare the structural features with other known γ-glutamylcyclotransferase enzymes. The unique flexible loop of ChaC2 seems to function as a gate to achieve specificity for GSH binding and regulate the constant GSH degradation rate. Structural and biochemical analyses of ChaC2 revealed that Glu74 and Glu83 play crucial roles in directing the conformation of the enzyme and in modulating the enzyme activity. Based on a docking study of GSH to ChaC2 and binding assays, we propose a substrate-binding mode and catalytic mechanism. We also found that overexpression of ChaC2, but not mutants that inhibit activity of ChaC2, significantly promoted breast cancer cell proliferation, suggesting that the GSH degradation by ChaC2 affects the growth of breast cancer cells. Our structural and functional analyses of ChaC2 will contribute to the development of inhibitors for the ChaC family, which could effectively regulate the progression of GSH degradation-related cancers.

Comparison of laboratory indices of non-alcoholic fatty liver disease for the detection of incipient kidney dysfunction.

Non-alcoholic fatty liver disease (NAFLD) is closely linked to insulin resistance and related adverse health outcomes. We investigated the non-invasive index of NAFLD that has the best performance in estimating the renal manifestations of metabolic disturbances. This nation-wide, cross-sectional study included 11,836 subjects, using various non-invasive assessments comprising routinely measured clinical and laboratory variables. The subjects were native Koreans aged 20 years or older and had no diabetes, history of liver or kidney disease. All participants were divided into quintiles according to their fibrosis-4 (FIB-4) results. Participants in the highest quintile were more hypertensive and obese with greater glycemic exposure, poor lipid profiles, and impaired kidney function, than those in the other quintiles. Multiple logistic regression, adjusted for age, sex, smoking, systolic blood pressure, white blood cell, platelet, fasting plasma glucose, and triglyceride, demonstrated that FIB-4, the hepatic steatosis index, the aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, Gholam's model for non-alcoholic steatohepatitis, and the BARD score were independently associated with kidney dysfunction. ROC curve analysis revealed that FIB-4 (AUC = 0.6227, 95% CI [0.5929-0.6526], p = 0.0258) was the most precise in predicting kidney dysfunction. Our findings suggest that FIB-4 may be a favorable screening tool for the renal manifestation of hepatic metabolic disturbances.

Efficacy of the HLA-B∗58:01 Screening Test in Preventing Allopurinol-Induced Severe Cutaneous Adverse Reactions in Patients with Chronic Renal Insufficiency-A Prospective Study.

BACKGROUND: Thus far, human leukocyte antigen (HLA)-B∗58:01 has been recognized as the most important risk factor for allopurinol induced severe cutaneous adverse reactions (SCARs). OBJECTIVE: To determine the usefulness of prospective screening for the HLA-B∗58:01 allele to identify Korean individuals at risk for SCARs induced by allopurinol treatment. METHODS: We prospectively enrolled 542 patients with chronic renal insufficiency (CRI) from 10 hospitals nationwide and performed DNA genotyping to determine whether they carried the HLA-B∗58:01 allele. Of these, 503 HLA-B∗58:01-negative patients (92.8% of total) were treated with allopurinol, and 39 HLA-B∗58:01-positive patients (7.2%) were treated with febuxostat, an alternative drug. The patients then were followed up biweekly for 90 days using a telephone survey to monitor symptoms of adverse drug reactions, including SCARs. As a control, we used the historical incidence rate of allopurinol-induced SCARs in 4002 patients with CRI from the same hospitals who were enrolled retrospectively. RESULTS: Nineteen patients in the prospective cohort developed mild and transient adverse reactions but none showed allopurinol-induced SCARs. By contrast, we identified 38 patients with allopurinol-induced SCARs (0.95%) in the historical control. The difference in the incidence of allopurinol-induced SCARs between the prospective cohort and historical control was statistically significant (0% vs 0.95%, respectively; P = .029). CONCLUSIONS: The present study demonstrated the clinical usefulness of the HLA-B∗58:01 screening test before allopurinol administration to prevent allopurinol-induced SCARs in patients with CRI.

Curcumin interacts directly with the Cysteine 259 residue of STAT3 and induces apoptosis in H-Ras transformed human mammary epithelial cells.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is latent but constitutively activated in many types of cancers. It is well known that STAT3 plays a key role in inflammation-associated tumorigenesis. Curcumin is an anti-inflammatory natural compound isolated from the turmeric (Curcuma longa L., Zingiberaceae) that has been extensively used in a traditional medicine over the centuries. In the present study, we have found that curcumin inhibits STAT3 signaling that is persistently overactivated in H-Ras transformed breast epithelial cells (H-Ras MCF10A). Specific cysteine residues present in STAT3 appear to be critical for the activity as well as conformation of this transcription factor. We identified the cysteine residue 259 of STAT3 as a putative site for curcumin binding. Site-directed mutation of this cysteine residue abolished curcumin-induced inactivation of STAT3 and apoptosis in H-Ras MCF10A cells. The α,ß-unsaturated carbonyl moiety of curcumin appears to be essential in its binding to STAT3 in H-Ras MCF10A cells. Tetrahydrocurcumin that lacks such electrophilic moiety failed to interact with STAT3 and to induce apoptosis in the same cell line. Taken together, our findings suggest that curcumin can abrogate aberrant activation of STAT3 through direct interaction, thereby inhibiting STAT3-mediated mammary carcinogenesis.

Erratum: Affiliation and corresponding author correction: Laparoscopic resection of retroperitoneal benign neurilemmoma.

[This corrects the article on p. 149 in vol. 92, PMID: 28289669.].

Estimating Negative Effect of Abdominal Obesity on Mildly Decreased Kidney Function Using a Novel Index of Body-Fat Distribution.

Abdominal obesity is a major risk factor of chronic kidney disease (CKD). Conventional obesity-related indicators, included body mass index (BMI), waist circumference (WC), and conicity index (C-index), have some limitations. We examined the usefulness of trunk/body fat mass ratio (T/Br) to predict negative effect of abnormal fat distribution on excretory kidney function. We analyzed anthropometric, biochemical and densitometric data from a nation-wide, population-based, case-control study (the Korean National Health and Nutrition Examination Survey [KNHANES] IV and V). A total of 11,319 participants were divided into 2 groups according to estimated glomerular filtration rate (eGFR, mL·min⁻¹·1.73 m⁻²) as follows: Group I (n = 7,980), eGFR ≥ 90 and ≤ 120; and group II (n = 3,339), eGFR ≥ 60 and < 90. Linear regression analysis revealed that T/Br was closely related to eGFR (ß = -0.3173, P < 0.001), and the correlation remained significant after adjustment for age, gender, BMI, WC, C-index, systolic blood pressure (BP), hemoglobin, and smoking amount (ß = -0.0987, P < 0.001). Logistic regression analysis showed that T/Br (odds ratio [OR] = 1.046; 95% confidence interval [CI] = 1.039-1.054) was significantly associated with early decline of kidney function, and adjustment for age, gender, BMI, C-index, systolic BP, hemoglobin, serum glucose level, high-density lipoprotein (HDL)-cholesterol, and smoking amount did not reduce the association (OR = 1.020; 95% CI = 1.007-1.033). T/Br is useful in estimating the negative impact of abdominal obesity on the kidney function.

Association of prediabetes-associated single nucleotide polymorphisms with microalbuminuria.

Increased glycemic exposure, even below the diagnostic criteria for diabetes mellitus, is crucial in the pathogenesis of diabetic microvascular complications represented by microalbuminuria. Nonetheless, there is limited evidence regarding which single nucleotide polymorphisms (SNPs) are associated with prediabetes and whether genetic predisposition to prediabetes is related to microalbuminuria, especially in the general population. Our objective was to answer these questions. We conducted a genomewide association study (GWAS) separately on two population-based cohorts, Ansung and Ansan, in the Korean Genome and Epidemiology Study (KoGES). The initial GWAS was carried out on the Ansung cohort, followed by a replication study on the Ansan cohort. A total of 5682 native Korean participants without a significant medical illness were classified into either control group (n = 3153) or prediabetic group (n = 2529). In the GWAS, we identified two susceptibility loci associated with prediabetes, one at 17p15.3-p15.1 in the GCK gene and another at 7p15.1 in YKT6. When variations in GCK and YKT6 were used as a model of prediabetes, this genetically determined prediabetes increased microalbuminuria. Multiple logistic regression analyses revealed that fasting glucose concentration in plasma and SNP rs2908289 in GCK were associated with microalbuminuria, and adjustment for age, gender, smoking history, systolic blood pressure, waist circumference, and serum triglyceride levels did not attenuate this association. Our results suggest that prediabetes and the associated SNPs may predispose to microalbuminuria before the diagnosis of diabetes mellitus. Further studies are needed to explore the details of the physiological and molecular mechanisms underlying this genetic association.

Acute and chronic effects of dietary sodium restriction on renal tubulointerstitial fibrosis in cisplatin-treated rats.

BACKGROUND: Renal interstitial fibrosis is a major complication of cisplatin (CP) treatment, and increased sodium intake may accelerate its progression by stimulating transforming growth factor (TGF)-ß/Smad signaling. However, it is not clear whether a low-sodium diet has beneficial effects on the development of interstitial fibrosis because it activates the renin-angiotensin-aldosterone system. Here, we tested whether the TGF-ß/Smad signaling pathway is stimulated in CP-treated rats, and whether the development of tubulointerstitial fibrosis in CP nephropathy can be checked by dietary sodium restriction. METHODS: Male Sprague Dawley rats were randomly divided into controls, CP treatment and CP treatment with low-sodium diet. The acute experiment lasted 7 days with a single intraperitoneal injection (6 mg/kg) of CP, and the chronic experiment involved weekly injections (2 mg/kg) for 7 weeks. RESULTS: In both sets of experiments, CP treatment produced pronounced tubulointerstitial injury, increased infiltration of ED1-positive cells and increased expression of monocyte chemotactic protein-1 (MCP-1), α-smooth muscle actin (SMA), TGF-ß1, phosphorylated Smad3, fibronectin and collagen III proteins. In the acute experiment, the increases in expression of osteopontin, MCP-1, α-SMA, TGF-ß and collagen III were significantly reduced by dietary sodium restriction. In the chronic experiment, however, none of the measurements were improved by a low-sodium diet. Examination of CP-treated rat kidneys revealed de novo vimentin expression in tubular epithelial cells and invasion of α-SMA-positive tubular epithelial cells through the basement membrane into the interstitium. CONCLUSIONS: The pro-fibrotic effect of TGF-ß in CP nephropathy appears to be associated with the epithelial-mesenchymal transition and is ameliorated by dietary sodium restriction only during the acute phase.

The role of proximal nephron in cyclophosphamide-induced water retention: preliminary data.

Cyclophosphamide is clinically useful in treating malignancy and rheumatologic disease, but has limitations in that it induces hyponatremia. The mechanisms by which cyclophosphamide induces water retention in the kidney have yet to be identified. This study was undertaken to test the hypothesis that cyclophosphamide may produce water retention via the proximal nephron, where aquaporin-1 (AQP1) and aquaporin-7 (AQP7) water channels participate in water absorption. To test this hypothesis, we gave a single dose of intraperitoneal cyclophosphamide to male Sprague-Dawley rats and treated rabbit proximal tubule cells (PTCs) with 4-hydroperoxycyclophosphamide (4-HC), an active metabolite of cyclophosphamide. In the short-term 3-day rat study, AQP1 protein expression was significantly increased in the whole kidney homogenates by cyclophosphamide administration at 48 (614 ± 194%, P < 0.005), and 96 (460 ± 46%, P < 0.05) mg/kg BW compared with vehicle-treated controls. Plasma sodium concentration was significantly decreased (143 ± 1 vs. 146 ± 1 mEq/L, P < 0.05) by cyclophosphamide 100 mg/kg BW in the long-term 6-day rat study. When primary cultured rabbit PTCs were treated with 4-HC for 24 hours, the protein expressions of AQP1 and AQP7 were increased in a dose-dependent manner. Quantitative polymerase chain reaction revealed no significant changes in the mRNA levels of AQP1 and AQP7 from cyclophosphamide-treated rat renal cortices. From these preliminary data, we conclude that the proximal nephron may be involved in cyclophosphamide-induced water retention via AQP1 and AQP7 water channels. Further studies are required to demonstrate intracellular mechanisms that affect the expression of AQP proteins.

Application of cystatin C reduction ratio to high-flux hemodialysis as an alternative indicator of the clearance of middle molecules.

BACKGROUND/AIMS: Although high-flux (HF) dialyzers with enhanced membrane permeability are widely used in current hemodialysis (HD) practice, urea kinetic modeling is still being applied to indicate the adequacy of both low-flux (LF) and HF HD. In comparison with urea (molecular weight, 60 Da) and beta(2)-microglobulin (beta(2)MG, 12 kDa), cystatin C (CyC, 13 kDa) is a larger molecule that has attractive features as a marker for assessing solute clearance. We postulated that CyC might be an alternative for indicating the clearance of middle molecules (MMs), especially with HF HD. METHODS: Eighty-nine patients were divided into LF and HF groups. Using single pool urea kinetic modeling, the urea reduction ratio (URR) and equilibrated Kt/V(urea) (eKt/V(urea)) were calculated. The serum CyC concentrations were measured using particle-enhanced immunonephelometry. As indices of the middle molecular clearance, the reduction ratios of beta(2)MG and CyC were calculated. RESULTS: The beta(2)MG reduction ratio (beta(2)MGRR) and CyC reduction ratio (CyCRR) were higher in the HF group compared to the LF group. However, the URR and eKt/Vurea did not differ between the two groups. The CyCRR was significantly correlated with the eKt/V(urea) and beta(2)MGRR (r = 0.47 and 0.69, respectively, both p < 0.0001). CONCLUSIONS: Compared to the LF dialyzer, the HF dialyzer removed CyC and beta(2)MG more efficiently. Unlike the beta(2)MGRR, the CyCRR was correlated with the eKt/V(urea) and beta(2)MGRR. This study suggests a role for the CyCRR as an alternative indicator of the removal of MMs.

Hyponatraemia induced by low-dose intravenous pulse cyclophosphamide.

BACKGROUND: Cyclophosphamide is an alkylating agent and was traditionally known to potentiate the renal action of vasopressin. Although low-dose intravenous pulse cyclophosphamide therapy is being used extensively in the treatment of malignant and rheumatological diseases, there have been only a few case reports of cyclophosphamide-induced hyponatraemia. METHODS: Clinical data were retrospectively analysed from 84 patients (42 lupus nephritis; 42 non-Hodgkin's lymphoma; a total of 112 treatment episodes) admitted for intravenous pulse cyclophosphamide (500-750 mg/m(2)) therapy. In all patients, half-isotonic saline was used for prophylactic hydration. Cyclophosphamide-induced hyponatraemia was defined as serum sodium concentration <135 mEq/L at 24 hours after the therapy in patients whose basal serum sodium concentrations were normal. RESULTS: After the low-dose intravenous pulse cyclophosphamide, serum sodium concentration significantly decreased from 139.9 +/- 3.5 to 137.9 +/- 5.1 mEq/L (P < 0.001). Cyclophosphamide-induced hyponatraemia occurred in 15 treatment episodes (13.4%) from 12 patients (14.3%). Patients with hyponatraemia were significantly older than those without hyponatraemia (57.3 +/- 14.7 vs. 40.0 +/- 17.0 years, P < 0.01). Hyponatraemia was associated with male sex on univariate analysis (P < 0.05), but not on multivariate analysis. No factors were found to independently predict the occurrence of cyclophosphamide-induced hyponatraemia when multivariate analysis was performed including parameters age, sex, underlying disease, presence or absence of comorbidities associated with hyponatraemia, presence or absence of concurrent medications associated with hyponatraemia and dose of cyclophosphamide. CONCLUSIONS: Hyponatraemia occurring after low-dose intravenous pulse cyclophosphamide is not rare, especially when hypotonic solutions are adopted for hydration protocol. Thus, the use of hypotonic fluids should be avoided when using cyclophosphamide. Instead, isotonic solutions should be used if a forced diuresis is required.

High Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation for Persistent/Relapsed Ovarian Cancer.

PURPOSE: High dose chemotherapy (HDC) is increasingly being used for ovarian cancer. Although early studies of autotransplantation for advanced ovarian cancer have been encouraging, most reported series were small, and no randomized trials have been reported. HDC and autologous hematopoietic stem cell transplantation were rarely performed in patients with ovarian cancer in Korea, and no results have been reported with the exception of one case report. MATERIALS AND METHODS: We retrospectively analyzed 10 patients with refractory or relapsed ovarian cancer having received HDC and autologous peripheral blood stem cell transplantation (APBSCT), between January 1996 and September 1998, at the Soon Chun Hyang and Ajou University Hospitals. RESULTS: Ten patients were treated with HDC and APBSCT. Six patients achieved complete response (CR) and 1 a partial response (PR), with a response rate of 70%. Three patients did not respond following mobilization chemotherapy, and failed to respond after HDC. The median duration of progression free survival (PFS) and overall survival (OS) were 6 (4~46) and 13 (3~50+) months, respectively. The median duration of OS of the responders following mobilization chemotherapy was 23 (8~50+) compared with 12 (3~18) months of the non- responders. With regard to the treatment related toxicity, 8 patients had neutropenic fevers, and bacteremia was documented in 4. The non-hematological toxicities were never life threatening, and there were no treatment related deaths. CONCLUSION: HDC, followed by APBSCT, is well-tolerated patients with refractory or relapsed ovarian cancer, and following mobilization chemotherapy the responders survived longer than the non-responders.