Median Survival Time (median + survival_time)

Distribution by Scientific Domains
Distribution within Medical Sciences


Selected Abstracts


Factors affecting treatment outcomes following complicated crown fractures managed in primary and secondary care

DENTAL TRAUMATOLOGY, Issue 4 2006
N. G. Jackson
Abstract,,, The aims of this retrospective observational study were to determine the factors which affect treatment provision and the Median Survival Time (MST) for maintenance of tooth vitality following complicated crown fracture. The survey was carried out for patients treated at Newcastle Dental Hospital (NDH) according to departmental guidelines over a 2-year period following the introduction of a new protocol for management of these types of injuries. Seventy-three cases of complicated crown fracture were identified in 69 children with a mean age of 10.3 years (SD = 2.5 years). Seventy-one percent of the fractures occurred in males (M:F ratio was 2.5:1). Fifty-one percent of the complicated crown fractures were in immature teeth. Of the 73 traumatised teeth, 45% presented initially in general dental practice (GDP), 37% at the dental hospital and 8% at local accident and emergency departments with the remaining 10% seen at other or unrecorded locations. Of the 41 fractures, which presented initially at a location other than the dental hospital, 38% were referred to the dental hospital without the provision of an emergency pulp bandage. The overall definitive treatments provided for the 37 open apex teeth included pulp cap (19%), partial pulpotomy (32%), cervical pulpotomy (8%) and pulpectomy (35%), while for the 36 closed apex teeth it was pulp cap (28%), pulpotomy (11%), and pulpectomy (61%). Of the 30 teeth, which underwent vital pulp therapy (18 open and 12 closed apex), the MST for the 15 teeth treated with pulp caps was 1460 days (95% CI: 1067, 1853) while for the 15 teeth treated with pulpotomies it was 1375 days (95% CI: 964, 1786). There was no statistically significant difference in the MST between teeth treated with pulp caps and pulpotomies. In conclusion, the proportion of patients referred to secondary care with complicated crown fractures without provision of a pulp bandage is of some concern. More conservative treatment of closed apex teeth sustaining complicated crown fractures, utilizing vital pulp therapy techniques would appear to be appropriate. [source]


A retrospective study of treatment provided in the primary and secondary care services for children attending a dental hospital following complicated crown fracture in the permanent dentition

INTERNATIONAL JOURNAL OF PAEDIATRIC DENTISTRY, Issue 3 2000
A. Maguire
Objectives. To investigate treatment provision in primary and secondary dental care following complicated crown fracture of permanent teeth. Design and methods. Retrospective observational survey of dental records of all patients attending a dental hospital trauma clinic during a 2-year period with complicated crown fracture. Results. Eighty children (70% male) aged 6,16 years (mean age 10·3 years) with 98 complicated crown fractures were identified. Of these children, 54% were seen for emergency treatment on the day of their injury, 75% within 48 h. Of the 98 injured teeth, 60% were seen initially in general dental practice but only 56% of these 59 cases were provided with emergency treatment in practice, the others being referred immediately to the trauma clinic for treatment. The main cause of fractures was transport, in particular, bicycles. Radiographs were available for 96 teeth; for the 43 open apex teeth, the definitive treatment was pulp capping (44% of cases) and pulpotomy (30%), with vitality maintained in five cases up to 4·8 years after trauma. The 53 closed apex cases were treated definitively with pulp capping (38%) and pulpectomy (36%) and six teeth had maintained their vitality up to 4·3 years after trauma. Sixty-seven per cent of the pulp caps and 47% of the 19 pulpotomies provided relied on a doubtful coronal seal. This was primarily due to the extensive use of a conventional glass ionomer cement as an emergency bandage. The use of an etched or bonded material at initial presentation extended the Median Survival Time for vitality in open apex teeth from 188 to 377 days and in closed apex teeth from 15 to 64 days. Conclusions. Emergency treatment of complicated crown fractures, particularly in primary care services is often inappropriate or inadequate with regard to emergency management of the exposed pulp and provision of a hermetic coronal seal. [source]


Clinical features and predictors of survival of AIDS-related non-Hodgkin's lymphoma in a population-based case series in Sydney, Australia

HIV MEDICINE, Issue 5 2004
MC Robotin
Objectives To analyse clinical features and predictors of survival for AIDS-related non-Hodgkin's lymphoma (NHL) in the era of highly active antiretroviral therapy (HAART), compared to earlier in the HIV epidemic. Methods All AIDS-NHL cases diagnosed at three inner Sydney hospitals caring for people with AIDS during 1985,2001 were identified through medical record searches. Demographic, clinical, immunological and histopathological information was recorded. Year of NHL diagnosis was grouped into three periods, corresponding to whether monotherapy (1985,1991), dual therapy (1992,1995) or HAART (1996,2001) was the main treatment for HIV infection. Statistical comparisons were made between the pre-HAART and post-HAART eras. Results Three hundred cases of AIDS-NHL were identified. Divergent trends were identified for systemic and primary central nervous system (CNS) NHL. For systemic NHL, the CD4 count at NHL diagnosis increased markedly to 208 cells/,L in the post-HAART era (P=0.014) and there was a trend towards presentation as the first AIDS-defining illness (69%, P=0.053), and as earlier stage NHL disease (42%, P=0.048). Median survival time increased from 4.2 months in 1985,1991 to 19 months in the post-HAART era (P<0.001). In a multivariate model, predictors of poor survival from systemic NHL included: NHL diagnosis after another AIDS-defining illness (P<0.001), stage 4 NHL (P<0.001), presentation at extra lymphatic sites (P=0.001), and nonreceipt of chemotherapy (P=0.002). After adjusting for the factors, those diagnosed in the era of HAART had a significant 56% reduction in rate of death (P<0.001). In contrast, for CNS NHL, clinical features were little changed and survival did not improve in the era of HAART. Conclusions Systemic NHL is presenting earlier in the course of HIV disease, and at a less advanced NHL stage. There has been a marked improvement in survival in the era of HAART even after adjustment for other prognostic variables. In contrast, primary CNS NHL remains a disease which presents late in the course of HIV infection and is associated with a very poor prognosis. [source]


Prognostic value of p27kip1 expression in adenocarcinoma of the pancreatic head region

HPB, Issue 3 2006
Jerzy Mielko
Abstract Background. p27kip1 is a tumour suppressor gene, functioning as a cyclin-dependent kinase inhibitor, and an independent prognostic factor in breast, colon, and prostate adenocarcinomas. Conflicting data are reported for adenocarcinoma of the pancreas. The aim of this study was to establish the prognostic value of p27kip1 expression in adenocarcinoma of the pancreatic head region. Patients and methods. The study included 45 patients (male/female ratio 2:1; mean age 59, range 38,82 years) with adenocarcinomas of the pancreatic head region: 24 , pancreatic head, 18 , periampullary and 3 , uncinate process. The patients underwent the Kausch-Whipple pancreatoduodenectomy (n=39), pylorus-preserving pancreatoduodenectomy (n=5), or nearly total pancreatectomy (n=1). Eight patients received adjuvant chemotherapy postoperatively. Follow-up time ranged from 3 to 60 months. Tumours were staged according to the pTNM classification (UICC 1997). Immunohistochemistry was done on paraffin-embedded blocks from tumour sections. Quantitative determination of p27kip1 expression was based on the proportion of p27kip1 -positive cells (< 5%= negative). Survival analysis was carried out using the Kaplan-Meier method and Cox regression model. Results. Positive p27kip1 expression was detected in 22 tumours (49%), whereas 23 tumours (51%) were p27kip1 -negative. There were no significant correlations between p27kip1 index and stage or lymph node involvement. Median survival time in patients with p27kip1 -positive tumours was 19 months, whereas in patients with p27kip1 -negative tumours it was 18 months (p=0.53). A significant relationship was found between p27kip1 -negative tumours and radical resection (p=0.04). Multivariate survival analysis revealed that the localization of the tumour (pancreatic head/uncinate process vs periampullary) was the only significant and independent prognosticator (p=0.01, Cox regression model). Resection margins involvement and grade remained nearly significant prognostic factors (p=0.07 and p=0.09, respectively). Conclusion. We conclude that p27kip1 has limited overall prognostic utility in resected carcinoma of the pancreatic head region, but its potential role as a marker of residual disease needs to be further assessed. [source]


Outcome of self-expandable metallic stents in low-grade versus advanced hilar obstruction

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 11 2008
Rungsun Rerknimitr
Abstract Background:, Self-expandable metallic stents (SEMS) are known to provide a longer patency time than plastic stents for malignant biliary obstructions including hilar obstruction. However, studies that focus on the efficacy of SEMS in low-grade and advanced hilar obstructions are still scanty. Methods:, Ninety four patients with malignant hilar obstructions were enrolled (six were later excluded). Patients were divided into two groups according to their Bismuth levels. Group A were patients with Bismuth I (n = 53). Group B were patients with Bismuth II, III and IV (n = 35). Technical success, complications, jaundice resolution, stent patency time, and patients' survival were analyzed. Results:, Our intention-to-treat analysis showed that group A had a significant lower rate of post-endoscopic retrograde cholangiopancreatography (ERCP) cholangitis than group B; 16.1% versus 44.7%, (P < 0.01). Four patients from group B still had persistent jaundice. Our per protocol analysis demonstrated that median stent patency time in groups A and B were not statistically different (74 vs 60 days). Median survival time in groups A and B were also not statistically different (90 vs 75 days). In both groups, those without liver metastasis had significantly better patency and survival time than those with liver metastasis (P = 0.010 and 0.027, respectively). Conclusions:, In patients with hilar obstruction, liver metastasis is one of the main factors that determine survival of the patient. Patency times of SEMS in both low-grade and advanced obstructions are comparable. However, in the advanced group, there is a significant risk of post-ERCP cholangitis. [source]


Prognostic factors in patients with small hepatocellular carcinoma treated by percutaneous ethanol injection

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 11 2002
Hitoshi Kuriyama
Abstract Background: Percutaneous ethanol injection (PEI) has been widely performed and is now accepted as a viable alternative to hepatic resection in patients with small hepatocellular carcinomas (HCC). However, only a few extensive investigations have been conducted regarding the prognostic factors for HCC patients treated with PEI. Methods: We investigated the prognostic factors in 100 patients with small HCC who had undergone PEI. Univariate analysis and multivariate analysis with Cox's proportional hazards model were used to determine the factors potentially related to survival. For clinical application, a prognostic index was calculated based on the regression coefficients of the independent variables identified from the multivariate analysis. Results: Median survival time and 1, 3 and 5 year survival rates were 71 months and 100, 84 and 62%, respectively. Among the 15 potential prognostic variables investigated, only three variables, namely a serum albumin level ,,3.5 g/dL, the presence of tumor stain and a serum glutamic oxaloacetic transaminase level>,66 IU/L, were identified as factors independently associated with a shorter survival. A prognostic index based on the regression coefficients of these three factors was proposed to classify patients into three groups, those with a good (5 year survival rate 91%), intermediate (64%) and poor prognosis (22%). Conclusions: The results of the present study may be useful in predicting the survival of HCC patients treated with PEI and in the design and analysis of future clinical trials of PEI for HCC. © 2002 Blackwell Publishing Asia Pty Ltd [source]


Treatment of Immune-Mediated Hemolytic Anemia with Individually Adjusted Heparin Dosing in Dogs

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 3 2010
S.E. Helmond
Background: A major cause of death in dogs with immune-mediated hemolytic anemia (IMHA) is thromboembolism. Previous studies suggest unfractionated heparin (UH) is not effective in preventing thromboembolism in IMHA; however, subtherapeutic dosing could explain the seeming lack of efficacy. Hypothesis: Providing therapeutic plasma concentration of UH by individually adjusting doses based on antifactor Xa activity would improve survival in IMHA. Animals: Fifteen dogs with primary IMHA. Methods: Randomized, prospective, controlled clinical trial. Dogs received standardized therapy for IMHA and either constant dose (CD) (150 U/kg SC) (n = 7) or individually adjusted dose (IAD) (n = 8) UH, monitored via an anti-Xa chromogenic assay, adjusted according to a nomogram. UH was administered every 6 hours until day 7, and every 8 hours thereafter. UH dose was adjusted daily in IAD dogs until day 7, weekly until day 28, then tapered over 1 week. Dogs were monitored for 180 days. Results: At day 180, 7 dogs in the IAD group and 1 in the CD group were alive (P= .01). Median survival time for the IAD group was >180 days, and 68 days for the CD group. Thromboembolic events occurred in 5 dogs in the CD group and 2 dogs in the IAD group. Doses of UH between 150 and 566 U/kg achieved therapeutic anti-Xa activity (0.35,0.7 U/mL). Conclusions and Clinical Importance: This study suggests that IAD UH therapy using anti-Xa monitoring reduced case fatality rate in dogs with IMHA when compared with dogs receiving fixed low dose UH therapy. [source]


Primary Hepatitis in Dogs: A Retrospective Review (2002,2006)

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2009
J.H. Poldervaart
Background: Little is known about etiology, disease progression, treatment outcome, survival time, and factors affecting prognosis in dogs with primary hepatitis (PH). Objectives: To review retrospectively different forms of hepatitis in a referral population, by the World Small Animal Veterinary Association Standardization criteria. Animals: One-hundred and one dogs examined for histologically confirmed PH between 2002 and 2006. Dogs with nonspecific reactive hepatitis were excluded. Methods: Retrospective study. Medical records were reviewed for prevalence, signalment, clinical and clinicopathologic manifestation, outcome, survival time, and prognostic factors for shortened survival. Results: PH occurred in 0.5% of dogs in this referral population. Acute (AH) and chronic hepatitis (CH) were diagnosed in 21 and 67 dogs, respectively. Progression from AH to CH occurred in 5/12 of the repeatedly sampled dogs. CH was idiopathic in 43 (64%) dogs, and was associated with copper accumulation in 24 (36%) dogs. Median survival time was longer in dogs with AH than in dogs with CH (either idiopathic or copper associated), and dogs with lobular dissecting hepatitis had the shortest survival time. Prognostic factors predicting shortened survival were associated with decompensated liver function and cirrhosis at initial examination. Conclusions and Clinical Importance: The majority of PH in dogs is CH. Previous studies appear to have underestimated the etiologic role of copper in both AH and CH. Prognosis is reduced in dogs with hepatic cirrhosis or cirrhosis-related clinical findings. Further research into etiology and treatment effectiveness in all PH forms is needed. [source]


Treatment of Dogs with Oral Melanoma by Hypofractionated Radiation Therapy and Platinum-Based Chemotherapy (1987,1997)

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2003
Kim P. Freeman
This retrospective study in 39 dogs with incompletely resected oral melanoma examined the efficacy of hypofractionated radiation therapy and platinum-containing chemotherapy. All dogs were completely staged, with the majority of dogs classified as stage I. Dogs received 6 weekly fractions of 6-gray (Gy) megavoltage irradiation with a cobalt-60 unit or a 4-MeV (megaelectron volts) linear accelerator. Dogs received cisplatin (10,30 mg/m2 IV) or carboplatin (90 mg/m2 IV) chemotherapy 60 minutes before radiation delivery. Durations of local control, metastasis-free survival time, and overall survival time were recorded. By the Kaplan-Meier method, 15% of the dogs had local recurrence within a median time of 139 days. Fifty-one percent of the dogs developed metastatic disease within a median time of 311 days (range, 24,2,163 days). Median survival time for all 39 dogs was 363 days. The combined use of chemotherapy and radiation therapy in this protocol provided local control consistent with previous studies. Low-dose chemotherapy was used with the intent of enhancing radiation therapy for the local control of an incompletely excised tumor. Survival times were longer than previously reported for dogs with oral malignant melanoma. Additional studies are required to determine whether these results were due to the effects of chemotherapy on microscopic disease or the enhanced local control provided by chemoradiation therapy. [source]


Boron Neutron Capture Therapy for glioblastoma multiforme: advantage of prolonged infusion of BPA-f

ACTA NEUROLOGICA SCANDINAVICA, Issue 1 2010
K. Sköld
Sköld K, H-Stenstam B, Diaz AZ, Giusti V, Pellettieri L, Hopewell JW. Boron Neutron Capture Therapy for glioblastoma multiforme: advantage of prolonged infusion of BPA-f. Acta Neurol Scand: 2010: 122: 58,62. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives,,, To assess possible improved efficacy of Boron Neutron Capture Therapy (BNCT) for glioblastoma multiforme (GBM) using prolonged infusion and a correspondingly higher dose of l-boronophenylalanine, as the fructose complex (BPA-f). Materials and methods,,, The benefit of prolonged infusion was analyzed by comparing the results from a Phase II study using 6 h infusion of BPA-f with those obtained from a Phase I/II study using 2 h of infusion. Median survival time (MST) from diagnosis, patient baseline characteristics, salvage treatment and severe adverse events were considered in the comparison. Results,,, MST increased significantly, from 12.8 (95% confidence interval or CI: 10.3,14.0) months with 2 h infusion to 17.7 (95% CI: 13.6,19.9) months with 6 h of infusion. The fraction of patients with WHO grade 3,4 adverse events was similar in the two studies at 13% and 14%, respectively. Conclusion,,, Prolonged infusion was found to be beneficial for the efficacy of BNCT and it is suggested that 6 h infusion of BPA-f should be used in future trials of BNCT for GBM. BNCT, which is a single-day treatment with mild side effects, should be assessed in a controlled trial, as an alternative to 30 daily fractions of conventional fractionated photon therapy over a period of 6 weeks. [source]


Phase 2 trial of docetaxel and gefitinib in the first-line treatment of patients with advanced nonsmall-cell lung cancer (NSCLC) who are 70 years of age or older,

CANCER, Issue 9 2008
George R. Simon MD
Abstract BACKGROUND This is a phase 2 study of chemotherapy-naive patients, 70 years of age or older, with nonsmall-cell lung cancer (NSCLC) who were treated with docetaxel and gefitinib. The primary endpoint was response rate (RR). Secondary endpoints were overall survival (OS) and progression-free survival (PFS). METHODS Eligible patients were treated with docetaxel 75 mg/m2 every 3 weeks and gefitinib 250 mg orally, daily. Docetaxel and gefitinib were given for 2 cycles beyond maximal response. Gefitinib was continued until disease progression. Comorbidities and activities of daily living were assessed (IADL). RESULTS Forty-four patients initiated therapy between March 2003 and May 2005. Seventeen patients (40%; 95% confidence interval [CI], 26%,57%) had a partial response and 48% had stable disease. The median PFS was 6.9 months (95% CI, 3.95,7.8 months). Median survival time was 9.6 months (95% CI, 4.6,16.3 months). On univariate analyses, sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS), and Charlson comorbidities index (CCI) score were predictors of improved survival. On multivariate analyses female sex was a statistically significant predictor of survival. The median survivals were 22.8 months in women and 4.8 months in men. This regimen was well tolerated, with the most common adverse events being hyperglycemia, fatigue, and lymphopenia. CONCLUSIONS Docetaxel combined with gefitinib is active and well tolerated in patients with advanced NSCLC who are 70 years of age and older. This paradigm of treatment merits further investigation as a first-line treatment strategy. Female sex-specific confirmatory clinical trials with this regimen may be warranted. Cancer 2008. © 2008 American Cancer Society. [source]


Impact of primary tumour stage on survival in dogs with solitary lung tumours

JOURNAL OF SMALL ANIMAL PRACTICE, Issue 2 2008
G. A. Polton
Objectives: The objective of this study was to determine simple prognostic criteria for differentiation of canine solitary lung tumour cases into those that will and will not benefit from thoracic surgery. Methods: This was a retrospective study using the records of cases presented to Davies Veterinary Specialists, Hitchin, UK, from December 1998 to December 2005. Survival analyses were performed using the Kaplan-Meier and logrank methods. Potentially significant variables were evaluated by multivariate Cox analysis. Results: Forty-two patients met the inclusion criteria. Primary tumour stage T1, absence of neoplastic lymph nodes and metastases, and papillary tumour type were statistically significant favourable prognostic indicators on univariate analysis. Multivariate analysis attributed significance to primary tumour stage T1 and papillary type only. Median survival times were 555 days for T1N0M0 tumours of papillary type and 72 days for the remainder. Clinical Significance: Survival time following surgery in dogs with primary lung tumours was poor except in clinical stage T1N0M0 cases. These data support use of clinical techniques to dichotomise cases as T1N0M0 or other, improving decision making in thoracic surgery. These data validate initiation of prospective studies examining the role of chemotherapy in the management of advanced cases. [source]


Intra-arterial chemotherapy with mitomycin C in gallbladder cancer: A follow-up study

JOURNAL OF SURGICAL ONCOLOGY, Issue 2 2005
Michaela K. Bode MD
Abstract Background and Objectives There is only limited and somewhat controversial information available on hepatic artery infusion of cytotoxic agents in gallbladder cancer. We report the results of 5-year follow-up of all gallbladder cancer patients treated with surgery and intra-arterial mitomycin C or mitomycin C alone in our hospital during 15 years. Methods Thirty-five patients with gallbladder cancer were treated with superselective intra-arterial chemotherapy (SIAC) with mitomycin C during 1981,1996. Survival was measured from diagnosis, and all patients were followed up until death or the end of January 2002. Cumulative survival rates and median survival times were calculated for all patients, according to response to treatment and staging. The data are presented as 5-year survival. Results Median survival times after SIAC for all patients, responders, and non-responders were 48, 60+, and 8.5 months, respectively. Overall response rate was 60%. Survival was significantly better for tumors limited to the gallbladder wall, as expected. Drug toxicity occurred in half of the patients, requiring cessation of chemotherapy in 25% of the cases. Conclusions The median survival of gallbladder cancer patients treated with surgery and SIAC seems to be significantly better compared to the previously reported outcome of surgical treatment alone. Drug toxicity limits the use of i.a. chemotherapy and requires careful monitoring for early side-effects. J. Surg. Oncol. 2005;91:102,106. © 2005 Wiley-Liss, Inc. [source]


Impact of hemoglobin level on survival in definitive chemoradiotherapy for T4/M1 lymph node esophageal cancer

DISEASES OF THE ESOPHAGUS, Issue 3 2008
S. Zenda
SUMMARY., We retrospectively investigated the impact of the pre-chemoradiotherapy hemoglobin level (pre-CRT Hb level) for T4 and/or M1 lymph node (LYM) squamous cell carcinoma of the esophagus. Chemotherapy consisted of protracted infusion with 5-fluorouracil (5-FU) at 400 mg/m2/day on days 1,5 and 8,12, combined with cisplatin at 40 mg/m2/day on days 1 and 8, repeated twice at a 5-week interval. Concurrent radiation therapy was started on day 1 and delivered at 2 Gy/day for five days a week for a total radiation dose of 60 Gy, with a two-week break after a cumulative dose of 30 Gy. Several factors considered to be related with treatment outcome were evaluated by univariate and multivariate analysis. A total of 48 patients with T4/M1 LYM (lymphocyte) esophageal cancer treated with chemoradiotherapy (CRT) between September 2002 and April 2005 were enrolled. The complete response rate to this regimen was 44% and median survival time was 13.6 months, with a median follow-up period of 26.8 months. Median pre-CRT Hb level was 13.5 (10.4,15.3) g/dL. The CR rate in patients with a pre-CRT Hb level of 13 g/dL or less was only 24% but it was 60% in those with a level that was more than 13 g/dL (P=0.01). As for survival, anovarevealed that a pre-CRT Hb of 13 g/dL or less was a significant prognostic factor with a hazard ratio of 0.45 (95% confidence interval [CI]); 0.21,0.97, P=0.04), while on manova, including performance status, tumor size, TNM stage and pre-CRT Hb level, a pre-CRT Hb level of 13 g/dL or less was the only significant prognostic factor, with a hazard ratio of 0.35 (95% CI; 0.13,0.90, P=0.03). In conclusion, the pre-CRT Hb level may be an important determinant of outcome in patients with T4/M1 LYM squamous cell carcinoma of the esophagus. [source]


Putative functional polymorphisms of MMP9 predict survival of NSCLC in a Chinese population

INTERNATIONAL JOURNAL OF CANCER, Issue 9 2009
Guangfu Jin
Abstract Matrix metalloproteinases (MMPs) play a crucial role in cancer progression and their over-expression is often associated with unfavorable survival of non-small cell lung cancer (NSCLC). Because genetic variants can alter expression level or biological activity of MMPs, we hypothesized that potentially functional single nucleotide polymorphisms (SNPs) in key MMP genes may be associated with the survival of NSCLC patients. We selected and genotyped 14 putative functional SNPs in six MMP genes (MMP1, MMP2, MMP3, MMP7, MMP9 and MMP12) using PCR-RFLP methods in 561 NSCLC patients. Kaplan-Meier method with the log-rank test and Cox proportional hazard models were used for the survival analyses. The C-1562T, Arg279Gln and Arg668Gln polymorphisms in MMP9 were significantly associated with survival of patients with NSCLC (log-rank p values = 0.032, 0.038 and 0.036, respectively). The C-1562T and Arg668Gln loci were in complete linkage disequilibrium (r2 = 1). Patients carrying the 668Gln allele had improved survival with a median survival time (MST) of 51.6 months, compared with 21.8 months for those with the 668Arg/Arg genotype (log-rank p = 0.010). In contrast, the 279Gln/Gln genotype was associated with a significantly shortened MST (17.3 months, log-rank p = 0.030) in the recessive model. In the final multivariate Cox regression model, 279Gln/Gln was identified as an independent prognostic factor with an adjusted hazard ratio of 1.60 (95% confidence interval 1.07,2.41). The MMP9 Arg279Gln and Arg668Gln SNPs are potential predictors of survival in NSCLC patients. © 2008 Wiley-Liss, Inc. [source]


Intra-arterial 5-fluorouracil/interferon combination therapy for hepatocellular carcinoma with portal vein tumor thrombosis and extrahepatic metastases

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 6 2010
Yoshio Katamura
Abstract Background and Aims:, We investigated the efficacy of intra-arterial 5-fluorouracil (5-FU) and systemic interferon (IFN)-, (5-FU-IFN) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis in the first branch or trunk (Vp3/4) and extrahepatic metastases. Methods:, We examined 17 HCC patients with Vp3/4 and extrahepatic metastases (meta group) and 31 HCC patients with Vp3/4 (non-meta group). Baseline intrahepatic tumor factors and the hepatic reserve were similar between groups. The extrahepatic metastases of the meta group were not considered prognostic factors. Following the administration of 5-FU/IFN to all patients, we compared the survival rates, response, time to progression (TTP), and safety between groups. Results:, For intrahepatic HCC, complete response, partial response, stable disease, progressive disease, and drop out were observed in no (0%), one (6%), seven (41%), nine (53%), and no (0%) patients of the meta group, and in five (16%), seven (23%), 13 (42%), five (16%) and one (3%) patient of the non-meta group, respectively. The response rate was significantly lower in the meta group (6% vs 39%, P = 0.018). The median TTP of intrahepatic HCC and the median survival time were significantly shorter in the meta group than in the non-meta group (1.6 vs 6.3 months, P = 0.0001, and 3.9 months vs 10.5 months, P < 0.0001, respectively). The multivariate analysis showed that the absence of extrahepatic metastases was a significant and independent determinant of both TTP of intrahepatic HCC (P < 0.001) and overall survival (P < 0.001). No patient died of extrahepatic HCC-related disease. Conclusions:, The efficacy of 5-FU/IFN for advanced HCC with Vp3/4 and extrahepatic metastases was markedly limited. [source]


Which patients benefit from hemodialysis therapy in hepatorenal syndrome?

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 12 2004
OLIVER WITZKE
Abstract Background and Aim:, Hepatorenal syndrome (HRS) occurs in patients with advanced liver cirrhosis and has a poor outcome. The aim of the present study was to investigate which patients with HRS are likely to benefit from hemodialysis. Methods:, Data were collected prospectively from 30 patients with Child-Pugh C liver cirrhosis and HRS. Patients were either treated with continuous veno-venous hemodialysis (CVVHD) if they were mechanically ventilated, or with intermittent hemodialysis (HD) if they were not mechanically ventilated. Prognosis was assessed by the Child-Pugh and by the Model for End-Stage Liver Disease (MELD) score. The primary aim of the study was the analysis of overall and 30-day patient survival during hemodialysis therapy. To identify predictive factors of survival, variables obtained before the initiation of dialysis therapy were evaluated. Results:, Patients' 30-day survival was 8/30 (median survival time 21 days). Among patients treated with mechanical ventilation, 30-day survival time was 0/15 while 8/15 patients without mechanical ventilation survived more than 30 days (P < 0.001). Using a multivariate model, the relative hazards for serum albumin, international normalized ratio (INR) and catecholamine therapy were not different from one another (P > 0.05), indicating that these parameters were not independent predictors of survival. Mechanical ventilation was an independent risk factor for 30-day (relative hazard 6.6 [1.6,27.7], P < 0.001) and overall survival (relative hazard 6.3 [1.5,26.5], P = 0.01). Child-Pugh (P < 0.01) and the MELD (P < 0.01) score were predictive for overall survival independent of mechanical ventilation. Conclusions:, Patients with HRS without mechanical ventilation may benefit from hemodialysis, whereas hemodialysis seems to be futile in patients with mechanical ventilation. [source]


Effect of monensin liposomes on the cytotoxicity of anti-My9-bR immunotoxin

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2003
Madhu Sudhan Shaik
The purpose of the study was to evaluate the utility of monensin liposomes in the enhancement of in-vitro cytotoxicity, apoptosis and in-vivo antitumour activity of anti-My9-bR immunotoxin. Monensin liposomes were prepared and studied for the enhancement of in-vitro cytotoxicity and apoptotic response of anti-My9-bR immunotoxin against both sensitive and resistant human promyelocytic leukemia HL-60 cells by MTS/PES method and acridine orange staining, respectively. Further, the in-vivo cytotoxicity enhancement of anti-My9-bR immunotoxin by monensin liposomes was studied in a survival model of severe combined immunodeficient (SCID) mice bearing intraperitoneal HL-60 tumours. The in-vitro cytotoxicity of anti-My9-bR immunotoxin was enhanced 580 fold and 4.7 fold against sensitive and resistant HL-60 cells, respectively, by monensin liposomes (5 times 10,8m). The combination of anti-My9-bR immunotoxin (50 ng mL,1) with monensin liposomes (5 times 10,8m) produced apoptosis in 40% of cells, whereas the apoptotic response was minimal (< 10%) in anti-My9-bR immunotoxin- or monensin liposome (alone)-treated HL-60 (resistant) cells. In SCID mice bearing HL-60 tumours, anti-My9-bR immunotoxin (75 ,g kg,1 administered intravenously every other day for a total of five courses) showed a median survival time of 20 days, which was no different than that of vehicle control- or monensin liposome-treated mice. However, anti-My9-bR immunotoxin (75 ,g kg,1) in combination with monensin liposomes (4 ,g kg,1 monensin), administered every other day for a total of five courses, was found to prolong the survival of 20% of mice for more than 46 days. Our results indicate that, despite anti-My9-bR immunotoxin being ineffective in the HL-60 tumour model, its combination with monensin liposomes could improve the antitumour response. [source]


Ciclosporin use in multi-drug therapy for meningoencephalomyelitis of unknown aetiology in dogs

JOURNAL OF SMALL ANIMAL PRACTICE, Issue 9 2007
P. F. Adamo
Objective: To evaluate the efficacy and safety of ciclosporin therapy alone or in combination with corticosteroids and/or ketoconazole in dogs with diagnosis of meningoencephalomyelitis of unknown aetiology. Methods: Medical records of 10 dogs diagnosed with meningoencephalomyelitis of unknown aetiology and treated with ciclosporin therapy alone or in combination with corticosteroids and/or ketoconazole were reviewed at the Veterinary Medical Teaching Hospital, University of Wisconsin-Madison. Laboratory abnormalities, side effects, clinical and cerebrospinal fluid responses to treatment and association between blood ciclosporin level and response to treatment were evaluated. Histopathological diagnosis was available in three patients. Results: No significant abnormalities were detected on serial complete blood count and serum chemistry panel in any of the dogs. Side effects of ciclosporin therapy included excessive shedding, gingival hyperplasia and hypertrichosis. Overall median survival time for all dogs in the study was 930 days (range, 60 to more than 1290 days). In all dogs, serial cerebrospinal fluid analysis showed a marked improvement in the inflammation. Clinical Significance: Results suggest that ciclosporin either alone or in combination with ketoconazole may be a safe and effective treatment for meningoencephalomyelitis of unknown aetiology in dogs. [source]


Efficacy and Toxicosis of VELCAP-C Treatment of Lymphoma in Cats

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2008
A.G. Hadden
Background: Lymphoma is the most common malignancy affecting cats. A protocol employing vincristine, l -asparaginase, cyclophosphamide, doxorubicin, and prednisone (VELCAP-S) is effective and well tolerated in dogs with lymphoma. A 24-week variation of this protocol (VELCAP-C) was developed for treatment of cats. Hypothesis: That VELCAP-C will result in survival times for cats with lymphoma that are similar to those obtained when cats are treated with a protocol that includes fewer chemotherapy agents. Animals: Sixty-one cats with lymphoma. Methods: Retrospective study. Outcomes evaluated were response to VELCAP-C therapy, toxicosis, and survival time. The effect of signalment, staging, CBC, and serum chemistry profile and dosage on these outcomes was examined. Results: Six cats (10%) completed the protocol with a median survival of 1189 days. Forty-three percent (23 of 61) of the cats achieved complete response (CR) with a median survival time of 62 days. Cats that required a dose reduction of any drug during induction were more likely to achieve CR. Weight loss and hepatomegaly at diagnosis were negatively associated with response to treatment. Increased lactate dehydrogenase (LDH) serum activity at the time of initial treatment correlated with decreased survival times. Conclusions and Clinical Importance: This multi agent protocol did not provide improved survival over historical data using protocols with fewer agents. Serum LDH activity levels might provide useful prognostic information for cats with lymphoma. [source]


Hepatorenal syndrome: A proposal for kidney after liver transplantation (KALT)

LIVER TRANSPLANTATION, Issue 6 2007
Richard Ruiz
Hepatorenal syndrome (HRS) is a well-recognized complication of end-stage liver disease. Once thought to be a reversible condition with liver transplantation (LT) alone, HRS may directly contribute to the requirement for long-term dialysis posttransplant. As a result, discussion has now focused on whether or when a kidney allograft should be considered for these patients. Using the International Ascites Club guidelines with a pretransplant serum creatinine (SCr) >2.0 mg/dL to define HRS, 130 patients undergoing LT over a 10-yr period were identified, for an overall incidence of 9%. Patient survival rates at 1, 3, and 5 yr were 74%, and 68%, and 62%, respectively. Survival was significantly worse when compared to non-HRS patients undergoing LT over the same study period (P = 0.0001). For patients presenting with type 2 HRS, 7 patients (6%) developed irreversible kidney failure posttransplant compared to 0.34% in the non-HRS population (P < 0.0001). Five of these patients died within 1 yr with a median survival time of 139 days. Combined liver and kidney transplantation (CLKT) for patients with HRS is not recommended. However, an improvement in outcome can be accomplished by addressing those patients who require dialysis greater than 60 days posttransplant. We propose a role for kidney after liver transplantation (KALT) in select HRS patients. Liver Transpl 13:838,843, 2007. © 2007 AASLD. [source]


Evaluation of anticancer activity of the alkaloid fraction of Alstonia scholaris (Sapthaparna) in vitro and in vivo

PHYTOTHERAPY RESEARCH, Issue 2 2006
Ganesh Chandra Jagetia
Abstract The anticancer effect of various doses of an alkaloid fraction of Sapthaparna, Alstonia scholaris (ASERS), was studied in vitro in cultured human neoplastic cell lines (HeLa, HepG2, HL60, KB and MCF-7) and in Ehrlich ascites carcinoma bearing mice. Treatment of HeLa cells with 25 µg/mL ASERS resulted in a time dependent increase in the antineoplastic activity and the greatest activity was observed when the cells were exposed to ASERS for 24 h. However, exposure of cells to ASERS for 4 h resulted in 25% viable cells and hence this time interval was considered to be the optimum time for treatment and further studies were carried out using this time. Treatment of various cells with ASERS resulted in a concentration dependent decline in the viable cells and a nadir was reached at 200 µg/mL in all the cell lines studied. The IC50 was found to be 5.53, 25, 11.16, 10 and 29.76 µg/mL for HeLa, HePG2, HL60, KB and MCF-7 cells, respectively. Similarly, administration of ASERS, once daily for 9 consecutive days to the tumor bearing mice caused a dose dependent remission of the tumor up to 240 mg/kg body weight, where the greatest antitumor effect was observed. Since 240 mg/kg ASERS showed toxic manifestations, the next lower dose of 210 mg/kg was considered as the best effective dose, in which 20% of the animals survived up to 120 days post-tumor-cell inoculation as against no survivors in the saline treated control group. The ASERS treatment resulted in a dose dependent elevation in the median survival time (MST) and the average survival time (AST) up to 240 mg/kg ASERS and declined thereafter. The surviving animals were healthy and disease free. The effect of ASERS was better than cyclophosphamide, which was used as a positive control, where all the animals succumbed to death by 40 days and the MST and AST were 19.5 and 18.3 days, respectively. The effective dose of 210 mg of ASERS was 3/10 of the LD50 dose, which increased the MST and AST up to 54 and 49.5 days, respectively. Copyright © 2006 John Wiley & Sons, Ltd. [source]


Purified Eicosapentaenoic Acid Induces Prolonged Survival of Cardiac Allografts and Generates Regulatory T Cells

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2009
D. Iwami
Fish oil, which is rich in eicosapentaenoic acid (EPA), has been found to have immunomodulatory effects. We examined whether administration of purified EPA affected survival of fully mismatched murine cardiac allografts. Hearts from C57BL/10 (H-2b) mice were transplanted into CBA (H-2k) recipients treated with one intraperitoneal dose of purified EPA the day of transplantation. Untreated CBA recipients and recipients given 0.1 g/kg of EPA rejected C57BL/10 hearts (median survival time [MST], 8 and 13 days, respectively). With a 1.0 g/kg dose of EPA, graft survival was markedly prolonged (MST >100 days). To determine whether regulatory cells were generated, naļve mice (secondary recipients) underwent adoptive transfer of splenocytes from EPA-treated primary recipients and cardiac allograft transplantation. Adoptive transfer of whole, CD4+ and CD4+CD25+ splenocytes from EPA-treated recipients induced indefinite survival in secondary recipients. Flow cytometry showed that the CD4+CD25+ cells were Foxp3+. In reverse transcriptase-polymerase chain reaction (RT-PCR) studies, the expression of peroxisome proliferator-activated receptor , (PPAR,) mRNA was upregulated by EPA treatment. A PPAR, antagonist abrogated the prolongation of graft survival induced by EPA treatment (MST, 13 days). Thus, in our model, purified EPA induced prolonged survival of fully mismatched cardiac allografts and generated regulatory T cells dependent on PPAR, activation. [source]


Efficacy of repeat hepatic resection for recurrent hepatocellular carcinomas

ANZ JOURNAL OF SURGERY, Issue 10 2009
Yasuhiko Nagano
Abstract Background:, This study evaluated the efficacy of repeat hepatic resection for recurrent hepatocellular carcinoma (HCC) and the clinicopathological factors influencing overall survival after resection. Methods:, From 1992 to 2005, 231 patients underwent curative hepatic resection for HCC at Yokohama City University, Japan. Of these, 105 patients developed intrahepatic recurrence, and 24 repeat hepatectomies were performed for recurrent HCC. Survival data were analysed, and prognostic factors for repeat hepatic resection were determined. Results:, The overall cumulative 1-, 3- and 5-year survival rates and the median survival time of the patients after initial hepatic resection (n= 231) did not differ from those of the patients after repeat hepatic resection (n= 24), with values of 91.3, 70.2 and 49.1%, and 57 months, versus 91.7, 73.1 and 50.9%, and 61.5 months, respectively (P= 0.875). The operative time and blood loss in patients who underwent repeat hepatic resection did not differ from those who underwent primary resection. Multivariate analysis identified portal invasion at the first hepatic resection and a disease-free interval of ,1.5 years after primary hepatic resection as independent risk factors for survival after repeat hepatic resection. The 12 patients who did not show either of the two prognostic factors had 3- and 5-year survival rates of 91.7 and 68.8%, respectively, after repeat hepatic resection. Conclusions:, Our findings suggest repeat hepatic resection as the treatment of choice for recurrent HCC patients without portal invasion at the first resection whose recurrence develops after a disease-free interval of >1.5 years since the previous surgery. [source]


Effects of dietary docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6) on the growth, survival, stress resistance and fatty acid composition in black sea bass Centropristis striata (Linnaeus 1758) larvae

AQUACULTURE RESEARCH, Issue 9 2010
Troy C Rezek
Abstract The objectives of this study were to determine the effects of the dietary docosahexaenoic acid (DHA) to arachidonic acid (ARA) ratio on the survival, growth, hypersaline stress resistance and tissue composition of black sea bass larvae raised from first feeding to metamorphic stages. Larvae were fed enriched rotifers Brachionus rotundiformis and Artemia nauplii containing two levels of DHA (0% and 10% total fatty acids=TFA) in conjunction with three levels of ARA (0%, 3% and 6% TFA). On d24ph, larvae fed the 10:6 (DHA:ARA) treatment showed significantly (P<0.05) higher survival (62.3%) than larvae fed 0:0 (DHA:ARA) (27.4%). Notochord length and dry weight were also significantly (P<0.05) greater in the 10:6 (DHA:ARA) treatment (8.65 mm, 2.14 mg) than in the 0:0 (DHA:ARA) (7.7 mm, 1.65 mg) treatment. During hypersaline (65 g L,1) challenge, no significant differences (P>0.05) were observed in the median survival time (ST50) between larvae fed 10% DHA (ST50=25.6 min) and larvae fed 0% DHA (ST50=18.2 min). The results suggested that black sea bass larvae fed prey containing 10% DHA with increasing ARA within the range of 0,6% showed improved growth and survival from first feeding through metamorphic stages. [source]


Growth, salinity tolerance and microsatellite analysis of the F2 reciprocal hybrids of Oreochromis niloticus×Sarotherodon galilaeus at different salinities

AQUACULTURE RESEARCH, Issue 9 2010
Biao Yan
Abstract Oreochromisniloticus (O), the sixth generation of Genetic Improvement of Farmed Tilapia, shows rapid growth but poor salt tolerance, while Sarotherodon galilaeus (S) exhibits opposite traits. To combine the traits, F1 progeny was obtained through artificial fertilization. Fertile F1 produced F2 by natural spawning. The mean survival times, the median survival time (ST50) or the survival rate of hybrids was greater than O. niloticus in a gradual or an acute salinity change. Plasma osmolarity, [Na+] and [Cl,] of the hybrids fluctuated in 32 g L,1 water during a 24-h period, but eventually reached levels similar to fish in freshwater. O. niloticus,×S. galilaeus, (OS F2) or S. galilaeus,×O. niloticus, (SO F2) showed the fastest growth at 22.5 g L,1, equal to about 78.2% or 69.7% of O. niloticus at 0 and 3.87 or 3.45 times that of S. galilaeus at their individual optimum growth. Growth in OS F2 was 12% faster than SO F2. Microsatellite analysis showed that F2 had more alleles, a higher polymorphism information content and greater observed and expected heterozygosity than O. or S. Population differentiation was not detected between F1 and F2. All the results indicated that F2 could be exploited for commercial production under saline conditions. [source]


Extraosseous osteosarcoma: Single institutional experience in Korea

ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 2 2010
Soohyeon LEE
Abstract Aim: Extraosseous osteosarcoma (EOO) is a rare soft tissue form of osteosarcoma without involvement of the skeletal system. Due to the rarity of disease, its clinical features and optimal treatment are yet to be defined. Methods: Between 1 January 1999 and 30 June 2008 ten patients were pathologically confirmed with extra-skeletal osteosarcoma. A retrospective analysis of the ten patients was performed. Results: The anatomical distribution of the osteosarcomas was as follows: lower extremities (n = 3), upper extremities (n = 2), breast (n = 2), lung (n = 1), cheek (n = 1) and retroperitoneum (n = 1). Nine patients initially underwent resection of the primary mass. One patient, who received six cycles of adjuvant doxorubicin and cisplatin chemotherapy was alive in remission at 42.6 months. One patient with postoperative radiotherapy after curative surgery was alive in remission at 6.2 months. However, all three patients who received curative resection but no postoperative radiotherapy or chemotherapy died of the disease at 10.7, 11.1 and 15.6 months after surgery. The median time to failure was only 4.4 months (95% CI, 0.6, 8.2 months) and the median survival time of all patients was only 11.1 months (95% CI, 5.6, 16.6 months). At the time of analysis, seven patients were dead and all died of the disease recurrence. Conclusion: EOO should be treated as a soft tissue sarcoma with aggressive behavior and multimodality treatment should be actively sought to improve treatment outcome. The impact of adjuvant chemotherapy on survival of EOO needs further investigation. [source]


How should we quantify the performance of KPro's?

ACTA OPHTHALMOLOGICA, Issue 2009

Purpose To report a method of standardized data collection and reporting and statistical assessment that can be used for all KPro“s available on the market. The database (will be presented) should be , Usable for different types of KPro“s , Easily adaptable to changes in technique , Allow for complete entry of relevant data Methods Visual Acuity data should be reported in different international surgical centres in a standardized manner: Best spectacle corrected VA, unless BCVA only possible with CL (> useful time of wear). A complete entry of all relevant data is possible in this database. The statistical analysis should be agreed upon by all centres. For Survival Time = Retention of KPro > the Kaplan-Meier method For Visual Acuity over the Course of Time > the Monte-Carlo method Results A database will be demonstrated that can be used free of charge by all KPro centres interested. The VISUAL ACUITY BY TIME- INDEX (VAT- Index) will also be presented, whose theoretical basis published in: Journal of Theoretical Medicine, 2002 / 4, 183-190, W. Hitzl and G. Grabner [bdquo]Application of the Monte Carlo Method for the Assessment of Long-term Success in Keratoprosthesis Surgery". Example of its use will be give, based in data, courtesy Barraquer Eye Clinic, Barcelona. Conclusion With the Kaplan-Meier method: + analysis is done quickly, uses all data available, hypotheses tests are available for comparisons and mean and median survival time can be computed - no information about relation between time and best corrected visual acuity and the definition of terminal event is arbitrary to a certain extent. Monte-Carlo method (VAT-index): + Method is based on a so-called non-parametric longitudinal model + Reliabel estimation of relation between time and best corrected visual acuity at any given time point (patient as well as surgeon is basically interested in this relation). + statistically valid analysis and better comparison of different KPro techniques + easy comparison of defined postoperative periods + comparison of different initial clinical findings and diseases possible + long-time follow-up of BCVA - shorter follow-up time as compared with Kaplan-Meier method (e.g. with strict [bdquo]80%data complete" criteria) [source]


Intra-arterial chemotherapy with mitomycin C in gallbladder cancer: A follow-up study

JOURNAL OF SURGICAL ONCOLOGY, Issue 2 2005
Michaela K. Bode MD
Abstract Background and Objectives There is only limited and somewhat controversial information available on hepatic artery infusion of cytotoxic agents in gallbladder cancer. We report the results of 5-year follow-up of all gallbladder cancer patients treated with surgery and intra-arterial mitomycin C or mitomycin C alone in our hospital during 15 years. Methods Thirty-five patients with gallbladder cancer were treated with superselective intra-arterial chemotherapy (SIAC) with mitomycin C during 1981,1996. Survival was measured from diagnosis, and all patients were followed up until death or the end of January 2002. Cumulative survival rates and median survival times were calculated for all patients, according to response to treatment and staging. The data are presented as 5-year survival. Results Median survival times after SIAC for all patients, responders, and non-responders were 48, 60+, and 8.5 months, respectively. Overall response rate was 60%. Survival was significantly better for tumors limited to the gallbladder wall, as expected. Drug toxicity occurred in half of the patients, requiring cessation of chemotherapy in 25% of the cases. Conclusions The median survival of gallbladder cancer patients treated with surgery and SIAC seems to be significantly better compared to the previously reported outcome of surgical treatment alone. Drug toxicity limits the use of i.a. chemotherapy and requires careful monitoring for early side-effects. J. Surg. Oncol. 2005;91:102,106. © 2005 Wiley-Liss, Inc. [source]