Hepatocellular carcinoma is a common complication of chronic liver disease (CLD), and is conventionally diagnosed by radiological means. We aimed to build a statistical model that could determine the ...risk of hepatocellular carcinoma in individual patients with CLD using objective measures, particularly serological tumor markers.
A total of 670 patients with either CLD alone or hepatocellular carcinoma were recruited from a single UK center into a case-control study. Sera were collected prospectively and specifically for this study. A logistic regression analysis was used to determine independent factors associated with hepatocellular carcinoma and a model built and assessed in terms of sensitivity, specificity, and proportion of correct diagnoses.
The final model involving gender, age, AFP-L3, α fetoprotein (AFP), and des-carboxy-prothrombin ("GALAD") was developed in a "discovery" data set and validated in independent data sets both from the same institution and from an external institution. When optimized for sensitivity and specificity, the model gave values of more than 0.88 irrespective of the disease stage.
The presence of hepatocellular carcinoma can be detected in patients with CLD on the basis of a model involving objective clinical and serological factors. It is now necessary to test the model's performance in a prospective manner and in a routine clinical practice setting, to determine if it may replace or, more likely, enhance current radiological approaches.
Our data provide evidence that an entirely objective serum biomarker-based model may facilitate the detection and diagnosis of hepatocellular carcinoma and form the basis for a prospective study comparing this approach with the standard radiological approaches.
OBJECTIVE AND BACKGROUND:Local and distant disease recurrence are frequently observed following pancreatic cancer resection, but an improved understanding of resection margin assessment is required ...to aid tailored therapies.
METHODS:Analyses were carried out to assess the association between clinical characteristics and margin involvement as well as the effects of individual margin involvement on site of recurrence and overall and recurrence-free survival using individual patient data from the European Study Group for Pancreatic Cancer (ESPAC)-3 randomized controlled trial.
RESULTS:There were 1151 patients, of whom 505 (43.9%) had an R1 resection. The median and 95% confidence interval (CI) overall survival was 24.9 (22.9–27.2) months for 646 (56.1%) patients with resection margin negative (R0 >1 mm) tumors, 25.4 (21.6–30.4) months for 146 (12.7%) patients with R1<1 mm positive resection margins, and 18.7 (17.2–21.1) months for 359 (31.2%) patients with R1-direct positive margins (P < 0.001). In multivariable analysis, overall R1-direct tumor margins, poor tumor differentiation, positive lymph node status, WHO performance status ≥1, maximum tumor size, and R1-direct posterior resection margin were all independently significantly associated with reduced overall and recurrence-free survival. Competing risks analysis showed that overall R1-direct positive resection margin status, positive lymph node status, WHO performance status 1, and R1-direct positive superior mesenteric/medial margin resection status were all significantly associated with local recurrence.
CONCLUSIONS:R1-direct resections were associated with significantly reduced overall and recurrence-free survival following pancreatic cancer resection. Resection margin involvement was also associated with an increased risk for local recurrence.
CONTEXT Patients with periampullary adenocarcinomas undergo the same resectional surgery as that of patients with pancreatic ductal adenocarcinoma. Although adjuvant chemotherapy has been shown to ...have a survival benefit for pancreatic cancer, there have been no randomized trials for periampullary adenocarcinomas. OBJECTIVE To determine whether adjuvant chemotherapy (fluorouracil or gemcitabine) provides improved overall survival following resection. DESIGN, SETTING, AND PATIENTS The European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary trial, an open-label, phase 3, randomized controlled trial (July 2000-May 2008) in 100 centers in Europe, Australia, Japan, and Canada. Of the 428 patients included in the primary analysis, 297 had ampullary, 96 had bile duct, and 35 had other cancers. INTERVENTIONS One hundred forty-four patients were assigned to the observation group, 143 patients to receive 20 mg/m2 of folinic acid via intravenous bolus injection followed by 425 mg/m2 of fluorouracil via intravenous bolus injection administered 1 to 5 days every 28 days, and 141 patients to receive 1000 mg/m2 of intravenous infusion of gemcitabine once a week for 3 of every 4 weeks for 6 months. MAIN OUTCOME MEASURES The primary outcome measure was overall survival with chemotherapy vs no chemotherapy; secondary measures were chemotherapy type, toxic effects, progression-free survival, and quality of life. RESULTS Eighty-eight patients (61%) in the observation group, 83 (58%) in the fluorouracil plus folinic acid group, and 73 (52%) in the gemcitabine group died. In the observation group, the median survival was 35.2 months (95%% CI, 27.2-43.0 months) and was 43.1 (95%, CI, 34.0-56.0) in the 2 chemotherapy groups (hazard ratio, 0.86; (95% CI, 0.66-1.11; χ2 = 1.33; P = .25). After adjusting for independent prognostic variables of age, bile duct cancer, poor tumor differentiation, and positive lymph nodes and after conducting multiple regression analysis, the hazard ratio for chemotherapy compared with observation was 0.75 (95% CI, 0.57-0.98; Wald χ2 = 4.53, P = .03). CONCLUSIONS Among patients with resected periampullary adenocarcinoma, adjuvant chemotherapy, compared with observation, was not associated with a significant survival benefit in the primary analysis; however, multivariable analysis adjusting for prognostic variables demonstrated a statistically significant survival benefit associated with adjuvant chemotherapy TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00058201
Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection.
Microarrays from 434 ...patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided.
Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval CI = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)₁= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)₁ = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)₁ = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients.
Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.
Hydration in advanced cancer is a controversial area; however, current hydration assessments methods are poorly developed. Bioelectrical impedance vector analysis (BIVA) is an accurate hydration ...tool; however its application in advanced cancer has not been explored. This study used BIVA to evaluate hydration status in advanced cancer to examine the association of fluid status with symptoms, physical signs, renal biochemical measures and survival.
An observational study of 90 adults with advanced cancer receiving care in a UK specialist palliative care inpatient unit was conducted. Hydration status was assessed using BIVA in addition to assessments of symptoms, physical signs, performance status, renal biochemical measures, oral fluid intake and medications. The association of clinical variables with hydration was evaluated using regression analysis. A survival analysis was conducted to examine the influence of hydration status and renal failure.
The hydration status of participants was normal in 43 (47.8%), 'more hydrated' in 37 (41.1%) and 'less hydrated' in 10 (11.1%). Lower hydration was associated with increased symptom intensity (Beta = -0.29, p = 0.04) and higher scores for physical signs associated with dehydration (Beta = 10.94, p = 0.02). Higher hydration was associated with oedema (Beta = 2.55, p<0.001). Median survival was statistically significantly shorter in 'less hydrated' patients (44 vs. 68 days; p = 0.049) and in pre-renal failure (44 vs. 100 days; p = 0.003).
In advanced cancer, hydration status was associated with clinical signs and symptoms. Hydration status and pre-renal failure were independent predictors of survival. Further studies can establish the utility of BIVA as a standardised hydration assessment tool and explore its potential research application, in order to inform the clinical management of fluid balance in patients with advanced cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The problem of associating a continuous covariate, or biomarker, against a time‐to‐event outcome, is that it often requires categorisation of the covariate. This can lead to bias, loss of information ...and a poor representation of any underlying relationship. Here, two methods are proposed for estimating the effects of a continuous covariate on a time‐to‐event endpoint using weighted kernel estimators. The first method aims to estimate a density function for a time‐to‐event endpoint conditional on some covariate value whilst the second uses a joint density estimator. The results are visualisations in the form of surface plots that show the effects of a covariate without any need for categorisation. Both methods can aid interpretation and analysis of covariates against a time‐to‐event endpoint.
Latent class methods can be used to identify unobserved subgroups which differ in their observed data. Researchers are often interested in outcomes for the identified subgroups and in some ...disciplines time-to-event outcome measures are common, e.g., overall survival in oncology. In this study Monte Carlo simulation is used to evaluate the empirical properties of latent class effect estimates on a time-to-event distal outcome using one, two and three-step approaches. Both standard and inclusive bias-corrected three-step approaches are considered. One-step latent class effect estimates are shown to be superior to the evaluated alternatives. Both the two-step approach and a standard three-step approach, where subjects are partially assigned to latent classes, produced unbiased estimates with nominal confidence interval coverage when latent classes were well separated, but not otherwise.
Keywords: latent class analysis, time-to-event, two-step, joint modeling
Abstract
The problem of associating a continuous covariate, or biomarker, against a time‐to‐event outcome, is that it often requires categorisation of the covariate. This can lead to bias, loss of ...information and a poor representation of any underlying relationship. Here, two methods are proposed for estimating the effects of a continuous covariate on a time‐to‐event endpoint using weighted kernel estimators. The first method aims to estimate a density function for a time‐to‐event endpoint conditional on some covariate value whilst the second uses a joint density estimator. The results are visualisations in the form of surface plots that show the effects of a covariate without any need for categorisation. Both methods can aid interpretation and analysis of covariates against a time‐to‐event endpoint.
Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid ...(HGA) in AKU but the dose-response relationship has not been previously studied.
Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone.
A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy.
In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range.
EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463.
PDF
