Relative Risk Of Recurrence Research Articles

Modification of Tamoxifen Response: What Have We Learned?

TO THEEDITOR:InarecentJournalofClinicalOncologyeditorial, Desta and Flockhart 1 asked a yes-no question about the germline pharmacogeneticsoftamoxifenresponse:“Havewelearnedenough?” They ultimately answer by writing that recommendations regarding genetic testing for CYP2D6 variants must await further data, but the list of open questions preceding this answer did not include the question of whether there is a main effect. We therefore raise this question about the main effect: “Has it been established that tamoxifen is a less effectiveadjuvanttherapyforestrogenreceptor‐positivebreastcancer patients with functionally variant CYP2D6 allele(s) than for those without functionally variant alleles?” Figure 1 depicts the results of the five epidemiologic studies of thisquestion. 2-6 Toexaminethedepartureofthedistributionofthese results from the null (ie, relative risk of 1.0), we first ranked the five relative risks of recurrence from lowest to highest (citations 2 to 6 in ascending order). We then plotted each study’s relative risk and its 95%CIagainsttheinversenormalofitsrankpercentile. 7 Thestippled lineshowstheregressionofinverse-varianceweightedlog-relativerisk against the inverse normal of rank percentile. If the accumulated evidenceisarandomsamplefromalognormaldistributionofrelative risks centered on the null, then the relative risks should fall along this line and the line should intersect the x-axis at zero. The results of the accumulated studies fit just such a pattern. Indeed, the inversevariance weighted geometric mean of the relative risks equals 1.04 (95%CI,0.77,1.41).Eachstudyhascertainstrengthsandlimitations, some of which were pointed out by Desta and Flockhart, and consideration of them against one another is of value. Nonetheless, the simplest explanation for the results to date is that they are sampled from an underlying null association. The integer above each interval in Fig 1 shows the number of women in the study (as best we can determine) with a recurrence and with the variant allele(s). Because both recurrence and the variant allele are rare, this number is the primary determinant of the study’s precision. Summed over all of the studies, there are only approximately sixty women with both a recurrence and the variant allele(s), about half from studies reporting a protective association and half fromstudiesreportingacausalassociation.Inourview,sixtywomen, evenlydistributedaboutthenull,istoosmallanumbertoconsiderthe association between CYP2D6-variant alleles and tamoxifen effective

Postpolypectomy Colonoscopy Surveillance Guidelines: Predictive Accuracy for Advanced Adenoma at 4 Years

Lack of confidence in postpolypectomy surveillance guidelines may be a factor in the observed low adherence rates among providers. To assess the 2006 postpolypectomy colonoscopy surveillance guidelines, which recommend 3-year follow-up colonoscopy for individuals with high-risk adenomas (defined as > or =3 adenomas or any advanced adenomas) and 5- to 10-year follow-up for patients with 2 or fewer nonadvanced adenomas, who are considered to be at low risk. Analysis of prospective data from the Polyp Prevention Trial. United States. 1905 patients who had colorectal adenomas removed at baseline screening or diagnostic colonoscopy and completed the trial. Baseline adenoma characteristics, risk-stratified according to definitions used in the guidelines, were examined as predictors for advanced adenoma recurrence. 125 patients (6.6%) had advanced and 629 (33.0%) had nonadvanced adenoma recurrence; 1151 (60.4%) had no recurrence within 4 years of follow-up. The probability of advanced adenoma recurrence was 0.09 (95% CI, 0.07 to 0.11) among patients with high-risk adenomas at baseline and 0.05 (CI, 0.04 to 0.06) among those with low-risk adenomas at baseline. The relative risk for advanced adenoma recurrence for patients with high-risk adenomas versus those with low-risk adenomas at baseline was 1.68 (CI, 1.19 to 2.38) when advanced adenoma recurrence was compared with no advanced adenoma recurrence and 1.76 (CI, 1.26 to 2.46) when advanced adenoma recurrence was compared with no adenoma recurrence. The c-statistics for these 2 comparisons were 0.68 and 0.72, respectively. Participants were self-selected and had restrictions on the degree of obesity. Although the risk for recurrence of advanced adenoma within 4 years is greater for patients with high-risk adenomas at baseline than for those with low-risk adenomas, the discrimination of this risk stratification scheme is relatively low.

Analysis of Recurrence Patterns Associated with Toxoplasmic Retinochoroiditis

Toxoplasmic retinochoroiditis is thought to recur randomly. We sought to determine whether there is, instead, a longitudinal pattern of recurrences and to identify risk factors for recurrence. Longitudinal cohort study. We collected the following data for 143 patients with toxoplasmic retinochoroiditis in The Netherlands: gender, first affected eye, age at first episode, mode of Toxoplasma gondii infection (congenital vs postnatal), treatment history, and presence of retinal scars at initial examination. For each episode, we determined age, duration since first episode, and interval since previous episode. We estimated the relationship between disease-free interval after an episode and recurrence risk. The influence of host and disease factors on recurrence risk was analyzed using Cox regression with frailty modeling for correlated intrapatient recurrence times. We performed a Monte Carlo test for occurrence of clusters after prolonged disease-free intervals. Follow-up ranged from 0.3 to 41 years (323 episodes in first-affected eyes). Recurrence risk was highest immediately after an episode, then decreased with increasing disease-free intervals, a pattern consistent with clustering. Relative risk (RR) of recurrence declined 72% (RR, 0.28; 95% confidence interval [CI], 0.22 to 0.36; P < .001) with each 10-year interval since first episode, and declined 15% (RR, 0.85; 95% CI, 0.71 to 1.01; P = .06) for each 10-year increase in age at first episode. Patients more than 40 years of age were at higher risk of recurrence than younger patients (RR, 1.74; 95% CI, 1.06 to 2.86; P = .03). Clusters of episodes occurred after prolonged disease-free intervals. Toxoplasmic retinochoroiditis occurs in clusters over time. Recurrence risk is influenced by patient age and duration of infection.

Familial risk of oral clefts by morphological type and severity: population based cohort study of first degree relatives

Objective To estimate the relative risk of recurrence of oral cleft in first degree relatives in relation to cleft morphology.Design Population based cohort study.Setting Data from the medical birth registry...

Polycyclic Aromatic Hydrocarbon–DNA Adducts in Prostate and Biochemical Recurrence after Prostatectomy

DNA adduct levels may be influenced by metabolic activity, DNA repair capabilities, and genomic integrity, all of which play a role in cancer progression. To determine if elevated DNA adducts are a marker for prostate cancer progression, we measured polycyclic aromatic hydrocarbon-DNA adducts by immunohistochemistry in prostate cells of 368 surgical prostate cancer patients treated at the Henry Ford Hospital in Detroit, Michigan, between September 1999 and July 2004. Patients were followed up to 5 years after surgery with relative risk for biochemical recurrence (BCR) estimated with a Cox proportional hazards model that adjusted for standard clinical risk factors. At 1 year of follow-up, patients with adduct levels above the median in tumor cells [hazard ratio (HR), 2.40; 95% confidence interval (95% CI), 1.10-5.27] and nontumor cells (HR, 3.22; 95% CI, 1.40-7.39) had significant increased risk of BCR, but these HRs decreased to 1.12 (95% CI, 0.68-1.83) and 1.46 (95% CI, 0.89-2.41) in tumor and nontumor cells at 5 years postsurgery. When we restricted our analysis to patients with advanced-stage (III+) disease, those with high adduct levels in either tumor (53.5% versus 30.2%; P = 0.07) or nontumor (55.2% versus 28.6%; P = 0.02) cells had BCR rates almost 2-fold higher. In race-stratified analyses, the greatest risk of BCR associated with high adduct levels (in nontumor cells) was for African American patients younger than 60 years old (HR, 3.79; 95% CI, 1.01-14.30). High polycyclic aromatic hydrocarbon-DNA adduct levels in nontumor prostate cells are most strongly associated with BCR between 1 and 2 years after surgery and in patient subsets defined by younger age, advanced tumor stage, and African American race.

Genetic variation in heme oxygenase 1 (HMOX1) and the risk of recurrent venous thromboembolism

Products of heme oxygenase 1 (HO1) possess antithrombotic properties, and impairment of HO1 activity may contribute to thrombus formation. Transcriptional activity of long GT-repeat alleles in HO1 gene (HMOX1) is lower as compared with short alleles. We hypothesize that these long alleles are associated with decreased HO1 anticoagulant activity and, thus, an increased risk of thrombosis.. In a prospective cohort study, we followed 860 patients with a first VTE, and investigated the impact of a promoter GT-dinucleotid length polymorphism in HOMX1 on the risk of recurrent venous thromboembolism (VTE). Allele groups short (S), medium (M) and long (L) of the promoter GT-dinucleotide length polymorphism were distinguished. L-alleles, but not M- or S-alleles, were found to be more frequent among patients with recurrence. Heterozygous carriers of L-alleles had a two-fold higher relative risk of recurrence [(RR 2.2 (95% CI: 1.4-3.4)] as compared to wild type, which was independent of other thrombotic risk factors. At five years, the cumulative probability of recurrence was 18% (95% CI: 15%-22%) in patients without an L-allele compared to 32% (95% CI: 19%-46%) in patients heterozygous for the L-allele (P = .001). Patients with first VTE and long GT-repeat alleles in HMOX1 have an increased risk of recurrence. Genetically determined alterations in HO1 function may represent a new pathomechanism in VTE.

Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study

The aim of the QUASAR trial was to determine the size and duration of any survival benefit from adjuvant chemotherapy for patients with colorectal cancer at low risk of recurrence, for whom the indication for such treatment is unclear. After apparently curative resections of colon or rectal cancer, 3239 patients (2963 [91%] with stage II [node negative] disease, 2291 [71%] with colon cancer, median age 63 [IQR 56-68] years) enrolled between May, 1994, and December, 2003, from 150 centres in 19 countries were randomly assigned to receive chemotherapy with fluorouracil and folinic acid (n=1622) or to observation (with chemotherapy considered on recurrence; n=1617). Chemotherapy was delivered as six 5-day courses every 4 weeks or as 30 once-weekly courses of intravenous fluorouracil (370 mg/m2) with high-dose (175 mg) L-folinic acid or low-dose (25 mg) L-folinic acid. Until 1997, levamisole (12 courses of 450 mg over 3 days repeated every 2 weeks) or placebo was added. After 1997, patients who were assigned to receive chemotherapy were given fluorouracil and low-dose folinic acid only. The primary outcome was all-cause mortality. Analyses were done by intention to treat. This trial is registered with the International Clinical Trial Registry, number ISRCTN82375386. At the time of analysis, 61 (3.8%) patients in the chemotherapy group and 50 (3.1%) in the observation group had missing follow-up. After a median follow-up of 5.5 (range 0-10.6) years, there were 311 deaths in the chemotherapy group and 370 in the observation group; the relative risk of death from any cause with chemotherapy versus observation alone was 0.82 (95% CI 0.70-0.95; p=0.008). There were 293 recurrences in the chemotherapy group and 359 in the observation group; the relative risk of recurrence with chemotherapy versus observation alone was 0.78 (0.67-0.91; p=0.001). Treatment efficacy did not differ significantly by tumour site, stage, sex, age, or chemotherapy schedule. Eight (0.5%) patients in the chemotherapy group and four (0.25%) in the observation group died from non-colorectal cancer causes within 30 weeks of randomisation; only one of these deaths was deemed to be possibly chemotherapy related. Chemotherapy with fluorouracil and folinic acid could improve survival of patients with stage II colorectal cancer, although the absolute improvements are small: assuming 5-year mortality without chemotherapy is 20%, the relative risk of death seen here translates into an absolute improvement in survival of 3.6% (95% CI 1.0-6.0).

No Difference in Risk of Recurrent Venous Thrombosis between Men and Women. Results from a Family Cohort Study in 3356 Subjects.

Recent studies have suggested that men are at higher risk of recurrent venous thrombosis than women. It has been proposed to continue anticoagulant treatment after the first episode of thrombosis for a longer period in men, and to search for unidentified prothrombotic abnormalities in men that could explain these findings. However, men and women differ with respect to hormonal risk factors (pregnancy, oral contraceptives), and known thrombophilic defects did not show to increase the risk of recurrence. Moreover, follow-up in previous studies was relatively short (maximum 8 years). We analyzed sex differences in risk of recurrence in a family cohort of 3356 subjects (877 probands, 2479 relatives), who enrolled 5 studies to assess the absolute risk of venous thrombosis associated with currently known thrombophilic defects. Life-time risk of recurrence was calculated, related to sex, follow-up time, type of first and recurrent event (provoked, idiopathic), and thrombophilic defects. Of 816 subjects with a first episode of venous thrombosis, 337 (41%) had a recurrence after discontinued anticoagulant treatment. Overall relative risk of recurrence was 1.8 (95% CI, 1.5–2.3) in men compared to women. Women were younger at time of their first event (mean 34 years vs. 44 years, P< 0.001) and at time of recurrence (40 years vs. 48 years, P< 0.001). Excluding provoked (recurrent) venous thrombosis, the relative risk was 1.2 (95% CI, 0.8–1.7), while mean age at recurrence was comparable in men and women (50 years vs. 49 years, P= 0.595). Women revealed recurrence after a longer period than men (P=0.003), but this difference was not demonstrated if only idiopathic events were considered (P=0.938) (Figure). Recurrences were observed in 111/187 subjects (59%) with antithrombin, protein C or protein S deficiency, compared to 159/479 subjects (33%) with factor V Leiden, prothrombin G20210A or high factor VIII levels (P< 0.001). Within these subgroups, the risk of recurrence after an idiopathic event was comparable in men and women. We conclude that life-time risk of recurrent venous thrombosis is not different between men and women. A difference can be observed when the follow-up period is relatively short and is explained by a younger age of women at time of the first episode of venous thrombosis due to pregancy/puerperium and oral contraception and a longer interval between provoked first episode and recurrence in women. [Display omitted]

The Polyp Prevention Trial–Continued Follow-up Study: No Effect of a Low-Fat, High-Fiber, High-Fruit, and -Vegetable Diet on Adenoma Recurrence Eight Years after Randomization

The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial to evaluate the effects of a high-fiber (18 g/1,000 kcal), high-fruit and -vegetable (3.5 servings/1,000 kcal), and low-fat (20% of total energy) diet on the recurrence of adenomatous polyps in the large bowel over a period of 4 years. Although intervention participants reported a significantly reduced intake of dietary fat, and increased fiber, fruit, and vegetable intakes, their risk of recurrent adenomas was not significantly different from that of the controls. Since the PPT intervention lasted only 4 years, it is possible that participants need to be followed for a longer period of time before treatment differences in adenoma recurrence emerge, particularly if diet affects early events in the neoplastic process. The PPT-Continued Follow-up Study (PPT-CFS) was a post-intervention observation of PPT participants for an additional 4 years from the completion of the trial. Of the 1,905 PPT participants, 1,192 consented to participate in the PPT-CFS and confirmed colonoscopy reports were obtained on 801 participants. The mean time between the main trial end point colonoscopy and the first colonoscopy in the PPT-CFS was 3.94 years (intervention group) and 3.87 years (control group). The baseline characteristics of 405 intervention participants and 396 control participants in the PPT-CFS were quite similar. Even though the intervention group participants increased their fat intake and decreased their intakes of fiber, fruits, and vegetables during the PPT-CFS, they did not go back to their prerandomization baseline diet (P < 0.001 from paired t tests) and intake for each of the three dietary goals was still significantly different from that in the controls during the PPT-CFS (P < 0.001 from t tests). As the CFS participants are a subset of the people in the PPT study, the nonparticipants might not be missing completely at random. Therefore, a multiple imputation method was used to adjust for potential selection bias. The relative risk (95% confidence intervals) of recurrent adenoma in the intervention group compared with the control group was 0.98 (0.88-1.09). There were no significant intervention-control group differences in the relative risk for recurrence of an advanced adenoma (1.06; 0.81-1.39) or multiple adenomas (0.92; 0.77-1.10). We also used a multiple imputation method to examine the cumulative recurrence of adenomas through the end of the PPT-CFS: the intervention-control relative risk (95% confidence intervals) for any adenoma recurrence was 1.04 (0.98-1.09). This study failed to show any effect of a low-fat, high-fiber, high-fruit and -vegetable eating pattern on adenoma recurrence even with 8 years of follow-up. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1745-52).

Elevated Serum Concentrations of Insulin and Glucose Increase Risk of Recurrent Colorectal Adenomas

Indicators of insulin resistance have been hypothesized to promote colorectal cancer. We assayed fasting serum from 375 subjects with and 375 subjects without a recurrent adenoma during the course of the Polyp Prevention Trial to determine baseline concentrations of insulin and glucose, as well as changes in these measurements over the course of 4 years of follow-up evaluation. To estimate the relative risk of adenoma recurrence for each of these serum measures, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression models adjusting for age, sex, body mass index, intervention group, and an interaction term for sex and intervention group. For both insulin and glucose, we found higher risk for subjects in the high quartile compared with the low quartile (OR, 1.56; 95% CI, 1.00-2.43 for insulin; OR, 1.49; 95% CI, 0.95-2.31 for glucose). The association for glucose was most apparent for advanced adenomas (OR, 2.43; 95% CI, 1.23-4.79) but for insulin, we did not observe this pattern. When we restricted the analysis to those without a family history of colorectal cancer, we observed an even stronger association between increased glucose at study entry and adenoma recurrence (OR, 1.78; 95% CI, 1.06-3.01 for all adenomas; OR, 3.52; 95% CI, 1.47-8.42 for advanced adenoma). Our findings suggest that patients with increased insulin and glucose are at higher risk of adenoma recurrence, and for those with increased glucose, the increase in risk for recurrence of advanced adenomas is even greater.

Stapled Hemorrhoidopexy and Milligan Morgan Hemorrhoidectomy in the Cure of Fourth-Degree Hemorrhoids: Long-Term Evaluation and Clinical Results

The long-term results after stapled hemorrhoidopexy compared with Milligan-Morgan procedure are discussed. The clinical data of 100 patients treated by Milligan-Morgan procedure or stapled hemorrhoidopexy for fourth-degree hemorrhoids have been reviewed. All patients were visited and submitted to a questionnaire to evaluate resumption of symptoms, functional results, and recurrence rate. The mean follow-up was 54 months for stapled hemorrhoidopexy and 92 months for the Milligan-Morgan procedure. Postoperative pain and return to normal activity were worse in the Milligan-Morgan procedure (Visual Analog Scale 8.56 vs. 5.46, P < 0.001; and 2.4 vs. 2 weeks, P value = 0.018). Eight percent of patients who had stapled hemorrhoidopexy complained of spontaneous pain or pain during defecation vs. 0 percent of patients who underwent the Milligan-Morgan procedure. We noted that there was bleeding in 14 percent of stapled hemorrhoidopexy vs. 0 percent of Milligan-Morgan procedure (P < 0.006), tenesmus in 32 percent of stapled hemorrhoidopexy vs. 0 percent of Milligan-Morgan procedure (P < 0.001), and pruritus in 4 percent of stapled hemorrhoidopexy vs. 0 percent of Milligan-Morgan procedure. Minor leakage was similar in the two groups. Flatus impaired control was less frequent in Milligan-Morgan. The relative risk of recurrence for stapled hemorrhoidopexy compared with Milligan-Morgan procedure was 1.18 (95 percent confidence interval 1< relative risk < 1.4). No statistical difference was noted in patients' satisfaction after the procedures. Long follow-up seems to indicate more favorable results in Milligan-Morgan procedure in terms of resumption of symptoms and risk of recurrence.

Reducing the Risk for Breast Cancer Recurrence After Completion of Tamoxifen Treatment in Postmenopausal Women

Background: In postmenopausal women with hormone-sensitive early stage breast cancer, the risk for relapse persists after 5 years of treatment with adjuvant tamoxifen. Because tamoxifen is not indicated for adjuvant therapy beyond 5 years, the need for another therapy in the extended adjuvant setting to reduce late recurrence risk is clear. The National Cancer Institute of Canada Clinical Trials Group MA.17 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33 trial found that extended adjuvant therapy with an aromatase inhibitor (AI) (eg, letrozole, exemestane, or anastrozole) rendered additional benefit in postmenopausal women with hormone receptor-positive breast cancer. The MA.17 trial was unblinded at the first interim analysis (median follow-up, 2.4 years) due to a significant reduction in relative risk for recurrence ( P < 0.001). Following the publication of the final analysis, several other MA.17 trial analyses and a postblinding analysis were also conducted. Recent data on the NSABP B-33 trial, which investigated exemestane in the extended adjuvant setting, and Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 6a, which evaluated anastrozole in the extended adjuvant setting, have also been reported. Objective: The goal of this article was to provide a current review of the MA.17 and NSABP B-33 resuits, together with additional data, to determine the benefit and tolerability of extended adjuvant AI therapy and the potential benefits of late extended adjuvant therapy with AIs after a prolonged (≤5 years) period after the completion of tamoxifen treatment. Methods: A literature search was performed. PubMed and MEDLINE were searched for descriptions of clinical trials published from 1990 to 2007 using the terms breast cancer, extended adjuvant, aromatase inhibitor, anastrozole, exemestane, and letrozole. Abstracts from several oncology meetings held between 2001 and 2007 also were searched to extract relevant data (disease-free survival [DFS], overall survival [OS]). Results: In MA.17 at 30 months, postmenopausal patients with early stage breast cancer who received extended adjuvant letrozole (n = 2593) experienced a significant (42%) improvement in DFS regardless of nodal status ( P < 0.001), and there was a significant (39%) improvement in as in node-positive patients ( P = 0.04), compared with placebo. At median follow-up (54 months), a postunblinding analysis found that patients who were switched to letrozole after a prolonged period (up to 5 years) after discontinuation of tamoxifen experienced a 69% improvement in DFS ( P < 0.001), a 72% improvement in distant DFS ( P = 0.002), and a 47% improvement in as ( P = 0.05) compared with patients who elected to continue with no treatment at trial unblinding. Results from 2 other extended adjuvant trials, the NSABP B-33, investigating exemestane in the extended setting (relapse-free survival, P = 0.03; no significant improvement in DFS or as), and the smaller ABCSG 6a, also support a benefit of extended adjuvant AI therapy. Conclusions: Current evidence supports the use of letrozole and perhaps exemestane in the extended adjuvant setting, while data on anastrozole are emerging. Based on the results from this review, initiation of letrozole treatment following a prolonged interval after completion of 5 years of tamoxifen treatment might be beneficial.

Overexpression of chemokine receptor CXCR4 in cancer specimens following neoadjuvant chemotherapy predicts outcome in patients with locally advanced breast cancer (LABC)

10578 Background: Despite significant advances made in the treatment of locally advanced breast cancer (LABC) with neoadjuvant chemotherapy, a significant number of patients continue to die. A molecular predictor to identify those who are at an increased risk for relapse is sorely needed. CXCR4 is a chemokine receptor that has been linked to breast cancer invasion and metastasis. We postulate that CXCR4 overexpression levels in cancer specimens following neoadjuvant chemotherapy predict cancer outcome in patients with LABC. Methods: 54 patients with LABC were prospectively accrued and analyzed. All had neoadjuvant chemotherapy, followed by definitive surgical and adjuvant chemo-radiation therapy. Study homogeneity was maintained by standardized treatment, surveillance, and compliance protocols. A 1 cm 3 cancer from the surgical specimens of each patient was retrieved for analysis. CXCR4 levels were detected using Western blots and results were quantified against 1 μg of HeLa cells (positive controls). CXCR4 expression was defined as low (&lt;6.6 fold) or high (= 6.6 fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazard model. Results: With a median follow-up of 30 months, patients whose tumors had high CXCR4 overexpression (= 6.6 fold) had a statistically significantly higher incidence of recurrence (p= 0.0009) and cancer-related death (p= 0.0168) than those in the low CXCR4 group (&lt; 6.6 fold). After adjusting for tumor size, nodal status, ER, PR and HER-2 status, the relative risk for recurrence and death in the high CXCR4 group was 27.3-fold (p=0.001; 95% CI: 6.2 to 120.8) and 4.8-fold (p=0.0076; 95% CI: 1.5 to 15.0) higher than those in the low CXCR4 group, respectively. Conclusion: High CXCR4 overexpression in cancer specimens following neoadjuvant chemotherapy was highly predictive of cancer recurrence and cancer death in patients with LABC. No significant financial relationships to disclose.

How common is repeat sudden infant death syndrome?

Recurrence of sudden infant death syndrome (SIDS) is rare but may give rise to confusion and controversy because of the differential diagnoses of familial disease or covert homicide. We examine...

FV Leiden mutation and risk of recurrent venous thromboembolism in Serbian population

The absolute rate of recurrence of venous thromboembolism (VTE) is approximately 5% per year. There is a lower rate of recurrence in provoked VTE, and higher in idiopathic one. So far, there is no consensus whether hereditary thrombophilia should be considered as a persistent risk factor, and whether it requires long-term anticoagulant therapy. The aim of our study was to estimate the risk of recurrent VTE in patients carrying FV Leiden mutation in Serbian population. In retrospective study (1994-2006), we have evaluated the risk of recurrent VTE in 56 patients who are carriers of FV Leiden mutation, in comparison to group consisting of 56 patients non-carriers of FV Leiden mutation. Patients with FII G20210A and MTHFR C677T mutations, antiphospholipid antibodies, antithrombin III, protein C or protein S deficiency, malignancies and diabetes were excluded from the study. Recurrent VTE occurred in 44.6% of the patients, carriers of the FV Leiden mutations, vs. 26.7% in non-carriers group (P<0.05). The incidence rate was 3.7 and 2.2% per year, respectively. The estimated relative risk of recurrence for FV Leiden carriers was 1.67 (95% CI 0.99-2.81, P=0.049). The 60% of patients with mutation and only 13% without mutation develop rethrombosis during first year after discontinuance of therapy (P<0.01). In our study patients with symptomatic VTE who are carriers of the FV Leiden gene mutations have a higher risk of recurrent VTE than non-carriers. Our data suggest the importance of the FV Leiden mutation detection and the estimation of the clinical condition for successful secondary prophylaxis of VTE.

Mild donor liver steatosis has no impact on hepatitis C virus fibrosis progression following liver transplantation

This study examines the impact of donor liver macrovesicular steatosis on recurrence of hepatitis C virus (HCV) disease after liver transplantation. Between 1998 and 2004, 113 patients underwent liver transplantation for HCV-related cirrhosis. Time to histologic recurrence (fibrosis score >or=2) was the primary endpoint of the study. Recurrence was graded according to the system of Ludwig and Batts. A Cox's proportional hazard regression model was used to analyse the association between donor liver steatosis and HCV recurrence. Recurrence-free survival for patients who received steatotic grafts was 82% and 47% at 1 and 4 years, respectively, and 81% and 52% for patients who received a non-steatotic liver. Donor macrovesicular steatosis (5-45%) was found to have no impact on HCV recurrence (P=0.47). Donor age (P=0.02) and cold ischaemia time (P=0.01) were found to increase the relative risk of HCV recurrence. The estimated risk of HCV recurrence increased by 23% for every 10-year increase in donor age. Similarly the risk of recurrence increased by 13% for every 1-h increase in cold ischaemia time. Mild-moderate donor liver macrovesicular steatosis has no impact on HCV recurrence after liver transplantation for HCV-related cirrhosis. Cold ischaemia time and donor age increased the likelihood of HCV recurrence.

Gene expression and promoter methylation of the XIAP-associated Factor 1 in renal cell carcinomas: Correlations with pathology and outcome

Transcriptional downregulation of the putative tumor suppressor gene XIAP-associated Factor 1 (XAF1) by promoter methylation has been shown to relate to tumor progression of gastric and bladder cancer. This study determined the mRNA expression levels and the methylation status of XAF1 by real-time RT-PCR and quantitative methylation specific PCR in tumor tissue obtained from 91 renal cell carcinoma (RCC) patients (median follow-up 50.5 months) following surgical treatment. Expression data was correlated to histopathological variables and outcome. XAF1 expression levels were not related to standard pathological parameters for outcome prediction but results from crude and explorative multivariable-adjusted analyses revealed low XAF1 levels to significantly increase the relative risk (RR) for tumor recurrence (RR 4.6; CI 95%: 1.4–14.6) and tumor-related death (RR 3.6; CI 95%: 1.4–9.7). The association of low XAF1 expression with an abbreviated recurrence-free ( p = 0.009) and disease-specific survival ( p = 0.005) was most pronounced in patients with locally advanced (pT3) tumors. XAF1 promoter methylation was rarely detected (10%) but, if present, XAF1 mRNA expression levels correlated inversely to the normalized index of methylation ( p = 0.01). Our findings suggest that low XAF1 mRNA expression levels relate to an unfavorable clinical course in RCC patients. Promoter methylation may be one, but probably not the essential mechanism for transcriptional downregulation of the XAF1 gene in RCC.

High-Density Lipoprotein and the Risk of Recurrent Venous Thromboembolism

High-density lipoprotein (HDL) protects against arterial atherothrombosis, but it is unknown whether it protects against recurrent venous thromboembolism. We studied 772 patients after a first spontaneous venous thromboembolism (average follow-up 48 months) and recorded the end point of symptomatic recurrent venous thromboembolism, which developed in 100 of the 772 patients. The relationship between plasma lipoprotein parameters and recurrence was evaluated. Plasma apolipoproteins AI and B were measured by immunoassays for all subjects. Compared with those without recurrence, patients with recurrence had lower mean (+/-SD) levels of apolipoprotein AI (1.12+/-0.22 versus 1.23+/-0.27 mg/mL, P<0.001) but similar apolipoprotein B levels. The relative risk of recurrence was 0.87 (95% CI, 0.80 to 0.94) for each increase of 0.1 mg/mL in plasma apolipoprotein AI. Compared with patients with apolipoprotein AI levels in the lowest tertile (<1.07 mg/mL), the relative risk of recurrence was 0.46 (95% CI, 0.27 to 0.77) for the highest-tertile patients (apolipoprotein AI >1.30 mg/mL) and 0.78 (95% CI, 0.50 to 1.22) for midtertile patients (apolipoprotein AI of 1.07 to 1.30 mg/mL). Using nuclear magnetic resonance, we determined the levels of 10 major lipoprotein subclasses and HDL cholesterol for 71 patients with recurrence and 142 matched patients without recurrence. We found a strong trend for association between recurrence and low levels of HDL particles and HDL cholesterol. Patients with high levels of apolipoprotein AI and HDL have a decreased risk of recurrent venous thromboembolism.

Intracranial Aneurysms: Treatment with Bare Platinum Coils—Aneurysm Packing, Complex Coils, and Angiographic Recurrence

To retrospectively assess, with three-dimensional rotational angiography, the relationship between packing, complex coils, and angiographic recurrence of aneurysms treated with coils. Informed consent was waived by the institutional review board that approved the study. Results at follow-up angiography of 255 aneurysms in 223 patients (161 female and 62 male patients; mean age, 48 years) were dichotomized into presence or absence of recurrence. The degree of packing of aneurysms treated with complex coils alone, with complex and helical coils, and with helical coils only was compared for significant differences. With generalized estimating equations analysis, relative risk (RR) for recurrence was calculated for mode of manifestation, duration of follow-up, aneurysm volume, packing, initial angiographic result, percentage of complex coils, aneurysm location, and multiplicity of aneurysms. Follow-up angiography revealed recurrence in 28.6% of aneurysms at a mean follow-up of 12 months; 5.5% were amenable to re-treatment. Aneurysms treated with complex and those treated with helical coils only had a mean packing of 27% and 26%, respectively. There was no significant difference between packing of aneurysms treated with complex and those treated with helical coils (P = .538). Recurring and stable aneurysms both had a mean packing of 27%. Generalized estimating equations analysis showed significant differences between duration of follow-up and recurrence (P = .001, RR = 3.39), between aneurysm volume and recurrence (P < .001, RR = 6.15), and between hemorrhagic manifestation and recurrence (P = .002, RR = 3.17). There was no significant difference between packing and recurrence, between initial angiographic result and recurrence, between percentage of complex coils and recurrence, between aneurysm location and recurrence, or between multiplicity of aneurysms and recurrence. More angiographic recurrences are detected over time. Complex coils do not augment aneurysm packing. Packing is not related to protection against recurrence.

Trastuzumab (Herceptin) in the adjuvant treatment of HER-2-positive early breast cancer

The prognosis of HER-2-positive breast cancer (characterized by amplification of the HER-2 oncogene and/or overexpression of HER-2 receptor) is unfavourable. Trastuzumab (Herceptin), a monoclonal antibody against HER-2 receptor can improve the outcome of HER-2-positive breast cancer. Up to now this was proven only in advanced disease. Recently five large multicentric phase III adjuvant trials gave level one evidence on the benefit of adjuvant treatment with Herceptin, concerning disease-free survival (DFS) and overall survival (OS). Herceptin has decreased the relative risk of recurrence with about 50% and that of death with nearly 30% in HER-2-positive early breast cancer. Based on these results Herceptin, together with chemotherapy, has been recently approved for the adjuvant treatment of HER-2-positive breast cancer.