Independent Prognostic Factor For Relapse Research Articles

Epigenetic Markers for Molecular Detection of Prostate Cancer

Prostate cancer is a highly prevalent malignancy, which is clinically silent but curable while organ-confined. Because available screening methods show poor sensitivity and specificity, the development of new molecular markers is warranted. Epigenetic alterations, mainly promoter hypermethylation of cancer-related genes, are common events in prostate cancer and might be used as cancer biomarkers. Moreover, the development of quantitative, high-throughput techniques to assess promoter methylation enabled the simultaneous screening of multiple clinical samples. From the numerous cancer-related genes hypermethylated in prostate cancer only a few proved to be strong candidates to become routine biomarkers. This small set of genes includes GSTP1, APC, RARβ2, Cyclin D2, MDR1, and PTGS2. Single and/or multigene analyses demonstrated the feasibility of detecting early prostate cancer, with high sensitivity and specificity, in body fluids (serum, plasma, urine, and ejaculates) and tissue samples. In addition, quantitative hypermethylation of several genes has been associated with clinicopathologic features of tumor aggressiveness, and also reported as independent prognostic factor for relapse. The identification of age-related methylation at specific loci and the differential frequency of methylation among ethnical groups, also provided interesting data linking methylation and prostate cancer risk. Although large trials are needed to validate these findings, the clinical use of these markers might be envisaged for the near future.

Clinical implications of FLT3 mutations in pediatric AML

AbstractActivating mutations of the FLT3 gene occur because of an internal tandem duplication of the juxta-membrane domain (FLT3/ITD) or point mutation of the activation loop domain (FLT3/ALM). The presence of FLT3 mutations as well as the allelic ratio of FLT3/ITD (ITD-AR, mutant–wild type ratio) may have prognostic significance. FLT3 mutation status of 630 children with de novo acute myeloid leukemia (AML) treated on CCG-2941 and -2961 was determined, and ITD-AR was calculated for patients with FLT3/ITD. Clinical characteristics and outcomes for patients with FLT3/ALM and FLT3/ITD at varying ITD-ARs was determined and compared with those without FLT3 mutations (FLT3/WT). FLT3/ITD and FLT3/ALM were detected in 77 (12%) and 42 (6.7%) of the patients. Progression-free survival (PFS) was similar in patients with FLT3/ALM and FLT3/WT (51% versus 55%, P = .862). In contrast, PFS at 4 years from study entry for patients with FLT3/ITD was inferior to that of patients with FLT3/WT (31% versus 55%, P < .001). PFS decreased with increasing FLT3/ITD-AR (P < .001), and those with ITD-AR greater than 0.4 had a significantly worse PFS than those with lower ITD-AR (16% versus 72%, P = .001) or with FLT3/WT (55%, P < .001). ITD-AR defines the prognostic significance in FLT3/ITD-positive AML, and ITD-AR greater than 0.4 is a significant and independent prognostic factor for relapse in pediatric AML.

Time to Post-Remission Therapy (PRT) Is an Independent Prognostic Factor for Relapse and Overall Survival in Adults with Acute Lymphocytic Leukemia (ALL).

Only 30% of adults with ALL are cured. The identification of modifiable prognostic factors is important in designing future treatment paradigms, and improving the outcome of patients. PRT is integral in the treatment of ALL, and eradicates minimal residual disease (MRD) after complete remission (CR) has been achieved with induction chemotherapy (IC). Decreasing the time from the start of IC to the initiation of PRT may improve prognosis by eradicating MRD at an earlier stage, and preventing the development of resistant leukemic clones. The goal of this study was to retrospectively evaluate the impact of time from the start of IC to PRT, and determine whether or not this affects progression-free survival (PFS) and overall survival (OS).Methods: We retrospectively evaluated adults with newly diagnosed ALL treated at CCF between the years 1996–2005. 116 patients with ALL were seen. 57 patients were newly diagnosed and received IC and PRT. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of CR, OS, relapse after remission, and PFS. Only variables significant in the univariate setting were included in multivariate analysis. Results were summarized as the hazard ratio (HR) with 95% confidence intervals (CI). The following variables were used in the analysis: pre-treatment characteristics (age, WBC, cytogenetic (CG) risk group, LDH), time to WBC recovery (time from the initiation of IC to an ANC of 500 after IC), CD20 expression, and time from the initiation of IC to start of PRT. CG risk was defined by CALGB criteria.Results: Characteristics at diagnosis: median age of 38 years [range 16–72], median LDH 673 U/L [112–5753], and median WBC 17.8 × 103/L [1.2–364]. 33.6% of patients had poor risk CG, 22.4% normal CG, 15% miscellaneous, and 29% unknown. Most patients received a vincristine/prednisone based IC (88%). However, 12% received high dose cytarabine/mitoxantrone IC. The CR rate was 75.3% for patients age < 60, and 60% for age ≥ 60. Median disease-free survival was 20.2% at 5 years. The median time from IC to PRT was 7.0 weeks [4.1–17.0]. On univariate analysis, increased age and increased time to WBC recovery were associated with a lower CR rate. Age and time from IC to PRT (per week increase (PWI)) [HR 1.17(CI 1.04–1.32), p=0.009] were significant predictors for relapse after remission. Increased age, poor risk CG, and time from IC to PRT (PWI) [HR 1.13(1.02–1.25), p=0.024] predicted decreased PFS. All of these factors (including time to WBC recovery) predicted decreased OS, with time from IC to PRT (PWI) having a HR of 1.11[(1.01–1.23), p=0.039]. On multivariate analysis, there was a trend for longer time from IC to PRT (PWI) [HR 1.53(0.92–2.54, p=0.10] predicting decreased OS and increased chance of relapse (PWI) [HR 1.12(0.98–1.29), p=0.09]. When patients age > 60 and poor risk CG were excluded, time from IC to PRT (PWI) was the only factor associated with decreased OS [HR 1.34(1.08–1.67), p=0.009], PFS [HR 1.27(1.04–1.55, p=0.019)], and an increased chance of relapse [HR 1.26(0.99–1.61), p=0.06].Conclusions: Strategies to improve the prognosis of ALL are needed. Time from IC to PRT is an independent prognostic factor for treatment outcome, and administering PRT on time may improve our outcomes in adult patients with ALL.

Outcome analysis of 300 prostate cancer patients treated with neoadjuvant androgen deprivation and hypofractionated radiotherapy

Neoadjuvant androgen deprivation and radical radiotherapy is an established treatment for localized prostate carcinoma. This study sought to analyze the outcomes of patients treated with relatively low-dose hypofractionated radiotherapy. Three hundred patients with T1-T3 prostate cancer were treated between 1996 and 2001. Patients were prescribed 3 months of neoadjuvant androgen deprivation before receiving 5250 cGy in 20 fractions. Patients' case notes and the oncology database were used to retrospectively assess outcomes. Median follow-up was 58 months. Patients presented with prostate cancer with poorer prognostic indicators than that reported in other series. At 5 years, the actuarial cause-specific survival rate was 83.2% and the prostate-specific antigen (PSA) relapse rate was 57.3%. Metastatic disease had developed in 23.4% of patients. PSA relapse continued to occur 5 years from treatment in all prognostic groups. Independent prognostic factors for relapse included treatment near the start of the study period, neoadjuvant oral anti-androgen monotherapy rather than neoadjuvant luteinizing hormone releasing hormone therapy, and diagnosis through transurethral resection of the prostate rather than transrectal ultrasound. This is the largest reported series of patients treated with neoadjuvant androgen deprivation and hypofractionated radiotherapy in the United Kingdom. Neoadjuvant hormonal therapy did not appear to adequately compensate for the relatively low effective radiation dose used.

Promoter Hypermethylation as an Independent Prognostic Factor for Relapse in Patients with Prostate Cancer Following Radical Prostatectomy

To analyze the prognostic significance of six epigenetic biomarkers (APC, Cyclin D2, GSTP1, TIG1, Rassf1A, and RARbeta2 promoter hypermethylation) in a homogeneous group of prostate cancer patients, following radical prostatectomy alone. Biomarker analyses were done retrospectively on tumors from 74 prostate cancer patients all with a Gleason score of 3 + 4 = 7 and minimum follow-up period of 7 years. Using quantitative methylation-specific PCR, we analyzed six gene promoters in primary prostate tumor tissues. Time to any progression was the primary end point, and development of metastatic disease and/or death from prostate cancer was a secondary point. The association of clinicopathologic and biomolecular risk factors to recurrence was done using the log-rank test and Cox proportional hazards model for multivariate analysis. To identify independent prognostic factors, a stepwise selection method was used. At a median follow-up time of 9 years, 37 patients (50%) had evidence of recurrence: biochemical/prostate-specific antigen relapse, metastases, or death from prostate cancer. In the final multivariate analysis for time to progression (TTP), the significant factors were age > 60 [hazard ratio (HR), 0.4; 95% confidence interval (95% CI), 0.2-0.8; P = 0.01], hypermethylation of GSTP1 (HR, 0.23; 95% CI; 0.09-0.64; P = 0.004), and hypermethylation of APC (HR, 3.0; 95% CI, 1.42-6.32; P = 0.004). In another multivariate analysis, a profile of hypermethylation of APC and cyclin D2 hypermethylation was significant as well: if either any one was hypermethylated (HR, 1.84; 95% CI, 0.92-3.72; P = 0.09) or if both were hypermethylated (HR, 4.3; 95% CI, 1.52-12.33; P = 0.01). Methylation status of selected genes in the prostate cancer specimen may predict for time to recurrence in Gleason 3 + 4 = 7 patients undergoing prostatectomy. These results should be validated in a larger and unselected cohort.

Preoperative PSA Velocity Is an Independent Prognostic Factor for Relapse After Radical Prostatectomy

Preoperative prostate-specific antigen (PSA) velocity (PSAV), or the rate of PSA rise before diagnosis, predicts for risk of cancer death after radical prostatectomy (RP). We evaluated the relative merit of established preoperative factors, including biopsy indices and preoperative PSAV, for their impact on relapse after RP. The outcomes of 202 men who underwent RP were reviewed. Biopsies were characterized for grade, percentage positive cores, and total linear tumor length. Surgical specimens were characterized for cancer volume, relative percentage by grade, extracapsular extension, and margin status. Univariate and multivariate analyses were performed with respect to relapse-free survival after RP. Thirty-one patients relapsed after RP (defined as PSA > or = 0.2 ng/mL), with a median time to failure of 16 months. Median follow-up was 48 months. Kaplan-Meier relapse-free survival at 5 years was 89%, compared with 73% for PSAV < or = 2 v > 2 ng/mL/year (P = .003). On multivariate analysis, only the biopsy Gleason sum (P < .008; relative risk, > 4.8) and the preoperative PSAV (P < .04; relative risk, 3.0 to 4.7) remained significant. Patients with a PSAV of > 2 ng/mL/year were more likely to be pT3 (P = .007), have positive margins (P = .01), have tumors > 1 mL (P = .05), and possess > 10% grade 4/5 tumors (P = .04). The preoperative PSAV is a significant independent clinical factor predicting for relapse after RP and also predicts for larger, more aggressive, and more locally advanced tumors. Its inclusion will be useful in risk stratification, evaluation for alternatives to surgery, and patient selection for neoadjuvant or adjuvant therapies as part of randomized clinical trials.

Asthma in Remission: Can Relapse in Early Adulthood Be Predicted at 18 Years of Age?

To determine the frequency of relapse of asthma in young adults in remission at 18 years of age, during a follow-up period of 8 years, and to identify possible prognostic markers for relapse.Longitudinal study of birth cohort (n = 1,037) born in New Zealand in 1972-1973.University hospital research clinic.Participants were assessed at 9, 11, 13, 15, 18, 21, and 26 years of age using a respiratory questionnaire (all ages), spirometry (all ages), bronchodilator response (18 years and 26 years of age), methacholine challenge (9, 11, 13, 15, and 21 years of age), and allergen skin-prick testing (13 years and 21 years of age).Approximately one third of study members (35%) with asthma in remission at 18 years of age relapsed by 21 years or 26 years of age. Atopy and lower FEV(1)/FVC ratio at 18 years of age were significant independent prognostic factors for relapse in multiple logistic regression analyses. Increased responsiveness to methacholine (provocative concentration < 8 mg/mL) or bronchodilator (improvement in FEV(1) >/= 10%) at 21 years of age were more common among those with relapse, but the positive and negative predictive values for a previous positive methacholine challenge test result at 15 years of age were low. Asthma after relapse was generally mild (mean FEV(1) 97.1% predicted). Totally new adult asthma developed by 26 years of age in 9% of study members who had no asthma or wheezing at any time up to 18 years of age.Subsequent relapse of previously diagnosed asthma in remission at 18 years of age occurs in one in three young adults. Such relapse is not easily predicted, especially by measurements of airway responsiveness. A history of asthma currently in remission should not be used to prejudice employment opportunities for young adults.

Lymphvascular space involvement: an independent prognostic factor in endometrial cancer

Purpose of investigation To evaluate whether lymphvascular space involvement (LVSI) is a risk factor for relapse of disease and lymph node metastasis in endometrial cancer. Methods From 1978 till 2003, 609 patients with epithelial endometrial cancer were treated at the Groningen University Medical Center. The association of LVSI and relapse of disease was evaluated in the total group of 609 patients and in a ‘low’ and ‘high’ risk stage I endometrial cancer group. In 239 surgically staged patients, the relation of LVSI and lymph node metastasis was investigated. Results The median age at diagnosis was 63 years (range 27–92 years) with a median follow-up of 58 months (range 0–236 months). More than half of the patients (56%) received adjuvant radiotherapy. LVSI was present in 123 patients (25,6%), and a prognostic factor for relapse of disease (multivariate analysis, P < 0.0001). In the ‘low’ and ‘high’ risk stage I endometrial cancer patients an increase of 2.6 times in relapse of disease was observed in the presence of LVSI. LVSI positive tumors were more likely to have metastasized to the pelvic lymph nodes (multivariate analysis, P = 0.001). In patients with proven negative nodes, LVSI was a prognostic factor for relapse of disease (univariate analysis, P = 0.02). Conclusion LVSI is a predictor of nodal disease and an independent prognostic factor for relapse of disease in all stages of endometrial cancer. Patients with stage I endometrial cancer with positive LVSI are at risk for relapse of disease and might therefore benefit from adjuvant therapy. Content The presence of lymphvascular space involvement (LVSI) in endometrial cancer is significantly and independently associated with an increased risk of pelvic lymph node metastases and/or relapse of disease.

Correlation between polyamines and apoptosis among Egyptian breast cancer patients

Objectives The polyamines putrescine, spermidine, and spermine, play an important role in cell proliferation, differentiation, and transformation. The aim of this study is to correlate the polyamines with apoptosis and clinico-pathologic events in Egyptian breast cancer patients. Methods PUT, SPD, and SPN were investigated using thin layer chromatography (TLC) and apoptosis in fresh frozen tissue specimens obtained from 40 patients suffering from breast cancer, as well as 20 patients with benign breast lesions. Results The levels of PUT, SPD, and SPN were higher in breast cancer tissues than in benign breast lesions ( p < 0.001). Polyamines were correlated well with apoptosis. Moreover, PUT was an independent prognostic factor for relapse. Also, SPD and SPN correlated significantly with early tumor grades. ROC curves were used to choose the best cut-off values for polyamines (70, 135, and 290 mmol/g tissue) for PUT, SPD, and SPN, respectively. At these cut-off values, the sensitivities were (75%, 60%, and 70%), and the specificities were (80%, 95%, and 95%) for PUT, SPD, and SPN, respectively. Conclusion Polyamines may be used as additional markers for detection of malignant transformation in breast tissue. Moreover, because of their ability to induce apoptosis in malignant tissues, polyamines are suitable targets for therapeutic intervention that is specifically directed to induce apoptosis.

Prognostic significance of the sequential detection of circulating melanoma cells by RT-PCR in high-risk melanoma patients receiving adjuvant interferon.

The purpose of this study was to address the prognostic significance of circulating melanoma cells by reverse transcriptase-polymerase chain reaction in the peripheral blood of stage IIB and III melanoma patients on high-dose adjuvant interferon at multiple sequential time points from initiation of treatment. Tyrosinase mRNA in peripheral blood from these patients was assayed by reverse transcriptase polymerase chain reaction prior to initiation of adjuvant interferon, at completion of 1 month of intravenous interferon and at 3 monthly intervals until progression. Four hundred and eighteen blood samples from 60 melanoma patients were analysed. The median follow-up time calculated from the time of inclusion in the study was 23 months (range 2–38 months). Tyrosinase mRNA in blood was detected in 42 (70%) of 60 patients: 16 (76%) of 21 stage IIB patients and 26 (66%) of 39 stage III patients. The presence of tyrosinase mRNA in blood was correlated with a shorter disease-free survival (P : 0.03) and in multivariante analysis was an indepent prognostic factor for relapse. Patients who seroconverted to a negative reverse-transcriptase-polymerase chain reaction after induction treatment had a significantly lower probability of recurrence. The presence of circulating melanoma cells is a marker of a high relapse risk and shorter disease-free survival whether detected postoperatively or during follow-up. Tyrosinase mRNA amplification by reverse-transcriptase-polymerase chain reaction may be a useful tool for monitoring the efficacy of adjuvant treatment in stage IIB and III melanoma patients.British Journal of Cancer (2002) 87, 181–186. doi:10.1038/sj.bjc.6600419 www.bjcancer.com© 2002 Cancer Research UK

Prognostic significance of young age in breast cancer

Breast carcinoma is relatively uncommon in younger women and whether or not young age at diagnosis is an adverse prognostic factor in this disease has been controversial. Our aim in this report is to determine whether the histopathologic features and outcome in young and old are different, and whether age is a prognostic factor for relapse. A retrospective study of consecutive 281 stage I or II breast carcinoma patients who had modified radical mastectomy was carried out. The patients with a median follow-up period of 45 months were divided two groups according to their ages. The histopathological features and survival of Group 1 and Group 2 were compared with each other. Univariate and multivariate prognostic factor analysis for relapse were carried out. The patients in Group 1 (younger than 35 years of age) had the worst histopathological features related to the prognosis than those in Group 2 and the difference between the two groups was statistically significant. Whereas the rates of 5-year overall survival were 65% in Group 1 and 98% in Group 2 (P < 0.05), the rates of 5-year relapse-free survival were 40% and 80%, respectively (P < 0.05). In univariate analysis of all patients, pathologic tumour size, pathologic axillary status, number of metastatic lymph nodes, pathologic stage, age, lymphatic vascular invasion were statistically significant factors associated with relapse. Multivariate analysis demonstrated that number of metastatic nodes (risk ratio RR:4.3 in more than three nodes) and age (RR:3.6 in Group 1) were the most important independent prognostic factors for relapse. In the patients without axillary involvement, both of univariate and multivariate analysis revealed that pathologic tumour size (RR:5.1 in pT(2)) and age (RR:4 in Group 1) were the independent prognosticators for relapse. Young patients with breast cancer had the worst histopathological features and the worst survival than their older counterparts. Age was an independent significant prognostic factor for relapse.

Survival of patients with colorectal carcinoma

An important goal of serum tumor marker research is to provide a test for detecting cancer in early stages. Expression of carbohydrate antigen (CA) 19.9 has been described in various malignancies. The possible prognostic value measuring cytosol CA 19.9 expression in tumors was evaluated in a study of 63 colorectal carcinoma (CRC) patients who were followed for at least 2 years. CA 19.9 expression in cytosol was determined by enzyme-linked immunoadsorbant assay, and measurement of this protein achieved by quantitative assay. Mean levels of cytosol CA 19.9 found in tumor samples were significantly higher than those in nontumoral areas in CRC patients (P<0.0005). Patients with more than 3 positive lymph nodes had a higher expression of the marker (P<0.05). Univariate and multivariate analyses revealed that cytosol CA 19.9 concentration was an independent prognostic variable for relapse. Furthermore, the probability of relapse increased 4.2 times for every increase in cytosol tumor marker of 5000 U/mg, and tumors located in the rectum had a probability of relapse 9.5 times greater. Cystol CA 19.9 expression in CRC can be an independent prognostic factor for relapse. Patients with high levels of CA 19.9 have worse prognosis than those with lower values. Therefore, this group of patients should receive special management with regard to their follow-up and treatment. Moreover, quantitative cytosol tumor marker measurement is an easy and highly effective method for determining the prognoses of CRC patients.

The prognostic value and relationships of patient characteristics, estrogen and progestin receptors, and site of relapse in primary breast cancer.

Estrogen and progestin receptor levels (ER and PgR) in tumors from 506 patients with primary breast cancer diagnosed in 1979, 1980, and 1981 were measured by a Scatchard plot analysis. At a median follow-up time of 3.5 years the prognostic value of the receptor levels was evaluated and compared with other tumor and patient characteristics. No relation was found between receptor levels and tumor, lymph node, metastasis (TNM) classification or location of the primary tumor. A significant positive rank correlation was observed between ER and PgR levels (rs = 0.57) and between ER level and age of the patients (rs = 0.39, P less than 0.001). The observed association between ER level and menopause status could not be maintained after correction for age. Independent prognostic factors for overall survival were tumor size (P = 0.002), the number of positive lymph nodes (P less than 0.001), age at primary surgery (P less than 0.001), the PgR level of the tumor (P less than 0.001), but not ER level. Independent prognostic factors for relapse were tumor size (P = 0.003), number of positive lymph nodes (P less than 0.001), age (P = 0.006), menopause status (P = 0.02), PgR level (P = 0.007), but not ER level. Finally, for death rate after relapse the following prognosticators were identified: size of the primary tumor (P = 0.03), number of positive lymph nodes (P = 0.03), age (P = 0.003), site of relapse (P less than 0.001), ER level (P = 0.02), and PgR level (P = 0.04). Patients with tumors containing low positive PgR levels (10 to 20 fmol/mg protein) had a slightly better prognosis than patients with PgR-negative tumors. It is concluded that the PgR level of the primary tumor is a better prognosticator than the ER level. The ER offered no additional ability for discriminating between low- and high-risk patients once PgR was included in the model. In contrast, PgR was capable of improving on the discriminating ability of ER. In addition, patients with tumors containing both PgR and ER showed the best prognosis. Therefore, it is recommended that ER and PgR should be assayed in all breast cancer biopsies.