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Prognostic factors in breast cancer: the predictive value of the Nottingham Prognostic Index in patients with a long-term follow-up that were treated in a single institution.

The Nottingham Prognostic Index (NPI) is an index, derived from a retrospective multivariate study, that is able to predict survival in patients with breast cancer. The index is based on tumour size, lymph node stage and histological grade and allows the stratification of patients into three different prognostic groups. The aim of this study was to verify, according to our experience with a long-term follow-up, the effect of some prognostic variables on survival and to establish the independent influence of each of them by means of a survival regression analysis. Then we applied the NPI to the same group of patients in order to assess the predictive power and reproducibility of the index. 402 patients treated from January 1979 to December 1987 were evaluated. In multivariate analysis (Cox proportional hazard model), only size, lymph node involvement and histological grade remained independent prognostic factors. The survival curves obtained after applying the NPI are similar to those for the factors with independent prognostic significance derived from our multivariate analysis. Our improved survival rates may be attributed to the administration of adjuvant therapies to a larger number of patients. The NPI allow us to accurately predict prognosis and we advocate its more common use.

Adult↗

Modelling predictions of cancer deaths in Northern Ireland.

BACKGROUND: An ageing population has service planners concerned about future levels of disease which are age dependent. Predictions of mortality for colorectal, lung and breast cancers, which account for 30% of cancer cases and 40% of cancers deaths, were calculated for 2010 and 2015, based on trends in death rates and the predicted change in the demography of the Northern Ireland population. METHODS: The U.S. National Cancer Institute's "Joinpoint" program was used to check for structural breaks in the time series of cancer death rates from 1984 to 2004. The prediction models applied to the data allowed variations in trends across age groups to be taken into account. A linear model was used for increasing or constant trends and a log linear model was used where the trend was decreasing. The models assume the number of deaths in each stratum, defined by age-sex and time-period, is Poisson distributed, with the average value determined by a log or linear function. RESULTS: Recent trends in rates of cancers studied were downwards except for female lung. Predictions include decreased colorectal cancer deaths in females and lung cancer deaths in males. In females, lung cancer deaths are predicted to more than double by the year 2015 (473 deaths), based on the 1984 level. Colorectal death rates in males are predicted to drop, but the number of deaths will increase by more than 10%, due to demographic change. Numbers of breast cancer deaths are likely to rise slightly, despite falling age standardised death rates, due to an ageing population. CONCLUSIONS: This work has provided estimates of early future trends, useful to service planners, and highlights the need for tobacco control, to reduce numbers of lung cancer deaths in females. The recently announced control of environmental tobacco legislation is one welcome development which should reduce lung cancer mortality in Northern Ireland.

Adolescent↗

Cross-Device Adaptation of Mirai for Mammography-Based Breast Cancer Risk Prediction.

Fine-tuning can adapt pretrained medical imaging models to new clinical datasets, but device-specific domain shifts may limit generalizability. We evaluated Mirai, a mammography-based deep learning model for breast cancer risk prediction, in a large screening cohort containing Hologic and General Electric (GE) full-field digital mammography systems, including GE Premium View (GE PV) and Tissue Equalization (GE TE) post-processing software. Native Mirai showed lower performance on TE images than on Hologic or PV images. Fine-tuning on TE images improved TE performance, particularly for short-term risk prediction, but substantially reduced performance on Hologic images, consistent with catastrophic forgetting. To mitigate this effect, we developed a device-invariant model using interleaved multi-device sampling and conditional adversarial training. This approach largely restored Hologic performance while maintaining improved TE performance, providing better robustness across heterogeneous imaging platforms. Comparison of cumulative and annual risk AUCs over a five-year time horizon further showed that performance gains were driven mainly by short- and intermediate-term predictions. These findings highlight both the value and dangers of device-specific fine-tuning and support balanced domain-adaptation strategies for deploying mammography-based risk models across diverse clinical imaging environments.

Journal Article↗

Urinary excretion of epsilondA is not predictive of cancer development: a prospective nested case-control study.

Human biomonitoring of the lipid peroxidation DNA modification 1,N6-ethenodeoxyadenosine (epsilondA) excreted into urine is thought to be a potential marker for oxidative stress-related DNA damage and human cancer. We have tested this hypothesis in a prospective, nested case-control study. During the years 1984-1989, 24-h urines were collected from 1956 men in the Kuopio Ischaemic Heart Disease (KIHD) Risk Factor Study. epsilondA concentrations were measured by LC-MS/MS in 24-h urine samples from 47 men with cancer diagnosed at follow up until 2001 and from 31 cancer free smoking-matched control subjects. Odds ratio for having higher than control median epsilon dA excretion rate and cancer, estimated by binary logistic regression, was 0.73 (95% CI 0.29-1.80, p = 0.49). In this study, the urinary excretion of epsilondA provides no additional prediction of cancer development in males after controlling for smoking.

Adult↗

Predicted lung cancer risk among miners exposed to diesel exhaust particles.

Several quantitative risk assessment models have been published for occupational and environmental exposures to diesel exhaust particles (DEP). These risk assessment models are reviewed and applied to predict lung cancer for miners exposed to DEP. The toxicologically based unit risk estimates varied widely (from 2 to 220 x 10(-6) per micrograms/m3). The epidemiologically based unit risk estimates were less variable and suggest higher risks (from 100 to 920 x 10(-6) per micrograms/m3). The wide range of risk estimates derived from these analyses reflects the strong assumptions and large uncertainties underlying these models. All of the models suggest relatively high risks (i.e., > 1/1,000) for miners with long-term exposures greater than 1,000 micrograms/m3. This is not surprising, given the fact that miners may be exposed to DEP concentrations similar to those that induced lung cancer in rats and mice, and substantially higher that the exposure concentrations in the positive epidemiologic studies.

Humans↗

Predictive and prognostic markers for invasive breast cancer.

Breast cancer is one of the most serious carcinomas among women worldwide, yet there are now encouraging signs that improvements in the mortality rate may be possible. The use of hormone therapy and chemotherapy has been widely accepted as treatment for breast cancer. Predictive factors can be used to predict response or lack of response to a particular therapy, and prognostic factors can be useful in making decisions about which patients should receive adjuvant therapy. Histopathology remains the universal basis of diagnosis, with the identification of new surrogate markers for potential new treatments. These are aimed at blocking tumor cell proliferation, neutralizing growth factors, stimulating apoptosis and blocking metastasis, and represent an integral part of new approaches for improving clinical management of patients with breast cancer. We review the standard predictive and prognostic factors that are routinely available today, and also describe some of the new, potential markers that are currently under investigation.

Biomarkers, Tumor↗

Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status.

PURPOSE: Ovarian cancers (OCs) frequently have HER2 activation in the absence of HER2 overexpression. Pertuzumab, a humanized antibody that prevents HER2 dimerization and inhibits multiple HER-mediated pathways, was studied in a phase II, multicenter trial in advanced, refractory OC. PATIENTS AND METHODS: Sixty-one patients (cohort 1) with relapsed OC received a loading dose of 840 mg pertuzumab intravenously followed by 420 mg every 3 weeks; 62 patients (cohort 2) received 1,050 mg every 3 weeks. Response rate was the primary end point. Fresh tumor biopsies were obtained in cohort 1 to assay for phosphorylated HER2 (pHER2). RESULTS: Median age was 57 years and median number of prior chemotherapy regimens was five. Fifty-five patients in cohort 1 and 62 patients in cohort 2 were assessable for efficacy. There were five partial responses (response rate [RR] = 4.3%; 95% CI, 1.7% to 9.4%), eight patients (6.8%) with stable disease (SD) lasting at least 6 months, and 10 patients with CA-125 reduction of at least 50% (includes two partial responses and four patients with SD > or = 6 months; total clinical activity, 14.5%). Median progression-free survival (PFS) was 6.6 weeks. Eight of 28 tumor biopsies (28.6%) were pHER2+ by enzyme-linked immunosorbent assay (ELISA; without gene amplification). Median PFS for pHER2+ patients was 20.9 weeks (n = 8) versus 5.8 weeks for pHER2- (n = 20; P = .14) and 9.1 weeks for unknown pHER2 status (n = 27). Pertuzumab was well tolerated with diarrhea in 69.1% (11.4% grade 3, no grade 4). Five patients had asymptomatic left ventricular ejection fraction decreases to less than 50% (one confirmed by central facility). CONCLUSION: Pertuzumab is well tolerated with a RR of 4.3% in heavily-pretreated OC patients. Further studies on pHER2 as a diagnostic are warranted.

Adult↗

Comparison of percentage of total prostate needle biopsy tissue with cancer to percentage of cores with cancer for predicting PSA recurrence after radical prostatectomy: results from the SEARCH database.

OBJECTIVES: Tumor volume in the prostate needle biopsy is an important prognosticator for patients with prostate cancer. However, the best method to measure tumor volume in the prostate needle biopsy is unknown. We compared the total percentage of biopsy tissue with cancer to the percentage of cores positive for their ability to predict adverse pathologic findings and biochemical failure after radical prostatectomy (RP). METHODS: A retrospective survey of 355 patients from the Shared Equal Access Regional Cancer Hospital database treated with RP between 1990 and 2002 was undertaken. Multivariate analysis was used to compare the percentage of cores and percentage of tissue with cancer to the standard clinical variables of age, prostate-specific antigen (PSA) level, biopsy Gleason score, and clinical stage for their ability to predict positive surgical margins, non-organ-confined disease, seminal vesicle invasion, and time to PSA recurrence after RP. RESULTS: On multivariate analysis, the percentage of tissue with cancer significantly predicted non-organ-confined disease and seminal vesicle invasion, but the percentage of cores did not significantly predict any of the pathologic features examined. In separate multivariate analysis, only the percentage of tissue with cancer, but not the percentage of cores with cancer, significantly predicted PSA failure. Moreover, when compared in the same multivariate analysis, only the percentage of tissue with cancer (hazard ratio 8.25, 95% confidence interval 3.06 to 22.22, P <0.001) was a significant predictor. The area under the receiver operating curves for predicting PSA failure was significantly greater for the percentage of tissue with cancer (0.697) than for the percentage of cores (0.644, P = 0.022). Cutpoints for the percentage of tissue with cancer (less than 20%, 20% to 40%, and greater than 40%) and the percentage of cores (less than 34%, 34% to 50%, greater than 50%) both provided significant preoperative risk stratification for biochemical failure, although the percentage of tissue with cancer cutpoints provided better risk stratification (higher hazard ratios and lower P value). Cutpoints for the percentage of tissue with cancer but not the percentage of cores positive further stratified patients who were at low (P = 0.041), intermediate (P = 0.002), and high (P = 0.023) risk on the basis of the PSA level and biopsy Gleason score. CONCLUSIONS: The percentage of tissue with cancer was better than the percentage of cores at predicting advanced pathologic features and PSA recurrence after RP. Unlike the percentage of cores, the percentage of tissue with cancer cutpoints further stratified low, intermediate, and high-risk patients on the basis of PSA level and biopsy Gleason score. Although the percentage of tissue with cancer is a slightly more cumbersome measurement than the percentage of positive cores, it provided statistically and clinically superior preoperative risk stratification for biochemical failure after RP.

Biopsy, Needle↗

The use of molecular profiling of early colorectal cancer to predict micrometastases.

BACKGROUND: Approximately one third of node-negative colorectal cancers (CRCs) recur, suggesting the failure to detect occult disease. Lymphatic mapping followed by focused analysis of the sentinel node is highly accurate in identifying micrometastases. HYPOTHESIS: Because aberrant genetic changes occur early in tumor progression and are associated with lymphatic metastases, we hypothesized that the molecular profiling of specific tumor markers in the primary tumor might predict that tumor's metastatic potential. DESIGN: A prospective patient series. PATIENTS AND INTERVENTIONS: Forty consecutive patients with early CRC underwent lymphatic mapping after subserosal injection of 1 mL of isosulfan blue dye. All lymph nodes were examined by hematoxylin-eosin (HE) staining, and multiple sections of each sentinel node were examined by HE and cytokeratin immunohistochemistry (CK-IHC) staining. Primary tumors were analyzed for p53 expression using IHC staining and for beta-human chorionic gonadotropin (beta-hCG), hepatocyte growth factor receptor (c-Met), and universal melanoma antigen (uMAGE) messenger RNA expression using reverse-transcriptase polymerase chain reaction and electrochemiluminescence. RESULTS: Nine patients (23%) had positive nodes by routine HE staining. Of the remaining 31 patients with negative nodes on HE staining, 8 tumors (26%) were upstaged by CK-IHC identification of occult micrometastases. There was a direct correlation between the number of markers and the T stage (P =.001). The expression of p53, beta-hCG, c-Met, and uMAGE in primary tumors was significantly higher in the presence of nodal micrometastases vs no metastases (P =.03). CONCLUSIONS: Sentinel lymphatic mapping is an accurate method of detecting micrometastases in CRC. Molecular profiling of primary CRC tumors, similar to that used for breast cancer, may be important in predicting metastatic potential and determining which patients may benefit from adjuvant therapy.

Adult↗

Optimized microvessel density analysis improves prediction of cancer stage from prostate needle biopsies.

OBJECTIVES: Clinical staging of prostate cancer is inaccurate, often with significant upstaging on final pathologic review. We previously demonstrated the ability to predict extraprostatic extension of cancer by use of the Gleason score and serum prostate-specific antigen (PSA) measurements. Herein we present an interim analysis of data from an ongoing multi-institutional study to determine the predictive power of an enhancement of microvessel density analysis in combination with Gleason score and serum PSA to predict extraprostatic extension. METHODS: We evaluated a total of 186 randomly selected biopsy samples and matched totally embedded radical prostatectomy samples with preoperative PSA concentrations and patient demographics. Gleason score and optimized microvessel density (OMVD) were determined from the needle biopsy samples; pathologic stage was verified by independent review of the radical prostatectomy samples. An automated digital image analysis system measured microvessel morphology and calculated the OMVD in the biopsy samples (Biostage; Bard Diagnostic Sciences, Seattle, Wash). RESULTS: Prediction of extraprostatic extension was increased significantly when OMVD analysis was added to Gleason score and serum PSA concentration (P = 0.003). CONCLUSIONS: Optimized microvessel density analysis significantly increases the ability to predict extraprostatic extension of cancer preoperatively when combined with Gleason score and serum PSA concentration. This method appears to be a useful tool that can assist with treatment decisions in selected patients.

Aged↗

Demonstration of the need for end point validation of putative biomarkers: failure of aberrant crypt foci to predict colon cancer incidence.

Seven-week-old Sprague-Dawley rats were fed a semipurified AIN76 diet and were given a weekly injection of the colon carcinogen 1,2-dimethylhydrazine for 8 weeks (initiation stage of carcinogenesis). The rats were divided into seven groups and each group of rats was placed on one of seven different modifications of the AIN76 diet for the next 24 weeks (promotional stage of carcinogenesis). The mean numbers of aberrant crypt foci/rat and the incidence of adenocarcinomas from some of the seven dietary groups were found to be significantly different. However, all attempts to show a significant correlation between the mean number of aberrant crypt foci/rat and the incidence of adenocarcinomas failed. Therefore, the number of aberrant crypt foci/rat cannot by itself be used as a reliable quantitative predictor (biomarker) of the efficacy of dietary intervention or of chemopreventive procedures on modulating the risk of developing colon cancer. This conclusion emphasizes the need for end point validation of potential cancer biomarkers before the biomarkers can be considered predictive of modulation of the risk for colon cancer.

Adenocarcinoma↗

Second primary lung cancer: possible prediction, treatment and prognosis.

The incidence of second primary lung cancer (SPLC) seems to have increased in recent years. In our series that included more than 4000 patients with lung cancer and 1600 operations, we observed 26 cases of SPLC up until June 1999. We considered the standard criteria accepted by most authors for the selection. Characteristics of patients and tumors at the time of the first operation were compared with the statistical data of our general series. Age, sex, performance status and smoking were all considered, as well as cancer site, histology, stage and type of first surgical operation. No significant independent factor could be identified for the prediction of a new tumor at that time. A second operation was possible in 16 cases: two patients died in the postoperative period, two survived for 12 and 24 months, respectively, 12 are still alive 8-87 months after the new resection. The high rate of surgical cases (16/26 = 62%) and a good survival rate is clearly correlated with an early diagnosis of SPLC.

Adult↗

V89L polymorphism of type-2, 5-alpha reductase enzyme gene predicts prostate cancer presence and progression.

OBJECTIVES: The valine (V) to leucine (L) polymorphism of the SRD5A2 gene is associated with 5-alpha reductase-2 activity; patients with the V allele have high activity and patients with the L allele have low activity. We examined whether this polymorphism predicts the presence of prostate cancer in 320 men without cancer who underwent biopsy and cancer progression in 318 men who underwent radical prostatectomy. METHODS: The effect of the SRD5A2 gene in predicting the presence of prostate cancer was examined using logistic regression analysis, controlling for established risk factors. The effect of the SRD5A2 gene in predicting prostate cancer progression was examined using a nested, matched, case-control design. Most of the participants were white. RESULTS: Of the 320 men, 158 (49.4%) were found on biopsy to have prostate cancer. The overall distribution of the V/V, V/L, and L/L genotypes was 47.5%, 42.5%, and 10.0%, respectively. The adjusted odds ratio for having prostate cancer for patients with at least one V allele was 2.53 compared with patients with the L/L genotype (P = 0.03). Of the 318 patients with cancer, 80 had biochemically detected recurrence and 238 had no evidence of recurrence. The odds ratio for progression for patients with at least one V allele was 3.32 (95% confidence interval 1.67 to 6.62, P = 0.0006) compared with patients with the L/L genotype. CONCLUSIONS: Men who have the V allele of the SRD5A2 gene have a twofold increase in the risk of prostate cancer development and an additional twofold increase in the risk of progression compared with men with the L/L genotype.

Aged↗

How do cancer risks predicted from animal bioassays compare with the epidemiologic evidence? The case of ethylene dibromide.

Cancer risks for ethylene dibromide (EDB) were estimated by fitting several linear non-threshold additive models to data from a gavage bioassay. Risks predicted by these models were compared to the observed cancer mortality among a cohort of workers occupationally exposed to the same chemical. Models that accounted for the shortened latency period in the gavaged rats predicted upper bound risks that were within a factor of 3 of the observed cancer deaths. Data from an animal inhalation study of EDB also were compatible with the epidemiologic data. These findings contradict those of Ramsey et al. (1978), who reported that extrapolation from animal data produced highly exaggerated risk estimates for EDB-exposed workers. This paper explores the reasons for these discrepant findings.

Animals↗

Cancer prognosis predicted by preoperative lymphocyte responsiveness in vitro.

The prognosis in cancer patients was studied in relation to their preoperative cell-mediated immune status. Thirty patients with various types of operable cancer were studied. Transformation of the lymphocytes in response to phytohaemagglutinin (PHA) in vitro was measured preoperatively. All the patients were followed up for 3 years. Those with normal preoperative lymphocyte responsiveness had a far better prognosis than those in whom this test was subnormal.

Follow-Up Studies↗

[Trend and prediction of cancer mortality in Beijing, China, during 1980-2001].

Mortality data gathered through registration system were analyzed systematically to predict the trend of cancer mortality. A grey-system model was established to forecast the epidemic trend for cancer mortality of Beijing in 2001. In result, the mortality of cancer in Beijing will increase annually upto 2001. The composition of various malignant tumer will charge notably. Rapid increase will occure in lung cancer. Liver cancer and colon-rectal cancer will aslo increase. Cancers of esophagus and cervix uteri will steadly decline. Stomach cancer begin to decrease. These information on the change of cancer mortality will provide scientific reference for the study of cancer prevention and control in Beijing.

Adolescent↗

The application of age, period and cohort models to predict Swiss cancer mortality.

In order to project trends in mortality from 11 major cancer sites in Switzerland to the end of the current century, a log-linear Poisson age/period/cohort model with arbitrary constraints on the parameters was used, fitted to the observed rates for the period 1950-84. One projection was based on the assumption of a total absence of change in the effect of period, the second was based on a linear extrapolation of the logarithms of the seven known periods, and the third was related to a series of a priori external epidemiological hypotheses, whenever available. For instance, coefficients below unity were used for lung and other tobacco-related neoplasms in men, since some decline in exposure to tobacco carcinogens was observed among Swiss men, and above unity for women since the prevalence of smoking has risen among successive generations of women. Although the method has limitations and uncertainties, several qualitative indications could be derived from this exercise. For instance, the various models suggest that the age-standardized mortality from oral cancer in men will probably increase up to the end of the century, even under the optimistic assumption of an appreciable decline in smoking, while cancer of the oesophagus is likely to level-off around current values, as other tobacco-related neoplasms, prostate cancer in men, and breast cancer in women will probably do. Some steady decline is predicted by various models fitted to the incidence of stomach and intestinal cancer in both sexes, and to ovarian cancer. Lung cancer will continue to rise in women but will stop rising in men, and it will possibly fall if the hypothesis of a decline in exposure to tobacco carcinogens proves correct. Although any prediction has, by definition, substantial difficulties and uncertainties, projections of cancer mortality in the near future are based on a substantial amount of information already available, and may offer valuable information for epidemiological inferences and health planning purposes.

Adult↗

A scoring algorithm to predict survival for patients with metastatic clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.

PURPOSE: We developed a clinically useful scoring algorithm to predict cancer specific survival for patients with clear cell metastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: We studied 727 patients treated with radical nephrectomy for clear cell RCC from 1970 to 2000 who had distant metastases at nephrectomy (285) or in whom metastases subsequently developed (442). A scoring algorithm to predict cancer specific survival was developed using the regression coefficients from a Cox proportional hazards model. RESULTS: There were 606 deaths from clear cell RCC at a median of 1.0 years (range 0 to 14) following metastatic RCC. Constitutional symptoms at nephrectomy (+2), metastases to the bone (+2) or liver (+4), metastases in multiple simultaneous sites (+2), metastases at nephrectomy (+1) or within 2 years of nephrectomy (+3), complete resection of all metastatic sites (-5), tumor thrombus level I to IV (+3), and the primary pathological features of nuclear grade 4 (+3) and histological tumor necrosis (+2) were significantly associated with death from RCC. All patients started with a score of 0 and points were added or subtracted as indicated in parentheses. Cancer specific survival rates at 1 year were 85.1%, 72.1%, 58.8%, 39.0%, and 25.1%, respectively, for patients with scores of -5 to -1, scores of 0 to 2, scores of 3 to 6, scores of 7 or 8, and scores of 9 or more. CONCLUSIONS: This scoring algorithm can be used to predict cancer specific survival for patients with metastatic clear cell RCC.

Adenocarcinoma, Clear Cell↗