A risk prediction model for the development of subsequent primary melanoma in a population-based cohort.

BACKGROUND: Guidelines for follow-up of patients with melanoma are based on limited evidence. OBJECTIVES: To guide skin surveillance, we developed a risk prediction model for subsequent primary melanomas, using demographic, phenotypical, histopathological, sun exposure and genomic risk factors. METHODS: Using Cox regression frailty models, we analysed data for 2613 primary melanomas from 1266 patients recruited to the population-based Genes, Environment and Melanoma study in New South Wales, Australia, with a median of 14 years' follow-up via the cancer registry. Discrimination and calibration were assessed. RESULTS: The median time to diagnosis of a subsequent primary melanoma decreased with each new primary melanoma. The final model included 12 risk factors. Harrell's C-statistic was 0·73 [95% confidence interval (CI) 0·68-0·77], 0·65 (95% CI 0·62-0·68) and 0·65 (95% CI 0·61-0·69) for predicting second, third and fourth primary melanomas, respectively. The risk of a subsequent primary melanoma was 4·75 times higher (95% CI 3·87-5·82) for the highest vs. the lowest quintile of the risk score. The mean absolute risk of a subsequent primary melanoma within 5 years was 8·0 ± SD 4.1% after the first primary melanoma, and 46·8 ± 15·0% after the second, but varied substantially by risk score. CONCLUSIONS: The risk of developing a subsequent primary melanoma varies considerably between individuals and is particularly high for those with two or more primary melanomas. The risk prediction model and its associated nomograms enable estimation of the absolute risk of subsequent primary melanoma, on the basis of on an individual's risk factors, and can be used to tailor surveillance intensity, communicate risk and provide patient education. What's already known about this topic? Current guidelines for the frequency and length of follow-up to detect new primary melanomas in patients with one or more previous primary melanomas are based on limited evidence. People with one or more primary melanomas have, on average, a higher risk of developing another primary invasive melanoma, compared with the general population, but an accurate way of estimating individual risk is needed. What does this study add? We provide a comprehensive risk prediction model for subsequent primary melanomas, using data from 1266 participants with melanoma (2613 primary melanomas), over a median 14 years' follow-up. The model includes 12 risk factors comprising demographic, phenotypical, histopathological and genomic factors, and sun exposure. It enables estimation of the absolute risk of subsequent primary melanomas, and can be used to tailor surveillance intensity, communicate individual risk and provide patient education.

Conserving large carnivores: dollars and fence.

Conservationists often advocate for landscape approaches to wildlife management while others argue for physical separation between protected species and human communities, but direct empirical comparisons of these alternatives are scarce. We relate African lion population densities and population trends to contrasting management practices across 42 sites in 11 countries. Lion populations in fenced reserves are significantly closer to their estimated carrying capacities than unfenced populations. Whereas fenced reserves can maintain lions at 80% of their potential densities on annual management budgets of $500 km(-2) , unfenced populations require budgets in excess of $2000 km(-2) to attain half their potential densities. Lions in fenced reserves are primarily limited by density dependence, but lions in unfenced reserves are highly sensitive to human population densities in surrounding communities, and unfenced populations are frequently subjected to density-independent factors. Nearly half the unfenced lion populations may decline to near extinction over the next 20-40 years.

Estimating the relative risk of developing melanoma in INK4A carriers.

Estimation of the relative risk of cancer due to rare germline mutations using population-based epidemiological techniques is challenging, since studies with very large numbers of subjects are required. In this pilot study using a novel study design, we evaluated the role of INK4A mutations in melanoma by comparing patients with multiple primary melanomas to those with single primaries. Patients were ascertained from the Surgery and Dermatology Clinics at Memorial Sloan-Kettering Cancer Center and at the Yale University Pigmented Lesion Clinic. Subjects completed a questionnaire covering risk factors for melanoma and were tested for INK4A mutations. Five (8%) of 65 patients with multiple primaries had a mutation, compared with none of 88 patients with single primaries (P=0.03). Examination of other factors, such as number of nevi on the arms of the patients, fair skin, hair and eye colour, and other phenotypic characteristics associated with the risk of melanoma, demonstrates that these factors exhibit higher prevalence in the multiple primary cases than in the single primaries. These results provide evidence of the utility of the new study design in evaluating the impact of rare but highly penetrant cancer risk factors.

Who gets adjuvant treatment for stage II and III rectal cancer? Insight from surveillance, epidemiology, and end results--Medicare.

PURPOSE: To examine the relationship between patient characteristics and the use of adjuvant pelvic radiation with and without chemotherapy among patients aged 65 years and older with stage II and III rectal cancer. PATIENTS AND METHODS: A retrospective cohort study using the Surveillance, Epidemiology, and End Results-Medicare linked database identified 1,411 patients aged 65 and older with resected stage II and III rectal cancers diagnosed between 1992 and 1996. From claims submitted to Medicare, we measured the use of pelvic radiation therapy with or without chemotherapy and pre- or postoperatively. RESULTS: Fifty-seven percent of patients received radiation, 42% received chemotherapy and radiation, and 7% had treatment delivered preoperatively. Age was the strongest determinant of treatment: 73% of patients aged 65 to 69, 66% aged 70 to 75, 52% aged 75 to 79, 39% aged 80 to 84, and 21% aged 85 to 89 received radiation. The age trend remained strong after adjusting for other factors that predict receipt of treatment and after exclusion of patients with any evident comorbidity (P <.001). Patients were more likely to receive radiation treatment if they had an abdominal perineal resection, stage III disease, or a T4 tumor. CONCLUSION: Because pelvic recurrences are a substantial cause of morbidity, further efforts are needed to ensure that elderly patients have the opportunity to make informed decisions regarding adjuvant treatment.

The influence of hospital volume on survival after resection for lung cancer.

BACKGROUND: Among patients who have undergone high-risk operations for cancer, postoperative mortality rates are often lower at hospitals where more of these procedures are performed. We undertook a population-based study to estimate the extent to which the number of procedures performed at a hospital (hospital volume) is associated with survival after resection for lung cancer. METHODS: We studied patients 65 years old or older who received a diagnosis of stage I, II, or IIIA non-small-cell lung cancer between 1985 and 1996, resided in 1 of the 10 study areas covered by the Surveillance, Epidemiology, and End Results Program, and underwent surgery at a hospital that participates in the Nationwide Inpatient Sample (2118 patients and 76 hospitals). RESULTS: The volume of procedures at the hospital was positively associated with the survival of patients (P<0.001). Five years after surgery, 44 percent of patients who underwent operations at the hospitals with the highest volume were alive, as compared with 33 percent of those who underwent operations at the hospitals with the lowest volume. Patients at the highest-volume hospitals also had lower rates of postoperative complications (20 percent vs. 44 percent) and lower 30-day mortality (3 percent vs. 6 percent) than those at the lowest-volume hospitals. CONCLUSIONS: Patients who undergo resection for lung cancer at hospitals that perform large numbers of such procedures are likely to survive longer than patients who have such surgery at hospitals with a low volume of lung-resection procedures.

Age and adjuvant chemotherapy use after surgery for stage III colon cancer.

BACKGROUND: Randomized trials have established that 5-fluorouracil-based adjuvant chemotherapy following resection of stage III colon cancer reduces subsequent mortality by as much as 30%. However, the extent to which adjuvant therapy is used outside the clinical trial setting, particularly among the elderly, is unknown. METHODS: A retrospective cohort study utilizing the Surveillance, Epidemiology, and End Results/Medicare-linked database identified 6262 patients aged 65 years and older with resected stage III colon cancer. The primary outcome was chemotherapy use within 3 months of surgery, as ascertained from Medicare claims. We examined the extent to which age at diagnosis was associated with adjuvant chemotherapy usage, and we adjusted for potential confounding based on differences in other patient characteristics with the use of multiple logistic regression. All P values were two-sided. RESULTS: Age at diagnosis was the strongest determinant of chemotherapy: 78% of patients aged 65-69 years, 74% of those aged 70-74 years, 58% of those aged 75-79 years, 34% of those aged 80-84 years, and 11% of those aged 85-89 years received postoperative chemotherapy. The age trend remained pronounced after adjustment for potential confounding based on variation in patients' demographic and clinical characteristics and after exclusion of patients with any evident comorbidity (all P values <.001). CONCLUSIONS: Adjuvant chemotherapy for stage III colon cancer is used extensively, especially for patients under the age of 75 years. However, treatment rates decline dramatically with chronologic age. Because patients in their 70s and even 80s have a reasonable life expectancy, further efforts are needed to ensure that elderly patients have the opportunity to make informed decisions regarding this potentially curative treatment.

The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations.

Several studies using families with multiple occurrences of breast cancer have provided evidence for a very high lifetime penetrance in carriers of BRCA1 or BRCA2 mutations. However, there are reasons to suspect that the estimates of penetrance from studies of cancer families may be inflated. Access to the genotypes of incident cases of breast cancer in three hospitals and from a large series of unaffected survey participants provided the basis for direct estimation of the age-specific relative risks attributable to these mutations, and the resulting lifetime penetrance, without any reference to familial aggregation of cancer. Cases were identified from incident series of Jewish patients treated for primary breast cancer at the three hospitals. Control data were obtained from the large series of Jewish women recruited in the Washington, D.C., area by investigators at the National Cancer Institute and limited to 3434 women with no previous history of breast or ovarian cancer. All subjects were genotyped for the three mutations that are relatively common in Ashkenazi Jews, namely 185delAG and 5382 insC in BRCA1 and 6174delT in BRCA2. For BRCA1, the relative risks of breast cancer were estimated to be 21.6 in women under 40 years of age, 9.6 in women 40-49 years of age, and 7.6 in women > or = 50 years of age. On the basis of these estimates, the penetrance of breast cancer at age 70 among BRCA1 mutation carriers is estimated to be 46% (95% confidence, 31%-80%) rising to 59% (95% confidence, 40%-93%) at age 80. For BRCA2, the relative risks in the same three age categories were estimated to be 3.3, 3.3, and 4.6, respectively, resulting in a penetrance at age 70 of 26% (95% confidence, 14%-50%) rising to 38% (95% confidence, 20%-68%) at age 80. The lifetime risk of breast cancer in Jewish women who are mutation carriers estimated via this approach is substantially lower than the reported lifetime risks estimated using multiple-case families. The risks appear to be different for carriers of BRCA1 and BRCA2 mutations.

The search for cancer risk factors: when can we stop looking?

In recent decades, countless cohort, case-control, and ecologic studies have been conducted in the search for cancer risk factors. On the basis of knowledge gained from these studies, various influential commentaries have endeavored to classify the extent to which the total cancer burden is attributable to general categories of risk, such as diet, tobacco, sun exposure, and others. These commentaries have led to the conventional wisdom that most of the cancer burden is caused by environmental factors and relatively little is directly attributable to genetic susceptibility. In the face of the apparent knowledge that the cancer burden is essentially fully "explainable" on the basis of known environmental risks, this article addresses the conceptual and empirical basis of the continued search for new risk factors. It proposes that the extent of the aggregation of cancer within individuals in the population--that is, the occurrence of second primary cancers--is a crucial statistic in this context. A study of the incidence of second primary melanoma suggests that the bulk of the risk variation in this disease cannot be explained by known risk factors. The implications of these ideas for research strategy and for public health policy are discussed.

Influence of hospital procedure volume on outcomes following surgery for colon cancer.

CONTEXT: Survival following high-risk cancer surgery, such as pancreatectomy and esophagectomy, is superior at hospitals where high volumes of these procedures are performed. Conflicting evidence exists as to whether the association between hospital experience and favorable health outcomes also applies to more frequently performed operations, such as those for colon cancer. OBJECTIVE: To determine whether hospital procedure volume predicts survival following colon cancer surgery. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of data from the Surveillance, Epidemiology and End Results-Medicare linked database on 27 986 colon cancer patients aged 65 years and older who had surgical resection for primary adenocarcinoma diagnosed between 1991 and 1996. MAIN OUTCOME MEASURES: Thirty-day postoperative mortality and overall and cancer-specific long-term survival, by hospital procedure volume. RESULTS: We found small differences in 30-day postoperative mortality for patients treated at low- vs high-volume hospitals (3. 5% at hospitals in the top-volume quartile vs 5.5% at hospitals in the bottom-volume quartile). However, the correlation was statistically significant and persisted after adjusting for age at diagnosis, sex, race, cancer stage, comorbid illness, socioeconomic status, and acuity of hospitalization (P<.001). The association was evident for subgroups with stage I, II, and III disease. Hospital volume directly correlated with survival beyond 30 days and also was not attributable to differences in case mix (P<.001). The association between hospital volume and long-term survival was concentrated among patients with stage II and III disease (P<.001 for both). Among stage III patients, variation in use of adjuvant chemotherapy did not explain this finding. CONCLUSION: Our data suggest that hospital procedure volume predicts clinical outcomes following surgery for colon cancer, although the absolute magnitudes of these differences are modest in comparison with the variation observed for higher-risk cancer surgeries.

Comparing tumour staging and grading systems: a case study and a review of the issues, using thymoma as a model.

We consider the problem of comparing alternative cancer staging and grading systems. Statistical comparisons are on the basis of the ability to predict survival, but more qualitative criteria, such as parsimony, and distinctive prognostic separability of the categories are relevant also. Furthermore, some staging systems are clearly ordinal, while others are not. Three candidate statistical measures are studied and compared: explained variation; area under the ROC curve; and the probability of concordance of stage and survival. Each of these has individual strengths and weaknesses. A data set involving the staging of thymoma is analysed in detail to motivate the problem and illustrate the results.

Staging of malignant pleural mesothelioma: comparison of CT and MR imaging.

OBJECTIVE: This article compares the accuracy of CT with that of MR imaging in staging of malignant pleural mesothelioma. SUBJECTS AND METHODS: Ninety-five patients were enrolled in a prospective staging protocol based on the International Mesothelioma Interest Group staging system. Sixty-five patients underwent CT and MR imaging and a surgical procedure (excluding percutaneous needle biopsy) to stage and resect the tumor. Receiver operating characteristic analyses were performed. CT and MR scans were interpreted independently by observers who were unaware of the results of the other imaging study; these imaging findings were compared with the results of surgery and pathologic examination. RESULTS: The areas under the receiver operating characteristic curves for eight of 10 features revealed by imaging showed no statistically significant differences between CT and MR imaging. However, MR imaging was superior to CT in revealing invasion of the diaphragm (A(z) = .55 for CT versus .82 for MR imaging) and in revealing invasion of endothoracic fascia or solitary resectable foci of chest wall invasion (A(z) = .46 for CT; A(z) = .69 for MR imaging). Several anatomic regions could not be evaluated because positive findings at surgery were rare. CONCLUSION: CT and MR imaging are of nearly equivalent diagnostic accuracy in staging malignant pleural mesothelioma. MR imaging is superior to CT in revealing solitary foci of chest wall invasion and endothoracic fascia involvement and in showing diaphragmatic muscle invasion; however, this advantage does not affect surgical treatment. For cost reasons, CT should be considered the standard diagnostic study before therapy.

Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma.

PURPOSE: Several single-institution phase II trials have reported that the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) can induce major tumor responses in 40% to 50% of stage IV melanoma patients. This study was designed to compare the overall survival time, rate of objective tumor response, and toxicity of the Dartmouth regimen with standard dacarbazine treatment in stage IV melanoma patients. PATIENTS AND METHODS: In this multicenter phase III trial, 240 patients with measurable stage IV melanoma were randomized to receive the Dartmouth regimen (dacarbazine 220 mg/m(2) and cisplatin 25 mg/m(2) days 1 to 3, carmustine 150 mg/m(2) day 1 every other cycle, and tamoxifen 10 mg orally bid) or dacarbazine 1, 000 mg/m(2). Treatment was repeated every 3 weeks. Patients were observed for tumor response, survival time, and toxicity. RESULTS: Median survival time from randomization was 7 months; 25% of the patients survived > or = 1 year. There was no difference in survival time between the two treatment arms when analyzed on an intent-to-treat basis or when only the 231 patients who were both eligible and had received treatment were considered. Tumor response was assessable in 226 patients. The response rate to dacarbazine was 10.2% compared with 18.5% for the Dartmouth regimen (P =.09). Bone marrow suppression, nausea/vomiting, and fatigue were significantly more common in the Dartmouth arm. CONCLUSION: There was no difference in survival time and only a small, statistically nonsignificant increase in tumor response for stage IV melanoma patients treated with the Dartmouth regimen compared with dacarbazine. Dacarbazine remains the reference standard treatment for stage IV melanoma.

Racial differences in the treatment of early-stage lung cancer.

BACKGROUND: If discovered at an early stage, non-small-cell lung cancer is potentially curable by surgical resection. However, two disparities have been noted between black patients and white patients with this disease. Blacks are less likely to receive surgical treatment than whites, and they are likely to die sooner than whites. We undertook a population-based study to estimate the disparity in the rates of surgical treatment and to evaluate the extent to which this disparity is associated with differences in overall survival. METHODS: We studied all black patients and white patients 65 years of age or older who were given a diagnosis of resectable non-small-cell lung cancer (stage I or II) between 1985 and 1993 and who resided in 1 of the 10 study areas of the Surveillance, Epidemiology, and End Results (SEER) program (10,984 patients). Data on the diagnosis, stage of disease, treatment, and demographic characteristics of the patients were obtained from the SEER data base. Information on coexisting illnesses, type of Medicare coverage, and survival was obtained from linked Medicare inpatient-discharge records. RESULTS: The rate of surgery was 12.7 percentage points lower for black patients than for white patients (64.0 percent vs. 76.7 percent, P<0.001), and the five-year survival rate was also lower for blacks (26.4 percent vs. 34.1 percent, P<0.001). However, among the patients undergoing surgery, survival was similar for the two racial groups, as it was among those who did not undergo surgery. Furthermore, analyses in which adjustments were made for factors that are predictive of either candidacy for surgery or survival did not alter the influence of race on these outcomes. CONCLUSIONS: Our analyses suggest that the lower survival rate among black patients with early-stage, non-small-cell lung cancer, as compared with white patients, is largely explained by the lower rate of surgical treatment among blacks. Efforts to increase the rate of surgical treatment for black patients appear to be a promising way of improving survival in this group.

N-type calcium channel/syntaxin/SNAP-25 complex probed by antibodies to II-III intracellular loop of the alpha1B subunit.

Neuronal voltage-dependent calcium channels are integral components of cellular excitation and neurosecretion. In addition to mediating the entry of calcium across the plasma membrane, both N-type and P/Q-type voltage-dependent calcium channels have been shown to form stable complexes with synaptic vesicle and presynaptic membrane proteins, indicating a structural role for the voltage-dependent calcium channels in secretion. Recently, detailed structural analyses of N-type calcium channels have identified residues amino acids 718-963 as the site in the rat alpha1B subunit that mediates binding to syntaxin, synaptosome-associated protein of 25,000 mol. wt and synaptotagmin [Sheng et al. (1996) Nature 379, 451-454]. The purpose of this study was to employ site-directed antibodies to target domains within and outside of the interaction site on the rat alpha1B to probe potential binding sites for syntaxin/SNAP-25/synaptotagmin. Our results demonstrate that both antibodies employed in this study have access to their epitopes on the alpha1B as evidenced by equivalent immunoprecipitation of native [125I]omega-conotoxin GVIA-labeled alpha1B protein from CHAPS-solubilized preparations. The N-type voltage-dependent calcium channel immunoprecipitated by Ab CW14, the antibody directed to a domain outside of the synprint site, is associated with syntaxin and SNAP-25 with the recovery of these proteins, increasing in parallel to the recovery of alpha1B. However, when we used the antibody raised to an epitope within the synprint site (Ab CW8) to immunoprecipitate N-type calcium channels, the alpha1B was depleted of more than 65% of syntaxin and 80% of SNAP-25 when compared to the recovery of these proteins using Ab CW14. This is the first report of a defined epitope on the alpha1B subunit II-III loop (amino acids 863-875) whose perturbation by a site-directed antibody influences the dissociation of SNAP-25 and syntaxin.

Properties of a nonparametric test for early comparison of treatments in clinical trials in the presence of surrogate endpoints.

A nonparametric test is derived for comparing treatments with respect to the final endpoint in clinical trials in which the final endpoint has been observed for a random subset of patients, but results are available for a surrogate endpoint for a larger sample of patients. The test is an adaptation of the Wilcoxon-Mann-Whitney two-sample test, with an adjustment that involves a comparison of the ranks of the surrogate endpoints between patients with and without final endpoints. The validity of the test depends on the assumption that the patients with final endpoints represent a random sample of the patients registered in the study. This assumption is viable in trials in which the final endpoint is evaluated at a "landmark" timepoint in the patients' natural history. A small sample simulation study demonstrates that the test has a size that is close to the nominal value for all configurations evaluated. When compared with the conventional test based only on the final endpoints, the new test delivers substantial increases in power only when the surrogate endpoint is highly correlated with the true endpoint. Our research indicates that, in the absence of modeling assumptions, auxiliary information derived from surrogate endpoints can provide significant additional information only under special circumstances.