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S N Goodman

Publications and source records attributed to S N Goodman.

At least 55 records · Page 3Linked to original sources
PubMed1996

Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms.

Although several morphological and molecular genetic studies have implicated various grades of pancreatic duct hyperplasia as precursor lesions to infiltrating pancreatic adenocarcinoma, the identity of preinvasive pancreatic neoplasms remains controversial. In the present study, the authors examined the expression of the epidermal growth factor receptor homologue, HER-2/neu (c-erbB-2), in pancreatic duct lesions adjacent to infiltrating pancreas cancers in a series of 19 cases of pancreatic duct adenocarcinoma. HER-2/neu expression was examined because it has been identified in a proportion of infiltrating pancreas cancers and because it may provide early neoplasms with a growth advantage over adjacent nonneoplastic epithelium. In normal pancreatic ducts and ductules, HER-2/neu expression was absent in all but one case. By contrast, HER-2/neu was expressed in 82% (P = .008 vs normal ) of ducts with flat mucinous hyperplasia, 86% (P = .03 vs normal) of ducts with papillary mucinous hyperplasia without atypia, 92% (P = .001 vs normal) of ducts with atypical papillary mucinous hyperplasia, and all specimens with carcinoma in situ. HER-2/neu expression was observed in 69% (P = .002 vs normal) of the moderately differentiated infiltrating carcinomas and none of the poorly differentiated infiltrating carcinomas. These data establish HER-2/neu as a potential mediator of growth factor-related signal transduction in pancreatic duct lesions, and provide additional support for the hypothesis that lesions formerly regarded as various grades of hyperplasia instead may represent intraepithelial neoplasms with the potential for subsequent invasion and metastasis.

Adenocarcinoma↗
PubMed1996

Can caretakers of children with IDDM accurately measure small insulin doses and dose changes?

OBJECTIVE: To determine if caretakers of young children with IDDM could consistently reproduce small incremental measurements of insulin (U100). RESEARCH DESIGN AND METHODS: Fifteen caretakers of children with IDDM were asked to deliver repeated small doses of insulin, including doses separated by only 0.25 U of insulin. A sensitive gravimetric technique was used to determine the error in measurement of these low doses of insulin. Statistical analysis was used to evaluate accuracy and internal consistency of each caretaker at each dose. RESULTS: The means +/- SD at each dose level were as follows: 2.75 +/- 0.13 U at 2.5 U, 3.19 +/- 0.13 U at 3.0 U, 3.55 +/- 0.13 U at 3.25 U, and 3.70 +/- 0.11 U at 3.5 U. All doses were biased toward overadministration. There was as statistically significant difference in the dose delivered when the target doses were varied by only 0.25 U. The average differences and standard errors between 2.5 U and 3.0 U, 3.0 U and 3.25 U, and 3.25 U and 3.5 U were 0.44 +/- 0.20 U, 0.36 +/- 0.018 U, and 0.15 +/- 0.017 U, respectively. CONCLUSIONS: Participants were not accurate in measuring small insulin doses, consistently overdrawing insulin by an average of 0.22 U. Caretakers are reasonably internally consistent with a given dose, since participants were able to measure statistically significant differences in 0.25 U dose changes. The error in insulin measurement does not vary with the intended dose level. Caretakers in the same family deliver insulin doses as variable from each other as they are from the population as a whole; however, when two or more individuals are responsible for one insulin dose in a child with IDDM, they have a combined variability that is approximately 40% greater than a single individual's variability.

Caregivers↗
PubMed1996

Relationship between CD44 expression and cell proliferation in epithelium and stroma of colorectal neoplasms.

The cell surface glycoprotein CD44 is expressed primarily in the region of cell replication in the lower crypt epithelium of colorectal mucosa, and its expression is markedly increased in colorectal neoplasms, suggesting that expression is linked to proliferation. The association between CD44 expression and replication in individual cells was therefore analyzed by double-label immunohistochemistry for CD44 and the cell-cycle-dependent protein proliferating cell nuclear antigen (PCNA). Enhanced expression of CD44 in colorectal neoplasms occurred not only in epithelial cells but also in stromal cells, including lymphocytes and macrophages. On a topographical basis, the cellular localization of CD44 and PCNA were commonly different. Quantitatively, in all cell types studied (epithelial cells and stroma of colorectal mucosa, adenomas, and carcinomas) PCNA was present most frequently in cells lacking CD44. Statistical analysis by logistic regression models indicated that cells negative for CD44 had a higher probability of being positive for PCNA than did cells positive for CD44 (P < 0.001). These data suggest that the enhanced level of CD44 in colorectal neoplasms is asynchronous with cell replication and reflects mechanisms that act on nonproliferative stromal lymphocytes and other mononuclear cells as well as the epithelial cells.

Adult↗
PubMed1995

Some practical improvements in the continual reassessment method for phase I studies.

The Continual Reassessment Method (CRM) is a Bayesian phase I design whose purpose is to estimate the maximum tolerated dose of a drug that will be used in subsequent phase II and III studies. Its acceptance has been hindered by the greater duration of CRM designs compared to standard methods, as well as by concerns with excessive experimentation at high dosage levels, and with more frequent and severe toxicity. This paper presents the results of a simulation study in which one assigns more than one subject at a time to each dose level, and each dose increase is limited to one level. We show that these modifications address all of the most serious criticisms of the CRM, reducing the duration of the trial by 50-67 per cent, reducing toxicity incidence by 20-35 per cent, and lowering toxicity severity. These are achieved with minimal effects on accuracy. Most important, based on our experience at our institution, such modifications make the CRM acceptable to clinical investigators.

Bayes Theorem↗
PubMed1995

Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck.

BACKGROUND: Although epidemiologic studies have long associated tobacco and alcohol use with the development of squamous-cell carcinoma of the head and neck, the molecular targets of these carcinogens have yet to be identified. We performed a molecular analysis to determine the pattern of mutations in the p53 gene in neoplasms from patients with squamous-cell carcinoma of the head and neck and a history of tobacco or alcohol use. METHODS: Sequence analysis of the conserved regions of the p53 gene was performed in tumor samples from 129 patients with primary squamous-cell carcinoma of the head and neck. We then used statistical analysis to identify any patient characteristics associated with mutation of the p53 gene. RESULTS: We found p53 mutations in 42 percent of the patients (54 of 129). Fifty-eight percent of the patients who smoked cigarettes and used alcohol (37 of 64; 95 percent confidence interval, 45 to 70 percent), 33 percent of the patients who smoked but abstained from alcohol (13 of 39; 95 percent confidence interval, 19 to 50 percent), and 17 percent of the patients who neither smoked nor drank alcohol (4 of 24, 95 percent confidence interval, 5 to 37 percent) had p53 mutations (P = 0.001). (Two patients used alcohol but did not smoke, and neither had a p53 mutation.) Furthermore, 100 percent of the mutations in the patients who neither drank nor smoked occurred at sites containing cytidine phosphate guanosine dinucleotides (potentially representing endogenous mutations) within the p53 gene (5 of 5 mutations; 95 percent confidence interval, 48 to 100 percent), whereas only 23 percent of those in cigarette smokers consisted of such changes (12 of 53 mutations; 95 percent confidence interval, 12 to 36 percent; P = 0.001). CONCLUSIONS: In our study, a history of tobacco and alcohol use was associated with a high frequency of p53 mutations in patients with squamous-cell carcinoma of the head and neck. Preliminary evidence linked cigarette smoking to p53 mutations at nonendogenous mutation sites. Our findings suggest a role for tobacco in the molecular progression of squamous-cell carcinoma of the head and neck and support the epidemiologic evidence that abstinence from smoking is important to prevent head and neck cancer.

Base Composition↗
PubMed1995

Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck.

BACKGROUND: Surgical oncologists rely heavily on the histopathological assessment of surgical margins to ensure total excision of the tumor in patients with head and neck cancer. However, current techniques may not detect small numbers of cancer cells at the margins of resection or in cervical lymph nodes. METHODS: We used molecular techniques to determine whether clonal populations of infiltrating tumor cells harboring mutations of the p53 gene could be detected in histopathologically negative surgical margins and cervical lymph nodes of patients with squamous-cell carcinoma of the head and neck. RESULTS: We identified 25 patients with primary squamous-cell carcinoma of the head and neck containing a p53 mutation who appeared to have had complete tumor resection on the basis of a negative histopathological assessment. In 13 of these 25 patients, molecular analysis was positive for a p53 mutation in at least one tumor margin. In 5 of 13 patients with positive margins by this method (38 percent), the carcinoma has recurred locally, as compared with none of 12 patients with negative margins (P = 0.02 by the log-rank test). Furthermore, molecular analysis identified neoplastic cells in 6 of 28 lymph nodes (21 percent) that were initially negative by histopathological assessment. CONCLUSIONS: Among specimens initially believed to be negative by light microscopy, a substantial percentage of the surgical margins and lymph nodes from patients with squamous-cell carcinoma of the head and neck contained p53 mutations specific for the primary tumor. Patients with these positive margins appear to have a substantially increased risk of local recurrence. Molecular analysis of surgical margins and lymph nodes can augment standard histopathological assessment and may improve the prediction of local tumor recurrence.

Aged↗
PubMed1995

Evaluation of p53 protein expression as a marker for long-term prognosis in colorectal carcinoma.

Mutation of the p53 gene is reported to be of prognostic importance in colorectal carcinomas. Immunohistochemical staining of the accumulated p53 gene product may be a simple alternative for p53 mutation analysis. Previous studies addressing the prognostic importance of p53 expression, however, yielded contradictory results. Therefore, we evaluated the importance of p53 expression as a marker for long-term prognosis in a well-characterised study population of 109 colorectal carcinomas. After antigen retrieval with target unmasking fluid (TUF), immunostaining of p53 was performed with both monoclonal antibody DO7 and polyclonal antibody CM1. Objective quantification of the p53 signal was assessed by a computerised image analyser. p53 expression was higher in non-mucinous tumours than in mucinous tumours (p53 labelling index = 30% and 17% respectively, P = 0.05), and in metastatic tumours compared with non-metastatic tumours (p53 labelling index = 37% and 22% respectively, P = 0.05). Other histopathological features were not related to p53 expression. In multivariate analysis, Dukes' stage (P = 0.02) and histological grade (P = 0.05) stood out as independent markers for prognosis. p53 expression was not an independent marker for prognosis. At present, p53 expression is not a useful marker for long-term prognosis. Further insight into the relationship between p53 mutations and p53 expression is needed to elucidate more precisely the clinical relevance of p53 alterations.

Adult↗
PubMed1995

Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients.

OBJECTIVE: This single-institution study examined the outcome after pancreaticoduodenectomy in patients with adenocarcinoma of the head of the pancreas. SUMMARY OF BACKGROUND DATA: In recent years, pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas has been associated with decreased morbidity and mortality and, in some centers, 5-year survival rates in excess of 20%. METHODS: Two hundred one patients with pathologically verified adenocarcinoma of the head of the pancreas undergoing pancreaticoduodenectomy at The Johns Hopkins Hospital between 1970 and 1994 were analyzed (the last 100 resections were performed between March 1991 and April 1994). This is the largest single-institution experience reported to date. RESULTS: The overall postoperative in-hospital mortality rate was 5%, but has been 0.7% for the last 149 patients. The actuarial 5-year survival for all 201 patients was 21%, with a median survival of 15.5 months. There were 11 5-year survivors. Patients resected with negative margins (curative resections: n = 143) had an actuarial 5-year survival rate of 26%, with a median survival of 18 months, whereas those with positive margins (palliative resections; n = 58) fared significantly worse, with an actuarial 5-year survival rate of 8% and a median survival of 10 months (p < 0.0001). Survival has improved significantly from decade to decade (p < 0.002), with the 3-year actuarial survival of 14% in the 1970s, 21% in the 1980s, and 36% in the 1990s. Factors significantly favoring long-term survival by univariate analyses included tumor diameter < 3 cm, negative nodal status, diploid tumor DNA content, tumor S phase fraction < 18%, pylorus-preserving resection, < 800 mL intraoperative blood loss, < 2 units of blood transfused, negative resection margins, and use of postoperative adjuvant chemotherapy and radiation therapy. Multivariate analyses indicated the strongest predictors of long-term survival were diploid tumor DNA content, tumor diameter < 3 cm, negative nodal status, negative resection margins, and decade of resection. CONCLUSIONS: The survival of patients with pancreatic adenocarcinoma treated by pancreaticoduodenectomy is improving. Aspects of tumor biology, such as DNA content, tumor diameter, nodal status and margin status, are the strongest predictors of outcome.

Actuarial Analysis↗
PubMed1994

The use of predicted confidence intervals when planning experiments and the misuse of power when interpreting results.

Although there is a growing understanding of the importance of statistical power considerations when designing studies and of the value of confidence intervals when interpreting data, confusion exists about the reverse arrangement: the role of confidence intervals in study design and of power in interpretation. Confidence intervals should play an important role when setting sample size, and power should play no role once the data have been collected, but exactly the opposite procedure is widely practiced. In this commentary, we present the reasons why the calculation of power after a study is over is inappropriate and how confidence intervals can be used during both study design and study interpretation.

Bayes Theorem↗
PubMed1994

Do readers and peer reviewers agree on manuscript quality?

OBJECTIVE: To study readers' judgments of manuscript quality and the degree to which readers agreed with peer reviewers. DESIGN: Cross-sectional study. SETTING: Annals of Internal Medicine. SUBJECTS: One hundred thirteen consecutive manuscripts reporting original research and selected for publication. Each of two manuscript versions (one before and one after revision) was judged by two readers, randomly sampled from those who said (based on the title) that they would read the article; one peer reviewer (peer), chosen in the usual way for Annals; and one expert in clinical research methods (expert). Each judge completed an instrument that included a 10-point subjective summary grade of manuscript quality. MAIN OUTCOME MEASURES: Agreement on the 10-point summary grade of manuscript quality between reader-expert, reader-peer, and reader-reader. RESULTS: Readers and peers gave high grades (77% and 73% gave a grade of 5 or better, respectively), while experts were more critical (52% gave a grade of 5 or better; P < .0001). Agreement was relatively high among judge groups (in all cases, > 69%) but agreement beyond chance was poor (kappa < 0.04). One third of readers (33%) thought that the manuscript had little relevance to their work. CONCLUSION: Readers, like most peer reviewers, are generally satisfied with the quality of manuscripts but would like research articles to be more relevant to their clinical practice.

Cross-Sectional Studies↗
PubMed1994

Transfer of technology from statistical journals to the biomedical literature. Past trends and future predictions.

OBJECTIVE: To investigate the speed of the transfer of new statistical methods into the medical literature and, on the basis of current data, to predict what methods medical journal editors should expect to see in the next decade. DESIGN: Influential statistical articles were identified and the time pattern of citations in the medical literature was ascertained. In addition, longitudinal studies of the statistical content of articles in medical journals were reviewed. MAIN OUTCOME MEASURES: Cumulative number of citations in medical journals of each article in the years after publication. RESULTS: Annual citations show some evidence of decreasing lag times between the introduction of new statistical methods and their appearance in medical journals. Newer technical innovations still typically take 4 to 6 years before they achieve 25 citations in the medical literature. Few methodological advances of the 1980s seem yet to have been widely cited in medical journals. Longitudinal studies indicate a large increase in the use of more complex statistical methods. CONCLUSIONS: Time trends suggest that technology diffusion has speeded up during the last 30 years, although there is still a lag of several years before medical citations begin to accrue. Journals should expect to see more articles using increasingly sophisticated methods. Medical journals may need to modify reviewing procedures to deal with articles using these complex new methods.

Forecasting↗
PubMed1994

Manuscript quality before and after peer review and editing at Annals of Internal Medicine.

OBJECTIVE: To evaluate the effects of peer review and editing on manuscript quality. SETTING: Editorial offices of Annals of Internal Medicine. DESIGN: Masked before-after study. MANUSCRIPTS: 111 consecutive original research manuscripts accepted for publication at Annals between March 1992 and March 1993. MEASUREMENTS: We used a manuscript quality assessment tool of 34 items to evaluate the quality of the research report, not the quality of the research itself. Each item was scored on a 1 to 5 scale. Forty-four expert assessors unaware of the design or aims of the study evaluated the manuscripts, with different persons evaluating the two versions of each manuscript (before and after the editorial process). RESULTS: 33 of the 34 items changed in the direction of improvement, with the largest improvements seen in the discussion of study limitations, generalizations, use of confidence intervals, and the tone of conclusions. Overall, the percentage of items scored three or more increased by an absolute 7.3% (95% CI, 3.3% to 11.3%) from a baseline of 75%. The average item score improved by 0.23 points (CI, 0.07 to 0.39) from a baseline mean of 3.5. Manuscripts rated in the bottom 50% showed two- to threefold larger improvements than those in the top 50%, after correction for regression to the mean. CONCLUSIONS: Peer review and editing improve the quality of medical research reporting, particularly in those areas that readers rely on most heavily to decide on the importance and generalizability of the findings.

Humans↗
PubMed1994

Overexpression of p53 protein in adenocarcinoma of the pancreas.

Mutations in the p53 tumor suppressor gene are frequently identified in human neoplasms. These mutations may be associated with stabilization and, therefore, with overexpression of the p53 protein product as determined by immunohistochemical staining. Using a new antigen retrieval method and a polyclonal antibody to p53 (CM-1), the authors examined 48 formalin-fixed paraffin-embedded adenocarcinomas of the pancreas for overexpression of the p53 gene product. These 48 carcinomas were obtained from a series of patients with well-documented clinical histories and extensive follow-up. The carcinomas had been analyzed previously for K-ras gene mutations, tumor ploidy, and tumor proliferating index. Specific diffuse nuclear staining for the p53 protein was identified in 19 of the 48 (40%) infiltrating carcinomas examined. Focal or negative staining was seen in the remaining 29 cases (60%). In addition, 17 of the neoplasms contained synchronous in situ carcinomas; two (12%) of these displayed diffuse nuclear staining for the p53 protein. Overexpression of p53 was associated with aneuploidy (P = .05), which had been a poor prognosticator in this series of adenocarcinomas of the pancreas. Although overexpression of p53 appeared to be associated with poor prognosis (hazard ratio, 1.8; P = .07), this was not statistically significant. Overexpression of p53 was not significantly associated with K-ras oncogene mutations or tumor proliferating index. The authors conclude that overexpression of the p53 protein occurs frequently in invasive adenocarcinomas of the pancreas and in some in situ carcinomas, as well.

Adenocarcinoma↗
PubMed1994

Peritransplant injury to the myocardium associated with the development of accelerated arteriosclerosis in heart transplant recipients.

Accelerated arteriosclerosis is now the major long-term complication of heart transplantation. Defining the risk factors associated with the development of accelerated arteriosclerosis will provide not only a means of identifying patients at risk for this complication but also clues to the etiology of accelerated arteriosclerosis. The purpose of this study was to examine the relationship between peritransplant myocardial ischemic injury and the development of accelerated arteriosclerosis. In a case-control study we examined the first three endomyocardial biopsies from 50 heart transplant recipients and graded the degree of ischemic injury present in these biopsies. The histologic changes graded in the biopsies included contraction band necrosis, coagulative necrosis, and macrophagic removal of ischemically injured myocytes. Of the 50 recipients included in the study, 25 had angiographic evidence of accelerated arteriosclerosis and 25 did not. In multivariate analysis, which included the number of class I major histocompatibility (MHC) antigen mismatches between the donor and the recipient, the recipient's post-transplant cytomegalovirus status, the donor's age, and the number of rejection episodes, the histologic degree of ischemic injury present in the biopsies emerged as the strongest predictor of the development of accelerated arteriosclerosis (RR 2.6, 95% CI 1.2-5.8, p = 0.02). These results suggest that ischemic injury to the heart during the peritransplant period significantly contributes to the development of accelerated arteriosclerosis in heart transplant recipients and that histologic changes in early posttransplant biopsies can be used to identify recipients at risk of developing accelerated arteriosclerosis.

Adolescent↗
PubMed1993

K-ras oncogene activation in lung adenocarcinomas from former smokers. Evidence that K-ras mutations are an early and irreversible event in the development of adenocarcinoma of the lung.

BACKGROUND: Point mutations in codon 12 of the K-ras protooncogene occur more frequently in lung adenocarcinomas from smokers (30%) than they do in lung adenocarcinomas from nonsmokers (7%), suggesting that smoking is an important factor in the induction of these mutations. The lack of well defined "early" premalignant or in situ glandular neoplasms of the lung, however, has not permitted direct evaluation of the chronology of ras activation in the development of lung adenocarcinomas. To circumvent the need to evaluate precursor lesions, we examined lung adenocarcinomas from former smokers for point mutations in K-ras. METHODS: Mutations in codon 12 of K-ras were detected using polymerase chain reaction amplification and mutation-specific oligonucleotide probes. The types and frequencies of mutations found in adenocarcinomas obtained from 57 former smokers were compared to those found in 27 adenocarcinomas from patients who never smoked and to those found in 27 adenocarcinomas from patients who were current smokers. RESULTS: The overall prevalence of K-ras point mutations in lung adenocarcinomas obtained from former smokers (32%) was not different from that seen in adenocarcinomas from patients who were current smokers (30%, P = 0.83), and was greater than that seen in adenocarcinomas from patients who never smoked (7%, P = 0.015). This pattern was independent of the duration of abstinence from smoking. Furthermore, the predominant type of mutation found in tumors from former smokers was a guanine-to-thymine transversion, the specific type of mutation induced by benzo(a)pyrene, one of the chemical carcinogens found in tobacco smoke. CONCLUSIONS: These findings support previous findings that suggest that codon 12 of the K-ras oncogene may be a specific target of the mutagenic activity of tobacco smoke, and suggest that DNA alterations at this site can occur early and irreversibly during the development of adenocarcinomas of the lung.

Adenocarcinoma↗
PubMed1993

p values, hypothesis tests, and likelihood: implications for epidemiology of a neglected historical debate.

It is not generally appreciated that the p value, as conceived by R. A. Fisher, is not compatible with the Neyman-Pearson hypothesis test in which it has become embedded. The p value was meant to be a flexible inferential measure, whereas the hypothesis test was a rule for behavior, not inference. The combination of the two methods has led to a reinterpretation of the p value simultaneously as an "observed error rate" and as a measure of evidence. Both of these interpretations are problematic, and their combination has obscured the important differences between Neyman and Fisher on the nature of the scientific method and inhibited our understanding of the philosophic implications of the basic methods in use today. An analysis using another method promoted by Fisher, mathematical likelihood, shows that the p value substantially overstates the evidence against the null hypothesis. Likelihood makes clearer the distinction between error rates and inferential evidence and is a quantitative tool for expressing evidential strength that is more appropriate for the purposes of epidemiology than the p value.

Epidemiologic Methods↗