Cecilia M. Fenoglio-Preiser

American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group.

The American Joint Committee on Cancer (AJCC), which regularly reviews TNM staging systems, established a working party to develop recommendations for colorectal carcinoma.

Phase III Study Comparing Gemcitabine Plus Cetuximab Versus Gemcitabine in Patients With Advanced Pancreatic Adenocarcinoma: Southwest Oncology Group–Directed Intergroup Trial S0205

PURPOSE Patients with advanced pancreas cancer present with disease that is poorly responsive to conventional therapies. Preclinical and early clinical evidence has supported targeting the epidermal growth factor receptor (EGFR) signaling pathway in patients with pancreas cancer. This trial was conducted to evaluate the contribution of an EGFR-targeted agent to standard gemcitabine therapy. Cetuximab is a monoclonal antibody against the ligand-binding domain of the receptor. PATIENTS AND METHODS Patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine alone or gemcitabine plus cetuximab. The primary end point was overall survival. Secondary end points included progression-free survival, time to treatment failure, objective response, and toxicity. RESULTS A total of 745 eligible patients were accrued. No significant difference was seen between the two arms of the study with respect to the median survival time (6.3 months for the gemcitabine plus cetuximab arm v 5.9 months for the gemcitabine alone arm; hazard ratio = 1.06; 95% CI, 0.91 to 1.23; P = .23, one-sided). Objective responses and progression-free survival were similar in both arms of the study. Although time to treatment failure was longer in patients on gemcitabine plus cetuximab (P = .006), the difference in length of treatment was only 2 weeks longer in the combination arm. Among patients who were studied for tumoral EGFR expression, 90% were positive, with no treatment benefit detected in this patient subset. CONCLUSION In patients with advanced pancreas cancer, the anti-EGFR monoclonal antibody cetuximab did not improve the outcome compared with patients treated with gemcitabine alone. Alternate targets other than EGFR should be evaluated for new drug development.

Serrated Polyps of the Large Intestine A Morphologic and Molecular Review of an Evolving Concept

Serrated polyps of the large intestine, including traditional hyperplastic polyps, traditional serrated adenomas, and more recently described sessile serrated adenomas, have gained increased recognition in recent years because of growing evidence that one of these lesions, the sessile serrated adenoma, might be the precursor lesion for some cases of microsatellite unstable colorectal carcinoma. Nevertheless, there has been some reluctance to embrace the concept of sessile serrated adenoma, and numerous diagnostic challenges exist. This article, which grew out of the Roger C. Haggitt Gastrointestinal Pathology Society Forum presented in Vancouver, Canada, March 6, 2004 as part of the annual meeting of the United States-Canadian Academy of Pathology, reviews the morphologic and molecular evidence for the concept of various polyps in the general category of serrated polyps of the large intestine, in particular the lesion known as the sessile serrated adenoma, and provides a conceptual framework for diagnosis of these lesions.

Phase II Trial of Erlotinib in Gastroesophageal Junction and Gastric Adenocarcinomas: SWOG 0127

PURPOSE A phase II trial of the oral epidermal growth factor receptor (EGFR) inhibitor erlotinib in patients with gastroesophageal adenocarcinomas stratified according to primary tumor location into two groups: gastroesophageal junction (GEJ)/cardia and distal gastric adenocarcinomas. PATIENTS AND METHODS Patients with a histologically proven diagnosis of adenocarcinoma of the GEJ or stomach (ST) that was unresectable or metastatic; presence of measurable disease; no prior chemotherapy for advanced or metastatic cancer; Zubrod performance status (PS) of 0 to 1; and adequate renal, hepatic, and hematologic function were treated with erlotinib 150 mg/d orally. Patient characteristics were median age, GEJ-63 years, ST-64 years; sex, GEJ-84% male and 16% female, ST-60 male and 40 female; Zubrod PS, GEJ-25 had a PS of 0 and 18 had a PS 1, ST-13 had a PS of 0 and 12 had a PS of 1. RESULTS Percentage of common toxicities were skin rash, 86% and 72%; fatigue, 51% and 44%; and AST/ALT elevation, 28% and 28%, respectively for GEJ and ST. There has been one confirmed complete response, three confirmed partial responses (PRs) and one unconfirmed PR for an overall response probability of 9% confirmed (95% CI, 3% to 22%), all occurring in GEJ stratum. No responses were observed in ST stratum. The median survival was 6.7 months in GEJ and 3.5 months in ST stratum. Neither intratumoral EGFR, transforming growth factor-alpha or phosphorylated Akt kinase expression nor plasma proteomic analyses were predictive of clinical outcome. No somatic mutations of the EGFR exons 18, 19, or 21 were detected and there was no gross amplification of EGFR by fluorescence in situ hybridization. CONCLUSION Erlotinib is active in patients with GEJ adenocarcinomas, but appears inactive in gastric cancers. The molecular correlates examined were not predictive of the patient therapeutic response.

Stability of Phosphoprotein as a Biological Marker of Tumor Signaling

Purpose: The purpose of the study was to evaluate the stability of phosphoprotein as a marker of signaling activity in human tumors using clinical samples and xenografts. Experimental Design: The expression of phospho-Ser473-Akt (p-Akt) was assessed by immunohistochemistry in paraffin-embedded samples from patients enrolled in a Southwest Oncology Group clinical trial of gastroesophageal junction tumors and by immunohistochemistry and Western blotting in human colon tumor xenografts at various times after removal from the animal. Results: Clinical samples had evaluable p-Akt staining only when obtained as biopsies (9 of 13) and no staining was observed in tumors obtained as surgically resected samples (0 of 15). In HT-29 colon cancer xenografts, p-Akt staining was present in fresh sample but not in tissue that had been allowed to stand for 30 minutes at room temperature. Western blotting of HT-29 tumor xenografts at room temperature showed a slow decrease in total Akt with a half-life of 180 minutes and a rapid decrease in p-Akt with a half-life of 20 minutes. Conclusions: Caution should be used when using phosphoprotein levels in human tumor specimens to measure intrinsic signaling activity or drug effects because of the potential for rapid dephosphorylation. Rapid processing of biopsies is essential and postoperative surgical samples may be of limited value because of the time to fixation.

Dietary Risk Factors for the Incidence and Recurrence of Colorectal Adenomatous Polyps: A Case-Control Study

Diet has long been thought to be an important factor in the etiology of colorectal cancer. The specific dietary nutrients or factors responsible for this disease, the second leading cause of cancer death in the United States [1], have not, however, been clearly elucidated. Colorectal adenomatous polyps (here referred to as polyps) are generally considered to be precursor lesions for most cases of colorectal carcinoma [2-4]; however, little is known about their risk factors. Since the introduction of fiberoptic endoscopy, especially colonoscopy, attention has focused on the potential for preventing colorectal cancer by screening for and resecting the adenomas [5, 6]. Because of their high recurrence rate after resection [7, 8], these polyps have been used as an end point for the study of potential chemopreventive agents. Four studies have explored potential dietary risk factors for incident colorectal adenomatous polyps [9-12]. No previous observational studies have explored the role of diet or other lifestyle factors in the recurrence of polyps after polypectomy. We discuss the results of a casecontrol study of colorectal polyps among patients from three colonoscopy practices and analyze dietary risk factors for both incident and recurrent polyps. Methods Our study sample included patients having colonoscopy at three colonoscopy practices in New York City between April 1986 and March 1988. In total, 2988 patients were evaluated. Of these, 2443 (81.8%) were eligible for our study (patients had to be between 35 and 84 years of age; reside in New York, New Jersey, or Connecticut; speak English or Spanish; and have colonoscopy to at least the splenic flexure). The colonoscopists completed data sheets indicating the reason for colonoscopy and the clinical findings at the time of colonoscopy. The study pathologist reviewed slides of all suspected neoplastic lesions. All eligible participants received a letter signed by their colonoscopist introducing the study. A trained interviewer then contacted and interviewed participants by telephone. Alternatively, the questionnaire was mailed for self-completion and was followed by a telephone interview to resolve any remaining questions. An earlier study indicated that the results obtained for dietary factors were similar for both interview methods [13]. The interview itself consisted of a general questionnaire that focused on demographic characteristics, medical history, lifestyle, family history, and other topics. The dietary interview consisted of the Block food frequency questionnaire and specified food intake for a period 3 to 5 years before the colonoscopy [14]. Ultimately, 1956 dietary questionnaires were completed (80.1% of eligible patients). Of these, 71% were conducted by telephone, and 29% were returned by mail. An incident case of adenomatous polyps was defined as an eligible participant with no history of colon carcinoma, adenomatous polyps, or inflammatory bowel disease who was found to have one or more pathologically defined polyps on the index colonoscopy. The incident control group consisted of persons who were found to be free of colorectal neoplasia on index colonoscopy and who were without a history of adenomatous polyps, colon cancer, or inflammatory bowel disease. A case of recurrent polyps was defined as an eligible participant with a self-reported history of one or more polyps who had a pathologically confirmed polyp on the index colonoscopy. The recurrent control was defined as a participant whose index colonoscopy showed no colorectal neoplasia but who had a history of one or more polyps. Cases and controls with a history of colorectal cancer or inflammatory bowel disease were excluded. Although we did not have pathologic confirmation of all initial polyps, we did obtain pathology reports on a random sample of 100 recurrent cases and controls and found 97 to be adenomatous. By these criteria, 286 incident cases (162 men and 124 women) and 480 incident controls (210 men and 270 women) were identified, whereas 186 recurrence cases (130 men and 56 women) and 330 recurrence controls (187 men and 143 women) were found. Food item and nutrient data were generated by software programs provided by Block and coworkers [14] at the National Cancer Institute. The main analyses were done using logistic regression modelling and maximum likelihood ratios [15] in the BMDP-LR program. Analyses were conducted separately for men and women. Age, Quetelet index, and caloric intake were entered as covariates for most analyses. A previous study by our group had shown obesity, as measured by Quetelet index, to be a risk factor for polyps among women; the trend for men was not significant [16]. Analyses in which nutrients were standardized per 1000 kilocalories were also done for comparison [17]. For each nutrient or food group, quartiles were defined by review of the control group data; the lowest quartile was given a reference value of 1.0, and odds ratios were calculated for each of the other quartiles, with 95% confidence intervals (CIs) for the highest-to-lowest quartile comparison. The probability of a linear trend was calculated by entering the four quartiles as ordered categories. Results The case and control groups for the incidence and recurrence studies were generally similar in age distribution and education. Table 1 shows a comparison of the characteristics of the case and control groups for both the incident and recurrent groups. Most polyps were 5 mm or larger in size and had at least some degree of atypia. The site distribution of the incident polyps showed a preponderance to the left. Most incident case and control participants had colonoscopy because of overt or occult rectal bleeding. A larger proportion of the recurrent polyps were right-sided (P = 0.005). The time interval from initial polypectomy to index colonoscopy was 4.3 years for cases and 3.7 years for controls (P > 0.2). Table 1. Polyp Characteristics for Incident and Recurrent Cases Tables 2 and 3 show the odds ratios by quartile, using the lowest quartile as the referent group, for some of the 15 nutrients and food groups evaluated. The results for vegetables, red meat, beef, cheese, protein, vitamin C, and carotene are not shown; however, no consistent differences were found. Table 2. Odds Ratios of Incident Polyps by Quartile of Selected Nutrients and Food Groups, Adjusted for Age, Quetelet Index, and Caloric Intake Table 3. Odds Ratios of Recurrent Polyps by Quartile of Selected Nutrients and Food Groups, Adjusted for Age, Quetelet Index, and Caloric Intake Men The only dietary risk factor statistically associated with the risk for colorectal adenomatous polyps in men was caloric intake; however, this association was in a direction opposite to that ordinarily expected [18]. Women In contrast, various dietary factors were observed to be associated with the risk for colorectal adenomatous polyps in women (Tables 2 and 3). Increased saturated fat, decreased fish and chicken, increased meat-to-fish and -chicken ratio, and decreased vitamin A intake increased the risk for incident polyps (Table 2). Increased caloric intake, increased total fat, increased saturated fat, and decreased fiber intake all raised the risk for recurrent polyps in women, whereas vitamin A and carbohydrate intake had borderline protective effects (Table 3). Analyses were also done using nutrient density (nutrient compared with caloric intake) instead of entering calories as a covariate. The results are not shown, but the same risk factors were statistically significant for incident polyps in women, although the estimated odds ratios were larger. In addition, fiber was protective for incident polyps in women (odds ratio, 0.6; CI, 0.3 to 1.1; P = 0.06). The same dietary factors were also associated with recurrent polyps in women, although the odds ratio estimates were again larger. Both vitamin A (odds ratio, 0.5; CI, 0.2 to 1.1; P = 0.06) and carbohydrate intake (odds ratio, 0.4; CI, 0.2 to 1.0; P = 0.001) were more clearly protective. Subgroup Analyses For each of the dietary factors associated with colorectal polyps in women, further subgroup analyses were done for right-sided polyps only, for left-sided polyps only, and for polyps 5 mm or larger in size. Generally, no major variations were observed for the various subgroups, although some reduction was seen in statistical power because of the smaller number of cases. To determine the independent effect of each of the variables found to be associated with polyps in women, we conducted further multiple logistic regression analyses using various dietary factors as covariates. The elevated risk associated with increased consumption of saturated fats remained after adjustment for fiber or vitamin A. Discussion Many studies have suggested that diet plays a role in the etiology of colorectal cancer [19-35]. Evidence suggests that increased consumption of saturated fat is a causal factor and that increased consumption of fiber, (particularly fruit and vegetable fiber) is protective [26]. Similarly, an increased risk has been associated with greater consumption of red meat compared with chicken or fish [19], and a protective effect has been linked to consumption of vegetables [35]. A protective effect of such micronutrients as vitamin A, carotene [32-34], and calcium [27-30] has also been suggested, although the evidence is less compelling. Because adenomatous polyps are known precursors for colorectal cancer, three casecontrol studies [9-11] have explored their association with diet. Despite their limitations, each study has suggested a protective effect for fiber. A recent cohort study [12] of male health professionals found saturated fat and decreased fiber, as well as increased red meat-to-fish and meat-to-chicken ratio, to be risk factors for left-sided incident polyps. A small study by our group also showed that supplemental vitamins had no influence on the development of

β-Catenin/Wnt Signaling Regulates Expression of the Membrane Type 3 Matrix Metalloproteinase in Gastric Cancer

Activation of Wnt signaling through beta-catenin dysregulation occurs in numerous human tumors, including gastric cancer. The specific consequences of Wnt signaling in gastric cancer, however, are not well characterized. This study shows that the introduction of mutant beta-catenin into gastric cancer cell lines by adenoviral infection enhances invasiveness and proliferation and up-regulates the expression of the gene encoding the matrix metalloproteinase (MMP) family member membrane type 3 MMP (MT3-MMP). Up-regulation of MT3-MMP is critical to the invasive phenotype as shown by small interfering RNA (siRNA) studies. Immunohistochemical staining also showed that MT3-MMP was highly expressed in gastric cancers with activating beta-catenin mutations. These observations suggest that Wnt activation may contribute to gastric cancer progression by increasing the invasiveness of neoplastic cells in the stomach via up-regulation of MT3-MMP expression.

Review Article: Aberrant Crypt Foci: A Review

laboratories at the VA Hospital. In 1990, she became the MacKenzie Professor and director of the Department of Pathology at the College of Medicine, University of Cincinnati. Dr. Fenoglio-Preiser has a longstanding interest in precursors to gastrointestinal malignancies Left) Cecilia M. Fenoglio-Preiser. Right) Amy Noffsinger. and has published over 300 articles, many relating to the pathological or molecular features of gastrointestinal malignancies. Dr. Noffsinger completed her pathology residency training at the University of Cincinnati College of Medicine and is currently an assistant professor of pathology and laboratory medicine in the same institution. She has received a number of awards, including a Clinical Oncology Career Development Award and a Cancer Research Fellowship from the American Cancer Society. She is a funded investigator in the area of molecular alterations. Our laboratory is involved in elucidating mechanisms of the development of gastrointestinal carcinomas as well as in defining molecular alterations that may predict therapeutic response and/or prognosis. We are interested in cancers

Cigarettes, alcohol, coffee, and caffeine as risk factors for colorectal adenomatous polyps

The possible association of colorectal adenomatous polyps, a precursor lesion for colorectal cancer, with cigarette smoking, alcohol consumption, and coffee and caffeine consumption was investigated in a case-control study. Between April 1986 and March 1988, 271 cases of patients with pathologically confirmed incident colorectal adenomatous polyps and 457 control subjects were collected from three colonoscopy practices in New York City. Information on exposure was obtained by structured interviews. After adjustment of age, statistically significant odds ratios (highest-lowest quartile) were found for cigarette smoking in males (2.2; 95% confidence interval (CI), 1.2 to 3.8) and coffee consumption in females (2.0%; 95% CI, 1.0 to 3.9). No significant associations were obtained for cigarette smoking in females, for coffee consumption in males, or for alcohol or caffeine consumption. After adjustments for alcohol, coffee, and caffeine consumption, the association of adenomas with cigarette smoking remained in males and significant associations were also observed in subcategory analysis for both left-side and right-side adenomatous polyps. Adjustment for cigarette smoking eliminated the association between colorectal adenomatous polyps and coffee consumption in females. Cigarette smoking appears to be a significant risk factor for colorectal adenomatous polyps in males.

The pattern of cell proliferation in neoplastic and nonneoplastic lesions of ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon characterized by repeated episodes of inflammation and epithelial regeneration. Patients with long‐standing UC have an increased risk for the development of dysplasia and subsequent colon carcinoma. Because dysplasia likely results from deregulated cell proliferation, the authors examined Ki‐67 immunoreactivity in tissues from UC patients to examine patterns of proliferation in neoplastic and nonneoplastic lesions.