Microarray Gene Expression Profiling for Predicting Complete Response to Preoperative Chemoradiotherapy in Patients with Advanced Rectal Cancer

Purpose Preoperative chemoradiotherapy is widely used to improve local control and sphincter preservation in patients with locally advanced rectal cancer. In the present study, we investigated whether microarray gene expression analysis could predict complete response to preoperative chemoradiotherapy in rectal cancer. Methods Tumor tissues were obtained from 46 patients with rectal cancer (31 for training and 15 for validation testing). All patients underwent preoperative chemoradiotherapy involving 50.4 gray radiotherapy, followed by surgical excision 6 weeks later. Response to chemoradiotherapy was evaluated according to Dworak’s tumor regression grade. Tumor regression Grades 1, 2, and 3 were considered partial responses, and tumor regression Grade 4 was considered a complete response. By using the 31 training samples, genes differentially expressed between partial response and complete response were identified, and clustering analysis was performed. Prediction analysis of response to chemoradiotherapy was performed on the 31 training samples by using a selected set of 95 “predictor” genes. Those findings were validated by independent analysis of the 15 test samples. Results The 31 training samples comprised 20 partial response and 11 complete response cases. A primary set of 261 genes was identified as differentiating between partial response and complete response. By supervised clustering using these 261 genes, 30 of 31 training samples were clustered correctly according to tumor response. A gene set comprising the top-ranked 95 genes displaying differential expression between partial response and complete response was applied to predict response to chemoradiotherapy. Complete response and partial response were accurately predicted in 84 percent (26/31) of training samples and 87 percent (13/15) of validation samples. Conclusions Microarray gene expression analysis was successfully used to predict complete responses to preoperative chemoradiotherapy in patients with advanced rectal cancer. Supported by a research grant from the National Cancer Center, Korea, and the BK21 project for Medicine, Dentistry, and Pharmacy. Presented in part and awarded the AACR-ITO EN, Ltd, Scholar-In-Training Award at the meeting of the American Association for Cancer Research, Washington, DC, April 1 to 5, 2006. I-J Kim and S-B Lim contributed equally to this article. Reprints are not available.     

Cancer Invasion to Auerbach’s Plexus is an Important Prognostic Factor in Patients with pT3-pT4 Colorectal Cancer

Purpose By defining perineural invasion of colorectal cancer as invasion to Auerbach’s plexus, we examined the usefulness of this pathologic finding as a prognostic factor. Methods A total of 509 consecutive patients who underwent curative surgery for pT3 or pT4 colorectal cancer between May 1997 and December 2001 were reviewed. All the surviving patients were followed for more than five years. All the pathologic findings, including perineural invasion, were described prospectively in the pathology report forms. Results Perineural invasion was detected in 132 of 509 patients (26 percent) and was significantly associated with lymph node status, lymphatic invasion, and venous invasion. Incidences of local and systemic recurrence were significantly higher in patients with perineural invasion than in those without perineural invasion. The disease-free survival of the perineural invasion-positive group was significantly poorer than that of the perineural invasion-negative group for Stages II and III colon cancer, irrespective of the use of adjuvant chemotherapy. This improved disease-free survival also was seen in patients with Stage II rectal cancer not treated with adjuvant chemotherapy. There was a nonsignificant difference in disease-free survival for Stage II rectal cancer and Stage III rectal cancer treated with chemotherapy, that of the perineural invasion-positive group being poorer. Multivariate analysis showed that lymph node status, perineural invasion, depth of invasion, and cancer site were significant prognostic factors. Conclusions Perineural invasion defined as cancer invasion to Auerbach’s plexus is an important prognostic factor for colorectal cancer. Supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan.     

A Patient's Race/Ethnicity Does Not Explain the Underuse of Appropriate Adjuvant Therapy in Colorectal Cancer

Introduction To improve colorectal cancer outcomes, appropriate adjuvant therapy (chemotherapy, radiation therapy) should be given. Numerous studies have demonstrated underuse of adjuvant therapy in colorectal cancer. The current study examines variables associated with underuse of adjuvant therapy. Methods Three population-based databases were linked: California Cancer Registry, California Patient Discharge Database, 2000 Census. All colorectal cancer patients diagnosed from 1994 to 2001 were studied. Patient characteristics (age, gender, race/ethnicity, comorbidities, payer, diagnosis year, socioeconomic status) were used in five multivariate regression analyses to predict receipt of chemotherapy for Stage III colon cancer, and receipt of chemotherapy and radiation therapy for Stages II, III rectal cancer. Results The overall cohort was 18,649 Stage III colon cancer and Stages II, III rectal cancer patients. Mean age was 68.9 years, 50 percent male, 74 percent non-Hispanic white, 6 percent black, 11 percent Hispanic, 9 percent Asian, and 65 percent had no significant comorbid disease. Receipt of chemotherapy was 48 percent for Stage III colon cancer, 48 percent for Stage II rectal cancer, and 66 percent for Stage III rectal cancer. Receipt of radiation therapy was 52 percent for Stage II rectal cancer and 66 percent for Stage III rectal cancer. In all five models, low socioeconomic status predicted underuse of chemotherapy or radiation therapy (P < 0.016). Race/ethnicity was not statistically associated with underuse in any of the models. Conclusions Most literature identifies race/ethnicity as the reason for disparate receipt of adjuvant therapy in colorectal cancer. Using a more robust database of three population-based sources, our analysis demonstrates that socioeconomic status is a more important predictor of (in)appropriate care than race/ethnicity. Explicit measures to improve care to the poor with colorectal cancer are needed. Supported by Limited Project Grant from The American Society of Colon and Rectal Surgeons; Asian American Network for Cancer Awareness, Research, and Training Grant from the National Cancer Institute (#5U01CA086322-06); and the Robert Wood Johnson Clinical Scholars Program at UCLA. Read at the meeting of The American Society of Colon and Rectal Surgeons, Philadelphia, Pennsylvania, April 30 to May 5, 2005; Recipient of the Piedmont Society of Colon and Rectal Surgeons Awards for Clinical Podium Presentation. Reprints are not available.     

The relative prognostic value of flow cytometric DNA analysis and conventional clinicopathologic criteria in patients with operable rectal carcinoma

The DNA histograms of resected rectal carcinomas from 121 patients were compared, along with a detailed clinicopathologic assessment of the same tumors, with the incidence of postresection tumor recurrence and patient survival over an extended period of 15-year follow-up. A poorer prognosis was found for patients with DNA aneuploid and DNA tetraploid rectal cancers as compared with patients with DNA diploid cancers. In addition, local tumor recurrence was twice as common among patients with DNA nondiploid rectal carcinomas. The DNA pattern of a rectal carcinoma was an independent prognostic variable in a Cox's multivariate analysis model. DNA nondiploid rectal carcinomas had a statistically significant increased incidence of vascular invasion, tumor fibrosis, and high Dukes' stage. Supported in part by the Mayo Comprehensive Cancer Center Grant, CA-15083, NCI DHHS.     

Relationship between cholecystectomy and colonic cancer in low-risk Japanese population

The relationship between colonic cancer and previous cholecystectomy was investigated in 90 Japanese patients treated surgically for colonic cancer during the period of 1971 to 1980. The patients were in an area where the inhabitants are considered to be at low risk for colonic cancer. The patients were matched for sex and age with other patients having gastric cancer or other digestive organ diseases. The results showed that previous cholecystectomy was prevalent, but the difference was not statistically significant, in the group of colonic cancer patients, compared with the groups of rectal cancer patients and matched controls. A positive association between the proximal colonic cancer and previous cholecystectomy, and between distal colonic cancer and asymptomatic gallstones found concomitantly with the cancer, was noted in the present study. To clarify the relationship between colonic cancer, and cholecystectomy and gallstones, further study of a large number of colonic cancer patients and a prospective study of the incidence of colonic cancer after cholecystectomy are proposed. Supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Science and Culture, and from the Ministry of Health and Welfare, Japan.     

Rectal lymphoscintigraphy

Regional lymph nodes of the rectum are not demonstrable by pedal lymphoscintigraphy. We have evaluated the technique of rectal lymphoscintigraphy, using a technique similar to that which has been used in the assessment of lymph nodes in breast and prostatic cancer. Thirty-five patients were studied: ten normal subjects and 25 patients with rectal cancer. In normal subjects, the lymph nodes accompanying the superior hemorrhoidal artery and the inferior mesenteric artery are demonstrable in succession; after three hours the aortic lymph nodes are demonstrable. The 25 patients with rectal cancer underwent resection of their primary tumor and the stage was defined according to Dukes (1932). In five patients (stage A) no alteration was demonstrable. In 11 patients (stage B) the demonstration of regional lymph nodes was delayed vs. the control group. In nine cases (stage C) the demonstration of regional lymph nodes was delayed and defective versus the control group. A preliminary report read at the First Congress of the European Society of Surgical Oncology, Athens, Greece, November 26 to 27, 1982. Read at the International Congress on Colon Cancer, Rotterdam, May 26 to 27, 1983. Supported in part by CNR Progetto Finalizzato Controllo della Crescita Neoplastica.     

Trends in the anatomical distribution of colorectal carcinoma in Hawaii, 1960–1978

The incidence of colorectal adenocarcinoma increased in the five major ethnic groups in Hawaii, but more in men than women. The highest rates were in the Chinese and Japanese. The site-specific time trend patterns revealed that the greatest increase occurred in rectosigmoid cancer, followed by cancer of the sigmoid colon and the transverse descending colon. Rectal cancer had minimal changes in rates over time. The comparison of site-specific rates between the Japanese in Hawaii and Miyagi Prefecture, Japan, showed that the occurrence of cancer of the rectosigmoid, sigmoid, and transverse descending colon was far greater in Hawaii than Miyagi with minimal differences in the rates of rectal cancer. The findings from this study indicate that the separate anatomical locations of colorectal cancer probably have some distinct etiologies that need further investigation.Supported in part by grant I-NOI-CA-15655 and contract NOI-CP-53511 from the National Cancer Institute, National Institutes of Health.     

Delayed Treatment for Rectal Cancer

PURPOSE Reports of the relationship between length of delay before diagnosis of rectal cancer and stage of the disease have been mixed. The present study documented the magnitude and medical ramifications of delay in diagnosing rectal cancer.METHODS One hundred twenty patients who had been recently diagnosed with rectal cancer provided information regarding history of symptoms and initial perceptions of those symptoms. Patients also estimated the time elapsed from onset of symptoms until their first consultation with a physician, as well as time elapsed from consultation until the diagnosis of rectal cancer was made. Stage information was gathered from patient charts.RESULTS For 106 of the patients, the first sign of rectal cancer was in the form of symptoms, and the most common first symptom was rectal bleeding. For the remaining 14 patients, their cancer was first discovered through routine examination. Over 75 percent of patients with symptoms did not initially believe that they were caused by cancer or any other serious problem, and over 50 percent attributed their symptoms to hemorrhoids. There was a clear trend, albeit statistically nonsignificant, toward worsening disease with longer delays. Median delay times in weeks were Stage I (10.0 weeks), Stage II (14.0 weeks), Stage III (18.5 weeks), and Stage IV (26.0 weeks).CONCLUSIONS Delayed diagnosis for rectal cancer remains a significant problem, with instances of delay attributable to both patient and physician. Delayed diagnosis can result in more serious disease and, when attributable to the physician, can result in damaged trust and sometimes legal action.Supported by the Alvin J. Siteman Cancer Center, National Cancer Institute Grant No. 1R03 CA84845 01, and The American Society of Colon and Rectal Surgeons (LPG 073).Reprints are not available.     

Pilot Study of the Quality Initiative in Rectal Cancer Strategy

INTRODUCTION Total mesorectal excision vs. traditional surgical techniques may lead to improved rates of permanent colostomy, local tumor recurrence, and survival for patients undergoing major rectal cancer operations. We developed the surgeon-directed, multipronged Quality Initiative in Rectal Cancer strategy to encourage surgeons to use total mesorectal excision techniques.METHODS The Quality Initiative in Rectal Cancer strategy interventions included a workshop, an operative demonstration of total mesorectal excision, and a postoperative questionnaire. The design of the strategy was informed by the industrial theory principles of continuous quality improvement. We assessed the logistics of implementing the strategy and the attitudes of surgeons toward the strategy through a pilot study at three community hospitals in the Central-West region of Ontario.RESULTS Seventeen of 19 surgeons participated in a workshop, and 12 of 17 workshop participants received at least one operative demonstration of total mesorectal excision. Ten of 11 surgeons who completed a postoperative questionnaire indicated their traditional approach to rectal cancer surgery varied with that of the operative demonstration. The attitudes of surgeons toward the Quality Initiative in Rectal Cancer strategy were positive. For the time periods before and after the pilot study, there was a trend toward a lower rate of permanent colostomy among patients treated by surgeons who participated in both the workshop and an operative demonstration of total mesorectal excision.CONCLUSION The Quality Initiative in Rectal Cancer strategy may be an effective method of introducing optimal rectal cancer surgery techniques to a large group of practicing surgeons.Supported by the Hamilton Regional Cancer Centre Foundation, Hamilton Health Sciences FoundationPresented at the meeting of the Society of Surgical Oncology Cancer Symposium, Denver, Colorado, March 14 to 17, 2002.     

The melbourne colorectal cancer study

The characteristics of 702 colorectal cancer patients are described in relation to the presence or absence of a family history of colorectal cancer in near relatives. No statistically significant associations were found between those with a family history of colorectal cancer and age at detection, sex, country of birth, religion, number of cancers (single, synchronous, or metachronous), previously removed benign colorectal polyps, and adenomatous polyps found in the resection specimen. The family history rate of colorectal cancer for colon cancer cases was statistically significantly higher than for rectal cancer cases (χ ₁ ² =3.8,P=0.5) and there was a gradient of decreasing risk from colon to rectum. The family history rate of colorectal cancer in parents of those who were less than 50 years old was twice that of those 50 or older (P=.07), consistent with the view that earlier age of onset is a characteristic of those with a family history of colorectal cancer. There was a statistically significantly higher family history rate of colorectal cancer in respondents who knew of the disease compared with those who did not (χ ₁ ² =5.5,P<.05). It is unclear if this effect represents recall bias or self-selection bias. In contrast, the rates for a family history of heart disease and stroke were similar, irrespective of the respondent's knowledge of their colorectal cancer status. Thus in the Melbourne study, the family history rate of colorectal cancer was higher in colon cancer than in rectal cancer, there was a decreasing gradient of risk from colon to rectum, and a tendency for earlier age of onset of colorectal cancer in those with a history of this cancer in a parent. This part of the “Melbourne Colorectal Cancer Study” was generously supported by the Nicholas and Elizabeth Slezak Cancer Research Fund and by a University of Melbourne Cancer Research Grant.     

Prospective assessment of primary rectal cancer response to preoperative radiation and chemotherapy using 18-fluorodeoxyglucose positron emission tomography

PURPOSE: The purpose of this prospective study was to determine the ability of fluorine-18 fluorodeoxyglucose positron emission tomography to assess extent of pathologically confirmed rectal cancer response to preoperative radiation and 5-fluorouracil-based chemotherapy. METHODS: Patients with primary rectal cancer deemed eligible for preoperative radiation and 5-fluorouracil-based chemotherapy because of a clinically bulky or tethered tumor or endorectal ultrasound evidence of T3 and/or N1 were prospectively enrolled. Positron emission tomography and CT scans were obtained before preoperative radiation and 5-fluorouracil-based chemotherapy (5,040 cGy to the pelvis and 2 cycles of bolus 5-fluorouracil with leucovorin) and repeated four to five weeks after completion of radiation and 5-fluorouracil-based chemotherapy. In addition to routine pathologic staging, detailed assessment of rectal cancer response to preoperative radiation and 5-fluorouracil-based chemotherapy was performed independently by two pathologists. Positron emission tomography parameters studied included conventional measures such as standardized uptake value (average and maximum), positron emission tomography-derived tumor volume (size), and two novel parameters: visual response score and change in total lesion glycolysis. RESULTS: Of 21 patients enrolled, prospective data (pretreatment and posttreatment positron emission tomography, and complete pathologic assessment) were available on 15 patients. All 15 demonstrated pathologic response to preoperative radiation and 5-fluorouracil-based chemotherapy. This was confirmed in 100 percent of the cases by positron emission tomography compared with 78 percent (7/9) by CT. In addition, one positron emission tomography parameter (visual response score) accurately estimated the extent of pathologic response in 60 percent (9/15) of cases compared with 22 percent (2/9) of cases with CT. CONCLUSIONS: This pilot study demonstrates that fluorine-18 fluorodeoxyglucose positron emission tomography imaging adds incremental information to the preoperative assessment of patients with rectal cancer. However, further studies in a larger series of patients are needed to verify these findings and to determine the value of fluorine-18 fluorodeoxyglucose positron emission tomography in a preoperative strategy aimed at identifying patients suitable for sphincter-preserving rectal cancer surgery.Supported in part by the Gerschel Foundation and the National Cancer Institute, R01 CA82534-01.Dr. Ruo is McEachern Fellow of the Canadian Cancer Society.     

Analysis of regional lymph node metastases from rectal carcinoma by the clearing method

PURPOSE: It has been reported that functional outcome following low anterior resection of rectal cancer is improved by construction of a colonic J-pouch compared with straight anastomosis. Hence, we tried to justify use of the sigmoid colon in the construction of a J-pouch by the analysis of regional lymph node metastases. METHODS: A total of 182 patients underwent resection for rectal cancer. Node metastases were examined by the clearing method. According to Japanese General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus (JGR), nodes were classified into the perirectal nodes (PR-N), pericolic nodes (PC-N), central intermediate nodes (C-IM-N), central main nodes (C-M-N), lateral intermediate nodes (L-IM-N), and lateral main nodes (L-M-N). RESULTS: Metastatic rate (number of patients with node metastases/ total number of patients) of PR-N was 57.1 percent. Metastatic rate of C-IM-N was 18.7 percent and that of C-M-N was 7.1 percent. Metastatic rates of L-IM-N and L-M-N were 8.8 and 3.3 percent, respectively, and both were highest in the case of lower rectal cancer. Metastatic rate of PC-N was only 1.1 percent. The number of cases without node metastases (n(–) cases) was 78, that with only PR-N metastases (PR-N cases) was 63, that with intermediate but not main node metastases (IM-N cases) was 29, and that with main node metastases (M-N cases) was 12. Five-year survival rate after curative resection was 88.5 percent for n(–) cases, 70.9 percent for PR-N cases, 65.9 percent for IM-N cases, and 41.7 percent for M-N cases. CONCLUSIONS: In low anterior resection, high ligation of the inferior mesenteric artery and dissection of C-M-N, C-IM-N and PR-N are necessary, with the addition of the L-IM-N and L-M-N in the case of lower rectal cancer. Resection of sigmoid colon is not required, and therefore, a J-pouch can be constructed using the sigmoid colon. Nodal classification according to the JGR was predictive of case distribution and five-year survival rate.Supported, in part, by a Grant-in-Aid for Cancer Research from the Japanese Ministry of Health and Welfare and Scientific Research from the Japanese Ministry of Education, Culture and Science.     

Adjuvant Radiation for Rectal Cancer: Do We Measure Up to the Standard of Care? An Epidemiologic Analysis of Trends Over 25 Years in the United States

PURPOSE In the United States, adjuvant radiation therapy is currently recommended for most patients with rectal cancer. We conducted this population-based study to evaluate the rate of radiation therapy and the factors affecting its delivery.METHODS We used the Surveillance Epidemiology and End Results database to assess treatment of patients with nonmetastatic rectal cancer diagnosed over a 25-year period (1976 through 2000). We evaluated the rate of radiation therapy use and its timing (preoperative vs. postoperative) and the influence of factors such as tumor stage and grade; patient gender and race; and geographic location.RESULTS In this 25-year period, 45,627 patients met our selection criteria. The rate of radiation therapy use increased dramatically over time: from 17 percent of advanced-stage patients in 1976 to 65 percent in 2000 (P < 0.0001). Until 1996, the increase was due almost entirely to postoperative radiation therapy. Since 1996, the rate of preoperative radiation therapy use has increased (P < 0.0001) and the rate of postoperative radiation therapy use has begun to decline. We found, after controlling for the year of diagnosis, that female patients, African Americans, older patients, and patients with low-grade lesions were less likely to undergo radiation therapy (P < 0.0001). Geographic location was also an important predictor of radiation therapy use.CONCLUSIONS The use of radiation therapy for patients with rectal cancer has dramatically increased over the 25-year period studied, with a recent shift to the use of preoperative radiation therapy; however, in 2000, over 30 percent of patients with advanced-stage nonmetastatic rectal cancer did not undergo radiation therapy. Given the variation in radiation therapy use that we found to be due to demographic factors, access to adjuvant radiation therapy can be improved.Supported in part by the University of Minnesota Cancer Center.Read at the meeting of The American Society of Colon and Rectal Surgeons, Dallas, Texas, May 8 to 13, 2004.Reprints are not available.     

Associations Between Exercise, Quality of Life, and Fatigue in Colorectal Cancer Survivors

Purpose  This study was designed to examine quality of life and fatigue in colorectal cancer survivors meeting and not meeting public health exercise guidelines. Methods  A Canadian provincial cancer registry identified colorectal cancer survivors who were mailed a questionnaire that assessed self-reported exercise, quality of life (Functional Assessment of Cancer Therapy - Colorectal), fatigue, medical, and demographic variables. Results  Completed questionnaires were received from 413 (61.3 percent) eligible colorectal cancer survivors. Only 25.9 percent of colorectal cancer survivors reported meeting exercise guidelines. Colorectal cancer survivors meeting public health exercise guidelines reported clinically and significantly better quality of life (mean difference, 6; 95 percent confidence interval, 2.3–9.8; P = 0.002) and fatigue (mean difference = 5.2; 95 percent confidence interval, 2.9–7.5; P < 0.001). Differences remained after adjusting for medical and demographic factors. Cancer site (i.e., colon vs. rectal) was the only variable to moderate this association (P < 0.05 for interaction). Conclusions  Colorectal cancer survivors meeting public health exercise guidelines reported significantly and meaningfully better quality of life and fatigue scores than colorectal cancer survivors who did not meet guidelines. Prospective observational studies and randomized, controlled trials are needed to further assess the causal nature of these relationships. Poster presentation at the Canadian Society for Psychomotor Learning and Sport Psychology, Halifax, Nova Scotia, Canada, November 1 to 4, 2006. Supported by the University of Alberta - Social Sciences Research Grant Program. This funding agency had no role in study design, collection, analysis, and interpretation of the data, writing the report, or the decision to submit the paper for publication. Ms. Peddle is supported by Full Time Health Research Studentships from the Alberta Heritage Foundation for Medical Research. Dr. Courneya is supported by the Canada Research Chairs Program and a Research Team Grant from the National Cancer Institute of Canada with funds from the Canadian Cancer Society and the Sociobehavioral Cancer Research Network.     

Defining Pelvic Factors in Sphincter-Preservation of Low Rectal Cancer with a Three-Dimensional Digital Model of Pelvis

Purpose Surgeons often can contribute failure of sphincter-preserving procedure to a limitation of pelvis anatomy; however, they cannot determine definitely which anatomic diameter or spatial factor actually affected the success of the procedure. Methods Colorectal surgeons, radiologists, and research fellows collaborated closely to establish a three-dimensional digital model of the pelvis with spiral computerized tomography scanning data of patients with rectal cancer. Retrospective analysis on data of 97 patients with low rectal cancer was performed with this model to identify geometric factors that might affect a successful sphincter preservation procedure for low rectal cancer. Results A digital pelvic model was established. Multivariate analysis demonstrated that distance from the anal verge, body mass index, and pelvic factors affected the success of sphincter preservation. Sphincter preservation was more likely to succeed when the distance from anal verge was ≥5 cm and body mass index was <25 kg/m². Shorter diameter from the upper pubis to the sacrococcyx, distance of sacrococcyx, and excessive curvature of the sacrum predicted failure of sphincter preservation in certain cases. Conclusions Pelvic diameters could affect the success of sphincter preservation for low rectal cancer patients besides the distance from anal verge and body mass index. Presented at the World Congress of International Society for Digestive Surgery, Pacifico Yokohama, Japan, December 8 to 10, 2004. Supported by Biomed-X Center of Peking University.     

Ras oncogene and the acquisition of metastasizing properties by rectal adenocarcinoma

To gain a better understanding of the biologic development of rectal adenicarcinomas, the authors evaluated the level ofras gene protein product (p21) in the available material of 74 Dukes'B adenocarcinomas, 64 Dukes' C adenocarcinomas, and 60 lymph-node metastases resected at the University of Chicago Medical Center between 1965 and 1981. Pathologic slides and archival paraffin blocks were retrieved for confirmation of the original diagnosis and measurement of p21 content. P21 titers were obtained using the RAP-5 monoclonal antibody in a semiquantitative immunohistochemical assay. Titer was expressed as the highest dilution giving definitive staining using the avidinbiotin peroxidase method. The analysis indicated that a higher percentage of Dukes' stage C rectal adenocarcinomas had high (≥1∶40,000) p21 titers than Dukes' B adenocarcinomas (68.8vs. 51.4 percent, respectively,P<0.05). In view of recent data suggesting thatras oncogene expression confers invasive and metastatic capabilities to NIH 3T3 cells, the authors believe this study offers evidence that overexpression ofras oncogene with overproduction of p21 protein product may be an important prerequisite for the acquisition of metastatic capabilities in the early stages of colon cancer. Supported in part by Award#87-100 of the American Cancer Society.     

Rectal Cancer in the Young Patient

Purpose The purpose of this national study was to evaluate the results of treatment for young rectal cancer patients. Methods This prospective study from the Norwegian Rectal Cancer Project includes all 2,283 patients younger than aged 70 years with adenocarcinoma of the rectum from November 1993 to December 1999. Patients younger than aged 40 years (n = 45), 40 to 44 years (n = 87), 45 to 49 years (n = 153), and 50 to 69 years (n = 1998) were compared for patient and tumor characteristics and five-year overall survival. Patients treated for cure (n = 1,354) were evaluated for local recurrence, distant metastasis, and disease-free survival. Results Patients younger than aged 40 years had significantly higher frequencies of poorly differentiated tumors (27 vs. 12–16 percent; P = 0.014), N2-stage (37 vs. 13–18 percent; P = 0.001), and distant metastases (38 vs. 19–24 percent; P = 0.019) compared with older patients. Among those treated for cure, 56 percent of the patients younger than aged 40 years developed distant metastases compared with 20 to 26 percent of the older patients (P = 0.003). Overall five-year survival was 54 percent for patients younger than aged 40years compared with 71 to 88 percent for the older patients (P = 0.029). Age younger than 40 years was a significant independent prognostic factor and increased the risk for metastasis and death. Conclusions Patients younger than aged 40 years had a more advanced stage at the time of diagnosis and poor prognosis compared with older patients. Young patients treated for cure more often developed distant metastases and had inferior survival. From the Norwegian Gastrointestinal Cancer Group and the Norwegian Rectal Cancer Group. Supported by a grant from the Norwegian Cancer Society.     

Number and Size of Lymph Nodes Recovered From Dukes B Rectal Cancers: Correlation with Prognosis and Histologic Antitumor Immune Response

Purpose In rectal cancer variation in lymph node recovery influences the detection of nodal metastases and prognosis among Dukes B (Stage II) cases. However, the possible prognostic importance of node size and inherent patient/tumor characteristics in determining node recovery has not been studied. Methods We examined 269 Dukes B (Stage II) rectal tumors, with a mean of 12 nodes per case. Primary tumor characteristics were correlated with the number and size of recovered nodes. Clinical follow-up permitted determination of long-term survival. Results The five-year survival of 94 Dukes B cases with nine or fewer nodes was 69.4 percent vs. 87.6 percent in 175 cases with ten or more nodes (P = 0.001). Lymph nodes were smaller in patients dying of recurrence; among 130 Dukes B patients whose mean node diameter was <4 mm, survival was 73.3 vs. 88 percent when mean nodal diameter was ≥4 mm. The number and size of recovered nodes was related to patient age, histologic antitumor immune response, and tumor growth pattern. By combining the number and size of nodes, a poor prognosis subgroup of 98 Dukes B patients with relatively few large nodes (no more than 5 measuring ≥4 mm) was identified with a five-year survival of 65.6 percent compared with 89.6 percent for the remaining 158 Dukes B cases (P < 0.0001). Conclusions In Dukes B rectal tumors, the number and size of lymph nodes are related to inherent patient and tumor characteristics and permit the identification of Dukes B cases at increased risk of recurrence. A valid comparison of nodal sampling efficiency between centers necessitates measuring and counting harvested lymph nodes. Supported by Cancer Research Appeal Mercy Hospital, Cork, Ireland and Cancer Research, United Kingdom     

Fecal skatole and indole and breath methane and hydrogen in patients with large bowel polyps or cancer

Summary The object of this study was to explore the use of fecal skatole and indole and breath methane and hydrogen as metabolic markers of the anaerobic colonic flora in patients with unresected large bowel cancer or polyps. Patients with descending or sigmoid colon cancer were more likely to be breath methane excretors than control subjects, patients with proximal colon cancer, and patients with rectal cancer. Control subjects excreting breath methane excreted less fecal skatole than breath methane excretors in the following groups: patients with adenomatous polyps, all patients with colorectal cancer, patients with proximal colon cancer, patients with descending and sigmoid colon cancer, and patients with rectal cancer. These data suggest that fecal skatole excretion equal to or greater than 100 g/g feces might be useful to discriminate colorectal cancer patients from control subjects. Twenty-nine percent (8 of 28) of the cancer patients had both high skatole levels and breath methane excretion compared with only 2% (1 of 41) of the control subjects (P<0.01).Supported by Public Health Service Grant CA-29056 from the National Cancer Institute     

Clinical Characteristics and Outcomes in Patients with Advanced Rectal Cancer: A National Prospective Cohort Study

Purpose At the time of diagnosis, approximately one third of patients with rectal cancer present with advanced disease. In this study we focus on a group of patients with primary advanced rectal cancer considered as not operable. We address various clinical aspects relevant for decision-making in a group of patients in need of palliative care. Methods Between January 1997 and December 2001, 4831 consecutive patients with rectal cancer were prospectively registered in the Norwegian Rectal Cancer Registry. In this national population-based cohort, 386 patients (8 percent) without surgical interventions were identified. These patients comprise the study population. Clinical characteristics and survivals were addressed. Results Patients not surgically treated were significantly older compared with other treatment groups (median age, 80 years; interquartile range, 72–86 vs. median age, 71 years; interquartile range, 62–79 years) (P<0.001). Median survival time was 4.5 (range, 3.5–5.4) months, regardless of age, gender, or hospital category. Patients who received radiotherapy had a significantly increased survival (P<0.001) compared with patients not treated with radiation, with a median survival time of 10.2 (range, 7.3–12.1) months vs. 2.8 (range, 2.1–3.6) months, respectively. Use of chemotherapy was not associated with improved survival. In multivariate analysis, only stage of disease and radiotherapy were independent predictors of better survival. Conclusion Higher age and comorbidity seem to influence choice of treatment in this subgroup of patients with advanced rectal cancer disease. In nonsurgically treated patients, radiotherapy was associated with an improved survival. Our prospective, population-based cohort study emphasizes the dismal prognosis of these patients, which also should challenge our efforts and clinical approaches in palliative care. Dr. H. K. Sigurdsson, M.D., is a Reseach Fellow sponsored by the Western Norwegian Regional Health Authorities (Project No. 911158). Reprints are not available.