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The present manuscript aimed to review the historical development and most important contributions regarding Lynch Syndrome since its first description, more than a century ago. In 1895, a reputed pathologist from Michigan University, Dr. Aldred Scott Warthin, got intrigued by the family history of a local seamstress called Pauline Gross. According to her prevision, she would present an early death due to cancer, which actually happened (from the uterus). Historically, her family was designated "Family G", comprising a group recognized as the longest and most detailed cancer genealogy that has ever been studied. Warthin concluded that its members had genetic susceptibility for cancer, and they are, nowadays, considered the first reported Lynch Syndrome family. At that time, however, the medical cancer community was far less receptive to the association between heredity and cancer, despite the description of other families with similar heredograms. Unfortunately, this historical fact remained somewhat dormant until another investigator inaugurated a new era in the understanding of family cancer clusters. After reports and studies from this family and many others, the condition initially called Cancer Family Syndrome was changed to the eponym Lynch Syndrome. This was a recognition of the extensive and dedicated work developed by Dr. Henry Lynch in describing various characteristics of the disease, and his efforts to establish the correct recommendations for its diagnosis and treatment. Although the future announces there is still far to go for a complete understanding of Lynch Syndrome, the remarkable contributions of Pauline's intuition, Warthin's perseverance, and Lynch's work consistency must never be forgotten by those who already have or will still benefit from this knowledge.

Background: Colorectal cancer (CRC) is a major public health issue due to high morbidity and mortality. Different screening programs were implemented to reduce its burden., Objectives: To estimate the prevalence of CRC screening uptake using fecal immunochemical test (FIT) or guaiac fecal occult blood testing (gFOBT) in Emirati nationals. Other objectives were to measure the incidence of CRC in the screened population, to measure the outcomes of follow-up screening colonoscopy after positive FIT/gFOBT and to identify the causes of not performing follow-up screening colonoscopy after positive FIT/gFOBT., Methodology: Adult Emirati nationals aged 40-75 years who visited Ambulatory healthcare services clinics, Abu Dhabi in 2015-2016 were included in the study. The electronic medical records of the eligible individuals were reviewed retrospectively. The prevalence of CRC screening was measured among the eligible population using the FIT/gFOBT. The IBM SPSS Statistics program, version 21.0.0, was used for analysis., Result: 45,147 unique individuals were eligible for screening, and only 23.5% were screened using FIT/gFOBT. Of the screened individuals, 13.5% had positive FIT/ gFOBT, and 30.5% of those underwent follow-up screening colonoscopy. CRC was diagnosed in 11 individuals. Colonic polyp were found in 30.5% of individuals who had undergone a follow-up colonoscopy. Collectively 933 individuals did not undergo follow-up screening colonoscopy after having a positive FIT/gFOBT, and about 36.3% had collected the result and referred to a gastroenterologist but did not attend the appointment., Conclusion: CRC screening uptake using FIT/gFOBT is low among the adult Emirati nationals., (© 2021. The Author(s).)

The National Colorectal Cancer Roundtable (NCCRT) is an organization of organizations with staffing, funding and leadership provided by the American Cancer Society (ACS) and guidance and funding by the Centers for Disease Control and Prevention (CDC). In 2014, ACS, CDC, and the NCCRT launched the 80% by 2018 campaign. This highly successful initiative activated hundreds of organizations to prioritize colorectal cancer screening, disseminated smart, evidence-based interventions, and ultimately led to 9.3 million more Americans being up to date with screening compared with the precampaign rate. It's new campaign, 80% in Every Community, is designed to address persistent screening disparities., Competing Interests: Disclosure No disclosures (R. Wender, D. Brooks). K. Sharpe – Has served as a consultant for Genentech for work not related to the topic of this article. K. Sharpe is a former director of the NCCRT. M. Doroshenk is employed by Exact Sciences Corporation that manufactures a colorectal cancer screening test that is not discussed in this article. She is a former director of the NCCRT., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Evidence from industrialized/developed countries showed that colorectal cancer (CRC) incidence rates have significantly dropped due to the widespread use of colonoscopy. In Arab countries, however, the CRC had been reported to have increased. Despite the concerted effort in the primary prevention and widespread use of colonoscopy, to our knowledge, there have been no reports of the prevalence rate of CRC among colonoscopy recipients from Oman. This study aims to explore the CRC prevalence estimates over selected sociodemographic characteristics among colonoscopy-recipients at a tertiary hospital in Oman over five years of follow-up. The regional variations in Oman were also examined in this study., Methods: This hospital-based cross-sectional study reviewed reports of colonoscopies performed over 5-years of retrospective follow-up at a tertiary hospital in Oman. CRC prevalence estimates were calculated over age, gender, governorate, and time of follow-up., Results: A total of 442 CRC cases were enumerated among 3701 colonoscopies, with an overall CRC prevalence estimate of 11.9 per 100 colonoscopies (95% CI: 10.9, 13.0). Gender-specific CRC prevalence was higher among males compared with females (13.3 vs. 10.5). Age-specific CRC prevalence increased with advancing age, from 2.8 among those less than 40 years of age to 26.5 among aged 70 years or more. Regional CRC prevalence was highest among residents in Batinah Governorate. Over the 5-years of follow-up, there was a slow rise in CRC prevalence with an annual increment of 0.59%., Conclusion: The study provides supportive evidence for a steady increase in CRC prevalence over age categories and years of follow-up and depicted the variations of gender-specific CRC prevalence estimates over increasing age categories. The study calls for timely formulation and adoption of national CRC screening programs centered on the colonoscopy use as primary prevention and maximizing its utilization and efficiency., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Alanoud F. Alsumait et al.)

The extent to which the increase in early-onset colorectal cancer (CRC) in the United States varies geographically is unknown. We analyzed changes in CRC incidence and risk factors among people aged 20-49 years by state using high-quality population-based cancer registry data provided by the North American Association of Central Cancer Registries and national survey data, respectively. Early-onset CRC incidence was mostly stable among blacks and Hispanics but increased in 40 of 47 states among non-Hispanic whites, most prominently in western states. For example, rates increased in Washington from 6.7 (per 100 000) during 1995-1996 to 11.5 during 2014-2015 (rate ratio = 1.73, 95% confidence interval = 1.48 to 2.01) and in Colorado from 6.0 to 9.5 (rate ratio = 1.57, 95% confidence interval = 1.30 to 1.91). Nevertheless, current CRC incidence was highest in southern states. From 1995 to 2005, increases occurred in obesity prevalence in all states and heavy alcohol consumption in one-third of states, but neither were correlated with CRC incidence trends. Early-onset CRC is increasing most rapidly among whites in western states. Etiologic studies are needed to explore early life colorectal carcinogenesis., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To analyze the detection rates of colorectal cancer (CRC) and polyps by population-based screening in Guangzhou., Methods: From January 2011 to December 2015, the residents aged 30-79 were selected for CRC screening. The residents were conducted Questionnaires and/or FOBT to assess high-risk groups, the free colonoscopy examination was recommended, and the results were evaluated in detail., Results: There were 98 927 residents involving screening, 5306 high-risk residents identified (males 1859 and females 3447), and 4713 subjects underwent colonoscopy (males 1690 and females 3023). CRC was seen in 55 individuals (males 28 and females 27), and the detection rates in male were higher than in female (P = 0.019). And the detection rates increasing with age, for people over 60 years old, were obviously higher than those younger (x 2  = 18.64, P = 0.000924). The polyps were seen in 1458 (30.94%) cases， and 1420 subjects received pathological examination (adenomas 971 and non-adenomatous polyps 449). Advanced adenomas were seen in 462 cases (males 240 and females 222) and 509 cases of non-advanced adenomas (males 255 and females 254). For advanced adenomas, the detection rates in male were higher than female (14.20% vs 7.34%, P = 2.64 × 10 -14 ). For the detection rates of adenomas or advanced adenomas by age, the people over 40 years were higher than younger (20.91% vs 3.61% P = 7.87 × 10 -6 ; 9.94% vs 2.41%, P = 0.009)., Conclusions: For Guangzhou residents, the detection rates of CRC and adenoma were 1.17% and 20.60%. The detection rates of CRC increasing with age, for people over 60 years old, were obviously higher than those younger. But for people over 40 years, the detection rate of adenoma and advanced adenoma was higher than younger. So for people over 40 years, the CRC screening is recommended., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Among colorectal cancer (CRC) survivors, how the prior tumor location affects the risk of subsequent primary colorectal cancer (SPCRC) and the outcome of those suffering from SPCRC remain unknown., Methods: CRC cases diagnosed from 1973 to 2012 were screened for SPCRC development using the Surveillance, Epidemiology, and End Results database. The relative risk of SPCRC was estimated using the standardized incidence ratio. Survivals were analyzed using the Kaplan-Meier and Cox regression model., Results: The overall risk of SPCRC increased by 27% in CRC survivors compared to that of the general population. The risk increased in patients with both prior right colon cancer (RCC) and left colon cancer (LCC), and was concentrated in the first 5 years after the prior diagnosis, and among young patients. Among the 6701 SPCRC patients identified, patients with prior RCC were more likely to be elderly, female, and with more low or undifferentiated disease than those with prior LCC or rectal cancer (ReC). The overall survivals differed by both prior tumor location (P < 0.0001) and age (P < 0.0001), and the difference by tumor location remained significant when adjusted or stratified by any other potential prognostic factor except age. The cancer specific survivals differed by age (P < 0.0001) rather than by prior tumor location (P = 0.455)., Conclusions: The overall risk of SPCRC increased among patients with both prior RCC and LCC, but not among those with ReC. The different survival outcomes in CRC survivors suffering from SPCRC were largely explained by the patient age but not by the prior tumor location.

Limited data are available for the epidemiology and outcome of colorectal cancer in relation to the three main surgical treatment modalities (open, laparoscopic and robotic). Using the US National Inpatient Sample database from 2004 to 2012, we identified 1,265,684 hospitalized colorectal cancer patients. Over the 9 year period, there was a 13.5% decrease in the number of hospital admissions and a 43.5% decrease in in-hospital mortality. Comparing the trend of surgical modalities, there was a 35.4% decrease in open surgeries, a 3.5 fold increase in laparoscopic surgeries, and a 41.3 fold increase in robotic surgeries. Nonetheless, in 2012, open surgery still remained the preferred surgical treatment modality (65.4%), followed by laparoscopic (31.2%) and robotic surgeries (3.4%). Laparoscopic and robotic surgeries were associated with lower in-hospital mortality, fewer complications, and shorter length of stays, which might be explained by the elective nature of surgery and earlier tumor grades. After excluding patients with advanced tumor grades, laparoscopic surgery was still associated with better outcomes and lower costs than open surgery. On the contrary, robotic surgery was associated with the highest costs, without substantial outcome benefits over laparoscopic surgery. More studies are required to clarify the cost-effectiveness of robotic surgery.

A "cancer predisposing syndrome" later labeled as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch Syndrome, was firstly described by Warthin, about one century ago. An increased predisposition to the development of multiple familial tumors is described as characteristic of this syndrome where visceral and cutaneous malignancies may appear at an early age namely endometrial, gastric, small bowel, ureteral and renal pelvis, ovarian, hepatobiliary tract, pancreatic, brain (Turcot Syndrome) and sebaceous glands (Muir-Torre Syndrome). The latter, a variant of Lynch Syndrome, is characterized by the presence of sebaceous skin adenomas, carcinomas and/or keratoacanthomas associated with visceral malignancies. Both Lynch Syndrome and Muir-Torre Syndrome have been recognized due to germline mutations in mismatch repair genes MLH1, MSH2 and MSH6. To date, 56 Lynch Syndrome founder mutations dependent on MLH1, MSH2 and, although less frequently found, MSH6 and PMS2 are described. Some of these founder mutations, principally of MSH2 gene, have been described to cause Muir-Torre phenotype and have been traced in large and outbreed Muir-Torre Syndrome families living in different US and European territories. Due to the evidences of highly specific Muir-Torre phenotypes related to the presence of widespread MSH2 founder mutations, preliminary search for these MSH2 common mutations in individuals carrying sebaceous tumors and/or keratoacanthomas, at early age or in association to visceral and familial tumors, permits cost-effective and time-saving diagnostic strategies for Lynch/Muir-Torre Syndromes., (Copyright © 2015. Published by Elsevier B.V.)

Circulating tumor cells (CTC) may be defined as tumor- or metastasis-derived cells that are present in the bloodstream. The CTC pool in colorectal cancer (CRC) patients may include not only epithelial tumor cells, but also tumor cells undergoing epithelial-mesenchymal transition (EMT) and tumor stem cells. A significant number of patients diagnosed with early stage CRC subsequently relapse with recurrent or metastatic disease despite undergoing "curative" resection of their primary tumor. This suggests that an occult metastatic disease process was already underway, with viable tumor cells being shed from the primary tumor site, at least some of which have proliferative and metastatic potential and the ability to survive in the bloodstream. Such tumor cells are considered to be responsible for disease relapse in these patients. Their detection in peripheral blood at the time of diagnosis or after resection of the primary tumor may identify those early-stage patients who are at risk of developing recurrent or metastatic disease and who would benefit from adjuvant therapy. CTC may also be a useful adjunct to radiological assessment of tumor response to therapy. Over the last 20 years many approaches have been developed for the isolation and characterization of CTC. However, none of these methods can be considered the gold standard for detection of the entire pool of CTC. Recently our group has developed novel unbiased inertial microfluidics to enrich for CTC, followed by identification of CTC by imaging flow cytometry. Here, we provide a review of progress on CTC detection and clinical significance over the last 20 years.

Colorectal cancer screening is thought to be an effective tool with which to reduce the mortality from colorectal cancer through early detection and removal of colonic adenomas and early colon cancers. In this article, we review the history, evolution, and current status of imaging tests of the colon-including single-contrast barium enema, double-contrast barium enema, computed tomographic (CT) colonography, and magnetic resonance (MR) colonography-for colorectal cancer screening. Despite its documented value in the detection of colonic polyps, the double-contrast barium enema has largely disappeared as a screening test because it is widely perceived as a labor-intensive, time-consuming, and technically demanding procedure. In the past decade, the barium enema has been supplanted by CT colonography as the major imaging test in colorectal cancer screening in the United States, with MR colonography emerging as another viable option in Europe. Although MR colonography does not require ionizing radiation, the radiation dose for CT colonography has decreased substantially, and regular screening with this technique has a high benefit-to-risk ratio. In recent years, CT colonography has been validated as an effective tool for use in colorectal cancer screening that is increasingly being disseminated.

With the recent advances in chemotherapy for colorectal cancer, the prognosis for patients with metastatic colorectal cancer has been significantly improved. The development of the implantable port system has also enabled patients to receive multiagent chemotherapy with a more satisfactory quality of life. Historically, chemotherapy using implantable port systems was begun to obtain an oncological benefit in the treatment of locoregional cancer. In the 1950s, there was an increasing interest in perfusion techniques for the application of chemotherapeutic agents, such as nitrogen mustard, in the locoregional treatment of metastatic cancer. Among them, the treatment of liver metastasis has interested oncologists for many years. On the other hand, implantable devices were developed during the intervening decades that have enabled patients with colorectal cancer with liver metastases to be treated effectively using hepatic arterial infusion; which became more common in the 1980s. The treatment of metastatic colorectal cancer increasingly requires a multimodal approach and multiple treatment options based not on convenience, but in terms of personalization and efficacy. Therefore, it is important to optimize the pharmacokinetics of chemotherapeutic agents. Implantable port systems for colorectal cancer patients have been essential for oncological practice, and the importance of these systems will remain unchanged in the near future.

Background: The long-term time trends of multiple gastrointestinal diseases are characterised by a striking rise and fall. These temporal changes provide important clues about disease aetiology., Aim: To highlight the importance of Helicobacter pylori infection in shaping the temporal trends of many common gastrointestinal diseases., Methods: Literature review of the time trends associated with common digestive diseases., Results: The general trends of gastric ulcer, duodenal ulcer, gastric cancer, colon cancer, rectum cancer have all been shaped by a similar underlying birth-cohort phenomenon. Mortality associated with these diagnoses increased in all generations born during the nineteenth century. It peaked among generations born shortly before the turn of the century and then decreased in all subsequent generations born throughout the twentieth century. These patterns can be observed in the incidence, hospitalisation and mortality data from many different countries. They reflect similar rising and falling trends of H. pylori infection in the general population. Diseases that are inversely associated with H. pylori, such as reflux disease, erosive oesophagitis, Barrett's oesophagus, and oesophageal adenocarcinoma, have seen a striking rise during the recent decline of H. pylori infection., Conclusion: The temporal variations of H. pylori infection have affected the occurrence of gastroenterology's most common disorders., (Published 2013. This article is a US Government work and is in the public domain in the USA.)

Background: Liver resection for metastatic colorectal cancer became established without randomized trials. Proponents of surgical resection point out 5-year survival approaching 50% whilst critics question how much of the apparent effect is due to patient selection., Method: A 2006 systematic review of reported outcomes provided the starting point for citation analysis followed by thematic analysis of the texts of the most cited papers., Results: 54 reports from 1988 to 2002 cited 709 unique publications a total of 1714 times. The 15 most cited papers were explored in detail, and showed clear examples of duplicate reporting and overlapping data sets. Textual analysis revealed proposals for a randomized controlled trial, but this was argued to be unethical by others, and no trial was undertaken., Conclusions: This critical review reveals how the case for this surgery was made, and examines the arguments that influenced acceptance and adoption of this surgery., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

King Ferrante I of Aragon, leading figure of the Italian Renaissance, died in 1494. The autopsy of his mummy revealed a tumor infiltrating the small pelvis. We examined the histologic and molecular features of this ancient tumor to investigate its primary origin. Hematoxylin-eosin, Van Gieson, and Alcian Blue staining showed neoplastic cells infiltrating muscular fibers and forming pseudo-glandular lumina disseminated in fibrous stroma with scarce mucus. A strong immunoreactivity of the neoplastic cells was shown for pancytokeratins and proliferating cell nuclear antigen. Molecular fingerprints were investigated by examining K-ras, BRAF, and microsatellite instability in ancient tumor DNA. Sequencing analysis showed G-to-A transition in codon 12 of K-ras. BRAF mutations and microsatellite instability were not observed. Because the presence of K-ras codon 12 mutation could be associated with exposure to chemical carcinogens, possibly present in some food items, paleodietary reconstruction of the King Ferrante I was carried out by carbon (δ(13)C ) and nitrogen (δ(15)N) stable isotopes analysis. δ(13)C and δ(15)N values found in bone collagen of the King were consistent with a massive intake of animal proteins. Overall, our data show that the tumor of Ferrante I was a mucinous adenocarcinoma with molecular fingerprints characteristic of colorectal carcinogenesis linked to K-ras pathway. Paleodietary reconstruction and historical chronicles indicate a strong consumption of meat by the King. The possible abundance of dietary carcinogens, related to meat consumption, could explain the K-ras mutation causing the colorectal tumor that killed Ferrante I more than 5 centuries ago., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The associations between colorectal cancer risk and several chronic illnesses, operations and various medications were examined in 715 colorectal cancer cases and 727 age- and sex-matched controls in data derived from a large, comprehensive population-based study of this cancer conducted in Melbourne, Australia. There was a statistically significant deficit among cases of hypertension, heart disease, stroke, chronic chest disease and chronic arthritis and a statistically significant excess of 'haemorrhoids' among cases, and all of these differences were consistent for both colon and rectal cancers and for both males and females. Although no statistically significant differences were found for other cancers, there were twice as many breast cancers among cases (16) than among controls (8) and also there were 9 uterine cancers among cases and only 2 among controls. There was a statistically significant deficit among cases in the use of aspirin-containing medication and vitamin supplements and this was consistent for both colon and rectal cancers and for both males and females. There was a statistically significant excess of large bowel polypectomy among cases. The modelling of these significant associations simultaneously in a logistic regression equation indicated that hypertension, heart disease, chronic arthritis and aspirin use were each independent effects and consistent for both colon and rectal cancers for both males and females and also that these effects were independent of dietary risk factors previously described in the Melbourne study. The possible relevance of these findings towards an understanding of colorectal cancer risk and aetiology is discussed.

Objectives: This report describes the historical development of medical theories and research concerning the relationship between dietary fat intake and breast and colorectal cancer and coronary heart disease (CHD)., Method: The historical and medical literature on this topic was analyzed with special reference to the Woman's Health Initiative (WHI) studies., Results: After 1900, changes in clothing fashions and life insurance mortality studies created strong preferences for slimness and emphasized reduced dietary fat intake as the preferred method of weight control. After midcentury, ecological correlations of countries found that national average dietary fat intake was related to national breast cancer and CHD rates. These relationships were not found in longitudinal studies of the same countries or in studies of dietary fat intake of individuals, including the WHI study. Dietary fat intake was found to affect colorectal cancer in some studies of individuals, although not the WHI. The WHI, like other intervention studies of dietary fat reduction, used unrepresentative samples and costly lifestyle change techniques that are not economically feasible in the community., Conclusion: The WHI concurred with many other studies in finding that dietary fat intake is not a significant risk factor for CHD or breast cancer.

Denis Burkitt was motivated by Christian Evangelism from his early years. It was a critical factor not only in his personal development and decision to work in Uganda, but also in his medical achievements. The events in his life which led to his description of Burkitt lymphoma in 1958 are described together with his discovery of the endemic nature of the condition and its treatment. His research on the aetiology of the condition is also described. The endemic form of the lymphoma is still a major cause of childhood mortality in Africa due to a lack of basic resources to treat the condition. Burkitt Lymphoma has been used as a model to advance research and treatment on a wide range of conditions in haematology and oncology. Burkitt's work in later life on dietary fibre and its implications are summarised.

This research uses the tools of modern medical science to examine the ancient descriptions of the symptoms suffered by King Jehoram who was affected by some disease. The Biblical texts were examined, and passages relating to the disease that afflicted King Jehoram, who ruled in Jerusalem 843-851 B.C., were closely studied. We have not included any commentaries, but referred only to the words of the Bible exactly as written. The Passages ''...the Lord smote him in his bowels with an incurable disease in the process of time, after the end of two years, his bowels fell out by reason of his sickness: so he died of sore diseases'' indicate that the King suffered from some kind of disease which affected his bowels. Among the various diseases which may be associated with prolapse of the bowel, colorectal carcinoma is the most acceptable. It seems that the colorectal carcinoma was poorly differentiated, invaded perirectal adipose tissue, blood vessels, and/or lymphatic vessels, and/or perineural areas, was lymph node positive and reached the 4th stage with the spread of metastases to the distal organs. Viewed by a modern physician, the story of King Jehoram unfolds as possibly the earliest description of a patient afflicted by colorectal carcinoma.

The hereditary predisposition to cancer dates historically to interest piqued by physicians as well as family members wherein striking phenotypic features were shown to cluster in families, inclusive of the rather grotesque cutaneous findings in von Recklinghausen's neurofibromatosis, which date back to the sixteenth century. The search for the role of primary genetic factors was heralded by studies at the infrahuman level, particularly on laboratory mouse strains with strong susceptibility to carcinogen-induced cancer, and conversely, with resistance to the same carcinogens. These studies, developed in the 19th and 20th centuries, continue today. This article traces the historical aspects of hereditary cancer dealing with identification and ultimate molecular genetic confirmation of commonly occurring cancers, particularly of the colon in the case of familial adenomatous polyposis and its attenuated form, both due to the APC germline mutation; the Lynch syndrome due to mutations in mismatch repair genes, the most common of which were found to be MSH2, MLH1, and MSH6 germline mutations; the hereditary breast-ovarian cancer syndrome with BRCA1 and BRCA2 germline mutations; the Li-Fraumeni (SBLA) syndrome due to the p53 mutation; and the familial atypical multiple mole melanoma in association with pancreatic cancer due to the CDKN2A (p16) germline mutation. These and other hereditary cancer syndromes have been discussed in some detail relevant to their characterization, which, for many conditions, took place in the late 18th century and, in the more modern molecular genetic era, during the past two decades. Emphasis has been placed upon the manner in which improved cancer control will emanate from these discoveries., (Copyright 2004 Wiley-Liss, Inc.)

The roots of colorectal cancer date back to antiquity. In this short history of colorectal cancer we trace its clinical and research origins from ancient times through the dark ages, middle ages, to the scientific and medical advances of the seventeenth to twentieth centuries and into the twenty-first century.

The classical standard surgical technique for rectal carcinoma, abdominoperineal excision (Miles operation), has been gradually replaced by sphincter-saving surgery and more than 70% of rectal carcinomas are treated by anterior resection in which autosuture machines have played a major role in recent years. Wide lateral lymphadenectomy has been replaced by autonomic nerve preservation because of the high frequency of sexual and urinary dysfunction. Total mesorectal excision (TME) proposed by Heald et al which ignores the lateral nodes of the pelvic wall is the most popular technique in Western countries. The concept of TME is contradictory to that of wide lateral lymphadenectomy and the true merits of the latter should be examined in the near future. Minimally invasive surgery, including various procedures of local excision of low rectal tumors and colonoscopic polypectomy, has given great benefits to many patients. In Japan there seems to have been a lack of interest in adjuvant radiotherapy and chemoradiotherapy in the past, but they should be more seriously considered for the adjuvant treatment of advanced rectal carcinoma in the future.

In view of the changing concepts of colorectal carcinogenesis during the past 20 years, a historical review of colorectal carcinogenesis is presented. The concept of colorectal carcinogenesis is presented in four different periods: 1) carcinogenesis based on surgical materials; 2) carcinogenesis based on polypectomy materials; 3) carcinogenesis based on nonpolypoid neomaterials; and 4) carcinogenesis based on molecular biology. In the first period, large adenomas were thought to play the most important role as precursors of colorectal carcinomas. The concept was referred to as the "adenoma-carcinoma sequence." However, in the second period, smaller and nonpedunculated adenomas were found to have a much higher malignancy potential than previously thought. The natural history of colorectal neoplasms revealed morphological changes from polypoid or sessile lesions to ulcerating carcinomas during a varying time span. The discovery of nonpolypoid neoplasms, including flat and depressed adenomas/carcinomas, shed light on new precursors of colorectal carcinomas that had not been recognized in the past. They tend to have a much higher malignant potential than polypoid neoplasms. Molecular biology clarified the absence of K-ras mutation in nonpolypoid, particularly depressed, neoplasms, suggesting the presence of a novel pathway of colorectal carcinogenesis different from that in polypoid neoplasms. The concept referred to as the "adenoma-carcinoma sequence" changed because colonoscopic polypectomy specimens were studied, and rather small nonpeduculated adenomas were found to play an important role as precursors of colorectal carcinomas. The discovery of nonpolyoid neoplasms provided us with new precursors of colorectal carcinomas. The genetic alterations in nonpolypoid neoplasms seem to differ from those in polypoid neoplasms. Carcinogenesis of so-called de novo carcinoma should be explained on a molecular basis. When sequential multistep genetic alterations take place very rapidly the carcinoma seems to arise de novo. Until the gene responsible for real de novo carcinoma is detected, the term de novo-type carcinoma should be used.

A great debate is still open in literature about the available staging systems of colorectal cancer. Therefore, an historical analysis of the several systems suggested in the last decades was performed; pathological, clinicopathological and more recent score clinicopathological staging systems were evaluated. From this historical review it appears that subsequent modifications of various classifications allowed only for a poor improvement in predictivity. A more careful histopathological examination of surgical specimen and more exact information about involvement of other organs and tissues allow a correct classification of patients affected by colorectal cancer independently of the staging system used.

A chronological overview of the various staging systems for colorectal cancer is presented in an effort to demonstrate the reason for the current state of confusion. The Dukes 1932 system is considered to be the gold standard because of its simplicity and accuracy and is the system most often referred to in the literature. Number of positive nodes and depth of invasion are two variables that have been found to be predictors of survival. In the future, other prognostic factors such as nuclear morphology, flow cytometric characteristics, histological grade, and vascular or lymphatic invasion may also be entered into the staging equation. Use of the TNM system at this time is recommended since it most completely describes appropriate prognostic factors and allows conversion of other staging systems into a common format. Future modifications could logically evolve from the TNM system.

Surgeons have never intervened in the life of a sick patient merely when technical expertise is required. The unique anatomic, physiologic, and oncologic perspectives the surgeon possesses mandates that he/she play a major role in diagnostic advances and the management of most forms of cancer, especially colorectal cancer. This article briefly outlines the historical posture of surgeons in pursuing diagnostic advances in medicine and particularly colorectal cancer. It also emphasizes that the modern surgical investigator, in collaboration with the basic scientist, should form a critical core of a team of investigators in the pursuit of diagnostic advances.

Fluorouracil-based chemotherapy regimens have been utilized in metastatic colorectal cancer for more than 30 years. Early attempts at defining an optimal treatment schedule and use in combination with other drugs failed to significantly improve results. In contrast, the clinical effectiveness of fluorouracil has been improved by continuous infusion administration and modulation with folinic acid. Both approaches have increased the response rate compared with results achieved with traditional bolus schedules; the effect on survival has been less significant. Unfortunately, expense and, in some instances, toxicity have also been increased, which detracts from their overall usefulness. Clinical studies that evaluate fluorouracil chemotherapy in combination with biological-response modifiers are ongoing and will be areas of intense research during the next few years.