Daniel L. Edelstein

Serrated polyposis: rapid and relentless development of colorectal neoplasia

Objective Serrated (hyperplastic) polyposis (SP) is a rare disorder with multiple colorectal hyperplastic polyps and often sessile serrated adenomas/polyps (SSA/P) or adenomas. Although associated with colorectal cancer, the course of SP is not well described. Design 44 patients with SP were studied. The results of 146 colonoscopies with median follow-up of 2.0 years (range 0–30) and a median of 1.0 years (range 0.5–6) between surveillance colonoscopies were evaluated. Findings from oesophogastroduodenoscopy examinations were analysed. Results The mean age at diagnosis of SP was 52.5±11.9 years (range 22–78). In two pedigrees (5%) another family member had SP. None of 22 patients had gastroduodenal polyps. All patients had additional colorectal polyps at surveillance colonoscopy. SSA/P or adenomas were found in 25 patients (61%) at first colonoscopy and 83% at last colonoscopy. Recurrent SSA/P or adenomas occurred in 68% of patients at surveillance colonoscopy. Three patients had colorectal cancer. Eleven patients (25%) underwent surgery (mean time from diagnosis of SP 2.0±0.9 years). After surgery all seven surveyed patients developed recurrent polyps in the retained colorectum (4/7 had SSA/P or adenomas). No association was found between colorectal neoplasia and sex, age at diagnosis of SP or initial number of colorectal polyps. Conclusions In SP, rapid and unrelenting colorectal neoplasia development continues in the intact colorectum and retained segment after surgery. These findings support the possibility of annual colonoscopic surveillance, consideration for colectomy when SSA/P or adenomas are encountered and frequent postoperative endoscopic surveillance of the retained colorectum.

Rapid Development of Colorectal Neoplasia in Patients With Lynch Syndrome

BACKGROUND & AIMS Patients with Lynch syndrome have a high risk for colorectal adenomas and carcinomas. We evaluated the development of colorectal neoplasia in these patients. METHODS We assessed serial colonoscopy findings from 54 persons from 29 pedigrees with pathogenic mutations in MSH2 or MLH1; we evaluated the development of colorectal neoplasia by age, sex, tumor location, and number (mean follow-up time, 9.3 years; colonoscopy interval, 1.7 ± 1.2 years; 112 adenomas and 31 cancers). Differences in colorectal phenotype were analyzed by genotype, and dwell time was calculated for advanced neoplasias. RESULTS Among mutation carriers, the cumulative risk of colorectal neoplasia was 43% by age 40 years and 72% by 80 years. There were no statistically significant associations between time to development of colorectal neoplasia and sex or mutation type. Most female patients had left-sided neoplasms, whereas most male patients developed right-sided lesions. The mean cumulative numbers of neoplastic lesions in patients were 1.3 ± 0.5 by age 30 years and 7.6 ± 6.8 by age 80 years. Polyp dwell time was 33.0 ± 16.2 months and 35.2 ± 22.3 months for advanced adenoma and colorectal cancer, respectively. The 5-year survival rate for patients with colorectal cancer was 96%. CONCLUSIONS High percentages of individuals with pathogenic mutations in MSH2 or MLH1 develop colorectal neoplasia by age 40. Left-sided colorectal neoplasias are more frequent in female patients. The development of 3 or more colorectal neoplasms by age 30 years indicates a possible polyposis syndrome rather than Lynch syndrome. Polyp dwell time is short for advanced neoplasias, arguing for annual colonoscopic screening and surveillance.

Occurrence of Colorectal Adenomas in Younger Adults: An Epidemiologic Necropsy Study

BACKGROUND & AIMS The colorectal adenoma is the precursor lesion in virtually all colorectal cancers. Occurrence of colorectal adenomas has been studied in older adults but analysis in younger adults is lacking. METHODS The prevalence by age, sex, race, and location, and the number of colorectal adenomas detected was investigated using epidemiologic necropsy in 3558 persons ages 20 to 89 autopsied from 1985 to 2004 at the Johns Hopkins Hospital. Results were standardized to the general population. Younger adults 20 to 49 years old were compared with older adults 50 to 89 years old. RESULTS The prevalence of colorectal adenomas in younger adults increased from 1.72% to 3.59% from the third to the fifth decade of life and then sharply increased after age 50. In younger adults, adenomas were more prevalent in men than in women (risk ratio, 1.09; 95% confidence interval, 1.07-1.11) and in whites than in blacks (risk ratio, 1.28; 95% confidence interval, 1.26-1.31). Overall, both younger and older adults had predominately left-sided adenomas, but blacks in both age groups had more right-sided adenomas. Occurrence of 2 or more adenomas in younger adults and 5 or more in older adults was greater than 2 SDs from the mean. CONCLUSIONS Colorectal adenomas infrequently occur in younger adults and are more prevalent in the left colon. Irrespective of age, blacks have more right-sided adenomas, suggesting the need for screening the entire colorectum. Two or more adenomas in younger adults and 5 or more in older adults represents polyp burden outside the normal expectation.

The latest options and future agents for treating male hypogonadism

Exogenous testosterone has long been used in medicine as a pharmaceutical agent. Its use in hypogonadism is well characterized and its development as a drug has undergone several modifications in an attempt to achieve clinical success. As native testosterone is rapidly degraded, modified analogs have been developed to obtain a better pharmacokinetic profile. The developmental goals of testosterone analogs have evolved since its first introduction as an orally available form to longer acting and more stable forms such as injectables, depots and transdermal therapies. Several modalities of testosterone replacement are presently available, each differentiated by their route of delivery, half life, cost and ability to deliver physiologic levels of testosterone. As hypogonadism is often a life-long condition, physicians are compelled to use an appropriate therapy that best matches the needs of their patients. An ideal testosterone therapy should be able to deliver physiologic levels of testosterone and be safe, simple to use and cost effective. Present trends show transdermal therapies (gels and patches) along with long-acting injectables, such as Nebido®, are quickly replacing intramuscular testosterone modalities. Compounds such as dihydrotestosterone, human chorionic gonadotropin, aromatase inhibitors and clomiphene are presently being studied in specific subgroups of men. Additionally, several new compounds, such as selective androgen-receptor modulators and 7-α-methyl-19-nortestosterone, are being developed to target androgen receptors in specific tissues. A further understanding of the androgen receptor and subsequent discovery of targeted drugs may yield more individualized treatment modalities. This will enhance the effectiveness of available therapies, while mitigating their undesirable effects.

Testosterone undecanoate in the treatment of male hypogonadism

Importance of the field: Testosterone undecanoate (TU) represents an exciting new testosterone replacement therapy for hypogonadal men due to its convenient dosing schedule and favorable pharmacokinetic and safety profiles. Areas covered in this review: Clinical, pharmacokinetic and safety characteristics of TU will be reviewed. The characteristics of currently approved testosterone therapies will be reviewed and compared with those of TU in order to determine which therapy most appropriately meets the clinical objective of properly matching a patient with a therapy that is best able to deliver physiological levels of testosterone for prolonged periods of time, while at the same time being safe, effective, inexpensive, simple to use, and with few side effects. What the reader will gain: TU represents the first long-acting injectable with an excellent safety profile that can be administered only four times annually to produce stable levels of testosterone. Long-term studies have validated the clinical efficacy of TU in maintaining therapeutic levels of testosterone. Patient preference for the convenient dosing schedule might also lead to better compliance and therapeutic benefit. No serious side effects have been noted with the use of TU, including long-term data on patients treated with TU over 8 years. Take home message: TU is both a desirable and safe option for the treatment of hypogonadal men. Patients will benefit from the stable testosterone levels and fewer required injections, while achieving the desired benefits of androgen replacement.

Emerging drugs for hypogonadism

Male hypogonadism is a common endocrine problem that affects men of all ages. Recently, there has been a surge in testosterone use among middle-aged and older men who in the past may have been considered to have borderline or even normal testosterone levels. This increasing use of testosterone therapy among men has paralleled the increasing improvements in the development of treatments for male hypogonadism that have been made over the past few decades. Current therapies using transdermal formulations and long-acting injectables such as testosterone undecanoate are quickly replacing the old injectable testosterone esters. In recent years, pharmaceutical sales and prescription data have readily shown a shift in the testosterone marketplace towards greater use of slightly more expensive treatments such as transdermal therapies, which are easier to administer and yield more physiological levels of testosterone. On the horizon are several new compounds in development, such as selective androgen receptor modulators (SARMS), 7α-methyl-19-nortestosterone, aromatase inhibitors, clomifene, dihydrotestosterone and human chorionic gonadotropin. Compounds such as SARMs are designed to selectively target androgen receptors in specific tissues (such as bone and muscles), in the hope of dispersing some of the side effects experienced on the prostate, which are presently associated with therapy of exogenous testosterone.

Risk of Colorectal and Other Cancers in Patients With Serrated Polyposis

Patients with serrated polyposis develop multiple colorectal hyperplastic and/or serrated sessile adenomas/polyps. We investigated the risk of colorectal and other cancers by analyzing data from 64 patients with serrated polyposis (mean age at diagnosis, 54 y; 41% men; 92% white) listed in the Johns Hopkins Polyposis Registry. Medical, endoscopic, and histopathology reports were evaluated. Six patients (9.4%) had a history of colorectal cancer, diagnosed at a mean age of 56 years; 6 additional patients (9.4%) had at least 1 advanced colorectal adenoma. Extracolonic cancers were found in 16% of the study population. The standard incidence ratio for colorectal cancer in patients with serrated polyposis was 18.72 (95% confidence interval, 6.87-40.74) and for extracolonic cancer was 31.20 (95% confidence interval, 14.96-57.37), compared with the Surveillance, Epidemiology, and End Results population. Patients with serrated polyposis therefore have a high risk for colorectal cancer and require vigilant colorectal surveillance, starting at the time of diagnosis of serrated polyposis. The risk of extracolonic cancer also appears to be increased, but this requires further evaluation.

Clinical Characteristics of Multiple Colorectal Adenoma Patients Without Germline APC or MYH Mutations

Background: Patients with multiple colorectal adenomas (MCRA) without genetic cause are increasingly being diagnosed. The characteristics and natural history of this condition are not well studied. Materials and Methods: Twenty-seven patients with MCRA, with cumulatively 10 to 99 colorectal adenomas and without deleterious mutations of APC or MYH genes, were investigated. Results of colonoscopies with a mean follow-up of 4.9 years (range, 0 to 27 y) were evaluated. Findings from esophagogastroduodenoscopy and extracolonic manifestations were assessed. Results: The mean age at polyp diagnosis and MCRA diagnosis was 47.8±13.1 years (range, 21 to 72 y) and 50.4±14.6 years (range, 21 to 72 y), respectively. In 22% of patients another family member had MCRA. At first colonoscopy, the mean number of adenomas was 35.0±35.9 (range, 0 to 99). Serrated polyps were rare. Esophagogastroduodenoscopy revealed 47% of patients had upper tract neoplasia. Patients with upper tract findings were diagnosed with MCRA at significantly younger mean age than those without findings, P<0.05. Eighteen patients (67%) underwent colectomy with a mean time from diagnosis of MCRA of 3.1±1.3 years. After surgery, surveyed patients developed recurrent adenomas in retained colorectum. Nine patients (33%) had extracolonic cancers. Conclusions: MCRA patients have a similar clinicopathologic phenotype to known syndromes of attenuated adenomatous polyposis and the majority have need for colectomy. The management of MCRA patients and families should parallel that of attenuated familial adenomatous polyposis and MUTYH-associated polyposis including surveillance of the upper tract.

Evaluating the biological activity and effects on human health of fish oil and its omega-3 fatty acids

This chapter reviews the background, chemistry and specific efficacy of fish oils, specifically ω-3 fatty acids in the treatment and prevention of disease. Epidemiologic evidence appears strong showing its protective effects, although clinical trials with definitive data are still deficient. The mechanism by which ω-3 fatty acids may work on the nervous system and its anti-inflammatory effects are presented. Efforts should be made to ensure dietary intakes should provide sufficient amounts of these essential fatty acids through moderate intake of cold water fatty fish.

Detection of familial adenomatous polyposis with polarized spectroscopic imaging and oral vascular density

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disease characterized by the development of multiple colonic polyps at younger age with a near 100% lifetime risk of colorectal cancer in later years. The determination of FAP is made after extensive clinical evaluation and genetic testing of at risk individuals. Genetic testing is expensive and in some cases deleterious mutations are not found in all patients with a clinical diagnosis of FAP. As such, the early identification of affected individuals could substantially eliminate associated morbidity and mortality. We investigated a novel spectro-polarimetric imaging system to capture images of the oral mucosa at different wavelengths in an attempt to distinguish patients with FAP from controls. Total diffused oral mucosal reflectance (OMR) and oral mucosal vascular density (OMVD) were calculated from spectral data collected from 33 patients with gene positive FAP, 5 patients who tested negative for FAP, and 45 controls. A statistically significant difference in OMVD (p < 0.001) was observed between individuals with FAP and controls. Analysis of OMR showed no significant difference between the two subject groups.