A recent retrospective study (Clin Gastroenterol Hepatol 2018; 16: 68-74) compared adult patients who had ulcerative colitis (UC) with (n=23) and without primary sclerosing cholangitis (n=120) (PSC). All patients had pancolitis and were in clinical remission.
- Patients with UC-PSC had more subclinical endoscopic activity (odds ratio (OR) 4.21) and histologic activity (OR 5.13) in the right colon compared with patients without PSC
It is known that the presence of PSC is a risk factor for colorectal cancer (CRC). A previous meta-analysis (RM Soetiknno et al. Gastrointest Endosc 2002; 56: 48-54) described a OR of CRC of 4.09.
My take: This study shows that UC patients with PSC who are in clinical remission have a greater degree of endoscopic and histologic inflammation in the proximal colon compared to patients without PSC. This increased inflammation is a likely factor in the increased risk for CRC.
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A recent study (SH Wong et al. Gastroenterol 2017; 153: 1621-33) highlights the potential role of the microbiota and colorectal cancer (CRC).
In this study, the stool from either patients with CRC or control patients was gavaged into mice twice a week for 5 weeks. One group of mice had received azoxymethane (AOM) which induces neoplasia and the other group were germ-free mice. Extensive studies involving immunohistochemistry, expresssion microarray, quantitative polymerase chain reaction, immunoblot, and flow cytometry.
- Conventional, AOM-treated mice who received gavage from patients with CRC had significantly higher proportions of high-grade dysplasia (P<.05) and macroscopic polyps (P<.01)
- Among the germ-free mice fed with stool from patients with CRC, there was a higher proportion of proliferating Ki-67-positve cells
- These findings correlated with more dysbiosis in the mice who received stool from patients with CRC and with upregulation of genes involved in cell proliferation, stemness, apoptosis, angiogenesis, and invasiveness
“This study provides evidence that the fecal microbiota from patients with CRC can promote tumorigenesis in germ-free mice and mice given a carcinogen.”
My take: This study shows that microbiota clearly influence the risk of CRC. I infer from this study that this could explain the potential healthy roles of diets with more fruits and vegetables, that promote healthier microbiota as well as the potential detrimental role of diets with more processed meats.
Related study: L Liu et al. Association between Inflammatory Diet Pattern and Risk of Colorectal Carcinoma Subtypes Classified by Immune Responses to Tumor Gastroenterol 2017; 153 1517-30. Using two databases from 2 prospective cohorts with followup of 124,433 participants, inflammatory diets had a higher risk of a colorectal cancer subtype.
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Bright Angel Trail
The ability to measure drug levels has changed how we think about refractory medical disease, particularly in patients with inflammatory bowel disease. Prior to the availability of therapeutic drug monitoring (TDM), in some situations poor response to therapy could be ascribed to variability in host immune response. Now, it is clear that many cases of refractory medical disease are due to insufficient drug level. TDM allows for dose individualization to target the right amount of medication.
TDM has an accepted role in anti-TNF therapy. Now, a study (R Battat et al. Clin Gastroenterol Hepatol 2017; 15: 1427-34) extends the concept of TDM to ustekinumab. This study which took place between 2014-2015 examined ustekinumab use in 62 patients with refractory Crohn’s disease (CD). Ustekinumab dosing: 90 mg SC at weeks 0, 1, and 2 for induction, then 90 mg every 4 or 8 weeks for maintenance.
- At week 26, 80.7% of patients had a clinical response, 66.1% had a clinical remission, and 58.9% had an endoscopic response.
- In those with an endoscopic response, the mean trough concentration of ustekinumab was 4.7 mcg/mL compared with 3.8 mcg/mL those without an endoscopic response.
- Using a trough threshold of 4.5 mcg/mL at week ≥26, 75.9% had an endoscopic response whereas those with a level below this trough had a 40.7% endoscopic response
- The authors did not detect antibodies to ustekinumab in any patient. The authors note that ustekinumab has low immunogenicity and prior UNITI studies indicated antibody formation in 0.2% after induction and 2.3% at 1 year.
- Unlike combination therapy with anti-TNF therapy, “concurrent immunosuppressive therapy does not explain low immunogenicity, as only 25.8% of patients received these and had neither improved clinical outcomes nor higher drug concentrations.”
Thus far, no clinical studies have demonstrated improved clinical outcomes with dose escalation in the setting of low ustekinumab levels. A prospective trial would be helpful.
My take: This study shows promising results for ustekinumab for refractory CD. The low immunogenicity indicates that monotherapy is likely appropriate. A target level of >4.5 mcg/mL indicates a higher likelihood of response.
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A recent study (RS Mehta et al. Gastroenterol 2017; 152: 1944 & summarized in editorial, 1821-23) examined the effects of a “Western” diet and a “prudent” diet on the risk of colorectal cancer (CRC). Data was derived from two large prospective cohorts involving more than 137,000 participants for up to 32 years; this equated to 3.6 million person-years of follow-up.
- Those in the highest quartile of a Western dietary pattern had a 31% increased CRC risk (RR=1.31) compared to those in the lowest quartile. In this context, a Western diet was characterized by consumption of red and processed meats, high-fat dairy products (such as whole milk), refined grains, and desserts.
- The prudent diet cohort, had a 14% reduced risk for those in the highest quartile compared to the lowest quartile. The ‘prudent’ diet included high intakes of vegetables, fruits, whole grains, and fish.
Based on this study and others, the editorial notes the following:
- Limit red and processed meat consumption to 0.5 servings or 42 g/day of lean red meat
- A more ‘prudent’ diet has health benefits beyond reduction of CRC, including lower cardiovascular disease mortality
Related blog post: Colon Cancer at Younger Ages
Piedmont Park, Atlanta
A good review on colorectal adenomas: WB Strum. NEJM 2016; 374: 1065.
A couple of points from review:
- There has been a wealth of new data in last 10 years.
- In 2016, ~134,000 persons in U.S. will be found to have colorectal cancer & 49.000 will die from it.
- Adenomas are present in 20-53% of the U.S. population older than 50 years of age.
- Adults in the U.S. have a lifetime risk of ~5% of adenocarcinoma.
- Two major pathways from adenomas to adenocarcinoma: chromosomal instability and micro satellite instability via predominantly ~25 genes.
- Screening interval recommendations (Table 1): 10 years for no polyps or juvenile polyps in rectum/sigmoid.
- Aspirin therapy may be beneficial but apply to persons who have no increased risk of bleeding and are willing to take low-dose aspirin (81 mg) daily. The greatest benefit is expected in persons 50 to 59 years and a potential benefit in 60 to 69 years of age.
- Diets that are low in fat, regular physical exercise, maintenance of an appropriate body-mass index, and avoidance of smoking are recommended to lower risk.
Related full text article: Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: USPSTF Recommendations Excerpt:
“The USPSTF recommends initiating low-dose aspirin use for the primary prevention of CVD and CRC in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years. (B recommendation)The decision to initiate low-dose aspirin use for the primary prevention of CVD and CRC in adults aged 60 to 69 years who have a 10% or greater 10-year CVD risk should be an individual one.”
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This blog entry has abbreviated/summarized this terrific presentation; most of the material has been covered in this blog in prior entries but still this was a useful review. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.
3rd Lecture: Prevention and management of malignancy in IBD –Dr. Thomas Ullman
Malignancy risk (colorectal cancer [CRC]) is present with prolonged ulcerative colitis, though more recent studies have shown lower risk than in the past –not much higher than the general population.
- CRC surveillance–colonoscopy monitoring after 8-10 years. Typically colonoscopy every other year for most patients, every year in higher risk patients (eg. PSC).
- Unclear if chemoprevention is effective (5-ASA, thiopurines, others).
- Chromoendoscopy “has not been consensus on its use in our field (yet).” It is time consuming and expensive and unclear if it will improve outcome.
Does medical therapy for IBD predispose to developing cancer?
- Thiopurines increase the risk of malignancy. (Pasternak et al) though the risk returns to near baseline when stopped according to study below.
- No overall increased risk with anti-TNF agents with RCTs (may not follow patients long enough) but also not seen in Danish registry either (JAMA study)
No increased risk of malignancy in this study with Anti-TNFs
- Lymphoma risks: age, immunodeficiency, EBV
- EBV negative are at risk for HLH with thiopurines
- HTSCL ~200, >90% men and >90% <35 years. NOT EBV-related. Has not been identified in anti-TNF monotherapy.
- Skin cancer –main concern is in non-melanoma skin cancer (possibly melanoma too). Skin cancer increase has not been noted with methotrexate. Prevention: Skin care, and annual dermatology visits.
- Cervical cancer—likely increased risk in IBD, probably due to thiopurine exposure and reduced immune surveillance. Prevention: HPV vaccination, Pap testing.
- Urinary Tract cancers –especially in those >65 years with thiopurine exposure
A useful article (AF Peery et al. Gastroenterol 2015; 149: 1731-41) provides data on the huge impact that GI & Liver diseases have.
Here are some key findings:
Leading GI symptoms (Ambulatory visits) in 2010 (Table 1):
- Abdominal pain 27.1 million
- Diarrhea 5.6 million
- Vomiting 5.5 million
- Nausea 4.7 million
- Bleeding 3.6 million
Most Common Diagnosis from Hospital Admissions in 2012 (Table 5):
- GI hemorrhage 507,440 admissions
- Cholelithiasis with cholecystitis 389,180 admissions
- Acute pancreatitis 275,170 admissions
- Intestinal obstruction 256,775 admissions
- Appendicitis 248,080 admissions
- Chronic liver disease/viral hepatitis 243,170 admissions
Causes of Death in U.S. in 2012 (Table 7):
- Colorectal cancer 51,139
- Pancreatic cancer 38,797
- Liver/bile duct cancer 22,973
- Cirrhosis 17,495
- Alcoholic liver disease 17,419