Surprising Genetic Mutations in Polyposis Study

A recent cross-sectional study (PP Stanich et al. Clin Gastroenterol Hepatol 2019; 17: 2008-15, editorial 1942-44) identified a high frequency of genetic mutations among adults with at least 10 colonic polyps (cumulative burden of either adenomatous or hamartomatous).

This study had 3789 subjects who underwent multigene panel testing (MGPT) from 2012-16.

  • All subjects had at least 14 CRC-associated genes tested: APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53
  • A subset had 3 more newly recognized polyposis genes: GREM1, POLD1, and POLE

Key findings:

  • A mutation in at least 1 gene was found in 13.7%
  • In those with fewer than 20 cumulative adenomas, 7.6% had a disease-associated genetic mutation with the majority (5.3%) being nonpolyposis CRC genes
  • Younger patients, 18-29, were more likely to have mutations in any gene.  For example, among patients with 10-19 polyps, these younger patients had a mutation in one of these genes in 27.8%; this is more than double the rate in any other age group.
  • Hamartomatous polyps, regardless of number, had a very high yield with genetic testing: 40% with 10-19 polyps and 72% with 20-99 polyps.

Limitations:

  • There is a referral bias in that the population was derived from a testing laboratory (Ambry)
  • In clinical practice, genetic testing frequently results in variants of unknown significance

My take: This study shows that genetic mutations are fairly frequent in patients with cumulative polyp burden of 10 or more, especially in younger age groups.  The surprising finding is the high frequency of nonpolyposis CRC genes.  Thus, in patients with adenomatous polyposis, testing beyond APC and MUTYH may be needed.

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Atlanta Botanical Garden

#NASPGHAN19 Postgraduate Course (Part 1)

Here are some selected slides and notes from this year’s NASPGHAN’s postrgraduate course.  My notes from these lectures may contain errors in omission or transcription.

Link to the full NASPGHAN PG Syllabus 2019

8:00 – 9:00 Module 1 – Endoscopy

11  David Brumbaugh, MD, Children’s Hospital Colorado  Management of foreign bodies

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22 Petar Mamula, MD, Children’s Hospital of Philadelphia Advanced endoscopic techniques for gastrointestinal bleeding

This talk had some terrific videos (not available in syllabus) and useful practical points.  For example, with cautery, the speaker recommended not just quickly taping the lesion, count for several seconds when applying.  For hemospray, the speaker considers this technically much easier but is using this mainly as a backup option.

Here are two screenshots (not from lecture) which provide information from manufacturer on Hemospray use (link to PDF on Hemospray Manufacturer’s PDF on Hemospray)

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36 Srinadh Komanduri, MD, Northwestern Medicine  Cancer screening top to bottom

Some of the key points:

  • IBD and colorectal cancer (CRC) screening 8-10 years after disease onset
  • ~10% of CRC in general population occurs between 20-49 years
  • Chromoendoscopy results in higher detection rates of dysplasia

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Disclaimer: NASPGHAN/gutsandgrowth assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. The discussion, views, and recommendations as to medical procedures, choice of drugs and drug dosages herein are the sole responsibility of the authors. Because of rapid advances in the medical sciences, the Society cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. Some of the slides reproduced in this syllabus contain animation in the power point version. This cannot be seen in the printed version.

IBD Briefs August 2019

A Levine et al. Gastroenterol 2019; 157: 440-50.  This study found that a Crohn’s Disease Exclusion Diet plus partial enteral nutrition induced sustained remission in a 12-week prospective randomized controlled trial with 74 children.  At week 12, “76% of 37 children given CDED plus PEN were in corticosteroid-free remission compared with 14 (45.1%) of 31 children given” EEN followed by PEN.  The associated editorial on pages 295-6 provides a useful diagram of various dietary therapy components for a large number of diets that have been given for IBD.  The editorial recommends:

“For now, simple dietetic recommendations such as consuming a well-balanced diet prepared largely from fresh ingredients and thereby avoidance of emulsifiers and additives and processed foods are appropriate for all patients.  In select patients,…a trial of dietary therapy alone with a diet such as CDED could be attempted for a short period of time, with close follow-up, and with agreement with the patient that failure to fully respond is an indication to escalate therapy.”  More dietary trials are ongoing.

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NJ Samadder et al Clin Gastroenterol Hepatol 2019; 17: 1807-13. In this cohort from Utah 1996-2011 with 9505 individuals with IBD, 101 developed colorectal cancer.  Standardized incidence ratio (SIR) for CRC in patients with Crohn’s disease was 3.4, in ulcerative colitis 5.2, in patients with primary sclerosing cholangitis 14.8.  A family history of CRC increased the risk of CRC in patients with IBD to 7.9 compared to general population.  Family hx/o CRC increased the SIR by about double the CRC risk in IBD patients without a family hx/o CRC.

CR Ballengee et al. Clin Gastroenterol Hepatol 2019; 17: 1799-1806. In this study with 161 subjects from the RISK cohort, the authors found that elevated CLO3A1 levels in subjects with CD was associated with the development of stricturing disease but was not elevated in those with strictures at presentation and in those who did not develop  strictures.

AL Lightner et al IBD 2019; 25: 1152-68.  Short- and Long-term Outcomes After Ileal Pouch Anal Anastomosis in Pediatric Patients: A Systematic Review.  This review included 42 papers.

  • Rates of superficial surgical site infection, pelvic sepsis, and small bowel obstruction at <30 days were 10%, 11%, and 14% respectively.
  • Rates of pouchitis, stricture, chronic fistula, incontinence and pouch failure were 30%, 17%, 12%, 20% and 8% respectively with followup between 37-109 months.
  • Mean 24-hour stool frequency was 5.

MC Choy et al IBD 2019; 25: 1169-86.  Systematic review and meta-analysis: Optimal salvage therapy in acute severe ulcerative colitis.  Among 41 cohorts (n=2158 cases) with infliximab salvage, overall colectomy-free survival was 69.8% at 12 months.  The authors could not identify an advantage of dose-intensification in outcomes, though this was used more often in patients with increased disease severity, “which may have confounded the results.”

Hood River, OR

Five Ways to Lower the Risk of Colon Cancer

A recent study (PR Carr, et al. Gastroenterol 2018; 155: 1805-15) used an ongoing population-based case-control DACHS study (in Germany since 2003) to determine the effects of lifestyle factors on the risk of colorectal cancer (CRC).

Among 4092 patients with CRC and 3032 control patients without CRC, the investigators examined five factors:

  • Smoking – For smoking, one point was given for being a nonsmoker or a former smoker with <30 pack years.
  • Alcohol consumption –  For alcohol, a point was garnered if consumption was moderate according to AICR recommendations.
  • Diet –  Diet quality was assessed based on WCRF/AICR recommendations (supplement table 1 [https://doi.org/10.1053/j.gastro.2018.08.044]). 1 point was given with highest diet scores.
  • Physical activity – A point was given with favorable physical activity which was based on moderate-intensity aerobic exercise for at least 150 minutes per week or 75 minutes of vigorous activity.
  • Body fatness – Those with a BMI between 18.5 and 25 which was considered a healthy weight were awarded a point.

 Key findings:

Compared to patients with 0 or 1 healthy lifestyle factor:

  • Participants with 2 points had odds ratio of 0.85
  • Participants with 3 points had odds ratio of 0.62
  • Participants with 4 points had odds ratio of 0.53
  • Participants with 5 points had odds ratio of 0.33

My take (borrowed from authors): Overall, 45% of CRC cases could be attributed to these lifestyle factors.  This occurred despite the patient’s genetic profile

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Screening for Colorectal Cancer in Cystic Fibrosis

Briefly noted:

A Gini, et al. “Cost Effectiveness of Screening Individuals with Cystic Fibrosis for Colorectal Cancer” Gastroenterol 2018; 154: 556-67.

  • Key point: “Colonoscopy every 5 years, starting at age of 40 years was the optimal colonoscopy strategy for patients with cystic fibrosis” without prior organ transplantation.

D Hadjuliais, et al. “Cystic Fibrosis Colorectal Cancer Screening Consensus Recommendations: Gastroenterol 2018; 154: 736-45.

  • There are 10 Task Force recommendations. These include “initiation of screening at 40 years” in those without organ transplantation. Among those who have had organ transplantation, CRC screening is recommended at age 30 years and/or within 2 years of transplantation. Link: Abstract

My take: Fortunately, more individuals with cystic fibrosis are living long enough to benefit from CRC screening.  Due to increased risk, these guidelines recommend screening at a younger age than the general population.

More pics from Hoover Dam. The figure in this picture is a art piece honoring those who died while working on the construction

 

Why Does Primary Sclerosing Cholangitis Increase the Risk of Colorectal Cancer in Ulcerative Colitis?

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.

Key finding:

  • 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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Colorectal Cancer: Of Mice and Microbiota

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.

Key findings:

  • 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

Therapeutic Drug Monitoring: Ustekinumab (Stelara)

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.

Key findings:

  • 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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Diet, Meat, and Colorectal Cancer

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.

Key findings:

  • 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

Colorectal Adenomas

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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Colonic adenoma