Page 57 – Practical Gastro

Anna Patsy,

Adriana Panciu,

Nizar Senussi

Patients requiring long term parenteral nutrition (PN) may choose to travel at some point. Traveling with PN requires collaboration among the patient, prescriber, and the infusion pharmacy. Coordination of PN deliveries and supplies, as well as managing clinical concerns and safety, must be addressed prior to traveling. Self-monitoring, as well as necessary lab tests must be coordinated to effectively monitor electrolytes and hydration. Knowing how to reach their providers and where medical facilities are located in the event that an emergency should arise is important. While traveling with PN can sometimes be challenging to coordinate, it should not discourage medically stable patients from doing so. This article provides suggestions to clinicians to help their HPN patients travel safely.

Anna Patsy, MS RD LD CNSC, Home Nutrition Support Clinician, Cleveland Clinic, Digestive Disease & Surgery Institute. Cleveland, OH Adriana Panciu, PharmD BCNSP, Nutrition Support Pharmacist, Cleveland Clinic, Center for Connected Care, Independence, OH Nizar Senussi, MD, Liver Care Network, Swedish Medical Center, Seattle, WA

INTRODUCTION

Home Parenteral Nutrition (HPN) is often used in patients with intestinal failure, or others unable to consume or absorb nutrients.¹ HPN may be short or long term, depending on the patient’s condition, underlying disease state and future plan of care. Since patients on HPN are typically hooked up to their infusions 10-14 hours, patients often inquire about the ability to travel with PN. Many HPN patients do travel and count on their health care team to provide guidance on how to plan their travel around their PN infusions.

As a clinician, it is important to identify the method of travel, final destination as well as the duration of the trip. A travel letter signed by the patient’s HPN physician, stating the need for their medical supplies, can be provided for air travel at the patient’s request (see Table 1). It is important that patients contact their infusion pharmacy about their upcoming travel well in advance of travel dates. Infusion pharmacies play an integral role in providing accommodations for travel. If a patient is going to be traveling to multiple locations during a trip, the patient’s infusion pharmacy may need to arrange for multiple pharmacies or branches to service the patient throughout their travels. While traveling with HPN may be a challenge, it can certainly be done with proper preparation.

Case Presentation

A 35 year old female reports that she is going on a 10 day trip next month. She will be flying to her travel destination. She has many questions regarding if and how she can travel with HPN, as she has not done so before. She is concerned about keeping the bags refrigerated during her travels. She has been on the home nutrition service for 6 months and is currently getting weekly labs drawn due to high stoma output related to short bowel syndrome. Her labs have been relatively stable for some time now. It is difficult for her to always time her anti-diarrheal agents (loperamide, diphenoxylate-atropine, codeine, etc.) 30-60 minutes prior to meals. Additionally, she will be traveling south to a warmer climate. She has a single lumen Hickman catheter and is independent with dressing changes. After finding out that she cannot swim in the ocean due to her Hickman catheter, she is disappointed, but looking forward to swimming in the chlorinated pool at the hotel (Note: prescribing physicians vary on their willingness to approve their HPN patient swimming in a public facility). The patient, PN prescriber, and infusion pharmacy must all collaborate and be informed of travel plans. Good communication is crucial, especially if the HPN solution needs to be altered for traveling.

Clinical Concerns

Discussing the signs and symptoms of dehydration along with electrolyte abnormalities is important. Review with the patient that if they develop any of the following:

Signs and symptoms of electrolyte abnormalities/dehydration
Signs of infection, (fever, or shakes and chills during their infusion)
Central line occlusion/damage, etc.

They should report to the closest emergency room (ER) for evaluation. Travelers should always know where the closest ER is should something unexpected happen. Identifying location of hospitals along travel route in advance would also be beneficial to the traveler. Patients should be able to reach their PN prescriber and infusion pharmacy while they are traveling.

It is helpful to know if a patient is traveling to a warmer climate so that steps can be taken to prevent dehydration. Additional liter bags of appropriate intravenous (IV) fluids would be beneficial to have on hand during their travels. It is not uncommon for patients to express that traveling with HPN bags is quite cumbersome (each bag can weigh up to 10 pounds). They may be concerned about refrigeration or the amount of space they can take up in a vehicle due to pumps and necessary supplies (see Figure 1 for an example of PN supplies for one week).

Patients traveling will need to ensure that they have enough of their oral prescriptions, such as anti-diarrheal agents, anti-secretory agents, etc.; prior to leaving for their trip and the name and phone number of a pharmacy close to their destination should they need something called in. A word document with all medications used, dose and frequency is a good idea for patients to keep readily available in their wallet. The patient may also work with the pharmacy to create a list of supplies needed including a backup infusion pump and even a copy of their HPN prescription should they require admission while away.

Monitoring

Laboratory draws are sometimes changed to accommodate travel plans. There are some patients who are so stable they do not require weekly lab draws anymore. However, if labs are unstable, labs will need to be ordered for the patient locally, if possible. Locating an outpatient center/lab where labs can be drawn prior to travel is important. Most outpatient labs will accept orders from an out-of-state physician. However, home care nursing services may require an in-state physician to provide orders for lab draws and dressing changes.

Infusion Pumps and Supplies

Patients may carry intravenous (IV) fluids that can be administered in an emergency without using a pump. For example, via gravity or controlled rate infusion device such as a tubing set, with or without drip chamber and control clamps that adjust the rate of infusion. In this situation, patients will need to carry a collapsible IV pole with them for ease of transportation.

Patients may arrange for their usual infusion pump, along with a backup pump, to be shipped to their final destination on the day of their arrival or in advance (note comments by HPN travelers regarding this issue in Tables). Prior to the trip they can confirm that their pump made it to its destination and is secured for them to use upon arrival. If this cannot be accomplished with their own infusion company, plans can be made with another infusion company to deliver their infusion pump and tubing sets to patient’s travel destination. This pump may be a different brand than the patient’s usual infusion pump, and training may be necessary. Some patients transfer their infusion service to a national company while traveling, then transfer back to their original company upon returning home. Those that travel frequently may want to select a national company that can provide consistent service wherever they are.

Planning ahead will save patients the trouble caused by the unexpected, but sometimes this may not be enough. In order to prevent damage to the HPN bags, it is recommended to pack them correctly in coolers (as instructed by the home care pharmacy), maintain the proper temperature (36-46 degrees Fahrenheit) by using a thermometer to monitor temperature during transportation, mark the coolers and boxes as fragile/ handle with care, and take them on the same flight with the traveler, etc. Correct packing includes sealing PN bags in plastic overwrap and laying air bubble sheets in between bags. Cooler size should allow all cooler space to be used, including enough ice packs for the duration of the transportation. A “keep refrigerated” sticker should be in place, as well as a seal that identifies that the cooler has not been tampered with. Packing one or more PN bags separately as a carry on is a good idea, so that back up bags are available in case any are damaged in transit.

In the event that PN bags are damaged during transport, patients should be educated to obtain replacement bags by contacting the home infusion pharmacy as soon as possible. PN bags can be shipped to their destination in advance of their arrival and arrangements may be made to re-send them in case the shipment did not arrive or arrived damaged and deemed not safe for use. It is prudent for patients to carry contact information for their physician, pharmacy and nursing agency for fast and easy communication with their healthcare team. Depending on the duration of travel, the home nursing agency may stop services and require a new referral upon the patient’s return.

Premixed multi-chamber PN products are manufacturer-prepared PN solutions that may or may not include lipids, depending on the brand. These solutions are stable at room temperature for up to two years.² The ingredients of premixed solutions are in separate chambers that are combined when the patient is ready for administration. They are available in preset volumes (1-2.6 liters depending on solution and manufacturer). For patients with excessive GI losses and high potassium requirements, special consideration should be given to choosing a pre-mixed solution. Supplementation with oral electrolytes may also be an option in maintaining serum levels if deemed appropriate given the patient’s anatomy and absorptive capacity. If premixed multi- chamber PN solutions are used, the patient may need additional training to ensure ability to activate all sections of the bag. This should be done before the trip so that he/she is ready for administration during their trip.

Once compounded, PN is stable for only 9 days, hence longer trips will require multiple shipments. The pharmacy may choose to send these via shipping carriers such as UPS or FedEx for overnight or same day delivery. Keep in mind that the ideal temperature for storing PN is 36-46 degrees Fahrenheit, hence, the providing pharmacy or the patient will pack PN in insulated coolers and use ice packs during transit. Although ice packs may melt during transportation, the PN will be safe to use as long as it remains between 36-46 degrees Fahrenheit. Another option may be to use portable electric coolers if the patient travels by car.

Prior to arriving at their final destination, patients will need to request or confirm a refrigerator for their room that has been turned on and cooled properly. Many small refrigerators come with thermostats that display the temperature as a range from cool to coldest, rather than degrees. Monitoring the temperature is crucial for the stability of the PN solution as it becomes unstable and not usable if it freezes. Electric thermometers are relatively inexpensive and may be used for monitoring the temperature of PN while in transit and/or in small or portable refrigerators.

Information about security checkpoint screening policies and procedures for medical supplies and prescriptions can be obtained by calling the Transportation Security Administration’s helpline, or TSA Cares, at 1-855-787-2227, or by visiting their website: www.tsa.gov/travel.³ While not required, making arrangements for any special assistance in advance of the travel will help patients have a less stressful, smooth and enjoyable trip. Patients traveling for the first time with PN may wish to contact TSA with additional questions or concerns. A signed travel letter (Table 1) should be available to present to TSA staff to get through security with PN supplies and a central catheter.

Depending on the infusion pharmacy’s policy, the pharmacy will pay for the transport of PN only to those states where the pharmacy is licensed. If the pharmacy is not licensed in the state where their patient will travel, with the patient’s consent, the pharmacist can assist in finding a local company and arrange for the smooth transition of patient’s care to that company upon patient’s arrival and until patient returns home. These arrangements may include finding another infusion pharmacy (see Table 2), home care nursing agency, laboratory, sometimes even a local ordering physician that are ideally in the patient’s health insurance network, as some states require that the ordering physician be licensed in that state. Coordination of who will transfer prescriptions /HPN solution, etc. will need to be determined well in advance of travel (a month is a good goal), and communication with the health care providers identified to assume temporary care during travel will need to be arranged between all parties involved.

Some pharmacies may be part of a national specialty group or nationwide company and may have a partner pharmacy in the state where their patient is traveling. In this case, the transition may be easy to facilitate; it is recommended that patients check with their pharmacist regarding this possibility.

Swimming

Patients often inquire about swimming with a central line in place. The existing literature is inconsistent and there are no evidence-based guidelines or consensus recommendations. A review article identified a lack of consistency regarding swimming with a central line across various HPN programs.⁴ Some programs do not permit swimming at all, while others allowed swimming in chlorinated pools. All programs recommended site care and dressing change after swimming. The length of time that the catheter must be in place prior to swimming differed among HPN programs. The nurses in the Cleveland Clinic Home Nutrition Support Service use the following physician guidance to educate patients:

“Swimming is not recommended with a peripherally inserted central catheter (PICC) or with an accessed port; swimming in a chlorinated pool is acceptable with tunneled catheters in place for >1 month. Regardless of the catheter type, swimming in hot tubs, lakes, streams, or the ocean, or other natural body of water is not recommended. Those with a de-accessed port may participate in all water-related activities with no restrictions. Patients traveling with PN should either know how to change their own dressing (with the exception of a PICC), or have a caregiver or outpatient location set up for dressing changes. Should the dressing become wet or soiled, it should be changed immediately.”

Case Study Continued

The patient was able to arrange with her infusion pharmacy to ship the PN supplies to the hotel, since the pharmacy was able to transfer service to the company’s branch at her destination. The pharmacy shipped 9 bags of PN and 7 bags of IV fluids in case she would need additional fluids during her stay. The local pharmacy branch servicing her would need to make a second delivery to the patient at her hotel during her stay. She did not need to obtain labs on her trip, as the trip was 10 days in duration and she has been stable on PN for a long time. Lab results and home care would resume as usual upon her return from her vacation.

CONCLUSION

PN should not be a limitation to travel? It just requires some additional planning. Advance planning ensures a smooth transition back to the local pharmacy upon patient’s return home. See Table 3 for the steps to take when a patient plans to travel with PN. Clear communication between the pharmacies and prescribers involved including the most current PN orders, recent lab results, new referral to the nursing agency for restart of services upon returning home, supplies needed, and when to send them, and any changes in the place where patient will stay locally. For those with additional questions, patients can utilize the resources available from the Oley Foundation5 (see Table 4). Resources include travel tips, guidelines on swimming, and information to network with other people who are well versed in traveling with PN. Tips from PN patients that frequently travel can be found in Table 5.

The Microbiome And Disease, Series #1

The Microbiome and Clostridium Difficile

Sabine Hazan,

Daniel Frochtzwajg,

Jessica Murray

A new, emerging paradigm suggests that the susceptibility, severity, and duration of some diseases, even some previously thought to be independent of microbial involvement, are mediated by a complex interplay of host and microbe genomes. Already, nearly 10 million different microbial genes have been isolated from the human gut. In this series, we aim to shed light on some of the most promising research to date that addresses the intestinal microbiome as it relates to common chronic diseases.

Sabine Hazan, MD Daniel Frochtzwajg, DO Jessica Murray, BS Ventura Clinical Trials, Ventura, CA

INTRODUCTION

Cdifficile is a gram-positive, spore forming bacillus that is an obligate anaerobe and has been identified as one of the most common causes of nosocomial infection in the developed world, causing mild to severe cases of diarrheal illness to life-threatening pseudomembranous colitis and toxic megacolon,³ with increasing incidence over the last decade.^2,4 C. difficile infection (CDI) risk factors include extended hospital stay, protracted antibiotic regimens, other illnesses and comorbidities, and age greater than 65 years.¹ In addition to the logistic complications of identifying, diagnosing, and containing infections in a hospital, and even community setting, there is substantial cost incurred as a result of CDI and the high risk of recurrent infection. In The Economic Impact of Clostridium difficile Infection: A Systemic Review, Nanwa et al. analyzed 45 cost-of-illness (COI) studies and determined that, for hospitalized patients, CDI costs range from $8,911 to $30,049.¹¹ For decades, the standard treatment of CDI included antibiotic therapy with either metronidazole or vancomycin, however, even with the development of tapered or pulsed antibiotic regimens demonstrating improvement in recurrence rates, still some 14-31% of patients would experience repeat bouts of CDI.¹⁰ Furthermore, the risk of recurrent infection increases with every subsequent infection and by the third episode, rates become greater than 50%.^4,10 Despite medical professionals’ increased awareness of the burden of CDI, there is still no consensus on treatment regimens and no standardized optimal approach to treating recurrent CDI exists.

The solution to the worsening burden of CDI may exist in the intestinal microbiome. There is already substantial evidence that fecal microbiota transplantation (FMT), the implantation of either a patient’s own stool (autologous transplant) or healthy donor stool (heterologous transplant) into a patient with gut dysbiosis caused by CDI, is a preferable alternative to traditional antibiotic therapy.⁷ A 2013 review and meta-analysis in the American Journal of Gastroenterology demonstrated that FMT resulted in resolution of infection in nearly 90% of patients affected by recurrent CDI.^6,9 To reiterate the ideas addressed in our introduction, the suggestion of a mechanism of action is the restoration of the healthy composition of an individual’s intestinal microbiome. In addition to its efficacy, FMT presents an almost adverse event free means of cure. While some adverse events, including fever, abdominal pain, bloating, nausea, vomiting, diarrhea, flatulence, anorexia, and constipation have been reported after FMT, there have been no severe adverse events and no death attributable to FMT alone.8 Earlier research suggested that lower gastrointestinal FMT delivery resulted in high rates of clinical resolution than oral capsular implantation.⁶ However, in a very recent randomized controlled trial by Kao et al published in the November 2017 issue of JAMA, rates of minor adverse events were as low as 5.4%.⁵ In the same study, Dr. Kao demonstrates the noninferiority of oral capsule FMT to colonoscopy-delivered FMT, an important finding given that the colonoscopic method was reported as less pleasant than the capsule.⁵ Not only are delivery methods for FMT being refined, but models for the risk of FMT failure in the treatment of CDI have been developed. In Predictors of Early Failure After Fecal Microbiota Transplantation for the Therapy of Clostridium difficile Infection: A Multicenter Study published in the American Journal of Gastroenterology, Fischer et al. define risk score based on severity of CDI, number of CDI-related hospitalizations prior to FMT, and inpatient status.⁴ Although standard algorithm for the use of FMT as a treatment for recurrent CDI does not yet exist, this risk calculator will help to guide physicians as the use of FMT is pioneered.

The microbiome and its associations with disease states, and hence its potential to offer insight into new cures is in a fledgling state.

Introduction To A New Series: The Microbiome And Disease

The Microbiome and Disease

Sabine Hazan

INTRODUCTION

TO A NEW SERIES: THE MICROBIOME AND DISEASE Sabine Hazan, MD Ventura Clinical Trials, Ventura, CA

Simply and elegantly defined by Lynch and Pedersen in their December 2016 article in the New England Journal of Medicine, a microbiome is the collection of all genomes of microbes in an ecosystem.³ In the context of human beings and our health, it is the vastly diverse genetic information observable in the microbes colonizing the distal GI tract. Historically, the study of human microbiology has been one of a singular relationship cause and effect, microbe and infection, and our approach to treating the disease states caused by pathogenic bacteria and viruses has been one of nearly indiscriminate eradication. The problem inherent in this approach is that no microbe is an island. A new, emerging paradigm suggests that the susceptibility, severity, and duration of some diseases, even some previously thought to be independent of microbial involvement, are mediated by a complex interplay of host and microbe genomes. Already, nearly 10 million different microbial genes have been isolated from the human gut.² With the use of contemporary, culture – independent tools for analyzing fecal microbiota, e.g., biomarker sequencing, metagenomics, metatranscriptomics and metabolomics, the genetic diversity will likely continue to expand rapidly.³

Starting at birth and continuing throughout human life, commensal microorganisms function to aid in the development of temporally favorable phenotypes.

For example, in preadolescents, the gut microbiota is relatively rich with organisms that augment vitamin B12 and folate synthesis, promoting growth.¹ In adulthood, the intestinal microbiota remains comparatively constant in composition.⁴ In addition to biosynthesis, the gut microbiota influences immune maturation, host cell proliferation, vascularization, neurologic signaling, endocrine function, bone density, drug and food metabolism.³ Considering the seemingly global influence on host function, it is but a small leap to infer that the intestinal microbiome has indications for disease, and in turn, that interventions in microbiome makeup could aid in the treatment of disease states identified to correspond to specific dysbiosis. Despite the wealth of research to date, there are obvious limitations to our current understandings of the human microbiome and its implications in human health and disease. There are also limitations to even the most contemporary of research methods and study techniques. For example, patient stool samples are assumed to be accurately representative of intestinal microorganism content and, despite there being robust research evidence connecting changes in the microbiome to disease states, there have been few, if any, studies elucidating the biochemical mechanisms responsible for the changes in disease states with microbiome intervention.³

Many factors affect the composition of the gut microbiota. Diet, genetics, antibiotics and other medications, environment, and even geography result in differences in individual host microbiome.^1,3

In this series, we aim to shed light on some of the most promising research to date that addresses the intestinal microbiome as it relates to common chronic diseases.

Inflammatory Bowel Disease: A Practical Approach, Series #104

Management of the Ileal Pouch-Anal Anastomosis in the Elderly

Irving Levine,

Shannon Chang

The ileal pouch-anal anastomosis (IPAA) has become standard of care in maintaining fecal continence after colectomy. Select elderly patients are now candidates for IPAA surgery. When caring for these patients, many of the medications prescribed for management of pouchitis or diarrhea should be used with caution, with or without dose adjustments. Other special considerations in the elderly population include history or use of radiation therapy, dysplasia surveillance, and sphincter dysfunction. In this article, we review the medical management and functionality of pouches in the elderly population.

The ileal pouch-anal anastomosis (IPAA) has become standard of care in maintaining fecal continence after colectomy. Elderly patients are able to undergo IPAA surgery safely with similar functional outcomes compared to those of younger patients. Overall, elderly patients with IPAA report satisfaction and high quality-of-life scores. When caring for the elderly patient with IPAA, many of the medications prescribed for management of pouchitis or diarrhea should be used with caution, with or without dose adjustments. Other special considerations in the elderly population include history or use of radiation therapy, dysplasia surveillance, and sphincter dysfunction.

Irving Levine, M.D. NYU Langone Health, Department of Medicine Shannon Chang, M.D. NYU Langone Health, Inflammatory Bowel Disease Center, Division of Gastroenterology, New York, NY

INTRODUCTION

The ileal pouch-anal anastomosis (IPAA) is the surgery of choice for patients requiring total proctocolectomy who wish to maintain continence. First described in the 1970s by Drs. Parks and Nicholls, multiple types of “pouches” may be fashioned including the “J,” “S,” “W” and “K” pouches. The most frequently created pouch is the “J-pouch,” irrespective of the indication for total proctocolectomy (eg, medically refractory ulcerative colitis or intermediate colitis, familial adenomatous polyposis syndrome (FAP), dysplasia or malignancy in inflammatory bowel disease). The creation of a pouch allows patients to maintain fecal continence and avoids the need for a permanent ileostomy.

Select elderly patients are now candidates for IPAA surgery. In this article, we review the medical management and functionality of pouches in the elderly population.

Pouch Creation in the Elderly

Initially, the IPAA surgery was reserved for younger patients, with the belief that older patients would have poorer surgical outcomes. However, recent studies demonstrate that postoperative complications from pouch formation are not specifically linked to age at the time of surgery,¹ with safety, functionality, and improvement in quality of life demonstrated even in patients over the age of 70 years.²

The age that defines “elderly” in the medical literature is highly variable, with age cutoffs ranging from 45 to 65 years of age.^1,3-7 Given evidence of successful IPAA formation in the elderly, end ileostomies are decreasing in patients ages 61 to 70.⁴ We suggest that age alone should not constitute an absolute contraindication to pouch surgery. Rather, the overall health, functional status, and sphincter function of the patient should be considered. Detailed specific pre- operative discussions regarding expectations of quality of life after IPAA should focus on risks of surgery, postoperative bowel frequency, risk of pouchitis, and potential incontinence.

Pouch Function Over Time

Up to 30 years after pouch creation, 93% of patients with pouches report continued functionality, defined based on daytime and nocturnal bowel movements.⁸ However, there may be slight changes in pouch functioning over time. For example, patients report an increased number of bowel movements per day, with an average of 5.7 daily bowel movements at 1 year increasing slightly to 6.2 daily bowel movements at 30 years. Nocturnal bowel movements also increase in frequency, on average, from 1.5 to 2.1 bowel movements. Stool quality changes, with higher numbers of patients reporting liquid stools. These changes may occur within the initial 5 years after pouch formation but stabilize thereafter.⁸ Despite these changes in bowel frequency and consistency, quality-of-life scores remain stable over time, as most patients remain satisfied with their pouch. As patients with pouches age, small changes in bowel habits are expected with preservation of overall pouch function. Any significant changes in pouch function should prompt an evaluation for infection, pouchitis, mechanical disorders, or sphincter dysfunction.

Pouchitis

Pouchitis, an inflammatory condition of the pouch, is the most commonly reported complication after pouch creation. Patients often present with a constellation of nonspecific symptoms such as increased stool frequency, liquid stool, tenesmus, abdominal cramps, and pelvic pressure. The pathogenesis of pouchitis has not been fully elucidated but likely relates to an aberrant immune response to changes in mucosal bacteria.

There is a reported lifetime risk of 80.2% of developing pouchitis after IPAA.⁸ Interestingly, patients who have a pouch and diagnosis of FAP have less pouchitis than patients with underlying autoimmune diseases such as ulcerative colitis. Most patients with pouchitis will have self-limited episodes. However, a small number of patients will progress to chronic pouchitis, requiring long-term therapy.

Differentiating pouchitis from other infectious or inflammatory conditions is of paramount importance. Clostridium difficile infection should be ruled out when patients present with symptoms suspicious for pouchitis.

The mainstay of initial treatment for acute pouchitis includes antibiotics, most commonly ciprofloxacin (500 mg by mouth twice daily), metronidazole (500 mg by mouth every 8 hours), or dual therapy with ciprofloxacin and metronidazole (Table 1). Common side effects of metronidazole include nausea, vomiting, dysgeusia, headache, and occasionally dizziness. Tinidazole, also a nitroimidazole, may be better tolerated than metronidazole. Rifaximin and tinidazole are utilized as second-line treatment for pouchitis, partially due to insurance obstacles or high co-pay and need for prior authorization. For patients with recurrent antibiotic- dependent pouchitis, treatment with mesalamines (5-ASAs), thiopurines such as 6-mercaptopurine (6MP) or azathioprine, or biologics may be necessary, though there is very limited high-quality data available (Figure 1). The highest quality evidence in one report supports use of probiotics such as VSL#3 for secondary prophylaxis.⁹

Medical Management of IPAA in the Elderly Patient with Common Medical Comorbidities

Elderly patients commonly take medications that may need to be adjusted in the setting of common medical comorbidities such as cardiac arrhythmias, heart failure, renal insufficiency, hepatic impairment, malignancy, and neurologic conditions. We review different medications used in patients with pouches, focusing on potential dosing adjustments and contraindications for the elderly (Tables 1, 2, and 3).

Treatment of Pouchitis in the Elderly

Adjustments to pouchitis treatment regimens may be necessary in the elderly patient. Moreover, potential side effects of medications may be more pronounced in the elderly. Close monitoring for polypharmacy (stopping medications that may be superfluous) is necessary. Elderly patients with renal or hepatic dysfunction require adjustments to antibiotics dosing (Table 1). Ciprofloxacin dosing should be adjusted in patients with renal impairment. In patients with end-stage renal disease (ESRD), ciprofloxacin should be given after dialysis. Additionally, ciprofloxacin is known to cause tendinopathy and tendon rupture and must be used with caution in the elderly population. Ciprofloxacin may also predispose patients to Clostridium difficile infection. Elderly patients may suffer from particularly virulent strains of Clostridium difficile.¹⁰

Metronidazole metabolites accumulate in patients with ESRD, and therefore patients should be monitored for adverse events, including headache, nausea, as well as rare adverse reactions, including central nervous system, gastrointestinal, genitourinary and pulmonary side effects. For patients with severe hepatic impairment (Child-Pugh Class C), the use of extended-release metronidazole is not recommended. Furthermore, metronidazole may cause peripheral neuropathy, a particularly hazardous side effect in an elderly population already prone to neuropathy and gait disturbances. While the neuropathy associated with metronidazole is often reversible with discontinuation of the drug, it may take years for complete reversal of symptoms.¹¹

Rifaximin requires no adjustments for renal impairment. In patients with severe hepatic impairment (Child-Pugh Class C), rifaximin has increased systemic exposure and therefore should be used with caution. However, no dose adjustments are recommended as rifaximin is presumed to act locally. Also of note, rifaximin is commonly used for treatment of portosystemic encephalopathy in cirrhotic patients.

When pouchitis is refractory to antibiotic therapy or patients develop a contraindication (eg, Clostridium difficile infection) or intolerance to antibiotics, current treatment options for pouchitis revert back to the conventional medications used to treat IBD (Figure 1). Mesalamines (5-ASAs), immunomodulators (azathioprine, 6-mercaptopurine), corticosteroids, or biologic therapy have all been used with limited evidence and success in antibiotic-refractory pouchitis. Adjustments to IBD medications may be warranted in elderly patients who have had IPAA and have renal disease, hepatic impairment, or with concomitant medications (Table 2).

Oral and topical 5-ASAs have been shown in limited small studies to improve symptoms of pouchitis.¹² However, the topical use of mesalamine enemas and suppositories may be more challenging for the elderly patient with decreased dexterity, impaired mobility, or sphincter dysfunction. Renal function should be monitored while on 5-ASAs given the risk of interstitial nephritis (Table 2).

Immunomodulators, such as azathioprine and 6-mercaptopurine (6MP), have been shown in small studies to improve symptoms of pouchitis as well as facilitating tapering of steroids.¹² Thiopurine methyltransferase (TPMT) activity should be checked before initiation of a thiopurine to gauge risk of leukopenia and hepatotoxicity. After starting a thiopurine, a complete blood count (CBC) and hepatic panel should be checked twice monthly for the first several months. Doses of both immunomodulators should be decreased based on creatinine clearance. If the patient suffers from gout and is taking allopurinol or febuxostat, two inhibitors of xanthine oxidase, the dose of azathioprine or 6MP should be decreased by 50 to 75% to avoid myelosuppression. Potential serious risks of pancreatitis, skin cancer, and lymphoproliferative disorders or more common side effects of nausea, vomiting, malaise, and photosensitivity should be taken into account before starting an elderly patient on an immunomodulator.

Biologic medications can be used in cases of antibiotic-refractory pouchitis, particularly if an underlying autoimmune process is suspected to be driving the symptoms. As the tumor necrosis factor alpha inhibitors (anti-TNF’s) have been in use longer than the anti-integrin vedolizumab, there is more data available regarding the use of TNFs for antibiotic- refractory pouchitis,¹³ but vedolizumab also has reported efficacy in pouchitis with a good safety profile.^14,15

Anti-TNF medications, while safe for use in the elderly, should be used with caution. Patients taking anti-TNFs may develop a severe infection, a complication that is increased fivefold in the elderly.¹⁶ Anti-TNFs should be avoided in patients with advanced heart failure (New York Heart Association Class III or IV) and in those with demyelinating disorders.

Vedolizumab, approved for IBD in 2014, appears safe in elderly patients,¹⁷ though studies promoting its use in the elderly have been limited in numbers.¹⁸ However, there appear to be no signals for increased risk of infection or malignancy associated with vedolizumab. Adverse events with vedolizumab may include nasopharyngitis, headache, arthralgias.

Medical Management of Diarrhea with IPAA

A major function of the colon is water reabsorption, and as such, the stool of patients with IPAA typically will be watery or soft. Several over-the-counter medications for diarrhea are routinely used to manage the frequency and consistency of bowel movements in patients after IPAA. These medications are relatively safe but must be used with caution in the elderly (Table 3).

Loperamide, a frequently used anti-diarrheal medication, is a locally acting opioid receptor agonist that inhibits peristalsis and has been reported to increase internal sphincter tone.¹⁹ Though rarely reported, loperamide may cause cardiac conduction abnormalities, including both QRS and QT prolongation, at very high doses.²⁰ Providers should monitor the patient’s QT interval, particularly if the elderly patient is known to have a prolonged QT interval or is taking other QT- prolonging medications.

Diphenoxylate-atropine, another anti-diarrheal agent, is a centrally acting opioid. The anticholinergic effects of atropine can cause side effects including dizziness, nausea, palpitations. Anticholinergic side effects are augmented in the elderly.²¹

Cholestyramine, a bile-acid sequestrant, may bind medications intraluminally and decrease serum concentrations of certain medications (e.g. atorvastatin, furosemide, propranolol).

Tincture of opium, another anti-diarrheal agent containing morphine, inhibits gastrointestinal motility and decreases digestive secretions. Tincture of opium should be used cautiously in the elderly, as it may cause central nervous system depression and hypotension, specifically in patients with cardiovascular disease.²²

Other Potential Concerns in the Elderly
Radiation and Pouch Function

Elderly patients are more likely than younger patients to have a history of radiation therapy. Radiation therapy, commonly part of treatment for prostate and endometrial cancer, is associated with acute and chronic toxicity to the gastrointestinal tract.²³ Pelvic radiation therapy alters pouch function, irrespective of whether radiation therapy preceded or came after pouch surgery. In patients who have had radiation after pouch formation, studies have demonstrated decreased pouch capacity and compliance, worsened pouch function, and increased potential for radiation-related pouchitis.^23,24 Among patients who receive radiation therapy prior to pouch formation, there is increased risk for chronic pouchitis and pouch failure.^25,26 While these findings do not represent a contraindication for the combination of pouch formation and radiation therapy, we do recommend an informed discussion to address the potential deterioration of pouch function that may occur with radiation therapy.

Sphincter Dysfunction

Aging may be associated with incontinence or fecal seepage. Some of the proposed mechanisms for worsening anorectal function in the elderly include thinning and atrophy of the anal sphincters, decreased rectal sensation, and decreased length of anal sphincter.²⁷ Additionally, the decreased volume of skeletal muscle predisposes elderly women to pelvic floor dysfunction and prolapse, as the remaining tissue fails to support the pelvic and abdominal organs.²⁸

The IPAA surgery itself has been associated with decreased anal sphincter pressure.²⁹ As such, patients with suspected anal sphincter dysfunction, pelvic floor dysfunction, or patients with a history of obstetrical complications, are at risk for partial or complete incontinence after pouch surgery. In cases of mild incontinence despite control of pouchitis symptoms, patients can be referred for anorectal manometry and possible biofeedback therapy.

Dysplasia Surveillance

The role of dysplasia and malignancy screening in patients who have undergone IPAA remains controversial. Neoplasia may develop in the retained rectal “cuff”or anal transition zone (ATZ), as well as within the pouch itself. The rate of colitis-associated dysplasia or cancer after IPAA is low. At 25 years after IPAA creation, the cumulative incidence of pouch neoplasia (dysplasia or malignancy) either at the anal transition zone (ATZ) or pouch body has been reported to be 5.1%, with an increased risk of pouch neoplasia in patients with a preoperative diagnosis of cancer or dysplasia.³⁰ However as patients’ pouch lifespans extend into the third and fourth decades, it remains to be seen whether the incidence of pouch neoplasia will increase. Current recommendations for dysplasia screening in patients with IPAA range from no screening at all to routine screening with stool DNA markers and imaging enhanced endoscopy.^30-33 It is our practice to do surveillance pouchoscopy yearly in patients with a history of neoplasia.

CONCLUSION

Despite the risk of potential complications, elderly patients with IPAA have reported a similar acceptable quality of life compared with younger patients with IPAA. However, in contrast to the less complicated, younger patient, elderly patients with IPAA are a special subset of patients who require extra consideration. Elderly patients frequently have more comorbidities and are at risk for polypharmacy and drug-drug interactions. Attention to the selection of medications and modification of traditional doses in elderly patients is needed to avoid adverse events. Prior history of the use of radiation therapy or sphincter dysfunction may further complicate treatment decisions. Patients with an IPAA and a history of dysplasia should undergo routine pouchoscopy surveillance.

A Case Report

Complicated Metastatic Melanoma to the Gastrointestinal Tract

November 2017 • Volume XLI, Issue 11

Joseph P. Kingsbery,David M. Poppers

Joseph P. Kingsbery, M.D. New York University, Department of Gastroenterology David M. Poppers, M.D., Ph.D., NYU Preston Robert Tisch Center for Men’s Health, Consultant/Educator for Olympus

INTRODUCTION

Metastatic melanoma to the gastrointestinal (GI) tract poses a unique clinical challenge. Previously believed to be rare, many patients have metastatic disease on autopsy yet rarely demonstrate GI symptoms.¹ In the era of targeted immunotherapy capable of rapidly reducing the size of space-occupying lesions in the GI tract, case reports of bowel perforation have emerged as previously unforeseen complications of treatment.^2,3 The following case of a patient treated with immunotherapy for malignant melanoma with known GI metastases highlights the importance of clinical evaluation prior to initiating potent immunotherapy and risk-stratifying patients due to potential treatment complications.

Case

A 57-year-old man presented with complaints of post- prandial epigastric abdominal pain for the past month as well as an unintentional 5-pound weight loss. His past medical history was unremarkable. His physical exam revealed a normal abdominal exam without tenderness to palpation or palpable masses. Initial laboratory studies were remarkable for an aspartate transaminase (AST) of 56 (units/L), alanine transaminase (ALT) of 65 (units/L), and alkaline phosphatase of 192 (IU/L), with a normal bilirubin, international normalized ratio (INR) and platelet count. He was seen by a gastroenterologist, and an upper endoscopy and colonoscopy were planned to evaluate his abdominal pain. In the interim, an abdominal ultrasound demonstrated multiple large, hypovascular peritoneal masses. Subsequent contrasted computed tomography scan of the abdomen and pelvis revealed innumerable tumor implants in the peritoneal cavity, mesentery, retroperitoneum and peritoneum with nodal metastases, a serosal implant in the pancreas as well as peri-and intra-gastric lesions (Figure 1). The primary site was unidentifiable.

The upper endoscopy revealed medium-sized, infiltrative mass lesions in the body of the stomach (Figure 2), as well as suspected external compression of stomach lumen; biopsies were taken of each lesion. Colonoscopy showed an infiltrating, non-obstructing 1 cm mass in the transverse colon (Figure 3) as well as a non-eroding lesion at the ileocecal valve and likely external compression of the cecum. Pathology from the lesions was consistent with malignant melanoma, BRAF wild-type. Staging was therefore reported as TxNxM1c with metastases to the lung, peritoneal cavity, peritoneal and mesenteric lymph nodes, pancreas, colon and stomach.

The patient was begun on combination PD-1 inhibitor (nivolumab) and CTLA-4 inhibitor (ipilimumab). His disease and treatment course were complicated by subsegmental pulmonary emboli, medication-induced pneumonitis, partial colonic obstruction by tumor burden, ongoing GI bleeding and septic shock secondary to a presumed intra-abdominal source. He ultimately died roughly two months after initial presentation; an autopsy was not performed.

Discussion

It is now recognized that malignant melanoma commonly metastasizes to the gastrointestinal tract, infrequently causing symptoms.^1,4,5 Upon autopsy of 100 patients with cutaneous melanoma without GI symptoms, over half had metastatic lesions in the small intestine, and roughly a quarter had lesions in the stomach and colon.¹ Gastrointestinal metastases portend a poor prognosis, with survival averaging 4-6 months.⁴ For symptomatic disease, including intussusception and obstructive symptoms, consensus is that surgical intervention is indicated for palliation.^5,6,7,8 However, there is no current recommendation to investigate for GI tract disease in asymptomatic patients as this typically does not alter clinical management.⁵

However, with the development of more targeted therapies for melanoma, specifically with biologic therapy including PD-1 or CTLA4 inhibitors, case reports have emerged identifying bowel perforation as a complication of a robust response to these potent therapies.^2,3 In the age of targeted immunotherapy, it is possible that asymptomatic lesions may cause unforeseen treatment complications. Whether or not GI disease should be investigated or ruled out prior to treatment with these new agents remains to be elucidated. It does seem clinically prudent that such patients should be screened carefully for any symptoms of GI involvement prior to initiating immunotherapy to risk stratify for these events, which may be devastating if not entirely preventable.

Frontiers In Endoscopy, Series #40

EUS-Guided Fiducial Placement – Role and Use in Clinical Practice

November 2017 • Volume XLI, Issue 11

Douglas G. Adler

Fiducial markers are used throughout medicine as a means of precisely localizing structures for diagnosis, treatment, imaging and other uses. In gastroenterology, fiducial markers are almost always placed via EUS, which allows precise placement of fiducial markers. In this article, we discuss the history, effectiveness and safety of the use of EUS guided fiducial placement to help precisely target therapy.

CASE REPORT

Douglas G. Adler MD, FACG, AGAF, FASGE, Professor of Medicine, Director of Therapeutic Endoscopy. Director, GI Fellowship Program, Gastroenterology and Hepatology. University of Utah School of Medicine, Huntsman Cancer Center, Salt Lake City, UT

A 55 year old man developed abdominal pain and underwent an abdominal CT scan with IV contrast. An ill-defined 4x3cm pancreatic head/genu mass was seen. The patient was referred for an endoscopic ultrasound (EUS). EUS revealed a large, hypoechoic, solid mass in the pancreatic head with abutment of the superior mesenteric vein (SMV) and the portal vein (PV). There was also a small degree abutment of the superior mesenteric artery (SMA). EUS-guided core biopsy was positive for adenocarcinoma. The patient was given a stage of T4N0M0 pancreatic cancer and underwent chemotherapy with FOLFIRINOX. Radiation therapy was consulted given the small amount of abutment of the SMA by the tumor and requested that gastroenterology place fiducial markers in the tumor at this location to help precisely target radiation therapy. On EUS the lesion manifested as a modestly hypoechoic solid lesion. (Figure 1) Using a preloaded EUS fiducial system, 4 gold fiducial markers were placed into the tumor under EUS and fluoroscopic guidance via a transgastric approach. (Figures 2 and 3) The patient tolerated the procedure well and there were no adverse events. The patient was referred back to radiation oncology for treatment.

Discussion

Fiducial markers are used throughout medicine as a means of precisely localizing structures for diagnosis, treatment, imaging, and other uses. In gastroenterology, fiducial markers are almost always placed via EUS. EUS allows precise placement of fiducial markers in tumors of the chest, abdomen, and pelvis as well as in lymph nodes in many locations. The fiducial markers can be left in place in patients with incurable disease or removed at the time of surgery along with the target organ or structure.

The use of EUS to place fiducial markers started over a decade ago.¹ Early studies used fiducial markers designed to be placed by radiologists or radiation oncologists and modified them for use in 19 gauge EUS needles. A variety of off-label approaches to keep the fiducials in the FNA needle until the precise time they were to be deployed were developed, often involving the use of bone wax to seal the tip of the needle after the fiducials were loaded.

In 2010, Park et al. reported on EUS guided fiducial placement in 50 patients with pancreatic cancer without the assistance of fluoroscopy. It should be noted that these authors attempted the procedure in 57 patients, but only had 50 successes. The authors used sterile water injection to pass the fiducials through a 19 gauge needle. The authors felt that fluoroscopy placement was not required for safe fiducial placement.² Also in 2010, Ammar et al. reported on a series of 13 patients undergoing EUS guided fiducial placement via 22 gauge needles, showing that the smaller needle size could potentially allow access to placing fiducials at a wider range of locations than allowed by the stiffer 19 gauge needle.³

Little has been written about the adverse events of EUS guided fiducial placement, likely because only a few centers have significant familiarity and experience with this technique. Sanders et al. reported on 51 patients with pancreatic cancer who underwent EUS guided fiducial placement prior to stereotactic body radiotherapy (SBRT). In this study, one patient developed post-procedure pancreatitis but this patient also underwent EUS guided celiac plexus neurolysis in the same session, so it is unclear if the pancreatitis was due to the fiducial placement, the neurolysis or some combination thereof.⁴ Drahdam et al. reported on a large series of 514 patients who underwent EUS guided fiducial placement and noted that minor bleeding was seen in two patients and two fiducials migrated as noted on follow up CT scans, further arguing for the safety of this technique.⁵

While most papers on EUS guided fiducial placement focus on pancreatic adenopcarcinoma, other have reported placement into the prostate, the celiac ganglia, other pancreatic tumors, and other sites.^6,7,8,9,10

Few comparative trials of different types of fiducials placed via EUS exist. Khasab published a comparative study of tradiational 5mm long, 0.8mm wide fiducials versus coiled fiducials measuring 10mm x 0.35mm. The authors looked at technical success, adverse events, visibility of fiducials and migration of fiducials after placement via different needle types (19 gauge and 22 gauge). Thirty-nine patients with pancreatic cancer underwent EUS-guided placement of 103 different types of fiducials (77 tradiaional fiducials versus 26 coiled fiducials). The mean number of fiducials that were placed in each patient was 2.66 (standard deviation 0.67) for the 19g needle and 2.60 (standard deviation 0.70) for the 22g needle (P = .83). There were no adverse events. The authors felt that the visible of the traditional fiducials was superior to that of the coiled fiducials. The rate of migration was not significantly different between traditional and coiled fiducials.¹¹

Recent years have seen the development of preloaded EUS fiducial needle systems as opposed to loading fiducials into existing off-the-shelf FNA needles. These preloaded devices provide an all-in- one needle kit to simplify ordering, as most GI labs do not have experience in purchasing fiducial markers. It is unknown if the preloaded devices work any better than traditional hand loaded devices, but they appear to be time and labor saving devices given the reduced need for set-up prior to the procedure.

One factor that has hampered the widespread use of EUS guided fiducials is that many endosonographers did not receive training in this technique as fellows. Furthermore, many institutions do not routinely utilize fiducials for GI tumor therapy (depending on the type of radiation therapy being delivered) so even high volume endosonographers may have only limited experience with this technique.

Overall, EUS guided fiducial placement appears to be a simple, effective, and safe technique to place fiducial markers into a variety of lesions to help precisely target therapy, most commonly radiation therapy.

Treatment of Hepatitis C in Patients with Compensated and Decompensated Cirrhosis

November 2017 • Volume XLI, Issue 11

Elie Ghoulam,

Nancy Reau

Hepatitis C virus (HCV) treatment of compensated and decompensated cirrhosis differs because of the marginal hepatic function, increased mortality and high risk of complications in decompensated cirrhosis. Before the development of oral direct acting antivirals (DAAs), treating patients with decompensated cirrhosis was not an option. This article will address the management, the most recent recommended treatment and post cure monitoring of patients with compensated and decompensated HCV cirrhosis.

The course of chronic hepatitis C virus (HCV) progression can take decades and differs among individuals. Many patients are unaware of their HCV infection and some will develop only mild inflammation and fibrosis of the liver. Yet, a significant number of these patients will develop cirrhosis, decompensated cirrhosis and hepatocellular carcinoma (HCC). Many studies have shown that attaining sustained viral response (SVR) in both groups decreases all cause mortality and reduces the risk of HCC development. HCV treatment of compensated and decompensated cirrhosis differs because of the marginal hepatic function, increased mortality and high risk of complications in decompensated cirrhosis. Before the development of oral direct acting antivirals (DAAs), treating patients with decompensated cirrhosis was not an option. This article will address the management, the most recent recommended treatment and post cure monitoring of patients with compensated and decompensated HCV cirrhosis.

Elie Ghoulam MD, MS Post-Doctoral Research Fellow, Section of Hepatology, Rush University Medical Center, Chicago, IL Nancy Reau, MD Professor of Medicine Chief, Section of Hepatology, Associate Director, Solid Organ Transplantation, Rush University Medical Center, Chicago, IL

INTRODUCTION

Hepatitis C virus (HCV) was previously identified as non-A non-B hepatitis until its existence was proven in 1989.¹. Hepatitis C is a contagious, blood borne, ssRNA virus and exists in multiple genotypes.² Risk factors for acquiring include injection drug use, inadequate sterilization of medical equipment and transfusion of unscreened blood and blood products.³ HCV can also be transmitted sexually and vertically, but these modes of transmission are less efficient. Globally, 130-150 million people have HCV.³ According to the Centers for Disease Control and Prevention (CDC), an estimated 3.2 million people in the United States (USA) are living with chronic hepatitis C infection, many of whom are unaware of their infection.4 There is a high seroprevelance of HCV infection in persons born from 1945-1965, one-half of whom already had severe fibrosis or cirrhosis based on a study by Klevens et al. This data prompted the CDC to recommend one- time hepatitis C virus antibody testing in this group of people.^5,6

The course of chronic HCV disease progression occurs over decades and is varied among individuals.⁷ Factors that impact disease progression are older age, male gender, diabetes, obesity, steatosis, iron overload, genotype 3, alcohol intake and human immunodeficiency virus (HIV) or hepatitis B (HBV) coinfection.^8,9,10 Over the first 20 years of infection, most patients do not develop liver disease beyond inflammation and moderate fibrosis.10 A percentage of these patients will then progress to cirrhosis, possibly decompensated or symptomatic, and HCC.8 The chances of developing decompensated cirrhosis in the cirrhotic populations are 11.7% with a four-year survival of 50%. The risk of developing HCC is 1%-5% annually.^8,11

Hepatitis C therapy has evolved significantly since first using interferon and ribavirin. This evolution has allowed the expansion of therapy to groups of individuals previously without treatment options. Although, even in the interferon era, individuals with well compensated cirrhosis could contemplate therapy, there were occasions of decompensation and significant toxicity. All-oral options have now made therapy commonplace for those with asymptomatic cirrhosis and an option to consider in those with decompensation.

The clinical benefit of viral eradication in those with advanced liver disease has been unarguably established through several long-term observational trials. Development of cirrhosis, decompensation and HCC are all considerably reduced after sustained viral response (SVR) with either interferon based or all oral direct acting antiviral (DAA) therapy. The rate of liver transplant wait-listing for HCV secondary to decompensated cirrhosis has decreased by 32% as a result of DAA therapy.¹² Not only has there been demonstrable benefit to liver-related mortality, but all- cause mortality is also improved with viral eradication.¹³ However, clinicians still need to be aware that not all patients with cirrhosis are the same. Those with symptomatic cirrhosis (decompensated cirrhosis) are at higher risk for adverse events and drug toxicity. Historically, treatment of this group of individuals was contraindicated. As the toxicity and efficacy of therapy improved, we have been able to expand therapy to increasingly sicker patients, although the benefit of doing so remains controversial.

Recognizing Cirrhosis

Our guidance recommends staging each patient with hepatitis C.14 Cirrhosis can be quite subtle, and can easily be missed.

Cirrhosis

Cirrhosis is defined as the late stage of progressive hepatic fibrosis characterized by change of hepatic architecture and the formation of regenerative nodules.¹⁵ In its advanced stages it is considered to be irreversible, but in its earlier stages it may improve or even reverse if specific treatments aimed at the underlying etiology of liver disease are addressed.¹⁶

Signs and symptoms of cirrhosis can be nonspecific such as anorexia, weight loss, weakness, fatigue or signs and symptoms of hepatic decompensation such as jaundice, pruritus, upper gastrointestinal bleeding, abdominal distension from ascites and confusion due to hepatic encephalopathy.¹⁶

Physical findings consist of spider angiomatas, palmar erythema, gynecomastia, testicular atrophy, amenorrhea, parotid/lacrimal gland hypertrophy, Dupuytren’s contractures, clubbing and jaundice.¹⁶

Laboratory abnormalities may be striking such as elevated serum bilirubin or coagulopathy. However, laboratory findings may be subtler such as a platelet count &tl;150 or AS>ALT. Several clinical calculators can help identify those at higher risk for cirrhosis such as APRI or FIB4.¹⁷

Diagnosis

If cirrhosis is evident clinically (nodularity on imaging, splenomegaly, low platelets, ascites, encephalopathy, jaundice, etc.), no further assessment is required. However, most patients with advanced disease lack these clinical cues. Several non-invasive means have been validated to assess for fibrosis. All have diagnostic utility, yet a combination of concordant serum markers and elastography is felt to have the most reliability outside of biopsy.14

Compensated vs Decompensated Cirrhosis

Patients who develop complications of cirrhosis are considered to have decompensated cirrhosis and those who have not developed major complications are classified as having compensated cirrhosis.¹⁸ The median survival of patients with compensated cirrhosis is >12 years.¹⁸ Patients that develop varices but not variceal bleeding are still considered as having compensated cirrhosis but have a 2.1 percent increase in one-year mortality.¹⁸ Several factors can predispose to decompensation in a patient with cirrhosis. Risk factors include bleeding, infection, alcohol intake, medications, dehydration, obesity and constipation.^19,20

Predictive Models

Two predictive models, the Child-Pugh classification (CP) and Model for End-Stage Liver Disease (MELD) score, are most commonly used today in attempt to predict the prognosis of cirrhotic patients. Based on clinical and laboratory information, these models have been derived from multiple studies.^21,22

Child-Pugh Classification

The variables included in the CP classification are the serum albumin and bilirubin, ascites, encephalopathy and prothrombin time. The score ranges from 5 to 15. Patients with a score of 5 or 6 have Child-Pugh class A cirrhosis (well-compensated cirrhosis), those with a score of 7 to 9 have Child-Pugh class B cirrhosis (significant functional compromise) and those with a score of 10 to 15 have Child-Pugh class C cirrhosis (decompensated cirrhosis).²¹

The Child-Pugh classification system is not only used in staging of cirrhosis but has been found to correlate with survival of patients not undergoing surgery with decrease survival rates as you progress from Child-Pugh A to C.²³ It is also associated with likelihood of developing complications of cirrhosis. Child-Pugh C patients are much more likely to develop variceal bleeding for example than Child-Pugh A.²⁴

MELD Score

Another model to predict prognosis in patients with cirrhosis is the MELD score 22. Based on bilirubin levels, creatinine, INR and the etiology of cirrhosis, the MELD score has been adopted for use in prioritizing patients awaiting liver transplantation and has an expanding role in predicting outcomes in patients with liver disease in the non-transplantation setting as well. In January 2016, Organ Procurement and Transplantation Network Policy 9.1 (MELD Score) was updated to include serum sodium as a factor in the calculation of the MELD score 25. The MELDNa score can be calculated online.

Consider Consequences of Cirrhosis

Individuals with advanced liver disease are at risk for complications of portal hypertension and liver cancer. Once cirrhosis is recognized, it is advised to obtain abdominal imaging with ultrasonography to screen for hepatocellular cancer (HCC). If ultrasound is of poor quality, cross sectional imaging should be done.

Ascites may be clinically evident, but is not infrequently identified first on imaging done for liver cancer screening. The development of ascites carries significant impact on prognosis, decreasing expected 5-year survival to <60%. If the ascites is refractory to diuretics, associated with dilutional hyponatremia or type 2 hepatorenal syndrome (HRS), the anticipated 1-year survival is 30%.²⁶

Several clinical algorithms exist to help identify those cirrhotics that are at higher risk for complications of portal hypertension. Those individuals with liver stiffness scores <20 kPa and serum platelet count >150,000/ mm³ are unlikely to have high-risk varices. Recently updated AASLD guidelines²⁷ recommended performing an upper endoscopy to evaluate for gastroesophageal varices for all individuals that do not meet those criteria. If high-risk for bleeding (the presence of medium/large varices), primary prophylaxis with either non-selective beta-blockers or band ligation should be initiated.

Other routine health maintenance includes vaccinating against hepatitis A (HAV), hepatitis B, yearly influenza and avoidance of hepatotoxins. Patients with a CP score of >7 or MELD score >18 are at high risk for complications and should be co-managed by an experienced clinician.²⁸

HCV and Genotypes and Treatment

Although pan genotypic therapy exits, the genotype of HCV remains an important variable as this may determine the efficacy and duration of therapy.¹⁴

Treatment of HCV in Patients with Compensated Cirrhosis

Individuals with HCV cirrhosis that lack symptoms (ascites, variceal bleeding, coagulopathy, jaundice, encephalopathy) are considered compensated. The Child-Pugh Class (CP) can be used to confirm prognosis. CP A is considered well compensated.²⁹

No therapeutic agent is contraindicated in a patient with compensated cirrhosis, however certain regimens are recommended depending on genotype and treatment experience. Recommended regimens are generally prioritized due to shorter duration and the omission of ribavirin (RBV) to achieve higher efficacy. The most up to date therapeutic recommendations can be found in the American Association for the Study of Liver Disease/ Infectious Disease Society of America (AASLD/ IDSA ) guidance document.¹⁴ Table 1 summarizes the recommended and alternative, or not recommended, treatment choices for treatment naïve and treatment experienced (exposed to interferon, ribavirin or sofosbuvir) patients with cirrhosis.

Treatment of HCV with Decompensated Cirrhosis

The treatment of patients with CP class B or C cirrhosis is controversial, as most will require liver transplantation for optimal long-term survival. In patients who are not transplant candidates, the goal is to achieve SVR with the hope that there will be an improvement in clinical condition. For patients who are transplant candidates, the goals are not as straightforward. SVR before transplantation prevents re-infection of the new liver which could improve post-transplant outcomes and survival of the graft.^14,30 However, viral eradication pre- transplant prevents the use of HCV exposed organs and treatment post-transplant is safe and effective.

Marginal hepatic function limits treatment options. In the era of IFN-based therapies, treatment in decompensated cirrhosis was contraindicated.31 All-oral therapy has significantly better efficacy and safety, however drug toxicity must still be considered. Although safe and effective in CP class A, protease inhibitors are not advised for those with CP class B/C cirrhosis.

Accordingly, the AASLD, IDSA and the European Association for the Study of the Liver (EASL) guidelines recommend only all-oral DAA regimens containing sofosbuvir, ledipasvir, daclatasvir and RBV as show in Table 2.³¹

Individuals with decompensated cirrhosis are at high risk for complications. It is advised that treatment should be performed by a highly experienced medical practitioner, preferably associated with a transplant center.^14,30

Post-Cure Monitoring

It is important to recognize that although SVR substantially lowers the risk of progression or liver cancer, it does not eliminate this risk. All patients with cirrhosis, despite demonstration of regression by biopsy or non-invasive measurements, still require longitudinal follow-up. Liver cancer screening remains necessary as risk for malignancy remains. Recent analysis of a large Veterans Administration (VA) database demonstrates that age, gender and diabetes increase this risk.³²

CONCLUSION

Compensated HCV cirrhosis has excellent long-term prognosis and a chance of reversal if SVR is attainable. Decompensated cirrhosis carries high risk of mortality and should be performed by highly experienced HCV providers. Early referral for transplant for patients with CTP >7 and MELD >18 is key for better patient outcomes as early treatment of HCV can prevent many life threatening complications and reduce HCC risk.

A Case Report

A Rare Finding of Colonic Malakoplakia

October 2017 • Volume XLI, Issue 10

Jordan Orr,Mohamed Shoreibah,Ali Ahmed

Jordan Orr, MD Mohamed Shoreibah, MD Ali Ahmed, MD The University of Alabama at Birmingham, Birmingham, AL

INTRODUCTION

Malakoplakia is a rare chronic inflammatory disease characterized by granulomatous formation from dysfunctional bacterial clearance by neutrophils and macrophages.1 Originally described in 1902, these inflammatory collections are characterized by a histiocytic infiltrate with round intracytoplasmic inclusions named Michaelis-Gutmann bodies.2 Since first discovered, the number of reported cases of malakoplakia is less than 500 in the United States.3 Malakoplakia is classically associated with the genitourinary tract but is also seen in the gastrointestinal (GI) tract, the second most common site of occurrence.4 Malakoplakia is largely an incidental finding, however colonic malakoplakia is particularly concerning because of its close association with colon adenocarcinoma.

Case Report

A 45-year-old female Jehovah’s Witness patient with a history of living donor kidney transplant (lupus nephritis) was admitted for further evaluation of a two-month history of rectal bleeding and severe symptomatic anemia resulting in weakness, tachycardia and general malaise. She denied hematemesis, melena, abdominal pain, nausea and vomiting but did report a five kilogram (11 lb) weight loss over the previous year. Her medication list included three immunosuppression drugs for her transplant (mycophenolate, tacrolimus and prednisone). Her admission labs revealed a hemoglobin (Hb) level of 6.2 gm/dL (MCV 76 fL), which decreased to 5.1 gm/dL after fluid resuscitation, and a creatinine (Cr) of 1.7 (baseline Cr 1.3). She refused red blood cell transfusion, in keeping with her religious beliefs. During her subsequent hospitalization, her hemoglobin improved with IV iron supplementation, darbepoetin alfa and limited blood draws.

Because of continued rectal bleeding and profound anemia she underwent endoscopic evaluation. Esophagogastroduodenoscopy (EGD) revealed a normal upper gastrointestinal (GI) tract without any source of bleeding. Colonoscopy revealed a large pedunculated polyp (2-3 cm, adenoma) in the proximal transverse colon and multiple small to large polyps (1-2.5 cm) in the remaining colon. Additionally, the mucosa in the rectosigmoid colon appeared nodular. Internal hemorrhoids were also found and was presumed to be the source of her lower GI bleed. Routine hematoxylin and eosin (H&E) stain of the colonic biopsies revealed numerous intramucosal macrophages with some showing nuclear changes compatible with Michaelis- Gutmann bodies, consistent with malakoplakia (Figure 1, Figure 2).

She remained hemodynamically stable following endoscopy, with improvement of her hemoglobin and resolution of her acute kidney injury, and was discharged from the hospital. Empiric antibiotic therapy (levofloxacin and azithromycin) was initiated as an outpatient upon biopsy result findings. Repeat colonoscopy four months after initial evaluation revealed normal appearing ascending and transverse colon, unlike previous colonoscopy, with a small sessile descending polyp (tubular adenoma). Infectious work up was negative for rhodococcus, tropheryma whipplei, mycobacterium tuberculosis, Epstein-Barr virus, and cytomegalovirus, however she was found to have high blood levels of BK virus by PCR. It was recommended that she return for surveillance colonoscopy in 12 months.

Discussion

Colonic malakoplakia, first reported by Terner and Lattes in 1965, is a rare manifestation of this chronic inflammatory condition.4 Malakoplakia can be seen throughout the entire GI tract and gives the gross appearance of mucosal plaques or nodules that are tan to yellow.4,5 This appearance gives rise to its name as it is derived from the classic Greek work “malacos” meaning soft and “placos” meaning plaque.5 These lesions can cause abdominal pain, diarrhea, hemorrhage and obstruction, however they are largely asymptomatic and rarely diagnosed clinically.3 Diagnosis is established histologically by determining the presence of large “Hansemann macrophages” which contain the Michaelis-Gutmann inclusions.1

The pathogenesis of malakoplakia is not well understood, but it has been proposed to be the result of an unusual infectious organism, an abnormal or altered immune response or an abnormal macrophage response due to defective lysosomal function.4 Escherichia coli has been identified as the most common bacterial pathogen, found in over 90% of affected patients, however other chronic bacterial infections, such as Proteus mirabilis, Staphylococcus aureus, Klebsiella spp, Mycobacterium Tuberculosis and Shigella boydii, have also been observed in malakoplakia.1,4 Malakoplakia has also been reported in association with coliform bacteria in patients on chemotherapy and Rhodococcus equi in patients with acquired immunodeficiency syndrome.5 Malakoplakia is closely associated with an impaired immune response, specifically organ transplant patients receiving immunosuppression to prevent organ rejection. Approximately 40% of malakoplakia cases that did not involve the urinary tract were associated with immunosuppression.6 Colonic malakoplakia has been reported in three cases with liver transplant, one case with cardiac transplant and five cases with kidney transplant from 1994-2010.1 Most significantly, malakoplakia is associated with colon adenocarcinoma. A review found 95 published cases of colonic malakoplakia, 24 of which had coexistent colonic adenocarcinoma.4 An early report found an association between malakoplakia of the GI tract and colorectal carcinoma in more than 30% of patients examined, however it appears to be an incidental finding in close proximity to the carcinoma in a majority of cases.5 Malakoplakia is also rarely associated with colonic adenoma, as seen in our case.2 It is unclear if malakoplakia is a precursor to tumor or if it is an inflammatory response in conjunction with tumor.5 Currently there are no additional recommended guidelines for colon cancer screening or surveillance.

Treatment for malakoplakia is not fully understood, but case reports demonstrate successful treatment with ciprofloxacin and lowering immune suppression. [6]

The significance of malakoplakia, a seemingly incidental finding, is not fully understood; however it is important to monitor patients with colonic malakoplakia because of its close relationship with colon adenocarcinoma.

Acknowledgements

We would like to thank Leona Council, MD, Assistant Professor, Division of Anatomic Pathology/Department of Pathology at The University of Alabama at Birmingham and Jessica Tracht, MD for providing expert opinion and pathology microphotographs.

A Special Article

A Practical Approach to Managing Inpatient Acute Severe Ulcerative Colitis

October 2017 • Volume XLI, Issue 10

Stephanie O. Eschete,

Kara M. De Felice

Hospitalized acute severe ulcerative colitis patients require a multidisciplinary team approach with a focus on early escalation of medical therapy and early surgical consultation. This review aims to provide a practical approach on the treatment of inpatient acute severe ulcerative colitis.

Stephanie O. Eschete, PA-C, Kara M. De Felice, MD Louisiana State University Health Science Center, Department of Gastroenterology, New Orleans, LA

INTRODUCTION

Acute severe ulcerative colitis (UC) is a medical emergency requiring hospitalization and a multidisciplinary team approach involving a gastroenterologist and colorectal surgeon. North American UC cohort studies report that 18 to 25% of patients with UC will experience at least one flare requiring hospitalization.^1,2

Severe UC is defined as having six or more bloody stools per day, tachycardia, fever, anemia (hemoglobin <10g/dL), and elevated erythrocyte sedimentation rate (ESR >30).¹

Intravenous (IV) corticosteroids are the initial treatment for inpatient acute severe UC, however only two-thirds of patients will respond.3 Predictors of nonresponse to IV corticosteroids are persistence of bloody stools and an elevated CRP on day 3 (≥8 stools/day or 3-8 stool/day plus CRP > 45 mg/L).4 Up to 30% of patients admitted with an acute severe UC flare will require a colectomy. Early medical treatment and surgical consultation have been shown to decrease mortality rates in these patients.³

The purpose of this review is to provide a practical approach (Figure 1.) for the management of inpatient acute severe UC.

Day 1

On initial presentation, the patient should be hemodynamically resuscitated as appropriate.

1. Stool Evaluation for Infectious Pathogens

Patients should have stool samples assayed for Clostridium difficile (C. difficile) and cultured for bacterial pathogens. Patients with inflammatory bowel disease (IBD) concomitantly infected with C. difficile have longer hospitalizations, increase need for colectomy, and higher mortality rates.⁵ The stool sample should be collected first, and if clinical suspicion for C. difficile infection is high, prophylactic oral vancomycin may be initiated. Oral vancomycin should be discontinued if C. difficle is negative. Routine use of antibiotics in the absence of infectious colitis is inappropriate.⁶

2. Laboratory Evaluation

On admission, labs should include complete blood count (CBC), basic metabolic panel (BMP), and albumin. C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) should be ordered to assess disease severity. Some patients may have a normal CRP despite having severe inflammation on endoscopy.

In preparation for possible biologic therapy, one should test for tuberculosis (QuantiFERON-TB Gold and chest x-ray), hepatitis B (hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody), and human immunodeficiency virus (HIV antibody). Some of these tests require several days to result; therefore, it is best to draw them on admission.

3. Abdominal Radiograph

Patients should have a baseline plain abdominal radiograph on admission to help identify conditions that require immediate surgical attention such as megacolon, pneumatosis intestinalis, and perforation. If the patient’s clinical course changes at any time throughout the hospitalization, it is important to repeat the abdominal radiograph and compare it to the initial film.

4. Endoscopic Evaluation

A flexible sigmoidoscopy with biopsies should be done within the first 48 hours to assess disease severity and biopsy for cytomegalovirus (CMV). A bowel preparation and full colonoscopy is unnecessary in the acute setting and can increase the risk for megacolon and perforation.⁷

Biopsies for CMV should be done in the center of the ulceration. The gold standard for diagnosis is immunohistochemistry. CMV is considered significant if more than five inclusion bodies per high power field is seen. The preferred treatment for CMV colitis is IV ganciclovir.⁸

5. Diet

Patients should be allowed a normal diet throughout their hospitalization. There has been no evidence that complete bowel rest or total parenteral nutrition (TPN) improves inflammation or changes disease outcomes.⁹ If a normal diet is not tolerated, enteral nutrition is indicated.

6. Deep Venous Thrombus Prophylaxis

Hospitalization and active inflammation increase an UC patient’s risk for deep venous thrombosis (DVT). In a meta-analysis of eight randomized controlled trials, there was no significant increase in bleeding in patients treated with heparin during hospitalization for acute UC flares.¹⁰ Therefore, despite having bloody stools, all hospitalized UC patients should receive DVT prophylaxis.

7. First Line Medical Therapy

IV corticosteroids (40 mg/day) should be initiated on admission. Studies have shown that there is no evidence to support increasing methylprednisolone beyond 60 mg/day and the benefits do not outweigh the risks when increasing the dose beyond 40 mg/day.³

Patients who fail to respond to IV corticosteroids by day 3, have poor outcomes and should be evaluated for surgery or rescue medical therapy. Steroid nonresponse is defined as ≥8 stools/day or 3-8 stools/day plus CRP > 45 mg/L on day 3.⁴

8. Medications to Avoid and/or Stop During Hospitalization

Aminosalicylates have been shown to cause paradoxical colitis in 3% of patients and therefore should be discontinued on admission.¹¹ Non-steroidal anti- inflammatory drugs (NSAIDs) can cause ulcers, increase risk for gastrointestinal bleeding, and can exacerbate flares and should be avoided.¹²

Narcotics increase morbidity and mortality in IBD patients.¹³ It can also increase a patient’s risk for megacolon. Narcotics are best avoided. Anti-diarrheals can also alter colonic motility and have no role in the treatment of UC.

Day 2
1. Clinical Assessment and Laboratory Evaluation

Clinical response should be assessed based on the trend in the number of stools, blood in stools, and CRP.

2. Colorectal Surgery Consultation

Early colorectal surgery consultation is important. Surgery should be considered as an equal option to rescue medical therapy in a patient who is not responding to IV corticosteroids. Early discussions about all possible options (medical versus surgical) between the patient, colorectal surgeons, and gastroenterologists will ensure optimal patient care.

Day 3
1. Clinical Assessment and Laboratory Evaluation

On day 3, response to IV corticosteroids will help to determine if rescue (medical or surgical) therapy is needed. Those patients that are responding to IV corticosteroids as defined by less than 8 stools per day with an appropriate downtrend in CRP can be switched to oral prednisone (40 mg daily). These patients should be discharged on oral prednisone (40 mg daily) with close outpatient gastroenterology follow up (preferably within one week). At follow up, maintenance therapy should be initiated (biologic and/or immunomodulator) and prednisone should be tapered.

Patients who fail to respond to IV corticosteroids by day 3, as defined by ≥8 stools/day or 3-8 stool/day plus CRP > 45 mg/L, should consider rescue medical therapy versus surgery.⁴

2. Rescue Medical Therapy

Either IV cyclosporine or infliximab is an appropriate choice as rescue therapy for patients who are failing IV corticosteroids and should be given on days 3-5.¹⁴ The choice of medication depends on the center’s expertise. Response should be assessed within 5-7 days after receiving rescue medical therapy.¹⁵ If no clinical response by day 7, surgery is indicated.

Patients who respond to IV cyclosporine should be switched to oral thiopurines for maintenance therapy.¹⁶ Combination therapy with a biologic may be required. Patients who respond to a single infusion of infliximab should complete induction doses at week 2 and week 6 followed by maintenance therapy every 8 weeks. Combination therapy with an immunomodulator should be considered.¹⁷

Low albumin levels and elevated CRP have been associated with lower infliximab serum levels due to rapid drug clearance.¹⁸ Studies have also found that infliximab is lost in the stool in the setting of severe inflammation resulting in lower serum infliximab levels.¹⁹ Therefore, higher and more frequent doses of infliximab may be required in patients with acute severe UC with elevated CRP levels and hypoalbuminemia. A recent retrospective study found that accelerated infliximab dosing (infliximab 5mg/kg, 3 doses within a median of 24 days) was associated with lower rates of colectomy compared to standard infliximab induction doses (infliximab 5mg/kg at week 0, 2, and 6).²⁰

3. Surgical Management

Indications for surgery include toxic megacolon, perforation, massive bleeding, nonresponse to IV corticosteroids by day 3, and nonresponse to rescue medical therapy with cyclosporine or infliximab. The surgery of choice is a total colectomy with end- ileostomy and Hartmann’s pouch.²¹ An ileal pouch-anal anastomosis can be considered three to six months after the initial colectomy.

CONCLUSION

All patients with acute severe UC flares requiring hospitalization should receive IV corticosteroids on admission. C. difficile infection is common and should be treated with oral vancomycin. An early multidisciplinary team approach is critical to ensure optimal patient outcomes. Early rescue medical therapy or surgery is indicated if patients do not respond to IV corticosteroids by day 3. Other biologics have not been thoroughly studied as rescue medical therapies. Future research should aim to characterize the use of other biologic and biosimilar agents in the setting of an acute severe ulcerative colitis flare requiring hospitalization.

Frontiers In Endoscopy, Series #39

Prognostic Biomarkers in Pancreatic Ductal Adenocarcinoma

October 2017 • Volume XLI, Issue 10

Valerie Gausman,

Tamas Gonda

Pancreatic ductal adenocarcinoma (PDAC) carries significant morbidity and mortality and remains one of the most difficult malignancies to treat. Individual patient and tumor factors need to be taken into account to provide an optimal, personalized approach. In this review, we highlight established and novel biomarkers that have the potential to be used as prognostic biomarkers in PDAC and some that may be used to guide therapeutic decisions. We briefly review some blood based biomarkers but focus on those that are tissue based and may be identified and characterized in pancreatic cancer biopsies.

Valerie Gausman, MD, Resident, Department of Medicine, NYU School of Medicine, New York, NY Tamas Gonda, MD, Assistant Professor of Medicine, Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY

INTRODUCTION

Despite major advances in the therapies of many solid tumors, survival in pancreatic ductal adenocarcinoma (PDAC) has not improved.¹ Delayed diagnosis, aggressive biology and marked chemoresistance have all contributed to this disappointing trend. Prognostic biomarkers inform of a likely cancer outcome (disease recurrence, progression or death) independent of type of treatment. A biomarker is predictive if there is a difference in treatment effect for biomarker positive patients compared to biomarker negative patients. General prognostic markers, not specific to a defined therapeutic regimen, can be useful in distinguishing which patients are at higher risk of a poor outcome and should therefore be managed more aggressively. While large gene expression panels have been identified for use in prognostication of other malignancies and some have been linked to therapeutic response, few such markers have been well characterized in pancreatic cancer and even fewer have been used in clinical practice. We provide an overview of the most promising markers and those that may be closest to clinical use.

BLOOD OR SERUM BASED BIOMARKERS
Established Serum Based Biomarkers

There are few established and widely clinically used biomarkers for PDAC compared to other malignancies. Carbohydrate antigen 19-9 (CA 19-9), or sialyl Lewis antigen, is the only biomarker recommended by the National Comprehensive Cancer Network guidelines in the evaluation of PDAC. Its role in carcinogenesis may be related to its association with an increased adherence of cancer cells to endothelial cells through E-selectin,² In addition to its well-known role in the diagnosis of PDAC, higher levels of pre-operative CA 19-9 have been shown to be correlated with advancing stage,³ less resectability,4,5 and decreased survival.^6-8 However, its sensitivity is limited due to 10% of the population being non-secretors of CA 19-9 and its specificity limited due to its secretion by normal biliary epithelium.⁷

Other commonly used pre-operative laboratory markers include carcinoembryonic antigen (CEA), an intercellular adhesion glycoprotein normally present in very low levels in the blood, lactate dehydrogenase (LDH), an enzyme involved in sugar metabolism and C-reactive protein (CRP), an acute phase reactant. Compared to normal levels, elevated LDH,⁹ CEA,^10,11 and CRP^12,13 have all been shown to be independent unfavorable prognostic factors of survival. However, similar to CA 19-9, these laboratory markers are limited in their specificity. Table 1 highlights the accuracy of these markers in distinguishing resectability and prognosticating survival.

Blood or Serum Based
Biomarkers in Development

The value of serum-based markers is their less invasive approach and ability to collect multiple samples for various analyses. The most notable serum-based markers currently under investigation include circulating tumor cells, circulating tumor DNA and microRNAs and are summarized in Table 2.

Metastatic spread is commonly perceived to be one of the latest steps in the progression of cancer; however, the presence of circulating tumor cells (CTCs) in early stages as well as in pre-invasive lesions have challenged this. CTCs are cancer cells that are shed off the primary or metastatic tumor and can travel through the blood stream, potentially leading to new metastasis. A meta-analysis has revealed that the presence of CTCs in PDAC corresponds with worse progression- free and overall survival.⁴¹ A recent study found that cytokeratin-expressing CTCs, but not mesenchymal- like CTCs, had prognostic utility, highlighting the importance of phenotypic identification of CTCs.⁴² The CellSearch system is the only FDA-approved CDC detection technology (since 2004), but it is expensive, requires a complicated enrichment step, has a long detection time, low sensitivity and does not allow for isolation of CTCs for further molecular analyses. Thus, new detection modalities are being investigated including line confocal microscopy, surface-enhanced Raman spectroscopy (SERS), new enrichment technologies and fluorescence in situ hybridization (FISH).^43,44

Cell-free DNA (cfDNA) is another minimally invasive potential sample source that is also referred to as a liquid biopsy. These are small fragments of DNA that are released after cellular necrosis or apoptosis and circulate in the bloodstream; when they are released from tumor cells, they are called circulating tumor DNA (ctDNA). ctDNA is, on its own, a negative prognostic marker,⁴⁵ and it can also be used to identify genetic mutations which can further prognosticate survival in PDAC.⁴⁶ One study looking at ctDNA in a variety of early and late stage malignancies found that ctDNA was detectable in some patients without detectable CTCs (but not vice versa), suggesting that these biomarkers are separate entities.⁴⁷

The majority of the human genome is made up of non-coding RNA molecules, which are not transcribed into proteins, but have been shown to play a major role in regulating gene expression. MicroRNAs (miRNAs) are small (18-25 nucleotide) single stranded transcripts of non-coding RNA, which are highly stable and can act as tumor suppressors or oncogenes depending on their dysregulation. Nearly 100 miRNAs are differentially expressed in pancreatic cancer and they have been analyzed in human blood, bile, pancreatic juice, pancreatic cysts and stool. miR-21 is commonly considered an oncogene as many of its targets are tumor suppressors such as programmed cell death 4 (PDCD4) and PTEN. A large number of studies have identified miR-21 as a strong negative prognostic marker of survival in PDAC. A meta-analysis of 11 studies found tissue miR-21 levels to be strongly associated with reduced survival.⁴⁸ In the serum, high levels of miR-21 have also been shown to be correlated with low survival and decreased time to recurrence.^49,50 Conveniently, miR-21 has been found to be elevated early in pancreatic carcinogenesis. Up-regulation of miR-21 in precursor lesions such as intraductal papillary mucinous neoplasms (IPMN) and pancreatic intraepithelial neoplasia (PanIN) is also associated with a worse prognosis.⁴⁸ A large supportive study analyzing miRNA levels in PDAC revealed high expression of miR-21 and miR-31 with low expression of miR-375 were associated with poor overall survival following surgical resection.⁵¹

HOX Transcript Antisense RNA (HOTAIR) is a powerful predictor of metastasis and poor prognosis in multiple cancers. It is a non-coding RNA that works via histone modifications to decrease the expression of multiple genes. In PDAC, high HOTAIR expression has been shown to be associated with decreased survival and more aggressive tumors (those that extend to lymph nodes and beyond the pancreas).⁵² HOTAIR has also shown potential to be quantified in salivary samples.⁵³

TISSUE BASED BIOMARKERS
High Quality Pancreatic Tumor Biopsies

There have been marked recent advances in the ability to obtain high quality histologically intact core biopsies from pancreatic cancer and this shift will likely allow a far greater use of tissue based biomarkers. Although few studies have evaluated different biopsy techniques and needle designs side-by-side, it is apparent that the newer generation “core” fine needle biopsies (FNB) will provide far better quality and quantity specimens than the first-generation fine needle aspirations (FNA). Several studies have demonstrated that the overall diagnostic accuracy of FNA and FNB is similar (92.5- 94.8% vs. 90-98.3%, respectively).^35-37 In some studies, FNB required a significantly lower number of needle passes and was associated with greater accuracy at onsite cytology.³⁷ However, more recent studies have found similar overall diagnostic accuracy and per path diagnostic accuracy.³⁸

In addition to the comparable and possibly superior accuracy, the main objective when using a core biopsy is to obtain histologically intact tumor architecture and greater tumor volume. Figure 1A-C demonstrates three of the new FNB needles and an example of a pancreatic cancer specimen obtained through FNB. There are multiple ways to perform tissue acquisition and no certain needle size has shown clear superiority. It appears that both the tumor biology and architecture, as well as the endoscopic position may determine the most successful method. Therefore, we recommend individualizing this approach. Negative suction in the needle may be created by withdrawing the stylet during tissue acquisition (“slow pull technique” associated with lowest suction force), by dry suction (attaching the needle to a syringe that contains a 10-50 ml of vacuum column) or by wet suction (preloading the needle with saline prior to attaching the syringe to create negative suction).^39,40 We recommend examining the specimen obtained by a low suction force method and if the material is minimal, attempt a higher suction method as second line. However, in hard fibrotic tumors (either based on expected histology such as sarcomas or NETs or by feel during the procedures), a higher suction force method would be reasonable to try first and only switch to a lower suction method if the aspirate is overwhelmingly bloody.

Handling of core biopsy specimens is possibly as important to acquiring high quality and quantity tissue as needle design. Perhaps the most reliable way of examining the specimen is by expelling the needle content on a glass slide. In our practice, we expel the tissue in a serpentine manner to allow visual examination of the entire content. Often, white materials can be seen interspersed with the red coagulum and these may be highest yield for diagnostic tissue. We use one of these suspected microcores to generate a smear for on site evaluation and for cytologic evaluation. Given that cytologic details such as nuclear and cytoplasmic details are often better preserved in CytoLyt, it remains important to have some material in this preservative. In addition, the quality of nucleic acid isolated from tissue material is somewhat better from CytoLyt than from formalin fixed material. The remainder, and the majority, of the microcores are placed in formalin. As shown in Figure 1D, the formalin-processed cell blocks often yield significant areas of intact tissue.

Prognostic Markers

Tissue-based markers harbor the benefit of being more specific to the tumor tissue, but at the expense of requiring more invasive collection techniques. Immunohistochemical (IHC) analysis is a widely- used process utilized to visualize specific molecular markers and identify their distribution in clinical tissue specimens. Though these markers may be useful in patients who undergo surgical resection, investigations are still needed to discern if there is prognostic value to these biomarkers in pre-operative brush or biopsy specimens. Perhaps the best characterized treatment predictive biomarker is human equilibrative nucleoside transporter 1 (hENT1). hENT1, ribonucleotide reductase subunit 1 and 2 (RRM1, RRM2), and excision repair cross-complementing gene-1 (ERCC1) are vital for cellular transport and DNA synthesis and are frequently implicated as poor prognostic factors in various malignancies.¹⁴ In one multivariate analysis, high expression of RRM2 and ERCC1, but not the others, were associated with worse recurrence-free survival (RFS) and overall survival (OS).14 Another study found low hENT1 expression to be associated with poor RFS and OS.¹⁵ As hENT1 plays a major role in the internalization of Gemcitabine by pancreatic cancer cells, the primary role of hENT1 is as a predictive marker to Gemcitabine chemotherapy, for which there is more data available. Table 3 summarizes the data for hENT1 and other tissue-based markers as prognostic markers for survival in PDAC.

Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein which undergoes epigenetic silencing in pancreatic adenocarcinoma, but is often strongly expressed at the interface between the tumor and stroma by stromal fibroblasts.¹⁶ Supporting data suggest this interaction is important for tumor progression, metastasis and chemoresistance. Stromal SPARC expression is observed in all disease stages suggesting early expression is critical for tumor progression.¹⁷ Strong stromal SPARC expression in patients with well to moderately differentiated cancer who underwent surgical resection was associated with decreased overall survival when compared to patients with no SPARC expression.^17,18 Furthermore, patients with diffuse stromal SPARC expression extending beyond the peri-tumoral region had a significantly worse prognosis.¹⁹ Most reports of cytoplasmic SPARC expression by malignant pancreatic cells have shown no prognostication value.¹⁷ Some studies have found no prognostic benefit in observational cohorts, but only a strong predictive association in patients who were treated with gemcitabine.²⁰ Elevated SPARC mRNA expression has similarly been found to be a negative prognostic marker for PDAC survival and can be beneficial in that this analysis can be run on samples that are too small for IHC, such as from pre-operative fine needle aspiration.²¹ Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, thus facilitating tumor growth and progression. In IHC analysis, staining for VEGF is mainly demonstrated within the cytoplasm and cell membrane of cancer cells. Increased VEGF expression has been associated with a poor prognosis, including lower survival and increased lymphatic vessel invasion and lymph node metastasis.^22-24 Similar to SPARC and hENT1, there are therapies targeted against VEGF, so it also has potential as a predictive marker.

Smad4 is a tumor suppressor gene involved in mediating transforming growth factor beta (TGF-B). As evidenced by its alternative name, DPC4 (deleted in pancreatic carcinoma, locus 4), loss or inactivation of Smad4 is seen in ∼50% of PDAC²⁵ and leads to increased cellular proliferation by upregulating the progression from G1-S in the cell cycle. Loss of Smad4 expression has frequently been shown to be associated with reduced survival in PDAC.^8,26 Interestingly, one study discordantly demonstrated that low expression of Smad4 was associated with improved overall survival and importantly, pancreatic resection only benefited (via longer survival) tumors who had lost Smad4 expression.²⁷

KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is a GTPase that activates proteins required for propagation of growth factors and other cell signaling receptors. Overall, KRAS mutations have correlated with a reduction in survival.^8,28,29 Interestingly, the different mutational subtypes show varying duration of survival, with wild type GGT (glycine) converted to GAT (aspartate) being the most common and the only one to be prognostic of poor survival.^8,28 Additionally, mutational analysis performed for these KRAS mutations can be performed with quantitative polymerase chain reaction (PCR) which is cheaper and faster than other sequencing methods and uses less DNA data, making it easier to perform multiple molecular analyses on the same sample.²⁸

Perhaps the most exciting development of cancer therapy in the last few years has been the remarkable progress of the use of immunotherapy. Despite the success seen in several solid malignancies (melanoma, lung cancer, urological cancers), response rates have been minimal in pancreatic cancer. However, an immune response is present in pancreatic cancer and emerging strategies to turn on this immune response or identify tumors with an immune sensitive phenotype are promising. Parallel to these efforts, there is increasing evidence that the native immune response in pancreatic cancer is predictive of treatment outcomes. Immunohistochemical analyses that identify T cell populations and myeloid cells in pancreatic cancer,³⁰ or the level of expression of negative checkpoint regulators (NCR)^31,32 have already demonstrated prognostic value. These markers may also serve as important predictors of response to immunotherapies in the future.

Smad4, hENT1 and SPARC possess another benefit as biomarkers, in that they have been shown to be effectively assessed on pre-operative biopsy specimens.^19,27,33,34 Since quantitative PCR of VEGF and KRAS has also been shown to be accurate, there may be a role for these biomarkers during the pre-operative assessment with the smaller samples associated with biopsies.

Treatment Predictive Markers

There are various imaging modalities involved in the diagnosis and staging of PDAC including computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), and endoscopic retrograde cholangiopancreatography (ERCP). The roles of these modalities have changed over time, but the relative importance of EUS greatly increased with the advent of EUS-guided fine needle aspiration (EUS- FNA) over 20 years ago. Though limited by relative invasiveness and operator variability, it has been demonstrated to have excellent sensitivity (91-100%) and specificity (94-100%) for the diagnosis of PDAC.⁵⁴

While many tissue-based biomarkers show promise in the evaluation of PDAC, most of these studies have relied on surgically resected material, which comprise less than 20% of all patients diagnosed with this disease. As EUS-FNA technology continues to improve, including the ability to obtain more histologically intact core biopsies with new needles and improved visibility with the use of contrast-enhancement and elastography, the clinical utility of these biopsies broadens. Though not yet in widespread use, we can reliably perform immunohistochemistry analyses to identify prognostic and predictive markers such as hENT1, VEGF and microRNAs on these tissue samples pre- operatively.^33,55-57 Unfortunately, truly targeted therapies in pancreatic cancer are not yet available, but as our understanding of the biology of cancer evolves, it is important that our tissue acquisition methods improve and are ready for “prime time.”

One could imagine that a combination of currently available and previously discussed biomarkers may help in the selection of therapies, but only if our ability to evaluate them in pancreatic cancer biopsies can be validated. There a few emerging examples of clinical trials that require specific markers in biopsies. Pegylated recombinant human hyaluronidase (PEGPh30) is an enzyme that has been shown to potentiate chemotherapy in PDAC by removing excess hyaluronic acid from the tumor microenvironment. A phase 1b trial of PEGPh30 in combination with Gemcitabine as first line therapy in metastatic disease demonstrated a good safety profile and promising therapeutic benefit.⁵⁸ There are several ongoing clinical trials of PEGPh30; participation not only requires histologically confirmed PDAC, but frequently also evaluation of PEGPh30 expression in biopsies.

In addition, from many other cancer treatment algorithms, we know that understanding changes in tumor biology following a first line treatment regimen is critical. Recent phase II trials of a VEGF inhibitor, Vatalinib⁵⁹ and nab-paclitaxel⁶⁰ as individual second line therapies in advanced PDAC have demonstrated a favorable survival outcome in some patients; however, serum-based biomarkers did not correlate with response and the predictive value of tissue-based biomarkers (SPARC) were inconclusive due to small sample size. With high quality biopsies, we can expect that most trials, and increasingly, the standard of practice, will emphasize the need for post-treatment biopsies.

CONCLUSION

This review focused on biomarkers that can be used to prognosticate outcome in PDAC, independent of treatment strategy. There are a multitude of potential biomarkers in the literature, but many are limited by specificity, heterogeneity of disease, difficulty in obtaining adequate samples and conflicting results. Also, the majority of the tissue-based biomarkers have been studied in resection specimens, and these patients only account for a minority of most PDAC cohorts. The most promising tissue biomarkers include hENT1, SPARC, Smad4, and VEGF as they may be valuable in the pre-operative period and may additionally have predictive value in guiding individualized pancreatic cancer therapy. The novel serum-based markers are also valuable due to their minimally invasive approach and foundation for genetic analysis. As both endoscopic methods to obtain high quality biopsy specimens and the molecular understanding of pancreatic cancer advances, it is likely that these and many other biomarkers will enter into routine clinical practice. It is increasingly important to obtain the highest quality tumor biopsies at the time of diagnostic procedures and assure that sufficient tumor tissue material is available for molecular and immunohistochemical analysis.