Page 67 – Practical Gastro

Brijesh B. Patel,Thure Caire,Prasad Kulkarni

We present two cases of insulinoma diagnosed by endoscopic ultrasound (EUS) after initial imaging was unrevealing. Both patients presented with refractory hypoglycemia and were found to have high c-peptide and insulin levels suspicious for insulinoma with evaluation for factitious causes (sulfonylurea, and meglitinides screening) being ruled out. However, imaging with computed tomography (CT) or magnetic resonance imaging (MRI) was not revealing of lesion location. Subsequently, EUS was pursued. In each case, EUS was able to localize and biopsy the lesion in the head of the pancreas and immunohistochemistry confirmed the diagnosis. Both patients underwent definitive treatment and had uneventful recovery. These cases highlight the utility of EUS in diagnosing and localizing insulinoma.

Brijesh B. Patel, M.D.^1,2 Thure Caire, M.D.^1,2 Prasad Kulkarni, M.D.^1,2 1University of South Florida, Division of Digestive Diseases and Nutrition Tampa General Hospital, ²Veteran’s Administration Department of Gastroenterology

INTRODUCTION

Insulinomas are rare neuroendocrine tumors (NET) with an annual incidence ranging from 1 to 4 people per million per year. Although rare, they are the most common of the NETs, with a higher female predominance and typical presentation in the 5th decade of life.¹ Only 5-10% of insulinomas are malignant. After gastrinoma, insulinoma is the second most common functioning pancreatic tumor, accounting for 10-30% and are associated with multiple endocrine neoplasia (MEN type 1).² They are usually small in size < 2 cm.³

The clinical presentation of insulinoma may include diaphoresis, tremor, palpitations and uncharacteristic hunger. This may progress to more severe neuro- glycopenenic symptoms including confusion, behavioral changes, personality changes, visual disturbances, seizure, coma and death.^4,5 The clinical Whipple’s triad is used to clinically diagnose one with insulinoma which includes: symptoms known or likely to be caused by hypoglycemia, low plasma glucose measured at the time of the symptoms and relief of these symptoms when the blood glucose is raised to normal.⁶

In many cases, insulinomas can be localized by non invasive imaging modalities such as CT or MRI. If unrevealing more invasive modalities need to be utilized, such as EUS and insulin sampling via selective arterial calcium stimulation (SACS) and somtostain receptor scintigraphy. While there is no head to head comparison of EUS and SACS, the sensitivity with SACS may exceed 90% and it is a provocative test with operator dependence and high cost.⁷ C peptide levels, sulfonylurea testing and meglitinides screening are used to rule out factitious causes. If tissue is available, immunohistochemistry (IHC) for insulin chromogranin and synaptophysin aid in confirming the diagnosis. No matter what diagnostic modality one uses, the treatment includes surgical resection vs. enucleation. The pharmacological treatments are available for patients who are poor surgical candidate but only surgery is curative.⁸ The medical management includes frequent carbohydrate meals, octreotide and diazoxide or somatostatin analogs help control hypoglycemic symptoms in only 50-60% of patients.^9,10

The most common cause of hypoglycemia in adults is iatrogenic; factitious use of anti-diabetic agents such as sulfonoureas or insulin. In healthy adults other causes include lack of hormones such as cortisol or glucagon or hyperinsulinism secondary to nesidioblastosis or autoimmune insulin hypoglycemia.^11-14 One of the rare causes of hypoglycemia includes tumors secreting endogenous analogs causing such symptoms. NETs are rare functional tumors of pancreas, they represent a small percentage of all pancreatic tumors (1.3%) but their incidence is rising.¹⁵ Insulinomas causes hypoglycemic episodes secondary to excess endogenous insulin production leading to metabolic derangements. They may exert these effects even when <1cm in size.

We present 2 cases that exemplify the importance of EUS in accurate diagnosis and location of insulinomas after primary imaging modality was unable to localize the lesion.

CASE # 1

A 65 year old male veteran with past medical history significant for prostate cancer s/p radical prostatectomy presented with episodes of dizziness and weakness. Initially the patient was found to have blood glucose (BG) levels of 40-60s mg/dL and he was unable to raise his glucose levels despite frequent snacks (every 2-3 hours). On presentation, he underwent CT of the abdomen and pelvis which was unremarkable. With consistently low BG levels, his labs revealed an insulin level > 40 mcU/mL (normal 2-25 mcU/mL), c- peptide level of 8 ng/mL (normal 0.78-1.89 ng/mL) and an octreotide scan was negative. With a high suspicion for insulinoma (given the negative sulfonylurea screen) our patient underwent EUS- with fine needle aspiration (FNA). A 14 mm x 16 mm homogenous lesion was noted in the head of the pancreas (Figure 1). The biopsy revealed plasmacytoid neoplastic cells (Figure 2) with pathology positive for chromogranin, synaptophysin and pankeratin and negative for CK 7, CK 19, CK 20 and CDX2. With IHC and staining, a diagnosis of pancreatic endocrine neoplasm was made, and with aspirate positive for insulin, the diagnosis of insulinoma was confirmed (Figure 3). Subsequently the patient underwent enucleation and is currently symptom-free.

CASE # 2

A 67 year-old female with past medical history significant for hypothyroidism, hypertension, recurrent hypoglycemia and hypoglycemia associated seizures was referred for EUS/FNA. She had been having recurrent episodes of hypoglycemia and witnessed seizures for two years. An abdominal MRI at an outside facility was normal. Her laboratory evaluation revealed an insulin level of 203 mcU/mL (normal 2-25 mcU/mL), c-peptide 44 ng/mL (normal 0.78- 1.89 ng/mL) and proinsulin 149.9 pmol/L (normal <18 pmol/L). Screening was negative for sulfonylureas and meglitinides. She underwent EUS/FNA which showed a well-circumscribed hypo- to isoechoic 8.4 mm x 9.6 mm lesion in the head of the pancreas (Figure 4). FNA showed cytology consistent with tumor cells positive for synaptophysin and chromogranin, findings again suggestive of pancreatic neuroendocrine tumor. Similarly this patient underwent surgical resection and IHC was positive for insulin stains and patient is symptom-free.

DISCUSSION

These cases highlight the importance of endoscopic ultrasound in the diagnosis of the insulinoma. The diagnosis can be made via biochemical assays and routine blood work although localizing the tumor may prove to be a challenge. The conventional imaging modality such as high resolution pancreatic protocol CT and MRI are often beneficial to localize the lesion. At this time, these modalities are more widely available than EUS. A small number of insulinomas still remain occult after conventional CT scan and MRI fail to identify them.⁹ The sensitivity of CT and MRI has been reported to be 33%-64% and 40%-90%, respectively with MRI being more sensitive and specific when compared to CT.^16-18 A study by Bonato et al. showed that CT was able to localize insulinoma in 4/16 patients with size > 1.5 cm and largest being 12 cm.¹⁹ Both of our cases had hypoglycemia on presentation with abnormal biochemical assay and negative sulfonylurea and meglitinides screen. After initial imaging CT scan and MRI were unable to identify or localize the lesion and strong clinical evidence supportive of insulinoma, EUS localized the lesion and obtained tissue that was helpful to the diagnosis. Preoperative use of EUS for insulinoma allows precise targeting of the lesion, preventing intra-operative (including unnecessary total pancreatectomy) complications, length of operating time and post-surgical complications. With this modern approach, EUS/FNA may also enable carbon-particle tattooing for easy localization. Overall sensitivities up to 94 % are reported in the localization of tumors using EUS.¹7 When combined with high resolution CT and EUS the sensitivity increases to 100 %.²⁰ Even with expert surgical experience, there is still a 10-20 % rate of not being able to detect lesion intra-operatively making pre-operative localization very important. The idea is that with precise location the surgical management resection vs. enucleation is more feasible. Key draw backs for EUS is that it is highly operator dependent, available only in tertiary care centers and has limited utility in localizing lesions in the tail or the distal body of the pancreas or if the tumors are pedunculated or if tumors are extra-pancreatic. Although with advent of intraductal ultrasound, these areas can be readily visualized with its detection rate as high as 90 % of lesion measuring 1-3 mm although it is not widely available.^21,22 Both of our cases involved lesions in the head of the pancreas. The importance in these cases is that use of EUS aided in the diagnosis and precise localization of even very small (<1 cm) tumors.

Histopathologically, insulinomas stain positive for insulin, pro-insulin, chromogranin A, synaptophysin, neuron specific enolase and cytokeratin.²³ Our patients’ IHC were positive for chromogranin, synaptophysin and pankeratin. Although these markers can be used to identify insulinoma, the importance lies in localizing where the biopsy needs to be taken which can be aided with EUS.

Other techniques such as somatostain receptor scintigraphy, selective arterial calcium stimulation and hepatic venous sampling are also used to diagnose previously missed tumors. Selective arterial calcium stimulation with hepatic venous sampling for insulin quantification has shown a high sensitivity (93%) for localization, these techniques can get cumbersome and yield can be significantly low.⁷ Combination with EUS allows one major advantage of tattooing and biopsy once tumor is localized.

These cases identify the crucial role of EUS in identifying the lesions which not only confirmed the diagnosis but also aided in the operative resection of the tumors. With the help of EUS, blind surgical approaches are rarely performed. The most common complication post surgery was noted to be hyperglycemia as expected, pancreatic psuedocyst formation, pancreatic fistula, wound infection and the longest hospital stay was 40 days.¹⁹ Once the tumor is identified the curative approach is still enucleation and or distal or partial pancreatectomy. Since the incidence of NET rising it will be critical in identifying the lesions that are missed or are too small to be seen on imaging. Our cases exemplify the important aspects in using primary EUS in diagnosing of insulinoma and management. In addition, cases such as ours can help spread awareness about the utility of EUS in diagnoses that are not amenable per primary imaging modality with strong clinical suspicion for NETs and target the lesion with tattooing for enucleation. Future studies need to be performed that will quantitate variables such as length of hospital stay, pre, intra, and post-operative complications when EUS is used in diagnosis vs. blind approach.

GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #13

Utilization of Complementary and Alternative Medicine in Irritable Bowel Syndrome

Christine Yu,

Richard W. McCallum

In the field of gastroenterology, there is scant evidence-based-medicine available for review in regards to alternative therapeutic options to treat or manage gastrointestinal disorders. The intent of this article is to first bring awareness to fellow gastroenterologists that numerous complementary therapies and alternative modalities to treat gastrointestinal disorders do exist and then to emphasize that utilizing such treatments may be of some benefit to our patients, specifically in patients with irritable bowel syndrome.

As gastroenterologists trained in Western medicine, our fund of knowledge and sensitivity to the concepts and applications of integrative, complementary, alternative, holistic, naturopathic or herbal medicines is quite limited. When endoscopic procedures, imaging and pharmacologic therapies fail to alleviate a patient’s symptoms, we find ourselves with few options in what we can offer our patients. There are numerous complementary modalities that can be considered as treatment for patients when western therapies fail or as adjunctive treatment in settings of partial responders. In the field of gastroenterology, there is scant evidence-based- medicine available for review in regards to alternative therapeutic options to treat or manage gastrointestinal disorders. Finding double-blinded randomized clinical trials for alternative treatments is almost impossible for multiple reasons, including the extensive funding needed to orchestrate such studies, although the new Center for Complementary Medicine at the NIH will potentially be a source of funding for these types of studies. The intent of this article is to first bring awareness to fellow gastroenterologists that numerous complementary therapies and alternative modalities to treat gastrointestinal disorders do exist and then to emphasize that utilizing such treatments may be of some benefit to our patients, specifically in patients with irritable bowel syndrome.

Christine Yu MD, ABIHM, Richard W. McCallum MD, FACP, FRACP, FACG, AGAF Texas Tech University Health Sciences Center, Department of Internal Medicine, Division of Gastroenterology, El Paso, TX

INTRODUCTION

In the past few decades, there have been an increased interest and utilization of complementary and alternative medicine (CAM) for treatment of all medical issues, including gastrointestinal disorders. There is a vast array of different terminology used when speaking of CAM ranging from holistic medicine, homeopathy, herbal medicine, botanical medicine, essential oils, aromatherapy, nutritional supplements including vitamins and minerals, probiotics, acupuncture, biofeedback therapy, Aruvedic therapy and body-mind therapy, to name a few. Most of these modalities have been used for thousands of years prior to the existence of modern western medicine by civilizations all over the world. Many patients may be utilizing CAM but forget to tell their physicians unintentionally or, most times, intentionally because they fear that their physicians will tell them that they should not take it or participate in such therapies for various reasons. For the most part it is true that there is limited evidence-based medicine available for CAM but also, many physicians are not aware or knowledgeable of such therapies, thus not recommending CAM to their patients. Recently there was an article published in the American Journal of Gastroenterology that found that CAM was used by 42% of respondents with a GI condition from the 2012 National Health Interview Study and over 80% of patients who used CAM found it helpful.¹ The GI conditions mentioned in the study were abdominal pain, acid reflux/ heartburn, digestive allergy, liver condition, nausea/vomiting and ulcer. The most commonly used modalities were herbs, supplements and mind body and manipulative therapies. Because of this explosive utilization of CAM therapies in recent years, the Center of Complementary and Alternative Medicine in National Institutes of Health has engendered opportunities to support rigorous scientific research in relevant topics and help integrate proven complementary and alternative approaches into conventional medicine.² This will undoubtedly lead to more scientific and more rigorous controlled trials to increase credibility for CAM. Irritable bowel syndrome (IBS) is recognized to occur in about 15% of people in the United States and up to 75% are females. IBS is defined as chronic or recurrent abdominal pain that is associated with constipation, diarrhea or both. The etiology of this disease is unclear and multifactorial in nature but has been found to be associated with abnormal peristalsis, infections, food insensitivities, altered neural sensitivity and inflammation. There have been studies indicating that up to 50% of patients suffering from IBS have utilized CAM therapy.³ In this article, we will review specific modalities of CAM that have been found to be beneficial in IBS beginning with the traditional first line approach- fiber- which actually relies on this CAM concept.

Fiber

Increasing fiber intake through either diet or via supplementation is most often the first recommendation we give to IBS patients.⁴ Soluble fiber, but not insoluble fiber, is thought to be beneficial. Soluble fiber consists of pectins, gums and mucilages but is usually administered as psyllium. Psyllium husk is the outer coat of psyllium seed known in India as ispaghula seed from the plant Plantago ovata.⁵ It is found in fruits, vegetables, whole grains, seeds and nuts. When mixed with water, it forms
a gel and is fermented by colonic bacteria, yielding metabolites that might decrease gut intracolonic pressure and gut transit time. Insoluble fiber which is found in wheat bran and corn bran, undergoes stool bulk and decreases transit time. Dietary fiber recommendations for adults generally range from 20 to 35 grams/day.⁶ Likely benefits from fiber intake include increase stool weight, normalization of defecation frequency,
improved glycemic control in patients with diabetes, lower blood cholesterol levels, with protective roles regarding diverticulosis, constipation, colon cancer and cardiovascular disease.⁴ The proposed mechanism of action for fiber in the treatment of IBS and constipation is acceleration of oroanal transit and decrease in intracolonic pressures either as a direct effect or by binding bile acids.⁷

Systematic review of clinical trials of fiber for IBS have found no clear beneficial effects for fiber supplementation or bulking agents. The American College of Gastroenterology Functional Gastrointestinal Disorders Task Force recommendations are that fiber is appropriate for the treatment of constipation dominant IBS but may not be recommended for the treatment of all subsets of IBS.⁸ A similar meta-analysis of therapies for IBS does not recommend use of bulking agents except as adjuvants.⁹

Herbals for IBS

The Cochrane Collaboration performed a review of herbal medicines for IBS and found that there were 75 randomized controlled trials in approximately 8000 patients. Although only 3 of those studies were judged to be of high quality, there were several Chinese and Ayurvedic preparations that were found to be better than placebo. There were also no serious adverse effects for any of the herbal preparations.¹⁰

Chinese Herbal Preparations – Traditional Chinese Medicine (TCM)

IBS patients were treated with either a standardized combination herbal formula, an individualized herbal formula or placebo. Both treatment groups showed a substantial benefit over placebo after 16 weeks of therapy, and the individualized treatment showed continued benefit 14 weeks after treatment ended. The mechanisms of the herbal formula’s action are unknown.¹¹

Tong sie yao fang (TXYF) is a combination of commonly used TCM. A meta-analysis of different variations of this formula included 12 Chinese studies examining its use in IBS.^{12, 13} TXYF was found to be more effective than placebo but the trials were heterogeneous, generally of poor quality and the TXYF formula itself was inconsistent. There were 3 trials from the English language literature using different TCM herbal formulas containing TXYF ingredients and two demonstrated efficacy,^11,13 but one did not.¹⁴

STW 5 (iberogast) and STW 5-II are a combination of nine herbs that are commonly used as digestive aids. A trial compared 208 patients with IBS who received STW 5, STW 5-II, a single-plant extract or placebo. Abdominal pain and IBS symptom scores were significantly improved among patients that received STW 5.¹⁵

Padma Lax, a Tibetan herbal digestive formula has been used in Europe for decades. In a trial involving 61 constipation-predominant IBS patients, screened for celiac disease or lactose intolerance, reported global improvement in 76% of those using Padma Lax versus 31% of those receiving placebo.¹⁶ In a Cochrane systematic review of herbal medicines for the treatment of IBS, Padma Lax, STW 5, and certain formulations of TXYF were shown to improve global IBS symptoms when compared to placebo.¹⁰

A systematic review of 22 randomized controlled
trials (RCTs) focused on the safety concerns with herbal
medicine and demonstrated that adverse events occurred
in 2.97% of patients, none of which was considered of
a serious nature. Of note, the authors did caution that
most of these trials were not of acceptable quality and
there might have been underreporting of adverse events.
Thus, clinicians should weigh the potential benefits and
risks of these therapies when advising patients.¹⁷

Ginger (Zingiber Officinalis Roscoe)

Ginger is one of the most common herbal medicines that are used for a variety of GI conditions, including IBS. Ginger was found to be the most popular alternative medicine in one study of IBS patients¹⁸ but there has not been any well conducted study examining its efficacy.

Ginger root is the rhizome of the perennial plant Zingiber Officinalis Roscoe. Ginger contains approximately 1-3% oils. Dosing is usually standardized according to gingerol content which is assumed to have antiemetic, analgesic, sedative and antibacterial effects.^19,20 Ginger is recognized by the American Food and Drug Administration relatively safe and is exempt from premarket review or approval before marketing.

As an antiemetic, studies have shown that ginger is effective in treating nausea and vomiting in pregnancy, after surgery and also during chemotherapy. Ginger has also been shown to improve gut motility as well as abdominal pain.²¹ Therefore, theoretically, ginger may be useful in reducing stool changes in IBS as well as pain.

A double-blinded randomized controlled trial was performed comparing the efficacy of ginger in treating IBS patients compared to placebo.²² This study had three groups: patients that received 1 gram of ginger daily, 2 grams of ginger daily and/or placebo for 28 days. There were 57.1% responders to placebo, 46.7% to 1 gram and 33.3% to 2 grams of ginger. Adequate relief was reported by 53.3% on placebo as well as both ginger groups combined. Side effects were mild and reported in 35.7% in the placebo group and 16.7% in the ginger groups. This double blind randomized controlled trial suggests that although ginger is well tolerated, it did not perform better than placebo. Larger trials are needed for further evaluation.

Peppermint oil (Mentha Piperita Linnaeus)

Peppermint is a leafy, green plant. Peppermint oil, which has been used for thousands of years, is extracted from the leaves and stems.²³ The active ingredients in peppermint are organic oils including menthol, which act as smooth muscle relaxers in the GI tract, likely on calcium channels. Peppermint oil is available in enteric coated capsules (containing 0.2ml of oil) and in liquid dropper form. The capsule form is preferred because direct consumption of the oil can reduce pressure in the lower esophageal sphincter theoretically leading to reflux. The recommended dose is one to two capsules three times daily for adults 15 to 30 min prior to meals.

In a study by Liu et al, IBS patients treated for one month with peppermint oil (Colpermin) had improved abdominal pain, distension, frequency of
bowel movements and flatulence over a placebo control group. Symptom improvements after Colpermin were significantly better than after placebo.²⁴ A meta-analysis of four randomized placebo controlled trials with approximately 400 subjects which showed peppermint oil to be superior to placebo for symptom reduction. The number needed to treat to prevent persistent symptoms was 2.5.²⁵ Another study that looked at patients taking four capsules daily for four weeks, showed symptom improvement in 75% of patients compared to 38% of those taking placebo (P<.01).²⁶

Peppermint oil is generally considered safe but there have been reports of renal failure or death if very high doses are taken, although the exact doses are not quantified. According to the FDA poisonous plant database, the lethal dose of peppermint oil that would cause death in 50% of the patients was 300 ml/kg. Common side effects at clinical doses include allergic reactions, rash, nausea, vomiting, perianal burning and heartburn. Drug interactions include potential interaction with medications metabolized through the cytochrome P450 1A2 system such as cyclosporine and simvastatin.²⁷ The safety of peppermint oil during pregnancy has not been demonstrated.

There has been a recent study supporting the use of peppermint oil (IBgard^®) which is a capsule of sustained release microspheres of Ultramen^®, an ultra-purified peppermint oil, the results of which were presented at the 2015 DDW meeting.²⁸ IBgard^® capsules contain L-menthol, the principal component of peppermint oil, with targeted delivery to the small intestines. A US-based, four week, placebo-controlled, multi-centered, randomized trial was completed which studied 72 patients with IBS-D and IBS-M. 79% of patients reported a reduction in unbearable or severe abdominal pain at four weeks and even showed a reduction in total IBS symptoms at 24 hours. 93% of patients were satisfied with the relief from their IBS symptoms in a post-study assessment and side effects were comparable to placebo. This agent – IBgard^®-is now officially approved for treating patients.

Mind-body therapies

Brain-gut interactions are increasingly recognized in the pathogenesis of IBS and almost half of IBS patients have comorbid psychiatric disorders.²⁹ Mind-body therapies are directed at using the connection between the brain and body to either alter how the mind perceives symptoms or to change the symptoms themselves. A systematic review of psychological treatments included controlled trials of cognitive-behavioral therapy (CBT),
biofeedback therapy, stress management, hypnotherapy, progressive muscle relaxation and relaxation; of these, hypnotherapy and CBT are supported by the most clinical evidence.³⁰

CBT teaches patients that they have a choice in how they respond to their internal and external environments. Patients undergoing CBT are trained to recognize and correct thoughts and behaviors that amplify symptoms or undermine well-being. This is often combined with psychological strategies for coping with symptoms and illness.^29,31 For example, patients who normally respond to abdominal cramping by anger and frustration may, through CBT, decide to respond to the cramping by sitting down and performing some breathing exercise while calming the mind instead of having his or her usual response.

A review of CBT for IBS found that when looking at 16 trials, all but three showed significant behavioral improvement in IBS symptoms. Most of these studies had small number of patients included in the study. The author concluded that “overall, the weight of evidence from published trials show CBT to be more beneficial than routine medical care for the treatment of IBS, and possibly more beneficial than attention-placebo control conditions (i.e. giving additional support as in education and emotional support)”.³²

Therapeutic suggestions have been given to patients in a state of deep relaxation and narrow focus since the 19th century.33 Gut-directed hypnotherapy is a specific technique that combines suggestions related to emotional well-being and intestinal health. Its use in IBS was first reported in a small trial of 30 patients, in which improvements in symptoms were greater after seven weekly sessions of hypnotherapy than they were with supportive psychotherapy.³⁴ Hypnosis teaches patients to place themselves in a relaxed state and give themselves suggestions about how their mind or body should respond. For example, patients who have chronic abdominal pain may be asked to associate a color with the pain; patients often choose the color red. A medical hypnotherapist will then work with patients in a relaxed state to image that red, painful color in his or her abdomen slowly changing to a more calming and comfortable blue color, and during that change, imagining the pain also diminishing. Patients will practice this with the hypnotherapist so that when the pain occurs outside the therapist’s office, they can use this technique on their own.³⁵

A Cochrane review in 2007 looked at multiple studies using hypnotherapy for IBS.³⁶ The results were positive in that the studies showed a beneficial effect of hypnotherapy. Another review looked at 14 studies, which found that 80% of the subjects had improvement of IBS symptoms with hypnotherapy but only six of the included trials had a control.³⁷ There is strong evidence supporting the use of hypnotherapy for treatment of
IBS. Safety and potential long-term benefits add to its appeal.³⁸ The evidence also suggests that some patients may be more “hypnotizable” than others,³⁹ but it is reasonable to advise patients to consider a trial with a
therapist trained in gut-directed hypnotherapy.

Mind-body therapies are useful modalities for treatment of IBS given they are unlikely to have side effects and most patients respond well, especially in children, where the data is strongest for a positive effect.

Acupuncture

Acupuncture has been used in Asia for thousands of years and is becoming more and more popular in the United States since the 1970s. Acupuncture is a therapeutic modality in TCM. Acupuncture uses small needles to pierce the skin at designated acupuncture points and is often used with electrical stimulation from devices that are similar to transcutaneous electrical nerve stimulation (TENS) unit. The physiology of acupuncture can be related to local changes in pain chemicals, such as substance P, bradykinin, central release of endogenous opioids, norepinephrine and serotonin. It has been used to treat several gastrointestinal symptoms in functional and organic diseases, and has been shown to influence visceral reflex activity, acid secretion and gastric emptying.⁴⁰ Brain-gut disturbances make it reasonable to consider treating the disorder with acupuncture.^40,41

A study showed that electroacupuncture could attenuate chronic visceral hypersensitivity in rats.⁴² Although animal studies have shown positive effects with acupuncture, human trials have had mixed results. There is difficulty in assessing the appropriate controls including needles used, sham procedures utilizing acupuncture points pay also result in some stimulation of these points, and it is difficult to blind either the patients or the clinician as to whether or not patients have had acupuncture. There have been studies that have found that patients treated with acupuncture were equivalent to sham acupuncture where some studies used non-acupuncture points as “sham control” and others used telescopic needles that did not penetrate the skin. Some used a standard set of points for the
intervention while others used different points for each patient that was selected after an assessment by a blinded acupuncturist. There has been one study that showed that acupuncture and psychotherapy were more effective that psychotherapy alone⁴³ and another study reported that acupuncture was superior to the herbal formula TXYF.⁴⁴

In 2006, the Cochrane Collaboration reviewed 6 acupuncture trials and found that overall the scientific quality of the studies was poor, and the results showed acupuncture to be no more effective than sham acupuncture in treating symptoms of IBS. It had recommended further studies before drawing definite conclusions.⁴¹ There was a subsequent study which showed that the IBS patients in both acupuncture and sham acupuncture groups improved significantly when compared with the waitlist group. However, they found no statistical different in the change in symptoms between the acupuncture and sham acupuncture groups.^45,46

Side effects of acupuncture usually tend to be transient and mild; they include sensation, aching at the sites of needle insertion, bleeding and infection.

A new modality, non-needle electroaccupuncture, has been described in the literature for treatment of various conditions including nausea, vomiting and gastroparesis. This might be a future direction for the treatment of GI conditions including IBS for patients who are afraid of needles and to decrease possible side effects of acupuncture. In addition, needless acupuncture

typically a vibrating signal from an electrode – can
be applied by the patient at home frequently (e.g.
before meals). Traditional acupuncture is limited to
certain days of therapy and effects cannot be sustained.
Finally, the cost of acupuncture is a hurdle for the needle
approach in the USA.
Probiotics

The World Health Organization defines probiotics as “live organisms that when administered in adequate amounts confer a health benefit on the host”.⁴⁷ The phenomenon of ingesting probiotic products started 100 years ago, when the first reports showed beneficial effects of probiotic bacteria on human health. Since then, probiotic preparations have become an essential element in the prevention and treatment of certain disease. Probiotic microorganisms are primarily lactic acid-producing bacteria (i.e. Lactobacillus, Bifidobacterium). Some probiotics have been shown to have anti-inflammatory properties, as evidenced by a recent article of efficacy of VSL#3 in Crohn’s patients,^48,49 while others have been shown to modulate
visceral hypersensitivity.^50,51

A systematic review and meta-analysis was completed were 35 RCTs were identified using probiotics in IBS, involving 3,452 patients. Fourteen trials were at a low risk of bias with the remainder being unclear. Nineteen trials used a combination of probiotics; eight used Lactobacillus, three Bifidobacterium, two E.coli, one Streptococcus, one Saccharomyces and one either Lactobacillus or Bifidobacterium. The systematic review and meta-analysis demonstrated that probiotics were effective therapies for IBS, in terms of both improvement in overall symptoms and improvement in global symptom, abdominal pain, bloating and flatulence scores. The number needed to treat to improve symptoms was 7. The most evidence was found to support the use of combinations of probiotics and L.planatarum DSM 9843. There was also a trend toward beneficial effect of Bifidobacterium in terms of improvement in global IBS symptoms and pain scores, although which particular strain or species remains unclear. Adverse effects were rare but more common in the probiotics group when compared to placebo.⁵²

Treatment with a probiotic containing L.plantarum 299 v (Lp 299 v) significantly reduced the main symptoms of IBS, such as abdominal pain, discomfort and bloating. Lp 299 v was administered once daily for four weeks.⁵³ Another study showed that long-term supplementation with probiotics like Bifidobacterium bifidum MIMBb75 and Saccharomyces boulardii could cause up to a 20% improvement compared to the placebo group.^54,55,56It has been found that formulations containing VSL#3 have reduced flatulence while lactobacillus GG may potentially reduce the risk of
diarrhea. The clinical effects of B.infantis 35,624 strain have been confirmed to be beneficial as well, showing that a preparation administered to patients at a dose of 100,000,000 CFU showed at least 20% decrease in all
major IBS symptoms compared to placebo.⁵⁷

General recommendations from the American College of Gastroenterology as well as expert consensus panels from both the United States and in Europe are similar. There is reasonable rationale for why probiotics may work as treatment for IBS and the FDA has granted probiotics GRAS status (generally recognized as safe). A therapeutic trial of probiotics is reasonable. Daily oral doses of 10-100 billion bacteria are most common. Side effects are believed to be negligible but caution is advised in preterm infants, immunocompromised patients, and critically ill patients in the ICU.

Fecal Enemas

Transplantation of stool for the treatment of gastrointestinal disease was first reported in 4th-century China by Ge Hong, who described the use of human fecal suspension by mouth for patients who had food poisoning or severe diarrhea.⁵⁸ In the 16th century, Li Shizhen described oral administration of fermented fecal solution, fresh fecal suspension, dry feces and infant feces for the treatment of severe diarrhea, fever, pain, vomiting and constipation. In the 17th century, fecal microbiota transplantation (FMT) began to be used in veterinary medicine, both orally and rectally, and was later termed “transfaunation”.⁵⁹

The pathogenesis of irritable bowel syndrome (IBS) is multifactorial and now believed to involve a complex interplay among the brain-gut axis, immune system and intestinal microbiota.⁶⁰ Perturbation of the intestinal microbiota has been shown to result in altered GI motility and visceral hypersensitivity, which have been observed in patients with IBS and are thought to play a role in disease pathophysiology.⁶¹ Additionally, observations have been made that link preceding gastroenteritis, small bacterial overgrowth (SIBO) and IBS, further implicating intestinal microbiota in the development of IBS.⁶⁰ Probiotics have been reported to improve post infectious IBS in animal models.⁶² Hence there has been interest in restoring the intestinal microbiota in IBS patients. FMT, or donated feces, may prove more beneficial, since they are the ultimate
human probiotic.

In a series of 55 patients with IBS and IBD treated with FMT, cure was reported in 20 (36%) patients, decreased symptoms in 9 (16%) patients, and no response in 26 (47%) patients. In another series, 45 patients with chronic constipation were treated with colonoscopic FMT and subsequent fecal enema infusions, 89% of whom (40 of 45 patients) reported relief in defecation, bloating, and abdominal pain immediately after the procedure. Normal defecation, without laxative use, persisted in 18 (60%) of 30 patients who were contacted 9 to 19 months later. In a recent study of 13 patients who underwent FMT for refractory IBS (9 IBS-diarrheal, 3 IBS-constipated, 1
IBS-mixed), 70% of patients reported improvement or resolution of symptoms, including abdominal pain (72%), bowel habit (69%), dyspepsia (67%), bloating (50%) and flatus (42%).⁶³ FMT resulted in improved quality of life in 46%. Conclusions of all these trials are limited by the lack of any control arm.

In another study of patients with refractory IBS, FMT resolved or improved symptoms in 70% of our patients with refractory IBS, including abdominal pain (72%), bowel habit (69%), dyspepsia (67%), bloating (50%) and flatus (42%). FMT also resulted in improved quality of life (46%).⁶³

In 2013, the US Food and Drug Administration (FDA) announced that fecal microbiota would require an investigational drug application (IND) to perform FMT for any indication. This decision to apply IND requirements made FMT largely unavailable to the community physician. Currently, FDA regulations permit a treating physician to perform FMT for Clostridium difficile infection (CDI) in patients who are unresponsive to standard therapy, without an IND, provided that the physician obtains adequate informed consent. The FMT product must be obtained from a donor known to either the patient or the treating licensed healthcare provider. Finally, the donor and the donor’s stool must be qualified by screening and testing performed under the direction of the licensed healthcare provider. The FDA still requires an IND for the use of FMT to treat all other GI and non-GI diseases.⁶⁴

In the only long-term follow-up study of FMT in IBS patients to date, which was a combined effort from 5 medical centers, 77 patients who had had FMT and were followed for more than 3 months experienced and maintained a 91% primary cure rate and a 98% secondary cure rate, the latter defined as cure enabled by use of antibiotics to which the patient had not responded before the FMT or by a second FMT.^64,65,66,67

In summary, FMT in IBS is undoubtedly work in progress. The patient may inquire with our Dr. Google society, yet at this stage there is no controlled trial data. Therefore our recommendation regarding this treatment
is “let’s wait”.

CONCLUSION

This is an attempt at a brief overview of the most common alternative therapies available to treat IBS. Although it is in no way comprehensive, gastroenterologists should be aware of the various alternative treatments available for our patients. There are many instances where our IBS patients come to us already on various Western medications and they are responding to some degree but are searching for more improvement in their quality of life or they initially responded well but now seem to be less sustained by usual medical approaches. At these encounters when the patients says, “Doctor, should I go to the Mayo Clinic?” the answer should be a resounding “No. We have a lot more options to try, specifically the following…” At that point, you can consider trying various complementary therapeutic options, often in the setting of the patient personally requesting alternative treatment approaches.

One important concept to emphasize from the beginning is the necessity to establish a good doctor- patient relationship and hence trust. To enhance this relationship, the clinician must remember to first and foremost listen to their patients. Although we are specialists in gastroenterology, we must not forget that in the end, we are treating the whole patient, not just their GI symptoms. To achieve this goal, the patient must be an active participant in his or her treatment strategy. IBS is a life-long disease where the goal is to maximize the good days since there is no magic cure. All possible approaches and therapies may be needed and in this review, we endorse and subscribe to them all, including those treatments with evidence supporting nontraditional therapies.

NUTRITION ISSUES IN GASTROENTEROLOGY, #147

Transition to Ready to Hang Enteral Feeding System

Wendy Phillips,Wendy Phillips,

Mallory Foster,

Carol Rees Parrish

Nursing time and supply costs to administer enteral feeding are substantial. One major academic medical center recently converted from an open system (OS) to a closed, or “ready to hang” (RTH) system for enteral feeding. This article reviews that transition from an OS to RTH and documents the costs, nursing perceptions, and lessons learned in the process.

Healthcare costs in the United States are soaring. Efforts to improve patient care, safety, and outcomes are ongoing goals particularly when they also result in a reduction in the cost of care. Enteral feeding is the primary means of providing nutrition support to patients who cannot meet their needs orally; nursing time and supply costs to administer that care are substantial. One major academic medical center recently converted from an open system (OS) to a closed, or “ready to hang” (RTH) system for enteral feeding. This article reviews that transition from an OS to RTH and documents the costs, nursing perceptions, and lessons learned in the process.

Mallory Foster, Dietetic Intern, University of Virginia Health System Dietetic Internship Program Capstone Project Wendy Phillips, MS, RD, CNSC, CLE, FAND, Director, Nutrition Systems, Regional Clinical Nutrition Manager, Morrison Healthcare Carol Rees Parrish MS, RD, Nutrition Support Specialist, University of Virginia Health System, Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville, VA

INTRODUCTION

Healthcare costs in the United States are the highest in the world¹ and have become a major concern in recent years. At the same time, undiagnosed and untreated malnutrition in the hospital setting is an often undetected contributor to the growing cost of medical care in this country, as it can lead to further health complications and increased length of stay.¹ Thus, efforts to advance nutrition care should be emphasized as a means to improve patient outcomes and decrease the cost of healthcare. Nutrition care practices and protocols should be reevaluated routinely to ensure that resources are used effectively and efficiently.

Enteral feeding is the primary means of providing nutrition support to patients who cannot meet their needs orally. Enteral nutrition (EN) is a cost-effective way of delivering nutrition support,² has inherent benefits to the gastrointestinal (GI) tract, and is the standard of nutrition care over parenteral nutrition.³ Thus, anything that can be done to improve the efficiency, safety, and delivery of EN is a worthwhile goal.

Open Vs. Ready to Hang System

EN delivery is available in two main systems: an open system (OS) or a “ready to hang” system (RTH), also sometimes called a “closed system.” Using an OS, formula from cans or bottles is “bolused” into a feeding tube with a syringe, or poured into a feeding bag, then administered via a feeding tube into the stomach or intestine using a feeding pump or gravity drip. RTH comes in a sterile, pre-filled formula container (typically 1 liter) that is spiked by the feeding tube, and then fed to the patient via a feeding pump.⁴ Boluses can also be delivered using RTH by setting the feeding pump to deliver boluses at predetermined times. Both systems have advantages and disadvantages in several areas, including cost, ease of use, and nursing time required.

COST

Factors to consider when evaluating the cost difference between an OS and RTH include actual cost of the formula and tubing, nursing labor, transportation to hospital units, storage, and waste.

OS has been used for many years to deliver EN to patients. Based on current pricing contracts between the Medical Center and formula companies, OS costs less compared to the same volume of a RTH formula.^4,5 OS is also convenient when a small volume of formula is needed, as is the case with bolus feeding or in the pediatric population,⁴ yet it can lead to increased labor and equipment cost.^4-8 According to nursing procedures at some facilities, including the hospital in question, only the amount of formula that will be infused within 4 hours (although in the real world, we know how hard this is to achieve) is to be hung at one time in an OS. So nurses must refill feeding bags frequently, up to 6 times per day.⁹ The tedious protocol (see Table 1) may also occasionally lead to missed EN if the nurse
is unable to refill the bag in a timely manner when it runs out. Additionally, OS requires more handling than the RTH prior to administration, potentially increasing the risk of bacterial contamination.^4-8,10-13 Proper prevention methods to decrease the chance of bacterial contamination in the OS increase nursing time.⁷ The additional time used to ensure an OS system is safe could be spent conducting other nursing tasks.

RTH, also known as a closed system, was developed with the express purpose to reduce the nursing time required to administer EN and to decrease the risk of bacterial contamination by requiring less handling.^5,7 Most studies cite an increased amount of nursing time related to an OS as compared to a RTH;^4-6 in fact, Luther et al.⁶ estimated that administering formula using the OS doubles the required nursing time when compared to RTH in a hospital intensive care unit due to the additional steps required to administer the OS (See Table 1). Per manufacturer guidelines, RTH containers are approved to hang for up to 48 hours, yet available tubing sets are only approved to hang for 24 hours; hence, all RTH formula containers must be discarded at 24 hours as they cannot be spiked more than once.^7,8 Regardless, 24 hours is a significant improvement over every 4 hours – or up to 6 times per day – if a patient is on a continuous feeding regimen. Although RTH formula has a higher cost when compared to the same volume of OS formula,^4,5,7 cost savings may be realized through decreased nursing time, a potential decrease in nosocomial infection, and improvement in delivery of EN to patients.⁴ Actual practices at individual hospitals should be evaluated to determine if transition to a RTH from an OS achieves these goals.

Handling of EN Contamination of EN

Contamination of EN can occur during preparation if modular supplements (such as protein powder/liquid) are added to the formula, when the feeding is transferred to the administration container, during assembly of the feeding system, and during administration to the patient.^5,7,11 Clean technique and proper hand washing should always be used to prepare and deliver formula in both an OS and RTH.²

Potential risk reduction from nosocomial infection from contamination of EN influences some clinicians in the selection of an OS vs. RTH. Whereas only the formula itself is sterile in an OS (not the bag it hangs in), the entire RTH system is sterile because it is not exposed to the outside environment; it is therefore associated with a decreased risk of contamination.^13,14 However, prospective trials demonstrating this perceived benefit are not available. C. difficile infection is one of the most life-threatening infections associated with hospitalized patients, especially those on EN.^17,18 Any measures that can be taken to prevent bacterial contamination and a culture of safe practices surrounding the use of EN should be the goal.

Both OS and RTH EN formulas are sterile when packaged, however, once administration has begun, retrograde movement of bacteria from the GI tract via the feeding tube is possible in both systems,^7,12 as the GI tract is a source of a myriad of microbes.⁷ Studies have shown that retrograde movement of bacteria in EN feeding systems is very slow, and while bacterial contamination has been found in the distal portions of the feeding tube closest to the patient, bacteria did not reach the feeding container over a 48 hour hang time.^7,12

Storage

RTH formula containers should not have long-term exposure to light as some nutrients in the formula such as riboflavin, vitamin B6, and vitamin A are photosensitive. Recommended storage of RTH containers is on covered
shelves or in a closed cabinet prior to use to avoid vitamin degradation. The opaque packaging of the OS protects the formula from light during storage.

Volume of EN Delivered

Others have reported an association between longer hang times in the RTH and increased percentage of prescribed EN actually received by the patient.^19,21 Perhaps because of the longer hang time, Atkins and Phillips20 found that, on average, an OS provided patients with 74% (range 43-104%) of the ordered EN volume compared to 84% (range 59-101%) with RTH
at one major academic medical center. Though small, (n=60), this study suggests that the RTH may provide patients with a greater volume of their nutrient needs, and confirms results found in other studies.19,21

Product Waste

Formula waste can be a significant cost regardless of which system is used, and the limited research in this area is mixed. Some studies have shown that the RTH leads to decreased formula waste because the EN can hang longer and thus the full volume is delivered to the patient.^2,4,7 However, others have noted that RTH can lead to increased formula waste if the entire volume of the container is not used within the recommended
hang time or if hospital culture is difficult to change from years of switching all bags, tubing, etc. at a certain time each day regardless of expiration time of hanging formula.⁴ Further studies are needed to determine whether one feeding system generates less wasted formula than another.

Cost Analysis

To evaluate the difference in cost between the OS and RTH, purchasing data for an eight month period after transition from the OS to RTH was obtained from the hospital storeroom purchasing department. A small inventory of OS supplies and formulas continued to be purchased even after the transition to the RTH system since not all formulas are available in RTH
containers and because OS containers are used for teaching those patients discharged home on the bolus feeding method. Total cost for formula and supplies for both the OS and RTH systems during the 8 month study period was $109,297.54. For practical purposes of this descriptive study, it was assumed that the same actual volume of formula would have been purchased had the OS alone been used during the study period, the expenses for formula and related supplies would have been $104,470.16. Therefore, RTH cost $4,827.38 more over the 8 month period than would have been spent on the OS system. Since the study period was 8 months, the monthly average increase in overall cost is $603.42 (see Table 2).

Feeding supply costs were also factored in. Total expenses for feeding supplies after the transition to the RTH system, including the cost of bags and tubing required to deliver water flushes as well as the remaining OS products (excluding enteral formula), during the 8 month period were $52,795.99. Had the OS continued to be used, the money that would have been spent on the equivalent tubing and bags would have been $54,549.64 (see Table 2), for a difference of $1,753.65 in favor of RTH. Overall, considering cost of formula and supplies, the OS would have cost the Medical Center $3,073.73 less during the 8 months under consideration. On the other hand, nursing time with each system, a considerable expense, was not factored into the cost differences. An interesting finding was the total expenditure on the feed/flush bags vs. the feed bag alone (see Table 3).

Nursing Satisfaction Survey An Unexpected, but Important Finding

Cost analysis is an important component of evaluating the transition to a RTH, but also important is the effect on nursing satisfaction. A nursing satisfaction survey (see Table 4) was distributed on six hospital units
(n=92). Survey results showed nurses perceive that RTH requires less time to prepare, hang, and manage when compared to OS, which is consistent with other studies^6,21 (see Table 5). Nurses also reported that RTH was easier to use, and they perceived formula waste to be comparable between systems. Overall, respondents overwhelmingly preferred the RTH over the OS system: 88% compared to 12%. Nurses play a vital role in patient care, therefore anything that makes their job easier, takes less time, and improves nursing satisfaction is always a worthy goal.

Open text comments left on surveys and visits to nursing units also provided valuable feedback. Nurses reported confusion about which tubing sets to use and the appropriate hang time of RTH EN. Additionally, they reported that the appropriate feeding sets were sometimes difficult to find. Based on these comments, the clinical nutrition team was able to provide improved guidance for nursing staff and in the future expect to see a decrease in costs based on improved selection of appropriate tubing and more efficient use of RTH.

Limitations and Lessons Learned

Actual nursing time associated with delivery of EN was not quantified, making it impossible to attach a monetary value to the nursing time required. The number of patients receiving EN and volume ordered and
delivered were not recorded for the RTH or OS. Amount of wasted formula and supplies due to administration error, confusion about hang times, expiration, labeling errors, or other unknown factors were not evaluated because data was based on retrospective purchasing information. However, total costs spent by an institution on supplies required to deliver EN should be measured and tracked, especially related to administration error and supply management. Evaluating data obtained from the purchasing department, as in this study, provides a place to start.

Comments recorded on the nursing satisfaction survey and visits to the unit supply room’s revealed opportunities for education and process improvement. In the future, observing actual delivery of EN using the RTH and conducting a root cause analysis of systemic issues needed to improve delivery will be used to improve EN practices. Designing clean supply rooms so all supplies are located in a standardized location on all units with clear labeling is important at all healthcare facilities. Nursing education should be delivered in regular intervals in collaboration with both the nutrition and nursing staff, to include overcoming the barriers identified in this project as well as factors identified ia other means related to EN feeding (see Table 6).

CONCLUSION

When considering the advantages and disadvantages of an OS or RTH EN feeding system, the most important factors to consider are patient outcomes, ease of use, safety, and cost. Review of the literature reveals that both the OS and RTH can be safely delivered to patients when proper procedures are followed. A RTH may also provide patients with a greater percentage of their nutrient needs, ultimately leading to improved nutritional status and improved patient outcomes, but this will require further study. Although a RTH is more expensive per unit of volume when compared to the OS, it is possible that if the RTH saves nursing time, it may in fact be significantly less expensive due to savings on labor costs. Other factors that need to be considered are whether there is a decrease in infectious risk and waste. Although insufficient evidence exists to determine if a RTH is superior to OS in terms of cost, it clearly increases nursing satisfaction, and has been shown to increase delivery of EN which could also decrease hospital costs by reducing the incidence of malnutrition.

FRONTIERS IN ENDOSCOPY, SERIES # 23

Image-Enhanced Endoscopy for Neoplasia Surveillance in Inflammatory Bowel Disease

Margaret Blayney,

Michael Chiorean

The risk of colon cancer is increased in patients with both ulcerative colitis and Crohn’s colitis and therefore surveillance colonoscopy is recommended in patients with elevated risk factors for neoplasia. The guidelines developed during the era of standard white light endoscopy recommend targeted biopsies of visible neoplastic lesions as well as random biopsies to detect invisible dysplasia. The practical adoption of these guidelines has been thwarted by low yield and limited effectiveness in preventing colon cancer. Image-enhanced endoscopy and particularly chromoendoscopy have demonstrated an increased diagnostic yield for dysplasia while essentially eliminating the need for random biopsies. Although very promising, additional studies are needed to assess the utility of image-enhanced endoscopy and to demonstrate the superiority of these techniques in preventing colon cancer in IBD.

Margaret Blayney, MD¹ Michael Chiorean, MD² ¹Department of Internal Medicine and ²Division of Gastroenterology and Hepatology, Virginia Mason Medical Center, Seattle, WA

INTRODUCTION

It is well established that both ulcerative colitis (UC) and Crohn’s disease (CD) involving the colon increase the risk of colon cancer (CRC) although the magnitude of the incremental risk varies considerably with the epoch and the study population.^1-5 Risk factors for colorectal neoplasia include duration and anatomic extent of disease, family history of colon cancer, persistence and degree of inflammation, coexistent primary sclerosing cholangitis and possibly male sex. ^1-4,6-9 In contrast to sporadic colorectal neoplasia, colitis- associated neoplasms are more frequently multifocal and flat, thus being more challenging to diagnose particularly in an inflamed colon. Furthermore, colon cancer in patients with colitis tends to occur at a younger age compared to non-IBD patients.^10-12 As is the case with sporadic colon cancer, dysplasia is believed to be the precursor of the majority of cases of colitis-associated carcinomas and thus surveillance guidelines have been developed by several professional societies based on limited supportive evidence. In the era of standard- definition white light endoscopy, these guidelines called for surveillance colonoscopy every 1-2 years after 8-10 years of established disease, with removal of all visible “suspicious” lesions and adjacent biopsies around lesions removed from within the area of colitis. In addition, random 4-quadrant biopsies every 10 cm were recommended in order to increase the detection of “flat” or invisible dysplasia. Based on a mathematical model developed in the early ’90s, a minimum of 32 random biopsies were required to achieve a sensitivity of 90% for detecting dysplasia or carcinoma.^13,14 Aside from the tedious and time consuming approach, this strategy has never been clearly shown to be effective in preventing or increasing survival from colon cancer in patients with IBD. The yield of random biopsies for dysplasia obtained using both standard- and especially high- definition white light endoscopy (WLE) is extremely low (< 1:500 biopsies).^15,16 In a large retrospective series from the St Mark’s hospital, more than 50% of the colon cancers detected in a cohort of patients enrolled in a surveillance program were interval cancers.^11,17 Moreover, given the considerable costs associated with frequent colonoscopies and multiple biopsies, any marginal benefit of surveillance may not be cost- effective.^18,19 Therefore, not surprisingly, many studies showed that the compliance with these guidelines was poor.^15,20

Chromoendoscopy for IBD Surveillance

Since a substantial proportion of colon cancers in IBD can be attributed to missed or unrecognized neoplastic lesions using white light colonoscopy and the yield of random biopsies is extremely low, several image-enhancing techniques have been developed in order to maximize dysplasia detection and to facilitate the performance of targeted biopsies and polypectomies. Chief among these has been dye-based chromoendoscopy (CE) which has been evaluated in multiple prospective and retrospective studies mostly from referral centers. CE consists in the application of dye onto the colonic mucosa via either a catheter or using the water-jet channel provided with most colonoscopes. The stained mucosa enables a superior visualization of both elevated and depressed polypoid and non-polypoid lesions. In addition, particularly with the use of high- definition endoscopy, the pit pattern of the glandular crypts becomes visible and may help differentiate between neoplastic and hyperplastic or inflammatory pathology^21,22. Indigo carmine at concentrations of 0.2- 0.4% and methylene blue at a concentration of 0.1% are the most commonly utilized dyes. Indigo carmine is commercially available both as a solution and as a powder – which is less expensive – although recent FDA restrictions on the use of non-sterile compounds in medical practice have limited drastically the use of the latter. Methylene blue is available as a 1% solution in vials containing either 1 or 10 mL and, in contrast to indigo carmine, is an absorptive dye which can penetrate the epithelial cell cytoplasm.²³

Chromoendoscopy Technique

The technique of chromoendoscopy has been well described elsewhere.^24-26 Most experts recommend the inspection of the colon mucosa on insertion using either standard or high-definition WLE. This allows a good evaluation of the level of disease activity, lavage and suction of excess fluid from the colon, and the identification of gross abnormalities that can be sampled or removed upon withdrawal. A solution of 5 or 10% N-acetyl cysteine may be sprayed during the introduction of the scope in order to wash off the mucus layer and allow a superior staining of glandular crypts and an improved visualization of subtle abnormalities.²⁷ Once in the cecum, the stain is sprayed on withdrawal, either using the water-jet device provided with the scope or a dedicated spray catheter introduced through the operative channel.²⁴ The water-jet device is faster and less messy but uses a larger volume of dye compared to the spray catheters (average 250 mL). A disadvantage of spray-catheters is that they have to be removed and reintroduced each time a lesion that requires an intervention is discovered thus increasing the down-time during the procedure. In our center, we prefer sequential segmental staining of the colonic mucosa after the excess fluid was adequately removed. An excellent quality of the prep is paramount and the use of anti-motility agents is optional. Most experts recommend against the use of random biopsies in patients with adequate mucosal healing.²⁷ When significant inflammation or distortion of the lumen (including strictures) is present, or in patients with PSC, random biopsies should still be considered.

Diagnostic Yield of Chromoendoscopy

Regardless of the agents utilized, CE increases the yield of dysplasia by 2-5 fold per procedure compared to standard or HD WLE (Table 1). The per patient incremental yield for dysplasia with CE and targeted biopsies vs. WLE with random biopsies is approximately 7% with a number needed to test of 14. Conversely, the odds ratio for missed lesions with CE compared
with WLE is 0.07.²⁶ Although no head to head studies are available, data suggests that indigo carmine and methylene blue produce equivalent results.²⁸ Using decision-analytic models, CE was found to be both more effective and less costly compared with WLE regardless of the surveillance interval.²⁹ Given the consistent superiority of CE for neoplasia detection,
some professional societies such as the British Society of Gastroenterology and the European Crohn’s and Colitis Organization have endorsed CE with targeted biopsies as the preferred surveillance method in patients with UC and Crohn’s colitis.³⁰

Despite its obvious advantages, there has been a relatively slow uptake of chromoendoscopy in gastroenterology practices in the United States. Among the shortcomings, the most frequently cited are lack of basic knowledge and expertise, lack of opportunities for training during or after fellowship, a relatively slow and steep learning curve, variation in detection and resection skills, additional equipment requirements, the need for additional time for lengthy procedures and lack of specific procedure codes for reimbursement. The increased procedure time associated with CE – average 10 minutes – may be offset in part by obviating the need for random biopsies. In addition, some IBD thought leaders have questioned the significance of the incremental yield of CE for neoplasia as prospective outcomes studies evaluating the utility of CE for colon cancer prevention have not been performed. This seems somewhat counterintuitive as a very similar outcome, the adenoma detection rate, is widely considered a quality indicator of the adequacy of screening colonoscopy in the general population.³¹ Furthermore, there is ample indirect evidence of the benefit of CE from one of the largest and oldest UC surveillance programs in the world. A recent 40 year retrospective review of the data from the St Mark’s Hospital in the UK has shown that, although the rate of colectomy for dysplasia has decreased during the era of chromoendoscopy, the number of cases of interval cancer and advanced (Duke’s stage C and D) colon cancer diagnosed during surveillance has also decreased.³² This implies that more patients with ulcerative colitis who are diagnosed with dysplasia at surveillance colonoscopy are able to preserve their colon after the dysplastic lesions are removed, without the risk of dying from colon cancer. Furthermore, the negative predictive value of CE seems to be substantially higher compared with WLE; patients diagnosed with high-grade dysplasia or cancer during surveillance were twice as likely to have had a previous normal white light colonoscopy than a normal chromoendoscopy.³² Taken together, this data suggests that CE may be more effective at reducing the cancer risk compared with WLE. Obviously this is heavily dependent on the success of removing neoplastic lesions as they are identified.

Narrow Band Imaging for IBD Surveillance

Narrow-band imaging (NBI) available on the Olympus endoscopy system utilizes an electronically activated filter placed in front of the light source which allows only limited wavelengths of 415 nm and 540 nm (narrow band) of the white light spectrum to reach the mucosa. The blue-green light has a lower depth of penetration in the colon tissue and coincides with the optimal absorption wavelengths of hemoglobin. This makes blood vessels in the lamina propria appear darker against the white background of the mucosa and superficial submucosa.^33-35 Angiogenesis and abnormal capillary patterns have long been associated with neoplasia and thus NBI is considered superior to WLE for differentiating between neoplastic and hyperplastic polyps.³⁶ However, what may be an advantage in a healthy colon can become a limitation when evaluating mucosa in patients with colitis as the vascular pattern is diffusely distorted due to chronic inflammation. In addition, the pit pattern with NBI is not as neatly seen as with chromoendoscopy. NBI has been evaluated for IBD neoplasia surveillance in a few studies and was found not to be superior to high-definition WLE and was inferior to CE for detecting neoplasia in patients with chronic colitis (Table 2). The obvious advantage of all forms of “electronic chromoendoscopy” is that they are extremely accessible and easy to use; however their potential application in IBD surveillance is unclear.

The SCENIC Consensus Statement

As of 2010, the American Gastroenterology Association has endorsed colonoscopy with multiple random biopsies as the standard method for dysplasia detection in IBD based on the available evidence at that time.¹³ However, major advances in this field in the last decade have resulted in a significant variation in guideline recommendations among different gastroenterological societies throughout the world. In 2015, an international multi-disciplinary panel of experts was convened with the goal of developing unifying consensus guidelines for the diagnosis and management of dysplasia in patients with IBD. This process was based on an extensive critical review of the literature, used Institute of Medicine standards of guideline development and incorporated the GRADE methodology.³⁷ In order to standardize reporting for both clinical practice and research purposes, the panel recommended abandoning the confusing terms of DALM (dysplasia-associated lesion or mass) and ALM (adenoma-like mass) in favor of ‘endoscopically resectable’ or ‘non-resectable’and ‘polypoid’ or ‘non-polypoid’ lesions. The defining elements of the appearance and resectability of a lesion are diameter, height, symmetry and appearance of the margins, along with endoscopic and histologic evidence of successful removal. Needless to say, these features are therefore, to some extent subjective and operator-dependent. The other recommendations of the SCENIC consensus panel regarding the detection and management of dysplasia in IBD are listed in Table 3. Overall, the SCENIC panel has endorsed chromoendoscopy and high-definition imaging as superior methods for neoplasia detection in IBD; however the panel stopped short of relinquishing the need for random biopsies. The SCENIC authors acknowledge the controversy surrounding this issue as well as the technological and logistic hurdles for adopting chromoendoscopy as the standard surveillance method. Nevertheless, these guidelines represent a big first step in the right direction which will undoubtedly create the foundation for further research in this field.

CONCLUSION

In conclusion, despite its rather modest contributions in routine screening colonoscopy, CE is an endoscopic technique with fairly obvious advantages for dysplasia detection in patients with inflammatory bowel disease at high risk for neoplasia. There is a mounting level of evidence supporting its superior performance for surveillance in patients with chronic colitis. Over time, additional studies will likely strengthen the evidence on improved outcomes for dysplasia diagnosis and management and ultimately, survival from colon cancer and improvement in the quality of life in patients with IBD. While easier to use and more accessible than dye- based chromoendoscopy, electronic chromoendoscopy such as narrow band imaging has an as yet undefined role in colorectal neoplasia surveillance in IBD.

A CASE REPORT

Syphilitic Hepatitis

November 2015 • Volume XXXIX, Issue 11

Lauren M. Bleich,Howard L. Taubin

Lauren M. Bleich, MD, MPH Gastroenterology Fellow Bridgeport Hospital Yale New Haven Health, Department of Medicine, Section of Gastroenterology Howard L. Taubin, MD, Attending Physician Clinical Faculty, Bridgeport Hospital Yale New Haven Health, Department of Medicine, Section of Gastroenterology

A 21 year-old homosexual male presented to his primary care physician with a five-day history of right upper quadrant abdominal pain exacerbated by meals. He also endorsed generalized pruritis, dark urine and fatigue. He denied fever, chills, nausea or vomiting. He had no significant past medical history, and denied taking medications or supplements. His social history was significant for a history of intravenous (IV) drug use in the past and several tattoos. On physical exam, he exhibited mild tenderness to palpating in the epigastrum but the exam was otherwise unremarkable. Blood work demonstrated abnormal liver enzymes including aspartate transaminase (AST) 314U/L, alanine transaminase (ALT) 627U/L, alkaline phosphatase 317U/L, total bilirubin 2.1mg/dL and GGT 654U/L. Synthetic hepatic function was preserved with an INR of 1.0. Abdominal ultrasound was significant for increased echogenicity suggestive of fatty infiltration. A complete hepatitis panel including Hepatitis B DNA and Hepatitis C RNA viral loads were normal.

The patient’s alkaline phosphatase continued to increase over the next few weeks and peaked at 590U/L, while the AST and ALT decreased but did not return to the normal range. Two weeks after the patient’s initial presentation, he returned with symptoms including night sweats, a maculopapular palmar rash, and a painless penile chancre. A skin biopsy was performed of the left palm, which demonstrated the presence of spirochetes, consistent with the diagnosis of secondary syphilis (Figure 1). Rapid plasma reagin (RPR) and fluorescent treponemal antibody-absorption (FTA-ABS) tests were both reactive. The patient was treated with a single dose of benzathine penicillin G 2.4 million units intramuscularly and his symptoms resolved. Repeat liver enymes three months later were normal including an alkaline phosphatase of 47U/L.

Described by William Osler as the great imitator, syphilis is thought to originate from the area now known as Haiti.¹ The New World theory proposes that Christopher Columbus acquired the disease and carried it to Europe in the 1400s. By 1495, syphilis was widespread throughout the continent. In 1905, Treponema pallidum was linked to the disease. Throughout history, many famous people are thought to have been infected with syphilis, including Naopleon Bonaparte, Vincent Van Gogh, Beethoven and Mussolini.

Early syphilis is a reportable infection in the United States. It is estimated that one fourth of syphilis cases in the United States were reported in HIV-infected patients.² In the early 1990s, a mini epidemic of syphilis occurred, corresponding with increasing number of HIV cases. In 2010, the rates of infection are highest among the group of men age 20-24, and African American men are 15 times more likely to be infected than their Caucasian counterparts.³ Syphilis continues to remain a worldwide issue. In 2009, according to the World Health Organization, there were 3-4 million new cases of syphilis in each Southeast Asia, Sub-Saharan Africa and Latin America.⁴

Transmission of Treponema pallidum usually occurs through direct contact with an infectious lesion during sexual intercourse. The spirochete accesses the new host via disrupted epithelium at sites of minor trauma. Early lesions of primary syphilis, including chancres, mucous patches, and condyloma lata, are infectious and transmission occurs in one-third of patients exposed to these lesions. Syphilis can also be acquired by passage through the placenta. Median incubation time before the onset of clinical symptoms is approximately three weeks, but can range from 3 to 90 days.

The natural course of untreated syphilis is well documented in history. In the late 19th century, a Norwegian physician described the progression of infection in over 1,400 patients with primary and secondary syphilis. Between 1932 and 1972, data was collected on 431 African American men with untreated syphilis in Tuskegee, Alabama. Although separate stages, there is no clear demarcation between primary and secondary syphilis. As many as one-third of patients with secondary syphilis will still have a primary chancre present. It had been reported that up to 60% of patients with secondary syphilis do not recall having a skin lesion.⁵ This is particularly the case in the female population, where primary lesions tend to be internal.

Before 1980, only a few cases of syphilitic hepatitis were reported in the literature. Clinical manifestations are varied, but include jaundice, dark urine, malaise, anorexia and arthralgias, similar to our patient’s presentation. The most common finding is an abnormally disproportionate elevation of the alkaline phosphatase. Minor elevations of AST, ALT and bilirubin can be seen as well. Histologic preservation of the liver architecture is usually seen, with occasional granulomas and focal hepatocyte necrosis. Treponema pallidum organisms within the liver biopsy confirm the diagnosis, however more commonly the spirochete is demonstrated within other tissue samples. Non-treponema tests including RPR and VDRL are used for primary screening. Secondary treponemal testing (ie: FTA-ABS) are used to confirm the diagnosis.

Clinical symptoms of syphilitic hepatitis are likely due to dissemination of Treponema pallidum from the site of primary infection to the liver. The pathogenesis of liver injury is not well understood. Hypotheses include direct injury by the spirochete to the portal venous system and an immune complex-mediated autoimmune reaction.⁶

Treatment for primary, secondary and latent syphilis includes a single dose of benzathine penicillin G (2.4 million units IM). If the duration of latent syphilis is unknown, the patient should be treated with 3 doses of benzathine penicillin G at 1-week intervals. A patient’s symptoms should decline along with liver function abnormalities when appropriate treatment is given, thereby confirming the diagnosis. A Jarisch- Herxheimer reaction may occur within 24 hours of treatment. This acute febrile reaction, accompanied by headache and myalgia, is thought to be the result of pyrogens released from the dying spirochete into the body. All patients should have re-examination of clinical symptoms and serologies at six and twelve months following treatment. Syphilitic hepatitis should not lead to sequelae of chronic liver disease.

A SPECIAL SUPPLEMENT

Efficacy, Safety and Tolerability of Rectal Therapies in Ulcerative Proctitis and Ulcerative Proctosigmoiditis A Special Supplement

November 2015 • Volume XXXIX, Issue 11

Elisa McEachern,Brian P. Bosworth

Ulcerative colitis (UC) is a chronic condition in which inflammation extends proximally from the rectum along the colonic mucosa. Most patients experience alternating periods of active disease and clinical remission. In patients with ulcerative proctitis or ulcerative proctosigmoiditis, inflammation is limited to the rectum, or rectum and sigmoid colon, respectively. Induction of clinical remission is the primary goal of treatment for patients with active UC, whereas maintenance therapy is recommended for patients with UC in remission.

Ulcerative colitis (UC) is a heterogeneous disease that varies in the extent of affected colon and the severity of symptoms. Studies have suggested that at the time of diagnosis, approximately 46% of patients have inflammation limited to the rectum (ulcerative proctitis) or limited to the rectum and the sigmoid colon (ulcerative proctosigmoiditis). For distal forms of UC, a number of treatment options are available, including rectal and oral formulations. Rectal therapies (i.e., suppositories, foams, enemas) may be recommended for the management of patients with distal forms of UC, either as monotherapy, or in combination with oral therapies. First-line treatment for patients with distal UC is often 5-aminosalicylic acid rectal therapies, and is supported by a history of safety and efficacy in this patient population. However, second-generation corticosteroid (i.e., budesonide, beclomethasone dipropionate) rectal therapies have also been developed to treat active distal forms of UC. Despite the demonstrated safety and efficacy of rectal therapies for the induction and maintenance of remission of UC, rectally administered agents are widely underused and associated with nonadherence to treatment. However, decreased dosing frequency and the introduction of formulations of rectal agents that improve retention may increase use of rectal therapies and help to overcome barriers associated with nonadherence. Data support the use of rectal therapies for the induction and maintenance of remission of distal forms of UC.

Elisa McEachern, BS and Brian P. Bosworth, MD; Jill Roberts Center for Inflammatory Bowel Disease, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY. Elisa McEachern reports no conflicts. Brian Bosworth has received research grants from Pfizer Inc., Salix Pharmaceuticals, Inc., and Takeda Pharmaceutical Company Limited. Acknowledgments: Technical editorial and medical writing assistance was provided under the direction of the authors by Sophie Bolick, PhD, Synchrony Medical Communications, LLC, West Chester, PA. Funding for this support was provided by Salix Pharmaceuticals, Inc., Raleigh, NC.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon, characterized in most patients by alternating periods of active disease and clinical remission.¹ Common clinical symptoms of active UC include diarrhea, rectal bleeding, urgency, abdominal pain, and tenesmus. In one study, diarrhea was the most common symptom observed in patients with active UC, affecting approximately 65% of patients, with abdominal pain reported in approximately 34% of patients.² The majority of patients with active distal UC had rectal bleeding (i.e., 70% of patients with ulcerative proctitis [UP] vs. 33 to 37% of patients with more extensive disease). In another study, 96% of patients with active UC passed blood and mucus in their stool.3 Thus, management of symptoms of active UC, which may cause concern for patients, is one of the goals of treatment.^4,5

The prevalence of UC has been estimated between 206 and 263 per 100,000 persons in the United States, thus UC affects approximately 600,000 individuals.^6-8 While diagnosis of UC can occur anytime, age at diagnosis typically has a bimodal distribution, with the first peak observed during the 20s and 30s, and a second, smaller, peak occurring during the 60s and 70s.⁹ Although it is not clear whether differences in incidence based on sex are apparent, some studies have suggested that males have slightly greater incidence of UC versus females.^9,10 In general, patients with UC have the potential for a relatively long and variable disease course, associated with a substantial economic burden. Overall total costs for UC were estimated to be $390 to $920 million in the United States (in 2010 US dollars), with mean annual direct expenditures (health insurance and patient out-of-pocket costs) estimated at $8700 per patient.¹¹

Whereas the etiology of UC remains to be elucidated, both genetic and environmental factors are thought to play a role in the development of the disease. A number of susceptibility loci associated with genes involved in barrier function and inflammatory and immune responses have been implicated as potential genetic risk factors for UC.^12-18 Further, environmental exposures (e.g., hormone therapy, smoking status) have been associated with both increased and decreased risk of UC.^19-22

Ulcerative colitis is a heterogeneous disease that varies in severity (i.e., mild to fulminant) and extent of the colon affected.²³ Inflammation typically extends proximally from the rectum along the colonic mucosa.¹ At the time of diagnosis, approximately 46% of patients had inflammation limited to the rectum (UP) or to the rectum and the sigmoid colon (ulcerative proctosigmoiditis [UPS]).^2,23,24 Disease extent is not static, as approximately 45% of patients with an initial diagnosis of UP or UPS progressed to left-sided colitis or pancolitis after 5 years,² and approximately 20% and 54% of patients with an initial diagnosis of UP experienced proximal extension of disease after 5 and 10 years, respectively.²⁵

Most patients begin an intermittent disease course after resolution of symptoms associated with an initial disease flare.^26,27 Approximately 40 to 50% of patients with UC are in clinical remission at any given point in time, and 90% of patients experienced relapsing disease within 25 years of diagnosis.²⁶ However, 83% of patients with UC experienced disease relapse within 10 years; 54, 71, and 57% of patients with UP relapsed within 1 year, between 1 and 5 years, or between 5 and 10 years after diagnosis, respectively.²⁷ Treatment choice affects the disease course of patients with UC, both during active disease and during disease in remission.²⁶

Rectal Therapies for Treatment of Ulcerative Colitis

For patients with UC, the goal of treatment is multifaceted and includes symptom resolution, mucosal healing, induction and maintenance of remission, improvement in quality of life, and prevention of infirmity, surgery, and hospitalization.^1,4,28-32 Approaches to treatment depend on the extent and severity of disease, but the initial goal of treatment is induction of clinical remission.^4,5 Mild to moderate active distal colitis is typically treated with oral 5-aminosalicylic acid (5-ASA), rectal 5-ASA or steroids, or a combination of oral and rectal therapies.^4,5 Maintenance therapy is recommended for patients with UC in remission, to reduce the risk of symptomatic relapse.⁵ Rectal 5-ASA is recommended as first-line therapy for the maintenance of remission of UP, and recommended as an option for patients with left-sided colitis.⁵ Oral 5-ASAs are also effective at maintaining remission as monotherapy and in combination with rectal 5-ASA.⁵ Rectal therapies differ in their proximal distribution: suppositories are limited to the rectum,^33,34 whereas foams and enemas have been shown to reach to the proximal sigmoid colon and splenic flexure, respectively.^34-38 In patients with UP, suppositories may be the most effective method for targeting the rectum.⁵ For the sigmoid or descending colon, enema and foams may be considered, with the greatest distribution of drug in these locations occurring within 2 hours of administration of enema or foam in patients with UPS or left-sided colitis.³⁵

5-ASAs

Sulfasalazine, a combination of the antibiotic sulfapyridine with the anti-inflammatory salicylate, was developed in the 1930s as a potential treatment for rheumatoid arthritis.³⁹ Whereas the efficacy of sulfasalazine in rheumatoid arthritis was limited, sulfasalazine was subsequently found to have efficacy in UC.^40,41 Sulfasalazine was widely prescribed for the treatment of UC in subsequent decades, but its use was associated with some toxicity (e.g., nausea, vomiting, anorexia, headache).⁴² A seminal study by Azad Khan et al43 demonstrated that 5-ASA was the active moiety of sulfasalazine. Sulfasalazine is not well absorbed in the small intestine and passes through to the colon, where colonic bacteria cleave the diazo bond, releasing 5-ASA and sulfapyridine.44-47 Ingesting a pure 5-ASA moiety administered orally does not reach the colon intact,^42,48 and thus oral 5-ASAs have been developed with pH- dependent and delayed-release mechanisms to facilitate colonic delivery of active drug.^42-44 The advantage of these agents is a reduction in adverse effects compared with sulfasalazine.^49,50 However, unmodified 5-ASA can be administered rectally; for distal forms of UC, this allows direct delivery to the site of inflamed mucosa, while minimizing systemic absorption.⁵¹

Overall, the safety and efficacy of rectal 5-ASA for the induction and maintenance of remission of distal UC have been well established.^52,53 In randomized, double-blind, placebo-controlled studies, clinical and endoscopic remission were achieved by a greater percentage of patients with UP, UPS, left-sided UC, pancolitis, or distal UC receiving 5-ASA suppositories compared with placebo after 4 weeks (Table 1).^54-68 In addition, a once-daily dosing regimen had comparable efficacy with 2- or 3-times daily dosing of 5-ASA suppositories after 6 weeks in patients with active UP.^57-59 However, patients preferred once-daily administration compared with 3-times daily administration of suppository.⁵⁷ Furthermore, a greater percentage of patients with UP, UPS, or left-sided UC maintained remission for at least 1 year, and up to 2 years, with 5-ASA suppositories.^60-62

In randomized, double-blind studies, 5-ASA enemas had greater efficacy than placebo in patients with active UP, UPS, or distal UC after 6 weeks.^63,64 Remission or improvement (clinical, endoscopic, or histologic) was achieved by a greater percentage of patients on 5-ASA enema therapy for 4 weeks compared with placebo.⁶⁵ Patients receiving 5-ASA enemas demonstrated improvement in the physician’s global assessment score and a decrease from baseline in the mean disease activity index (DAI) score after 6 or 8 weeks.^63,64,66 In a study of patients with mild to moderate active UP and UPS receiving either 5-ASA enema or foam for 4 weeks, the majority of patients achieved clinical remission, and there was no apparent difference in the efficacy of 5-ASA enema or foam.⁶⁷ 5-ASA enemas were also efficacious for the maintenance of remission for at least 46 weeks compared with placebo in a clinical study of patients with left-sided UC.⁶⁸ Finally, in addition to demonstrated efficacy, 5-ASA suppositories and enemas had a favorable safety profile in a number of clinical studies.^{54,55,57-64,66-68}

Corticosteroids

Truelove first described the efficacy of rectal corticosteroids (i.e., hydrocortisone) for the induction of remission of UC in 1956.⁶⁹ In this study, 67% of patients with mild to moderate UC receiving hydrocortisone enemas nightly for up to 3 weeks achieved clinical remission, usually within days of initiating treatment. Corticosteroids are efficiently absorbed across the colonic mucosa, with an estimated 30 to 50% of administered hydrocortisone enema absorbed through the rectal mucosa.^70,71 Thus, the potential for serious adverse effects (e.g., diminished adrenal function, hypothalamic-pituitary-adrenal [HPA] axis suppression, metabolic bone disease, ophthalmologic impairment, cushingoid features, metabolic issues) associated with long-term corticosteroid treatment must be considered.^4,72 Second-generation rectal corticosteroid therapies, including budesonide and beclomethasone dipropionate (BDP), with high first-pass hepatic metabolism (∼90% for budesonide)⁷³ and limited systemic toxicity,⁷⁴ have since been developed.

Budesonide

Patients with active UP, UPS, left-sided UC, or distal UC achieved remission, and endoscopic and histologic improvement, following treatment with budesonide enema for 4, 6, or 8 weeks (Table 2).^75-83 However, a greater percentage of patients treated with 5-ASA enema compared with budesonide enema achieved clinical remission after 4 and 8 weeks.⁷⁷ A similar percentage of patients with active UP or UPS achieved clinical remission with budesonide foam and budesonide enema after 4 weeks.⁸¹ However, the majority of patients preferred the foam to enema (83.6 vs. 6.2%, respectively). A significantly greater percentage of patients receiving budesonide foam achieved remission, a Mayo rectal bleeding subscore of 0, and endoscopic improvement (Mayo endoscopy subscore ≤ 1) after 6 weeks compared with placebo.⁸⁰ Further, a greater percentage of patients with distal UC or UP maintained remission with twice-weekly administration of budesonide enema compared with placebo for 6 months.⁷⁶ However, it is unknown what effect increased frequency of dosing will have on the percentage of patients maintaining remission of UC. Once- or twice-daily administration of budesonide foam or enema 2 mg or 8 mg for 4, 6, or 8 weeks was safe and, notably, did not adversely affect the HPA axis in most patients with active distal UC.^{75,78-80,82,83} However, in one study, twice-daily dosing with rectally administered budesonide for 8 weeks significantly increased the incidence of impaired adrenal function compared with once-daily dosing.⁷⁶ It should be noted that studies have not explored the safety profile of these agents beyond 1 year.

Several baseline factors associated with response to treatment with budesonide enemas or foams have been identified.^80-82 Less severe disease at baseline was associated with improved response to treatment, as patients with mild disease (not defined) at baseline had significantly greater odds of achieving clinical remission after 8 weeks of treatment than patients with more severe disease (odds ratio [OR], 4.25; 95% confidence interval [CI], 1.72-10.48).⁸² Further, a second study demonstrated that a greater percentage of patients with less severe disease at baseline (i.e., clinical activity index [CAI] ≤ 8) achieved clinical remission (defined as CAI ≤ 4) following treatment with budesonide foam or budesonide enema for 4 weeks compared with patients with more severe disease (i.e., CAI >8; foam, 59 vs. 49%, respectively; enema, 71 vs. 47%, respectively; OR, 1.4; 95% CI, 1.01-2).⁸¹ However, extent of disease (i.e., UP or UPS) and disease duration (i.e., ≤5 years or >5 years) had no significant association with achievement of clinical response with budesonide foam or budesonide enema after 4 weeks.⁸¹ Finally, a significantly greater percentage of patients receiving budesonide foam achieved remission (i.e., Mayo endoscopy subscore ≤1, rectal bleeding subscore = 0, and improvement or no change in stool frequency subscore) compared with placebo when subgroup analyses of baseline disease (i.e., moderate disease, established disease, and extent of disease [UP, UPS]) and demographic (i.e., age, sex, white race, and smoking history) characteristics were conducted.⁸⁰

The absence of exposure to previous therapeutic modalities was also associated with improved response to either budesonide foam or hydrocortisone foam, as patients who had not previously received treatment with rectal 5-ASA had significantly greater odds of achieving clinical remission compared with patients with prior exposure to rectal 5-ASA (OR, 2.97; 95% CI, 1.05-8.37).⁸² However, a second study reported that a greater percentage of patients with previous response (not defined) to oral or rectal 5-ASA achieved clinical remission (CAI =4) after 4 weeks of treatment with budesonide foam compared with patients with no previous response to oral or rectal 5-ASA, although the findings were not significant.⁸¹ Lastly, a randomized, double-blind, placebo-controlled study of budesonide foam found that remission was achieved with budesonide foam versus placebo regardless of a previous (baseline) 5-ASA use.⁸⁰

Beclomethasone Dipropionate

Rectal formulations of BDP are safe and efficacious for the induction of remission of active UP, UPS, or distal UC, with improvement or induction of remission following treatment with BDP enema comparable with that of 5-ASA enema after 4 to 6 weeks (Table 3).^84-92 A comparable percentage of patients with active, distal UC receiving BDP enema or foam, or 5-ASA enema or foam, achieved remission or response at 4 or 8 weeks.⁸⁶ In both studies, patients in all groups achieved significant improvement from baseline in the DAI (total and subscale) scores and endoscopy scores after 4, 6, or 8 weeks of treatment.^84,86 The safety profiles of BDP and 5-ASA were favorable in patients with UP or UPS.^84,86

Whereas BDP enema and 5-ASA enema induced clinical and endoscopic improvement in the majority of patients with UP, and histologic improvement in approximately half of patients, after 28 days, the combination of BDP and 5-ASA resulted in greater efficacy than monotherapy, with all patients experiencing clinical, endoscopic, and histologic improvement.⁸⁷ The efficacy of BDP enema was examined in patients with UC in 3 randomized, double-blind studies.^88-90 Mulder et al89 found no differences in clinical, endoscopic, or histologic improvement between groups receiving BDP or prednisolone after 4 weeks, while van der Heide et al⁸⁸ demonstrated improvement from baseline only in endoscopic scores in patients receiving prednisolone enema after 4 weeks. Further, a similar percentage of patients receiving BDP and prednisolone enemas achieved clinical and endoscopic remission after 4 weeks.⁹⁰ However, in these studies, the safety profile of BDP was more favorable than that of prednisolone, with significant decreases from baseline in mean basal cortisol concentrations occurring after treatment with prednisolone, but not BDP.^88-90

Clinical remission, clinical response, and endoscopic improvement were achieved by a comparable percentage of patients receiving either BDP enema or betamethasone (BMT) enema in 2 randomized, double- blind studies of patients with active, distal UC after 20 to 28 days.^91,92 However, BDP had a more favorable safety profile compared with BMT, with steroid-related adverse events and suppression of adrenal function occurring with greater frequency following treatment with BMT.

Rectal and Oral Combination Therapy

Patients with more extensive active UC may benefit from a combination of oral and rectal 5-ASA therapies, as opposed to monotherapy with an oral or rectal 5-ASA (Table 4).^93-98 Rectal therapies target sites of inflammation typically affected by distal forms of UC,^24,33,35 but D’Incà et al.⁹³ found that mucosal concentrations of 5-ASA following the administration of both oral and rectal drugs were greater in the sigmoid colons of patients with UC compared with when oral 5-ASA had been administered alone. Thus, in patients who are refractory to rectal therapies alone, a combination of oral and rectal therapies may be warranted.^4,5

The addition of 5-ASA enema to oral 5-ASA therapy significantly increased the rate of remission compared with oral 5-ASA therapy alone after 8 weeks in patients with extensive mild to moderate active UC.^94,95 However, the percentage of patients with extensive mild to moderate active UC achieving clinical or endoscopic remission after treatment with a combination of 5-ASA enemas plus oral 5-ASA for 6 weeks was similar to that of patients receiving 5-ASA enemas alone.⁹⁶ The majority of patients receiving either 5-ASA combination therapy or oral 5-ASA alone achieved mucosal healing after 4 weeks.⁹⁵ Resolution of rectal bleeding within 7 days of study initiation occurred in a greater percentage of patients receiving combination 5-ASA therapy versus oral 5-ASA monotherapy.

The combination of oral 5-ASA therapy and 5-ASA enemas had greater efficacy than oral 5-ASA monotherapy in 2 randomized, controlled studies of patients with UC in remission for up to 1 year.^97,98 A greater percentage of patients with UC maintained remission following treatment with a combination of oral 5-ASA therapy and weekend 5-ASA enema compared with oral 5-ASA alone.⁹⁷ Similarly, the combination of oral 5-ASAs with twice-weekly 5-ASA enemas was more efficacious for the maintenance of remission of UC after 12 months compared with oral 5-ASA monotherapy.⁹⁸ Further, the results of a case- control study of patients receiving the combination of oral 5-ASA 1.6 g/day with twice-weekly 5-ASA 2 g/50 mL enemas for a median treatment period of 6 years demonstrated that patients receiving combination therapy had a significantly lower incidence of relapse (1.59 vs. 2.76, respectively; p = 0.034) and fewer hospitalizations.⁹⁹ The safety profile of combination oral and rectal therapies for the induction and maintenance of remission of UC was favorable.^94,96-98

Limitations Associated with the Use of Rectal Therapy

Rectal 5-ASAs are efficacious both for the induction and maintenance of remission in patients with mild to moderate distal UC, and rectal corticosteroids have demonstrated efficacy for the induction of remission in patients with active, distal UC. However, rectal therapies for UC are currently underused. A European study noted that a comparable percentage of patients with UP received oral or rectal therapy (29.5 vs. 25.6%, respectively); however, a greater percentage of patients with UPS received oral versus rectal treatment (42.8 vs. 6.9%, respectively).¹⁰⁰ The percentage of patients with UP and UPS receiving combination oral and rectal therapy was 13.2% and 17.4%, respectively. Further, during 1992-2009, the number of prescriptions for all 5-ASAs increased 72%, yet those for rectally administered 5-ASAs remained generally at the same level, with a decline in the overall 5-ASA market share from 11% to 9%.¹⁰¹ Oral 5-ASAs accounted for ∼70% of 5-ASA prescriptions in 2009. Patients with UC, prescribed rectal therapies at time of diagnosis, have a high rate of discontinuation of therapy, often as soon as 1 month. Data from a US health insurance database demonstrated that patients with newly diagnosed UC, or UP and UPS were commonly prescribed oral 5-ASA (53%) or 5-ASA suppositories (42%), respectively.¹⁰² Within 1 month, approximately 40% of patients with UC discontinued treatment with oral 5-ASAs, and approximately 70% of patients with UP and UPS discontinued treatment with rectal therapy.

Underuse of rectal therapy may be related to a combination of patient preference for oral therapy and potential inconvenience and technical issues with administration of rectal agents.^103,104 An important aspect of any treatment is patient adherence.¹⁰¹

Adherence to any treatment is particularly challenging during periods of remission in patients with UC, as demonstrated by prescription refill data that estimated that only approximately 40% of patients with UC were adherent to oral 5-ASAs.¹⁰⁵ Other factors associated with a greater likelihood of nonadherence to treatment among patients with UC included less extensive disease and receiving >4 concomitant therapies (OR, 2.5; 95% CI, 1.4-5.7). Patients with UC receiving rectal therapy reported difficulty with use during work hours (OR, 4.4; 95% CI, 1.5-12.5; p = 0.003), pain and bloating (OR, 2.8; 95% CI, 1.20-6.54; p = 0.013), and difficulty with use (OR, 2.4; 95% CI, 1.00-5.73; p = 0.043) as reasons for nonadherence. Additional issues were associated with the use of rectal therapy, including retention of the medication (i.e., duration, position), leakage, and stained clothing with enemas,¹⁰⁶ and difficulty with administration and with anal or rectal pain that occur in some patients using suppositories.⁶¹

Nonadherence to treatment has implications for the course of a patient’s disease, significantly increasing the risk of relapse compared with patients who are adherent to treatment (relative risk [RR], 1.4; 95% CI, 1.08-1.94; p = 0.014). Patient nonadherence to enemas was signif.icantly higher compared with oral therapies (68% vs. 40%, respectively; p = 0.001).¹⁰⁷ However, in a clinical trial comparing enemas and foams, the majority of patients receiving enemas and foams reported no retention problems, unpleasant feeling, rectal or abdominal pain, or flatulence.⁸¹ Thus, although the issue of adherence to therapy is complex, providing patients with treatment options that include less frequent dosing and simplified administration may improve adherence and, ultimately, lead to more favorable outcomes for patients.¹⁰⁴

Adherence is an ongoing issue in the overall management of UC.^105,108,109 Common issues associated with nonadherence to treatment in patients with UC may be overcome by allowing for more flexible dosing regimens (i.e., weekend dosing) and addressing problems with insertion and retention with different formulations of rectal therapies. Rectal therapies (i.e., budesonide foam) have shown favorable safety profiles in clinical trials and are preferred by patients to enemas.^81,83 These therapies have the potential to provide additional safe and efficacious options for healthcare providers treating UC. The most effective way to preserve adherence is to forge a therapeutic bond with the patient and discuss the duration of therapy. Additionally, seeing patients at least every 6 months may improve adherence to both oral and rectal treatment regimens.

In conclusion, this review of published data of rectal therapies, including 5-ASAs and corticosteroids, supports that these agents are well tolerated, safe, and efficacious for the induction and maintenance of remission of distal forms of UC. Furthermore, combination oral and rectal therapy is also well tolerated and efficacious for the induction of remission in patients with mild to moderate extensive UC compared with oral therapy alone, and should be considered in appropriate patient populations. Rectal therapies are an underused, yet valuable part of the management paradigm for patients with distal forms of UC. They may be appropriate as monotherapy or in combination with oral therapy for the induction or maintenance of remission of mild to moderate UC, depending on disease extent and patient considerations.

Funded by an unrestricted educational grant from Salix, a Division of Valeant Pharmaceuticals North America LLC.

FRONTIERS IN ENDOSCOPY, SERIES # 22

Endoscopic Cryotherapy: Indications and Efficacy

November 2015 • Volume XXXIX, Issue 11

Sylvia Nai-Yu Hu,

Douglas G. Adler

Although widely used in various fields of medicine, cryosurgery is a relatively new addition to the endoscopic armamentarium. Endoscopic cryoablation has been used in esophageal dysplasia and cancer, to treat bleeding caused by gastral antral vascular ectasia (GAVE) and radiation proctitis, and in other contexts. This manuscript will review the current applications of endoscopic cryotherapy as well as their efficacy and safety.

INTRODUCTION

Endoscopic cryotherapy is a technique to achieve destruction of abnormal tissue within the GI tract with extremely cold temperatures. Controlled freezing and thawing of target tissues with a cryogen can result in therapeutic clearance of damaging lesions, thereby potentially allowing the return of normal tissue to these sites. Although widely used in various fields of medicine, cryosurgery is a relatively new addition to the endoscopic armamentarium. Traditional mucosal ablations in gastroenterology have been preformed with non-contact and contact-based thermal sources. By using a non-contact cold source, a two-part obliteration process effectively treats in a way that spares the underlying extracellular matrices, theoretically allowing for improved healing. Endoscopic cryoablation has been used in esophageal dysplasia and cancer, to treat bleeding caused by gastral antral vascular ectasia (GAVE) and radiation proctitis, and in other contexts. This manuscript will review the current applications of endoscopic cryotherapy as well as their efficacy and safety.

Mechanism of Action

Cooper first described the phenomenon of liquid nitrogen cryosurgery and reported localized tissue necrosis occurring after a minute exposure to -20°C in the 1960s.¹ Further investigations of cryotherapy revealed cellular apoptosis occurred between -70°C and -158°C.^2,3,4 Endoscopic cryoablation is a non- contact method for achieving tissue destruction using a low-pressure spray of liquid nitrogen or carbon dioxide as the cryogen. A cryogenic approach yields tissue injury via two distinct pathways: immediate and delayed destruction.^1,2,3,5 Immediate tissue destruction is accomplished by placing hypothermic stress on target cells; forcing cells into a low temperature environment causes a decrease in cellular metabolism. Once cells are exposed to freezing temperatures, water crystalizes to create a hyperosmotic extracellular matrix that withdraws water from the cells. As the water crystals grow and propagate, cells continue to shrink and cellular membranes and constituents are damaged. During the freezing stage, cells die in response to dehydration and cellular membrane and organelle disturbances.

Following the freezing cycle comes a thawing period that yields more immediate tissue destruction.^2,4 During the thawing process, the extracellular matrix becomes briefly hypotonic which encourages water to flow into the already damaged cells. This influx results in cell volume increase that may rupture the cell membrane.^1,4 When the tissue reaches -20°C to -25°C, the process of recrystallization is maximized. The hypotonic extracellular matrix created by thawing also contributes to an electrolyte disturbance. The resultant high solute concentration in the extracellular matrix that lowers the freezing temperature while a low solute concentration (due to the influx of water) in the cells favor more ice crystal formation and fusion to further damage the cellular organization.6 Completion of the thawing process is followed by additional rapid- freeze/slow-thaw cycles as needed, often 1-3 additional cycles in practice. After thawing is complete, affected tissues remain hypothermic for several minutes.¹ By immediately freezing the target tissue again, an enhanced cooling rate is accomplished that favors more intracellular ice crystal formation across a larger and deeper number of cells. The increase of crystallization creates extensive cellular membrane and organelle disturbances that ultimately cause cell death.^2,3,5

The delayed effects of cryoablation start hours after treatment and can continue for days.² Once the frozen lesion thaws, the treated tissue looks normal, but the rapid change from freezing-induced vasoconstriction to vasodilation seen during thawing compromises capillary integrity. Microcirculation in treatment area is subjected to edema, increased vascular permeability, platelet aggregation, and microthrombi formation.^1,4 The consequence of all these events is a decreased blood flow that results in vascular stasis. The combination of anoxia and necrosis in the target area leads to the apoptosis of target cells that survived the immediate tissue damages.³ This delayed damage is important for the periphery of the treatment area. The cells bordering the cryogenic legion may not have been exposed to enough cryogen to face immediate damage. The delayed effects “clean up” the peripheral tissue and induce apoptosis, thereby expanding the area of tissue death. Thus, cryotherapy yields a complete ablation of the target area while sparing the foundational extracellular matrix for normal tissue regeneration.⁷

By inducing apoptosis, cryoablation has the unique ability to stimulate immunological response to the target cells.^1,2,3,4 The inflammatory environment created by the ablative damage recruits cytotoxic T-cells and favors a Th1 response to antigens released by apoptotic cells. In the case of tumors/malignancies, the immune response could hypothetically create antitumor activity that can extend outside the original treatment area, although this remains unproven at this time.^2,3

Endoscopic Cryotherapy

Currently there are two cryoablation systems in the market that are used in gastrointestinal endoscopy: the liquid nitrogen-based CryoSpray Ablation System (CSA medical, Baltimore, Maryland, USA) and the carbon dioxide-based Polar Wand cryotherapy device (GI supply, Camp Hill, Pennsylvania, USA).^8,9 Both systems use cryogens that expand as they warm. The expanding nitrogen or carbon dioxide gases place patients at risk for gastrointestinal perforation, and need to be evacuated from the patient during the procedure. A 20-second liquid nitrogen treatment can expand into 6 to 8 liters of gas.³ In order to avoid perforation, the CryoSpray system uses a nasogastric and/or orogastric decompression tube.^2,6,7,10,11 The decompression tube is composed of two channels that perform passive ventilation and active suctioning to control gas build-up during treatment.⁹ Abdominal palpation is often performed during procedures to ensure full decompression.⁶ Polar Wand cryotherapy needs to be set at a flow of 6 to 8 liters of CO2 per minute to accomplish maximum tissue damage.^3,6 In contrast to the nasogastric and orogastric ventilation system, the Polar W.I.N.D. uses a suction catheter that is attached to the tip of the endoscope to remove gas distension throughout the procedure.⁶

Liquid Nitrogen versus Carbon Dioxide as Cryogen

There have been extensive studies involving both cryogens in the role of endoscopic cryoablation. A low-pressure (2-4 psi) spray of liquid nitrogen exposes target tissues to a minimum temperature of -196°C. In comparison, high pressure (>500 psi) carbon dioxide relies on the Joule-Thomson where rapid expansion of the gas at room temperature creates a cooling effect of -78°C.^12,13 Although the two cryogens differ by more than a 100°C, the lowest temperature accomplished by both gases are more than sufficient to induce cellular apoptosis.¹ The drastically lower temperature of liquid nitrogen translates to the potential to ablate larger areas and deliver a greater depth of treatment.⁷ The disadvantage to this super-low temperature is frequent stiffening and subsequent immobility of the endoscopic equipment in practice. Having the ability to deliver -196°C often results in freezing of the endoscope and catheter which may sometimes make it difficult to continue treatment and remove the scope.³ To avoid complications, liquid nitrogen treatments need a heating circuit built into the catheter for easy removal and a warm air pump to maintain mobility of the equipment.^3,6 This additional heating system is not necessary for a CO2 system because -78°C does not pose a danger to freezing the catheter and endoscope with use.

Although carbon dioxide does not carry the risk of freezing the endoscope or delivery catheter, the combined ventilating-endoscope probe is bulky and can be difficult to navigate through the esophagus.⁶ Another problem with using the CO2-based Polar Wand Cryotherapy device is lens fogging that compromises visualization during procedures.³ The Liquid nitrogen system, CryoSpray Ablation System, places a clear plastic cap at the end of the endoscope to decrease fogging during procedure.

Liquid nitrogen has been successfully used for more than 5 decades in various fields of medicine such as dermatology, oncology and ophthalmology. Added to its familiarity, liquid nitrogen is an attractive cryogen because it is a readily available, inert agent.^3,6,7 However the cost of using liquid nitrogen is higher than the cost of using carbon dioxide for several reasons. Foremost is the price of the CryoSpray Ablation system being higher than the Polar Wand Cryotherapy System.^6,14 To enter a liquid state, carbon dioxide gas needs to be compressed under intense pressures (60.4 psi). The reliance of pressure allows this cryogen to be stored at room temperature.^2,6 In contrast, liquid nitrogen’s cryogenic properties are reliant on being stored between -195.8°C to -210°C; therefore it needs to be stored in an expensive refrigerant system that can maintain the necessary temperature.^2,15 As stated before, liquid nitrogen uses a low-pressure spray to achieve therapy, so a 25 W external energy source is necessary for it’s delivery to target tissues.^5,8

Although there is no study directly comparing the efficacy of ablation by the two cryogens, carbon dioxide and liquid nitrogen are commonly used in treating Barrett’s esophagus and esophageal malignancies. The various studies will be discussed later in this paper but the results reflect high success rates when either cryogen is used. Along with favorable outcomes, both carbon dioxide and liquid nitrogen have similar minimal adverse effects.

Technique and Dosimetry

For endoscopic cryotherapy performed in the context of upper and lower endoscopy, standard preparations are required.^3,16 For esophageal cryotherapy, some recommend the addition of a high dose proton pump inhibitor (PPI) if the patient is not already on an regimen, at least one week before the first session and maintained throughout the length of treatment, although this is not universally performed.^3,8,17

Endoscopic cryotherapy treatment is typically delivered over multiple sessions. The number, duration, and time between the sessions are all variable based on the condition being treated and the severity of disease. At each session, a variable duration and number of freeze-thaw cycles will be administered to the several sites of the target tissue. During the freeze-thaw cycle, time of freezing starts after the frozen lesion is formed and thawing time is that amount of time necessary for the frosted lesion to return to normal mucosal appearance.^1,8

The amount of variability with treatment is due to the lack of studies concerning cryoablation dosimetry and clinical outcomes in humans.^3,8,9 In general, depth and degree of tissue destruction is proportional to the number of freeze-thaw cycles, the distance from the cryogen release point, and the duration of freezing.⁹ Initial dosimetry experiments based on short-term results have been conducted in animal models for both carbon dioxide and liquid nitrogen.⁸ Johnston et al.tested liquid nitrogen dosimetry effecting swine esophagus by varying freeze times from 10 to 60 seconds. The resultant tissue destruction ranged from superficial mucosal inflammation to submucosal necrosis without correlation to the freeze time.⁸ Raju et al. completed a similar study using varying freeze times (15 second to 120 seconds) with carbon dioxide as the cryogen on swine esophagus. Resultant range of tissue destruction was dose-dependent: 15 seconds of CO2 cryospray yielded minimal mucosal necrosis, 30 seconds of cryospray involved submucosal damage and 120 seconds of spray extended damage to the muscularis propria.¹⁵

There are several major contraindications to endoscopic spray cryotherapy.^2,3,8 In general, cryospray should be avoided in pregnant patients or if food is present in stomach and proximal duodenum.⁸ The lack of extensive studies involving cryotherapy and pregnancy means that effects of treatment are unknown.³ The presence of food is in the gastrointestinal tract may compromise decompression and ventilation efforts that may increase the risk perforation.^2,3 Cryogens should, in general, not be applied to compromised tissues.8 The presence of mucosal breaks or ulcerations promotes transmural necrosis by the cryogen that allows improper communication with the mediastinum or peritoneum that manifests into larger problems.³ Patients undergoing cryotherapy may be at increased risk if they have anatomic variations or alterations that could complicate equipment passage during treatment and gas decompression efforts.^2,8 Examples of such alterations include strictures, eosinophilic esophagitis, loss of tissue elasticity, or bariatric procedures that all increase the risk of perforation.^3,8,12

Indications for Endoscopic Cryotherapy
Gastral Antral Vascular Ectasia

Gastral antral vascular ectasia (GAVE) is the term used for the presence of friable gastric mucosal microscopic vessels. GAVE is a cause of iron deficiency anemia and can sometimes cause acute upper gastrointestinal (GI) bleeding. Accounting for 4% of non-variceal upper GI hemorrhage, GAVE is likely under-diagnosed; the true prevalence of the condition is likely unknown.^16,18 First described in 1953 by Rider et al., there is still mystery surrounding its pathogenesis and treatment.^16,18,19 GAVE in its classical presentation is called “watermelon stomach” due to the longitudinal stripes of erythematous vessels running from pylorus to the antrum along the antral rugae. The second form of GAVE presents as diffuse angiomas studding the antrum and is usually related to liver cirrhosis and/or portal hypertension.^16,18 In both forms, GAVE is primarily limited to the antrum but there have been cases arising in other GI mucosal sites including other parts of the stomach, duodenum, and rectum.¹⁸

Endoscopic ablation by argon plasma coagulation (APC) is the current gold standard endoscopic treatment for GAVE.^16,18,19 APC is a non-contact technique that generally avoids deeper mucosal damage and therefore decreases the risk of perforation. APC results in superficial mucosal ablation and destruction of the offending blood vessels in patients with GAVE. As the gastric wall reconstitutes itself, the tissue regrows without the offending vessels. APC results are generally favorable, with some rare reports of post-treatment complications such as antral stenosis from scarring.¹ APC can rarely result in inflammatory or hyperplastic polyps that can evolve to become future bleeding sources.^18,19 GAVE often presents as large, diffuse involved areas in the antrum and APC is the most commonly used treatment for this illness.¹⁹

Cryotherapy is a novel treatment for recurrent and non-APC responsive GAVE. Cryoablation is potentially advantageous in treating GAVE because it is able to treat large lesions with the non-contact spray and promote normal epithelial regrowth after mucosal or submucosal damage.^16,18 Using cryoablation as a secondary line of GAVE treatment is somewhat less appealing as it requires the purchase and training of specialized cryoablative equipment. Without proper dosimetry studies, variability in spray duration, number of cycles, and sessions are problems when using cryoablation. Although there is favorable improvement after treatment completion, several sessions are needed to accomplish a sustained response and long-term efficacy of cryoablation is not well studied.²⁰

In a small pilot study of cryotherapy and GI mucosal bleeding by Kantsevoy et al., 7 out of 26 participants were undergoing treatment for GAVE.²¹ All of the participants for the study had previously underwent endoscopic treatment but continued to have active bleeding. Using nitrous oxide as the cryogen, GAVE patients were considered responders to cryotherapy treatment as there was no evidence of subsequent melena and hematemesis as well a stable hematocrit level on follow up. Nitrous oxide is no longer widely used as a cryogen. After an average of 3.6 cryotherapy session, 5 out of the 7 (71.4%) of the GAVE patients displayed control of their upper GI bleeding. In all 26 patients, only one patient developed transient abdominal pain that was unremarkable in CT scan.

In a pilot study using CO2 to treat GAVE, Cho et al. recruited 12 recruits that fit their inclusion criteria.¹⁶

Of the 12 total participants, 8 had GAVE recurrence or failed prior APC treatment. Participants underwent three cryotherapy treatments that averaged 5 minutes, however CO2 spray duration decreased with following appointments. In 4 out of the 36 preformed sessions, less than 90% of the GAVE lesion was treated due to technical problems concerning overtube placement (1/4), cryogen unit (1/4), and learning curve of the endoscopists (2/4). In the other 32 treatments, more than 90% of the lesion was treated. Success of the procedure was determined by 3 month post-treatment hemoglobin levels and amount of blood transfused to counter participant blood loss from the ailment. The study had 6/12 patients achieve a complete response. In this group, there was an average of 2.6 g/dL hemoglobin increase and decrease of 5.7 units of blood transfused after three sessions of treatment. The remaining 6 participants experienced partial response with a 0.1 g/dL increase in hemoglobin levels and a decrease of 0.2 units of blood transfusion. There were four cases with minor adverse effects to the cryotherapy. Three patients developed asymptomatic antral scarring and ulcerations. During placement of the overtube, one patient experienced bleeding from a tear in n Schatzki’s ring that was managed with an adrenaline injection.

Radiation Proctitis

Radiation proctitis is common complication from pelvic radiation therapy especially in the treatment of anal, prostatic and gynecologic malignancies.²² Radiation damages the colorectal mucosa to produce endothelial dysfunction, fibrosis, microvascular injury, and neovascular lesions.^23,24 The neovascularization of the rectum is often the most prominent feature and the one typically requiring treatment. Radiation proctitis can have an endoscopic appearance very similar to that seen in the stomach in GAVE, with innumerable small mucosal vessels that are friable and lead to blood loss, both acute and chronic. Radiation proctitis manifests in two forms—acute and chronic; both forms presents as rectal pain and bleeding, diarrhea, tenesmus and passage of mucus with stools.²² The acute form is a more mild presentation of radiation proctitis. It commonly shows within 3 months after radiation treatment and is self-limiting with the discontinuation of radiation.^22,23,24 On endoscopy, lower colonic mucosa appears edematous and erythematous with possible ulcerations. Microscopically, there is microvillus disruption or loss due to processes of hyperemia, edema Figures 2d, 2e, and 2f. These images show the progressively deeper freezing of the lesion during the treatment cycle. Not that the cryotherapy is focally targeted onto the lesion of concern but there is some local effect in the surrounding tissues.

Chronic radiation proctitis (CRP) is a more severe disease that affects 2-20% pelvic radiation cases.²⁵ Symptoms of CRP present 8 to 12 months after completion of radiation therapy. As the disease progresses from an acute presentation, compromised blood supplies to the lower colon progresses to ischemia and fibrosis that increases the risk of obstruction and perforation.^22,24,26 On top of normal radiation proctitis symptoms, CRP also presents with severe bleeding and fistula. Endoscopically, CRP effected colons appear pale with telangiectasias and may also have strictures, ulcerations and fistulas.²⁷ Biopsy analysis exposes focal destruction and fibrotic change in small arteries.²² The persistent bleeding cumulates into iron deficient anemia requiring patients to undergo transfusions.²³ With its symptoms, CRP negatively impacts patients’ daily activities and quality of life.

In the small pilot study of endoscopic cryotherapy by Kantsevoy et al., 7 of the 26 patients recruited were undergoing secondary cryoablation treatment for radiation proctitis.²¹ During the study, participants were monitored for reduction in melena and hematemesis as well as improvement to hematocrit levels. The 26 participants underwent an average of 3.4 sessions and follow up endoscopy at 3 and 6 months. Cryotherapy had the best response in the radiation proctitis patients, where 7 out of 7 showed reduction of bleeding.

Hou et al. conducted a prospective study on the tolerability and efficacy of cryoablation in treating CRP.²⁵ Ten participants (all male) were recruited and underwent CO2 cryoablation. The participants received a single treatment composed of three sessions of 5 second freeze followed up by 45 second thaw. Follow- up endoscopy was performed an average of 3.3 months after treatment. Seven out of the 10 participants showed improvement in symptoms and on endoscopy. The rest of the patients (3/10) showed no change before and after treatment. In general, the patients tolerated cryotherapy well with prevalent adverse effect of discomfort during and immediately after. Two cases experienced complicated adverse effects. One of the patients experienced cecal perforation from distension caused by decompression tube failure and another patient developed a rectal ulcer post-treatment that healed on two subsequent endoscopies.

In another study, liquid nitrogen cryotherapy was used on ten patients (9 males and 1 female) with CRP.²⁸ None of the participants used prior pharmaceutical agents and 3 of the 10 previously underwent APC without improvement. Four cycles of 10 second freezing time and 90 second thawing time was performed per treatment. Participants received up to four treatments with four-week intervals or until symptoms resolution were achieved (6/10 received one treatment, 2/10 received two, 1/10 received three, and 1/10 received four). Of the ten participants, 7 reported their primary complaint as rectal bleeding; 6 of those 7 participants saw improvement in their bleeding. Overall 9 out of 10 participants reported relief from rectal bleeding and pain as well as overall wellbeing. Overall, the participants tolerated the cryotherapy well with one patient suffering from cecal perforation due to distension during treatment.

Barrett’s Esophagus and Esophageal Malignancies

Barrett’s esophagus (BE) is pre-cancerous condition of the distal esophagus where the normal squamous epithelium is replaced with goblet cell-containing columnar cells. BE is often a consequence of long- standing, uncontrolled gastroesophageal reflux disease (GERD), although some patients can develop BE in the absence of GERD symptoms. Generally, BE is treated as early possible because it’s progression from a low-grade dysplasia (LGD) to a high-grade dysplasia (HGD) is associated with an increased 30 fold risk of developing esophageal adenocarcinoma, a cancer with a 5 year survival of only 5-15%.^3,4,10 Globally, esophageal malignancies (encompassing esophageal adenocarcinoma and squamous cell carcinoma) are the eighth most common cancer and the sixth most common cause of cancer mortality.²⁹

BE is not a self-limiting condition and does not typically resolve when patients are treated with GERD medication therapies therefore specific treatment can be performed to prevent progression to malignancy. BE treatment includes esophagectomy, the standard care for early stage cancer, of the affected part and endoscopic ablation of the dysplastic lesion, although this is essentially only performed in patients with high-grade dysplasia in whom the risk of cancer is felt to be very high.^4,5,7 Ablative therapies destroy the pre-cancerous portion of the esophagus in a controlled fashion to allow normal re-epithelization. Radiofrequency Ablation (RFA) is the most studied ablative technique and is most commonly applied to patients with BE and dysplasia, either low-grade or high-grade. RFA can be used in a circumferential and focal ablative fashion to treat BE with LGD and HGD. It is associated with an excellent safety profile. When used in cases with previous mucosal resections or longer segments of disease, strictures have been seen on follow up in 1-8% of patients.¹⁰ RFA remains the most widely studied and used therapy to ablate BE.

Cryotherapy has often been used to treat refractory or recurrent BE after other forms of ablation, most commonly RFA. (Figure 1) In a pilot study using cryotherapy to treat BE, 11 patients were enrolled from a BE registery into a prospective study.¹³ The 11 participants had an average BE length of 4.6 cm. (range 1-8 cm) and had dysplasia ranging from no dysplasia to multifocal HGD. Liquid nitrogen treatment was applied in a hemi-circumferential fashion in monthly intervals until BE reversal was confirmed with biopsy. Each session was composed of varied cycles (maximum of three depending on the length of the BE) of 20 second freezing followed by complete thawing. An average of 3.6 treatments (range 1-6 treatments) were performed in this study. Nine out of the 11 participants completed the study with evidence of BE recovery. At the 6-month follow up, 2 out of the 9 patients showed presence of columnar cells distal to the squamo-colmnar junction while the other 7 patients still had complete histological BE eradication. Patients generally tolerated cryotherapy well. There were 2 cases of mild post- treatment complications: one patient reported solid- food dysphagia and another experienced chest pain. Both episodes resolved within a day of onset.

Dumont and colleagues further explored the potential of liquid nitrogen cryoablation by evaluating it’s efficacy in treating BE with HGD and intramucosal carcinoma (IMCA).³⁰ In this study, 30 participants were enrolled who were diagnosed with either HGD or IMCA and were deemed inoperable based on co- existing conditions or personal choice. The patient pool for this study was quite complex in makeup; 8 patients had previously received ablation therapy and the average BE length for the group was 6.1 cm (range 1-15 cm). A mean of 5 cryoablative treatments (range 3-6) were delivered at 6-week intervals until disease resolution or progression was observed. During each appointment, 3 to 6 sites would be treated. Dosimetry was initially performed at 3 cycles of 20-second spray time but was changed half way through the study to 4 cycles of 10-second spray time to decrease the amount of gas generation in response to a serious adverse effect that will be discussed later.

The study had four follow up appointments, with a median follow up at 12 month after treatment completion. At median follow-up, 92% of the HGD patients and 80% of the IMCA patients showed histological improvement; this accounts for 27 out of 30 participatants. Complete eradication of dysplasia was seen in 32% HGD patients and 40% IMCA patients. At final follow-up, 22 out of 30 patients were alive and cancer free. Minor complications of cryotherapy were self-resolving after 1-3 days post-treatment. The most common side effect was heartburn-like pain that was reported in 7 patients. Three of the 7 patients required narcotic analgesics due to severe pain that lasted up to a week. Three patients developed strictures that needed endoscopic dilation. While using the initial dosimetry protocol, a serious adverse event occurred in a patient with Marfan’s syndrome. Gastric overdistention from nitrogen gas production resulted in a gastric perforation. Surgical repair was performed and the patient was no longer treated with cryotherapy.

Greenwald et al. completed a liquid nitrogen based cryotherapy study in the treatment of esophageal cancers in patients who were ineligible or refused conventional esophagectomy.7 This multicenter, retrospective study recruited 79 participants (64 men and15 women) comprising 74 cases of adenocarcinoma and 5 cases of SCC. The average length of both cancers was 4.0 cm. (adenocarcinoma range 1-15 cm, SCC range 1-12 cm.) and 53 patients had undergone previous treatment for their malignancy. Participants underwent a median of three treatments (range 1-25) consisting of three sessions over 1-5 sites composed of 20 second freezing followed by 40 second thawing. Of the 79 participants that were recruited, 49 subjects were available for analysis while the other 30 were still receiving treatment. Patients who were available for analysis had various tumor stages: 36 cases were T1, 10 cases were T2, and 2 cases were T3. Complete response to cryotherapy was achieved in 30 out of the 49 patients: 26 T1 cases, 3 T2 cases and 1 T3 case. Of the patients who completed treatment, three of them received concurrent alternative treatments including endoscopic resection, chemotherapy, PDT, RFA, and APC. No serious adverse effects were reported. Ten of out 79 participants developed benign esophageal strictures but all ten of these patients had received previous treatment and nine of the ten had narrowing before initiating cryoablation. Twenty patients were administered narcotic analgesics due to post-cryotherapy pain.

Success in treating BE with carbon dioxide based cryotherapy appears to be comparable to those achieved with liquid nitrogen. A pilot study focused on BE was performed by Xue et al. and included 22 participants (14 males and 8 females).³¹ The patient pool had an average BE length of 2.6 cm. (range 1-6 cm.) and two participants had previously undergone APC therapy. Participants underwent a median of 2 treatments (range 1-3 treatments) at dosimetry of 5-7 cycles of 20-30 second freezing followed by complete thawing. Out of 22 patients, two declined to continue cryotherapy treatments. The remaining 20 patients had complete eradication of BE immediately after treatment. At 6 month follow-up, three patients developed recurrence of BE and two were lost during the follow-up interval. Cryoablation was well tolerated by the patients in the study. Two patients complained of mild chest discomfort that resolved without intervention. After two sessions, three patients developed esophagitis and one was found to have a small ulceration. All three cases were successfully treated with an omeprazole regimen.

The role of carbon dioxide cryoablation in the treatment of neoplastic BE was reported in two separate studies. Canto et al. evaluated the effects and safety of cryotherapy in 68 participants.¹⁷ The average length of BE for the group was 5.3 cm. and 47 patients had failed previous treatment. Early in the study, dosimetry was set at 4-8 cycles of 10-second freeze and 30-second thaw. Later in the study, cryogen dosage was increased to 15 seconds for 6-8 cycles. At study completion, 64 patients were deemed evaluable and of those, 56 showed complete response to the cryoablation. Of the patients with complete response, cryotherapy was the primary intervention for 29 patients and secondary for the remaining 27 patients. During the course of the study, two patients had to be hospitalized for post-treatment complications of bradycardia and presence of mild sub- diaphragmatic gas. Six other patients experienced mild complications that were resolved or addressed without hospitalization.

Verbeek et al. evaluated 10 participants, three of which had BE with HGD and seven had intramucosal carcinoma (ICM).³² None of the participants had received previous treatments for their diagnoses and EMR procedures were performed in the presence of abnormal nodules before initiation of cryotherapy. Cryoablation was performed at four week intervals until elimination of BE mucosa or for a maximum of 7 treatments. A median of 2.5 treatments was performed and 9 of the participants had nodular lesions resected. At 6-month follow-up, one patient had passed away for reasons unrelated to their disease so the participant pool was reduced to nine patients. A total of 5 of the 9 participants (one with ICM and four with HGD) had complete eradication of their condition. The study experienced early problems with dosimetry that resulted with adverse effects in 3 patients including gastric perforation and lacerations of the stomach and esophagus. After adjusting spray time to 20 seconds and refining catheter positioning, mild complications were usually self-resolving within 4 days and included odynophagia, dysphagia and retrosternal pain.

Palliative Use of Cryotherapy

Liquid nitrogen based cryotherapy has been studied as a palliative modality for esophageal squamous cell carcinoma and has been reported in a limited manner.³³ (Figure 2) One case focused on a 73-year-old African American male who presented with recurrent esophageal SCC. He was deemed unfit for both surgical and radiation therapy due to the combination of past maximum radiation treatments and the severity of the recurrent SCC. After two sessions of cryoablation, the patient remained disease free for over two years. The cryotherapy caused development of a stricture that was treated with dilation and stent placement. Future studies should be conducted to assess the efficacy of palliative care between cyrotherapy and other endoscopic and oncologic therapies.

CONCLUSION

Cryoablation is novel form of endoscopic ablation. Cryotherapy applications include treating primary and secondary GAVE, radiation proctitis, Barrett’s esophagus, and esophageal malignancies. Cryotherapy has shown clinical efficacy and favorable safety profiles in limited studies to date. In cases where patients are unable to receive traditional therapies, cryoablation is a viable alternative therapeutic option. Long-term cryotherapy effects have not been well studied in any of the currently used GI indications. To prevent serious complications in clinical application, dosimetry studies are needed for standardization of practice. Large, well- controlled studies involving direct comparison of both cryogens (liquid nitrogen and carbon dioxide) are still needed at this time.

The performance of cryotherapy in comparison to other ablative therapies has also not been extensively studied. Although there have been studies of cryoablation as second line treatment to diseases that have failed ablative treatments like APC and RFA, high-quality studies comparing cryotherapy to other treatment modalities are still very much needed.

A CASE REPORT

An Unusual Cause of Abdominal Pain

October 2015 • Volume XXXIX, Issue 10

Juan Echavarria,Alfredo Camero,Allan Parker

Juan Echavarria, MD¹ Alfredo Camero, MD² Allan Parker, DO¹ ¹University of Texas Health Science Center at San Antonio, Department of Gastroenterology and Nutrition ²University of Texas Health Science Center at San Antonio, Department of Medicine

INTRODUCTION

Primary appendiceal cancer is a very rare entity, constituting less than 0.5% of all gastrointestinal neoplasms.¹ First reported by Beger in 1882, it is found in 0.9-1.4% of appendectomy specimens. The International Classification of Diseases for Oncology (ICD-O) divides the malignant tumors of appendix into five categories: “colonic type” adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma (SRC), goblet cell carcinoid/adenocarcinoid and malignant carcinoid/adenocarcinoid.² In a previous study, Uihlein and McDonald reported a distribution for malignant tumors as follows: 88.2% carcinoid, 8.3% malignant mucocele and 3.5% adenocarcinoma.³ In a recent study, McCusker et al. reported an age- adjusted incidence of 0.12 cases per 1,000,000 people per year for primary appendiceal carcinoma. Mucinous adenocarcinoma was the most common histological type reported followed by colonic adenocarcinoma and malignant carcinoid. Signet ring cell adnocarcinoma was the least common type, accounting for less than 5% of all appendiceal malignancies.⁴

CASE REPORT

A 63 year-old Hispanic man with a past medical history of hypertension, gastroesophageal reflux (GERD), chronic constipation, anxiety, and benign prostatic hypertrophy (BPH) presented with a three month history of right lower quadrant abdominal pain, described as dull, intermittent, non-radiating and worsening over the last several weeks. His pain was not related to food intake or fasting, was not worse with movement, was not improved with defecation and improved with common over-the-counter analgesic medications. The patient denied weight loss, fever, bleeding and dysphagia. He had no significant family medical history.

Routine laboratory studies were all within normal limits. Diagnostic colonoscopy revealed an irregular, ulcerated mass in the appendiceal orifice, without other lesions (Figure 1). A computed tomography (CT) scan showed a thickened appendix measuring up to 18 mm at the base, with periappendiceal inflammatory stranding and numerous sub-centimeter ileocolic mesenteric lymph nodes (Figure 2). The biopsy revealed a poorly differentiated tumor with cells that possessed an extensive mucinous component and pale-staining cytoplasm, indicating an appendiceal adenocarcinoma, with signet ring cell carcinoma (SRC) features (Figure 3a, 3b). Esophagogastroduodenoscopy (EGD) and chest CT did not locate another primary site of malignancy, thus the diagnosis was consistent with a primary appendiceal SRC adenocarcinoma. The patient underwent a hand assisted laparoscopic right hemicolectomy (exploration of the abdomen showed no peritoneal implants), which later revealed a stage IIIc adenocarcinoma, with full-thickness penetration of muscularis propria into periappendiceal adipose tissue and extensive lymphovascular invasion (Figure 4). He was started on a modified FOLFOX6 regimen, and restaging CT chest/abdomen at 6 months showed no evidence metastatic disease.

Discussion

Primary appendiceal adenocarcinoma of the appendix is a rare event. In a 10 year retrospective study by Chen et al., the reported incidence was 0.28% identified from 2841 appendectomies, which is comparable to the incidence reported in similar studies.⁵ Several studies based on the Surveillance, Epidemiology and End Results (SEER) registry, have shown that mucinous adenocarcinoma is the most prevalent type of all malignant tumor of the appendix, followed by colonic type adenocarcinoma, malignant carcinoid, goblet cell carcinoid and lastly SRC adenocarcinoma. Upon diagnosis, 63% patients with mucinous adenocarcinoma and 76% with SRC adenocarcinoma have extension to adjacent organs or metastatic disease. Similarly, 64% of patients with SRC adenocarcinoma have lymph node involvement compared to 26% of patients with mucinous adenocarcinoma.³

Given their overall low incidence, primary appendiceal adenocarcinomas are seldom suspected before surgery and less than half of the cases are diagnosed preoperatively.⁵ These neoplasms tend to not have early signs or pathognomonic symptoms since the majority of them present with appendicitis.⁶ As opposed to other more typical gastrointestinal luminal neoplasms, this type of tumor does not classically present with occult blood, anemia, weight loss or change in bowel function. Rather, patients typically present with acute appendicitis or an abdominal mass. They are also frequently detected as an incidental finding during exploration for another surgical disorder.

Endoscopic detection of appendiceal adenocarcinoma has been reported sparingly through case reports and limited case series in the medical literature. The general consensus regarding appendiceal adenocarcinoma is that a colonoscopy is inconsequential, as a normal colonoscopy does not predict the absence of an appendiceal adenocarcinoma. However, colonoscopy is useful in detecting synchronous colonic polyps that may have a higher risk for malignant transformation in this patient population. Furthermore, findings of a smooth, submucosal lesion in the cecum near the appendiceal orifice or free-flowing mucin from the appendiceal orifice should raise concern for appendiceal adenocarcinoma.⁷

SRC carcinomas are highly virulent tumors associated with a very poor prognosis. One study showed a 5 year survival rate of 28.6% in patients with SRC of the colon.⁸ The patient we described was diagnosed with a primary SRC adenocarcinoma of the appendix with regional lymph node involvement without evidence of other metastatic disease, and was treated with a right hemicolectomy and a modified FOLFOX-6 regimen. This case highlights the rarity of SRC adenocarcinoma of the appendix and its implications on prognosis and treatment once discovered.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #146

How to Buy, Store and Eat Olive Oil

October 2015 • Volume XXXIX, Issue 10

Bethany E. Blalock

Olive oil has been a staple of the healthy Mediterranean style diet for centuries, while Americans have only recently caught on to its distinctive flavor and heart-healthy benefits. In this article we provide guidance on the meaning of the various olive oil standards, how to select and store it, and how to cook and serve olive oil while preserving its delicate flavor.

Olive oil consumption in the United States has increased dramatically since the 1990’s and continues to rise steadily, at least in part due to its favorable health profile. However, research has shown that Americans are not very good at distinguishing high quality from low quality oils, a fact that is perhaps not surprising given the dizzying array of options and considerable jargon encountered on the olive oil aisle at the market. Furthermore, confusion abounds regarding the proper usage of olive oil in the kitchen. This article aims to clarify the confusion and empower consumers to make more informed decisions when it comes to enjoying all the olive has to offer. Buying, storing and serving tips are provided.

Bethany E. Blalock, RDN, University of Virginia Health System, Charlottesville, VA

Olive Oil Consumption

Americans have been increasing their olive oil consumption since the 1990’s, when the health promoting appeal of the Mediterranean diet came into vogue, displacing the low-fat mantra that dominated the preceding decades.^1,2 Although Italy and Spain still consume the vast majority of the world’s olive oil, at 20% and 17% respectively (they also produce the lion’s share), the United States is in a distant third place, at about 10% of global consumption in 2013/2014, according to data from the International Olive Council (IOC).1 At over 301 metric tons, Americans have more than tripled their olive oil intake since 1990.¹ What is more, the rate of consumption has been increasing by an impressive 4-5% yearly since the turn of the 21st century, while just 40% of U.S. households purchased olive oil as of 2011 – indicating enormous growth potential.

Credit for this dramatic increase in olive oil demand in the U.S. is likely due in large part to the public’s association of the product with improved cardiovascular health, longevity, and the overall benefits of a Mediterranean style eating pattern.³ Table 1 provides a limited nutrient profile of olive oil,⁴ but the overall health benefits are beyond the scope of this paper and have been recently reviewed elsewhere.⁵ Red meat (beef, pork, lamb, other mammals) and dairy products provide the bulk of dietary fat in the typical American diet, whereas the Mediterranean diet uses little of these, instead relying heavily on olive oil for fat (as well as more fish). Higher intake of polyunsaturated and monounsaturated fats in place of the saturated fats that predominate in animal products (and certainly the trans fats common in packaged baked goods), is associated with a decrease in low density lipoprotein (LDL) cholesterol subfractions and an overall improved coronary heart disease risk profile. And while other foods and beverages such as fish, whole grains and legumes, limited red meat, plenty of fresh fruits and vegetables, and moderate alcohol intake are also staples of the Mediterranean diet plan, a switch from butter or margarine to olive oil is probably the change that comes easiest to most Americans. This helps explain why olive oil sales continue to rise, while red meat consumption, for example, has only very recently begun to slightly decline.⁶

Olive Oil Grades and Standards

Switching from butter or canola oil to olive oil seems easy enough, but choosing which kind of olive oil to buy can be another story. Many shoppers may find the array of options at their local supermarket overwhelming and the range of olive oil jargon confusing. For example, is virgin olive oil superior to “plain” olive oil? What about extra virgin? What is the difference between Spanish, Italian, and domestic olive oils? Is refined oil better or worse? What about cold pressed? Below, a primer on origins, terms, and grading sheds light on these questions.

Standards

In the United States, the Department of Agriculture (USDA) sets standards for grading olive oil, and the document that guides this process was last revised in

At that time, the U.S. changed its definitions to
line up with the standards imposed by the IOC, making
it possible to more easily compare American oils to
those produced in Europe and elsewhere.⁷
Both extra virgin and virgin olive oils are obtained using only methods that do not in any way alter the oil. For example, excessive heating and chemical refining are not permitted. The only processing these oils undergo is to remove debris, and acceptable methods include washing, decanting, centrifugation, and filtration; in other words, they are not chemically refined. Virgin and extra virgin oils are further distinguished from one another based on acidity, flavor, and fragrance: extra virgin olive oil has an acidity (as measured by oleic acid content), of no more than 0.8 gram per 100 grams of oil. Its flavor and odor must be deemed “excellent” in sensory evaluation. Virgin olive oil, by contrast, has an acidity of no more than 2 grams per 100 grams of oil, and its flavor and odor must be “reasonably good.” Olive oil that lacks the virgin designation is a blend of refined oil and virgin olive oil. It has low acidity (not more than 1%) and its fragrance and flavor must be like that of virgin olive oil. Finally, refined olive oil has been chemically treated, but still retains its fatty acid structure. It has no fragrance or flavor, and the antioxidant, alpha-tocopherol, is generally added back in to replace the naturally occurring alpha-tocopherol that is removed in the refining process. Thus, olive oils run the gamut from flavorful and expensive to completely flavorless and relatively cheap. Any of these might be the best choice, depending on the intended use. The next section outlines how to choose correctly so that neither flavor nor money is wasted. First however, a word on regional variations in flavor and quality. Region of Origin Most olive oil is produced in Italy, Spain, and Greece. Between harvest years 2008-2014, the European Union produced over 75% of the world’s olive oil, and of that proportion, Spain produced 61%, Italy 21%, and Greece about 14%.¹ Like wine, olive oil has a distinct terroir (pronounced ter-WAHR), or flavor and aroma unique to the soil and climate in which it is grown. Characteristics such as flavor, color, and aroma vary dramatically even within countries by region, olive varietal, microclimate, and harvesting practices, so any broad statements about, for example, “Italian olive oil” should be met with skepticism. Tasting various oils is the only way to appreciate the variation in flavor and quality. In addition, much oil that is actually grown elsewhere, such as Spain or Tunisia, is sent to Italy for bottling and then marked with the familiar phrase “Product of Italy” before it is exported to unknowing American consumers. Look for an estate name or place of harvest to be sure of where the product was actually grown. “Packaged in Italy” or “bottled in Italy” indicate the oil came from elsewhere. Finally, oils cannot be judged based on color – greener oils have simply been harvested earlier in the growing season, when the olives are less ripe, while golden-hued oil is pressed from darker, ripe olives. However in general, greener oils tend to be grassy and peppery, while golden oils are more nutty, mild, or buttery. How to Buy and Store Olive Oil Which Standard? A 2013 report by the U.S. International Trade Commission found that American consumers are, generally speaking, unable to distinguish between high and low quality olive oils. Understandably, we therefore gravitate toward cheap, poorer quality products.⁸ This is unfortunate because it means Americans are missing out on a world of wonderful flavor, and perhaps worse, they may even be wasting money on good oils and then using them improperly. Buying practices should depend on how the oil is intended to be used or consumed. Extra virgin oils, which are minimally processed, contain many desirable “impurities” such as minerals and compounds that degrade rapidly when heated, leading to rancid, off flavors. Thus, when the bright, grassy, fruity flavors of a good olive oil matter for serving, such as for dipping bread, dressing fully cooked foods, or as a base for salad dressing, consumers should limit their search to extra virgin varieties. On the other hand, cheaper, refined olive oils are a much more reasonable choice for cooking, especially at higher temperatures, since the refining process removes the compounds most susceptible to burning. Clarified butter provides an informative example of this process: By removing the water and other impurities and leaving only the milk fat behind, clarified butter can be heated to a much higher temperature without burning, compared to regular butter. Similarly, the smoke point (which technically refers to the point at which glycerol is converted to acrolein, an aldehyde that is the basis of acrid odors and flavors), of refined olive oil is about 410° F, compared with just 325° F or so for extra virgin.⁹ Thus, “middle-of-the-road” virgin oil is suitable for sauting, or perhaps even browning, but a cheaper, flavorless refined oil is a better choice for frying or stir-frying. Where to Buy If a refined oil is needed, such as for high heat cooking, the choice of which particular brand to purchase is less important, since no flavor is expected. In this case, it makes sense to choose based on low cost. However, for dipping, drizzling, and dressing, more knowledge is needed. In addition to heat, extra virgin olive oil has two more enemies: light and oxygen.^10,11 Over time, exposure to any of these three factors (heat, light, oxygen) degrades the quality of the oil. In general, olive oil has a shelf life of about 12 months, but grocery stores do not always rotate stock appropriately, and sell- by or best-by dates are not mandatory. Thus, look for brands that do have these dates, or alternatively, a date of harvest; the newer the better. Another good strategy is to shop in smaller stores where olive oils move more frequently, rather than a large supermarket with many varieties. As an additional advantage, such specialty stores typically encourage tasting before buying – the only true way to determine superior flavor. Although the oil will probably cost more in this setting, it will almost certainly be superior to a mass produced grocery store brand. Type of Container The type of container in which the oil is stored plays a role in its longevity as well. By far the most common bottle type, clear glass provides no protection from light, which is nearly as damaging as high temperature. Since light degrades tocopherols, the naturally occurring antioxidants that protect oils from rancidity, darker glass or opaque metal containers may be better options. On the other hand, tins of oil tend to come only in larger sizes, which can also be problematic because of olive oil’s third enemy: oxygen. The larger the container, the more oxygen will be available to create peroxides, which in turn form compounds that negatively impact the flavor of the oil. Thus, even though buying in bulk is more cost effective, shoppers are better off purchasing only the volume of oil that they will realistically use in a few weeks, as the oil will lose its superior flavor otherwise. Storage If economizing by purchasing large containers is of special consideration, or if olive oil is not commonly used in the household, consider decanting into a smaller bottle only what is needed for the week. Wrap the big bottle with foil and store it in the refrigerator. This method will protect the bulk of the supply from light and heat, though nothing can be done about the exposure to oxygen. Finally, never store olive oil, even the small “weekly” portion, over the stove, since the heat from cooking will rapidly lead to rancidity. Instead, keep all oils in a cool, dark cabinet. See Table 2 for tips on buying and storing olive oil. Tips for Enjoying Olive Oil There is no wrong way to enjoy olive oil, except by overheating it and destroying the delicate flavors of virgin or extra virgin oil. Table 3 below offers a few tips on ways to incorporate olive oil into your diet. CONCLUSION Olive oil has been a staple of the healthy Mediterranean style diet for centuries, while Americans have only recently caught on to its distinctive flavor and heart- healthy benefits. As such, confusion abounds when it comes to the meaning of the various olive oil standards, how to select and store it, and how to cook and serve olive oil while preserving its delicate flavor. In short, more expensive, extra virgin oils should be saved for raw purposes, while refined olive oil is appropriate for high heat cooking, even frying. Sampling different oils before buying is a great way to develop one’s palette to distinguish higher quality olive oils.

GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #12

Simultaneous Robotic Placement of Gastric Electrical Neurostimulation System and Pyloroplasty in Gastroparesis Patients

October 2015 • Volume XXXIX, Issue 10

Brian R. Davis,

Irene Sarosiek,

Alejandro Rios Tovar,

Richard W. McCallum

In this report, we review surgical approaches to treat refractory gastroparesis focusing on simultaneous pyloroplasty and gastric electrical neurostimulator placement demonstrating the safety and efficacy of combining these procedures. We believe the combination of these techniques prevents the negative spiral of hospitalization and malnutrition that creates chronic debilitation and disability in gastroparesis.

Early diagnosis and treatment of gastroparesis eludes pharmacologic solutions. Gastroparesis starts as a clinical disorder which progresses to nausea and emesis resulting from chronic food retention and gastric distention. The negative feedback loop occurs when this disease becomes refractory to pharmacologic treatments, limited by multiple side effects and when pain results in narcotic dependence. The deteriorating condition leads to malnutrition and recurrent hospitalizations. Since the 1990’s Dr. Richard McCallum has been a pioneer in gastric electrical neurostimulation to interrupt the cycle of nausea and emesis. Over the last 6 years our experience at Texas Tech University Health Sciences Center, El Paso has led to the evolution of a robotic technique for simultaneous gastric electrical neurostimulation and pyloroplasty. This provides a concise algorithm for treatment with advocacy for early surgical intervention using a novel robotic platform that minimizes the surgical insult thus speeding recovery from this debilitating disorder.

Brian R. Davis, MD, FACS, FASGE¹ Alejandro Rios Tovar, MD¹ Irene Sarosiek, MD, AGAF, FACG² Richard W. McCallum, MD, FACP, FRACP, FACG, AGAF² ¹Texas Tech University Health Sciences Center Paul L. Foster School of Medicine Department of Surgery and ²Department of Internal Medicine, El Paso, TX

Burden of Disease

Gastroparesis is a chronic motility disorder that affects an estimated 2-4% of the United States population.¹ Gastroparesis and its symptoms can drastically affect a patient’s quality of life. Frequent episodes of vomiting up to dozens of times per week, frequent ED visits and hospitalizations result in a great economic burden in the setting of patient disability. In 2004, gastroparesis as the primary diagnosis for hospital admission amounted to more than 200 million dollars in hospital costs.⁵ This is an increase of 138% from the prior decade, and appears to be increasing as more recognition of this entity leads to more testing to diagnose and manage the disease.²

Initial Presentation

In gastroparesis the stomach is not able to empty at its normal rate, due to a variety of mechanisms, and a constellation of symptoms results. Nausea, vomiting, abdominal bloating, and early satiety are typical symptoms that characterize gastroparesis. Epigastric abdominal pain and discomfort are variable, and may be a prominent aspect of the presentation in some individuals.³

Making the Diagnosis

Signs of gastroparesis can be variable; a definitive diagnosis can be sought from a gastric emptying study. Rumination syndrome, cyclic vomiting syndrome, anorexia, or bulimia must be excluded. Gastric emptying scintigraphy is performed by using a radiolabeled physiologic caloric meal and quantitatively measuring the percentage of the meal remaining in the stomach at one-hour intervals up to ⁴ hours. It is crucial to address the technique endorsed by ANMS (American Nuclear Medicine Society) involving a low-fat (2%) 250 calorie egg batter meal. This allows a consensus for interpreting the study which defines delayed gastric emptying as greater than 10% of the meal remaining in the stomach at 4 hours.4 Patients may have normal gastric emptying studies at one point, but later evolve to slow motility rate on a second exam, explained by increasing diabetic neuropathy from damage to neural cells.³ The major etiologies are diabetes mellitus-related, idiopathic, or post-surgical (e.g. post-vagotomy). Early diagnosis in diabetics is critical since they are susceptible to complications of nutrition which affects surgical wound healing; intervention will improve overall long-term morbidity and mortality.⁵

Pathophysiology of Disease

Suspected mechanisms of gastroparesis in diabetic patients include autonomic neuropathy, injured or depleted interstitial cells of Cajal, and impaired antral contractions.⁵ A recent report by Othman et al. (2015) described successful endoscopic ultrasound guided biopsies of the antral muscularis propria and demonstrate depletion of cells of Cajal in gastroparesis patients. This innovation may unlock one of the keys to early diagnosis since depletion of the cells of Cajal correlates strongly with response to gastric electrical stimulation.⁶

Initial Pharmacologic Therapy

Mainstays of treatment are optimizing oral nutritional support and pharmacologic therapy with pro-motility agents. The dopamine D2 receptor antagonist metoclopramide (Reglan) is the only FDA-approved medication used for the treatment of gastroparesis. Symptom improvement and accelerated gastric emptying have been noted in many small trials that studied metoclopramide versus placebo.⁷ Limiting factors for long-term use of this agent are potential side-effects which include acute dystonias and tardive dyskinesia. Domperidone (dopamine 2 antagonist) is used for the treatment of gastroparesis and has shown improvement in symptoms and overall reduction in hospital admissions and has none of the CNS side effects of metoclopramide. This medication is not FDA approved in the United States, and as such, is not readily available.⁸ Erythromycin, a macrolide antibiotic, acts as a motilin receptor agonist and promotes gastric motility – it is commonly used intravenously as a temporary treatment for delayed gastric emptying in critical care units. In various studies when given orally, it has been shown to significantly improve symptoms and accelerate gastric emptying in both idiopathic and diabetic gastroparesis initially but long-term use is limited by tachyphylaxis and as dose tolerance develops.⁹

Indications for Surgical Therapy

Traditional surgical therapy has included procedures extending from access for enteral nutrition to the radical options of subtotal and total gastrectomy. Enteral access (gastrostomy for venting of the stomach or jejunostomy) are largely temporizing measures to prevent muscular wasting. These enteral tubes fail to halt progression of the disease or prevent chronic overmedication for pain. These pain medications play a central confounding role since they inhibit gastric and small intestinal motility and the migratory motor complex (MMC).⁵ Subtotal and total gastrectomy procedures remove the source of chronic emesis. Despite the obvious logic behind removal of part or all of the stomach the resulting post operative side effects including chronic malnutrition has reduced acceptance of this radical option in addition to its own operative morbidity and mortality.¹⁰

Gastric Electrical Neurostimulation (GES) (Enterra Therapy)

This intervention has the best results to prevent the development of the complications of chronic gastroparesis. Gastric electrical stimulation has been pioneered for 20 years as the premier investigative therapy to address the chronic cycle of symptoms. Enterra therapy (Medtronix Corp, Milwaukee, WI) remains under investigative human device exemption (HDE) for use in IRB approved programs per FDA regulations. Gastric electrical stimulation is effective in the long-term reduction of nausea and emesis in up to 60% of patients.¹¹ Overall reduction in nausea and emesis leads to decreased frequency of hospitalization and reduced utilization of anti-nausea and pain medication. Abell et al. have reported a therapeutic response to endoscopic placement of temporary gastric electrical stimulator leads for 4-5 days and this may have a role in predicting positive responses to long- term implantation therapy. The implantation of the gastric electrical stimulator has neither positive effects on morphology of the stomach nor improving gastric motility and gastric emptying or correcting electrical dysrhythmias.¹²

The hypothesized function of the gastric stimulator is that it transmits signals through the afferent fibers in the vagus nerve to relay an inhibitory message to the chemo-recepter trigger zone in the hypothalamus which modulates the neural mechanism for reflex vomiting. The cycle of gastric retention followed by CNS modulated reflux emesis is interrupted allowing for better control of nausea and vomiting. In addition Enterra therapy also increases vagal function enhancing some relaxation of the proximal stomach facilitating some better food storage. However gastric emptying is not accelerated.¹³

The Texas Tech University Health Science Center,
El Paso experience has included 33 patients since

Thirty presented for initial surgical treatment of
gastroparesis, one presented for conversion to subtotal
gastrectomy following unsuccessful GES therapy,
another for replacement of GES antral stimulation leads
and the third for pyloroplasty and jejunostomy following
GES. Of the 30 who presented for initial GES therapy
lead insertion techniques included: laparotomy (20),
laparoscopy (6) and robotic (4) methods. Long-term
mortality (>90 days from surgery) in this group was
12% (cardiac arrest, respiratory arrest from aspiration,
sepsis from intestinal fistula formation, and necrotizing
fasciitis from wound infection). Morbidity includes
stimulator pocket (pulse-generator pocket) infection
(6%) that required pulse generator removal. These
infections occurred in 2 of our patients who also had
psychiatric disorders that promoted self-contamination
of these wounds.¹⁴
GES and Pyloroplasty The Texas Tech El Paso experience with simultaneous GES placement and pyloroplasty began in 2013 (12 laparotomy, 3 robotic). Techniques for pyloroplasty included 8 Heineke Mikulicz procedures (5 laparotomy, 3 robotic) and 4 applications of a circular stapler at the pylorus. Although intra-operative endoscopy demonstrated increased confirmation of visual patency and improved early gastric emptying with the circular stapler technique, short-term clinical follow up has demonstrated an increased tendency for dumping syndrome symptoms compared with the Heineke Mikulicz technique. The addition of simultaneous pyloroplasty has not increased the incidence of wound infections and there has been no incidence of abscess or enteric fistulas from the pyloroplasty site. All cases were accompanied by intra-operative EGD exam to confirm placement of GES stimulator leads and examine the pylorus to prevent possible enteric drainage from the site of pyloric reconstruction. This series demonstrated the safety and efficacy of combined pyloric reconstruction with implantation of the gastric electrical stimulator. Although this contradicts standard surgical wisdom we believe the use of pre-operative antibiotics that cover the spectrum of possible gut microbial flora combined with use of gastric endoscopy to confirm no lead penetrations or perforations minimizes risk of contamination. Long-term results of combined GES and pyloroplasty from the Texas Tech experience reported by Sarosiek et al (2015) have demonstrated a 50% improvement in overall gastroparesis score in 71% of patients (Table 1).¹⁴ Pyloroplasty Pyloroplasty has been a standard treatment for gastroparesis prior to implementation of the gastric stimulator. Empiric evidence for the functionality of the pyloroplasty has come from the iatrogenic form of gastroparesis where damage to the vagus nerve during anti-reflux or ulcer surgery causes failure of pyloric relaxation. Recent evidence that injection of botulinum toxin into the pyloric muscle and the use of self-expanding covered metallic stents have been helpful in reducing symptoms lends empiric evidence to the proposed efficacy of pyloroplasty in the relief of gastroparesis symptoms. The pyloroplasty allows rapid passage of nutrients bypassing the necessity of the trituration function of the stomach, which is incapacitated in gastroparesis.¹⁵ Standard pyloric modification, is the Heineke Mikulicz procedure which creates a radial incision through the pylorus with transverse closure of the enterotomy. This differs significantly from the Jaboulay and Finney modifications which are more commonly used with chronic strictures in the pyloric and duodenal bulb regions. Release of the pylorus muscular complex functionally accelerates delayed gastric emptying and allows faster transit of food boluses into the small bowel thus allowing for absorption and overcoming malnutrition. Robotic Platform Efficacy Treatment modalities have been prescribed separately or in combination depending on the patient’s constellation of symptoms. Sarosiek and Forster first wrote about the potential cure of gastroparesis using a combination of Enterra therapy and pyloroplasty.¹¹ Gastric electrical stimulators in the past were typically placed first to control symptoms of repeat nausea and emesis that lead to a cycle of constant hospital readmission. The gastric stimulator surgery is then followed by pyloroplasty when, some months later, symptoms have not been adequately relieved by GES alone. Reasoning for providing these therapies during different operative settings is that implant placement can be complicated by the entry into the stomach and pyloric complex. Reports of contamination of Enterra leads at time of surgery have been linked to delayed stimulator pocket infections.¹⁶ Operative Strategy The robotic platform completes pyloroplasty and gastric electrical stimulator implantation with expected operative time of 180 minutes followed by discharge on post-operative day 2-3. The pulse generator site should be marked prior to surgery in the left transverse umbilical line. An 8.5 mm camera is placed in a sub- umbilical position. The port placement allows arms to operate at the points of an isosceles triangle or upside- down pyramid which point toward the operative site. The assist port should be in the left mid abdomen and will be used for insertion of the Enterra leads and the pulse generator pocket. The pyloroplasty technique is described by Heineke- Mikulicz. The pylorus is divided in an axial direction with extension approximately 2 cm on the stomach and duodenum. This incision is then closed in a transverse fashion with an inner layer of running suture with full thickness mucosal to serosal bites. The second layer is created with interrupted Lembert stiches (Figure 1).¹⁵ An umbilical tape is then marked at 9.5 and 10.5 cm for measurement of distance on the greater curvature. Hook cautery is then used to mark lead insertion sites approximately 10 cm from the pylorus on the greater curvature. The tape is also used to mark 2 cm lead tracks to maintain a 1 cm distance between the two leads to achieve impedance between 500 and 800 Ohms.¹⁶ Leads are then inserted through the assist port. Ski needles are grasped and inserted through the serosa into the submucosa for a distance of 2 cm. EGD is then performed to demonstrate a negative leak testing of the pyloroplasty and examine the antrum for inadvertent perforation of the stomach. Mucosal perforation can lead to pulse generator pocket infections and intermittent shocking sensations. The leads are then delivered along the submucosal tract. The leads are tested for proper impedance (500-800 Ohms) and then sutured to the serosa of the stomach (Figure 2).¹⁷ The subdermal pulse generator pocket is then developed. Care should be taken to avoid use of electrocautery since electrical interference erases recorded settings on the pulse generator. Once the subdermal pocket has been developed the pulse generator is connected and impedance is recorded trans-dermally with the generator in its pocket. The generator is secured with permanent suture and the dermal incisions are closed. At this point the pulse- generator is turned on and programmed so that patients may experience significant symptom relief immediately following surgery. The first two patients underwent gastrografin swallow studies following surgery that we now feel are not necessary secondary to adequate leak testing at the time of EGD. The patient is started on a clear liquid diet on day one following surgery and can be discharged shortly thereafter. Complications of Surgical Therapy Consensus of many investigators is that adverse events include dislodgement of electrodes, penetration through the gastric mucosa, lead insulation damage, lead erosion or migration and bowel obstruction. The robotic approach has been documented to reduce the incidence of gastric perforation and improved functional tissue handling has led to reductions in erosion and damage to insulation. The robotic platform also reduces the incidence of lead dislodgment since suturing skills are improved. The incidence of subsequent small bowel obstruction problems is low with laparoscopy and robotics since scar formation is reduced dramatically. The most troublesome complication is still the potential for infection at the pulse generator pocket site.⁶ Minimally invasive approaches also have fewer wound complications due to a lower incidence of surgical stress with improved post-operative control of blood sugars and the sympatho-adrenal response. CONCLUSION This report reviewing surgical approaches to treat refractory gastroparesis has focused on simultaneous pyloroplasty and gastric electrical neurostimulator placement demonstrating the safety and efficacy of combining these procedures. The benefits of pyloroplasty on gastric emptying times and the reduction in nausea and emesis by gastric neurostimulation have both been documented in the literature. We believe the combination of these techniques prevents the negative spiral of hospitalization and malnutrition that creates chronic debilitation and disability in gastroparesis. This ultimate solution returns full function of the stomach as a digestive conduit with a low risk profile in the face of high levels of co-morbidities. The robotic platform reduces the risks because of the improved wrist-like articulation that facilitates suturing and electrode placement. Evolution of treatment includes early diagnosis with an endoscopic (non-surgical) approach to obtain gastric smooth muscle to identify the status of the interstitial cells of Cajal followed by developing a treatment strategy that leads to triage for surgery in some patients. The pioneering work of Richard McCallum and Dr. Sarosiek and their team of collaborators have led to this combination of diagnostic and therapeutic solutions that overcome chronic tube based enteral nutrition and total gastrectomy. The authors encourage our readers to observe this technique at our medical center. Future directions include the dissemination of this technique to the broader community of gastroenterologists and surgeons.