Frontiers In Endoscopy, Series #41

Use of Volumetric Laser Endomicroscopy in the Esophagus

February 2018 • Volume XLII, Issue 2

Advanced or optical imaging in the esophagus allows for a detailed view of the esophagus at a level beyond white light endoscopy. The newest commercially available endoscopic advanced imaging tool is volumetric laser endomicroscopy (VLE) or second-generation optical coherence tomography. VLE is currently being used in management of Barrett’s esophagus, squamous cell dysplasia and cancer of the esophagus, and during peroral endoscopic myotomy. This review describes VLE and its current clinical applications to the esophagus.

INTRODUCTION

The principle behind optical coherence tomography (OCT) is to measure the signal intensity of reflected light from a tissue sample. It is similar to endoscopic ultrasound but uses infrared light instead of an acoustic signal. OCT can produce high-resolution cross sectional imaging of the esophagus. The axial resolution is superior to high-resolution endoscopic ultrasound but at the expense of reduced depth of penetration compared to endoscopic ultrasound. The OCT probe is passed through a channel of an endoscope and once activated emits infared light. As light reflectivity from the esophageal tissue is measured, real time images of microscopic mucosal and submucosal changes are measured.

The mainstay of early OCT use in the esophagus was for Barrett’s esophagus. The older generation system consisted of a probe that was in gentle contact with the mucosa. A landmark study in 2001 showed that OCT could reliably distinguish between normal esophagus and intestinal metaplasia (IM).¹ The study showed that normal squamous esophagus contained layered strictures while IM had loss of this layering or effacement. In 2006, OCT criteria were introduced to distinguish neoplastic IM of the esophagus (high- grade dysplasia and intramucosal cancer) from non- neoplastic IM.² These criteria were derived from an in-vivo based study in which imaged areas with an OCT probe were then biopsied with a jumbo biopsy forceps. Histology was then compared to OCT images. Features indicative of neoplasia were 1) a high surface OCT signal to subsurface signal known as incomplete surface maturation and 2) glandular atypia. A scoring system, known as the OCT dysplasia scoring index (OCT-SI) or Evans criteria, was derived that indicated the likelihood of neoplasia in a Barrett’s segment imaged by OCT. When the dysplasia index is greater than or equal to two, a sensitivity and specificity of 83% and 75% was achieved, for diagnosing intramucosal cancer.

Second generation OCT, known as volumetric laser endomicroscopy (VLE), is somewhat different in that it is a balloon based system that contains the imaging probe. The probe is passed through the channel of the endoscope and the balloon is inflated to center the probe (Figure 1). The probe can then spin 360 degrees , emitting infrared light, and real time 360 degree cross sectional images of the esophagus are obtained. This technology is different from the probe-based system in that a whole 6 cm segment of the esophagus can be imaged in 90 seconds; a major improvement to the efficiency of this technology. In addition, the wide field imaging is a feature that other optical imaging platforms lack. This system is commercially available in the United States (Ninepoint Medical, Bedford, MA). The balloons currently come in 14 mm, 17 mm, and 20 mm. Specific details on the performing this procedure can be found in recent reviews of this topic but are beyond this review.^3,4

Normal VLE Images

Normal squamous esophageal mucosa can be seen in Figure 2. It consists of layered architecture without glands in the epithelium. Pits and crypts, a hyperreflective or dark surface, and lack of layered architecture can be seen on VLE in normal gastric cardia (Figure 2).^3-5?

VLE in Barrett’s Esophagus

In Barrett’s esophagus there is loss of layered architecture without any pits and crypts (to distinguish it from gastric mucosa). The features of neoplasia in VLE are generally the same features as first described in the probe based system.² Recently two studies have further characterized neoplasia criteria for VLE using endoscopic mucosal resection specimen that were scanned using VLE ex-vivo.^6,7 Leggett et al. devised a new scoring algorithm for neoplasia detection termed the VLE- DA.⁷ In this algorithm, the degree of effacement (loss of layering) is determined. If complete loss of layering is observed, then one observes the degree of surface to subsurface intensity. If the surface intensity is greater than the subsurface then dysplasia should be suspected. If partial effacement is observed then one determines the degree of atypical glands, if present. If greater than 5 atypical glands is present than one should suspect dysplasia. Based on this algorithm, the sensitivity and specificity for dysplasia detection was 86 and 88% respectively. Figure 3 shows examples of nondyspalstic and dysplastic Barrett’s esophagus. Swager et al. also looked at EMR specimens that underwent VLE scanning and determined three independent VLE features that predict dysplasia: effacement, higher surface to subsurface signal, and the presence of atypical dilated ducts/glands.⁶ They developed a VLE prediction score assigning certain points for each feature. Both criteria are similar, but in clinical practice the VLE-DA is somewhat more practical to use. In addition, effacement is commonly seen, and in our clinical experience not associated with dysplasia. Currently, physicians in practice use these criteria to help guide them when looking for images that possible contain dysplasia. The interobserver variability for VLE image interpretation is favorable.⁸ Given both the Leggett and Swager criteria are based on ex-vivo EMR specimens, in-vivo research is needed to validate these criteria.

In mid 2016, laser marking became commercially available, allowing physicians to mark abnormalities seen on VLE on the esophageal mucosa. The commercially available model was an upgrade from that used in human pilots.⁹ The physician has the option of placing one or two superficial laser marks at sites of VLE abnormalities. This allowed the ability to target lesions specifically rather than estimating where the abnormality was based on the registration line on the balloon and the VLE scan and relation to the abnormality from the GE junction. To date there are case reports and series showing the benefit of VLE in clinical practice.^5,10?-14 Figure 4 shows an example of a case where VLE with laser marking helped diagnose Barrett’s with high- grade dysplasia. Our group presented findings at the American College of Gastroenterology 2017 meeting showing an incremental yield of dysplasia detection in patients with Barrett’s esophagus who underwent surveillance endoscopy with VLE with laser marking compared to patients that underwent VLE without laser marking or patients that had traditional Seattle protocol surveillance biopsies.¹⁵ Currently there is an ongoing multi- center prospective dysplasia detection pilot to confirm in-vivo criteria of dysplasia.

An anticipated upgrade to the VLE system in the near future will be computer automated detection of VLE abnormalities. Although the learning curve for VLE image interpretation seems favorable,¹⁶ many VLE image frames are presented to the user at one time and thus it is possible to miss a suspicious area. A recent computer algorithm pilot based on VLE EMR specimens showed good performance to detect Barrett’s associated neoplasia.¹⁷ Addition of this feature will make VLE more user friendly to endoscopists.

VLE in Squamous Cell Dysplasia and Cancer

The vast majority of esophageal cancers occur in the non-western world with ninety percent of these being esophageal squamous cell carcinoma (ESCC).¹⁸ The precursor to ESCC is squamous intraepithelial neoplasia (SIN).19 Endoscopic therapy is accepted for ESCC and SIN if the lesions are limited to the epithelium or lamina propria.^19,20 Lesions limited to the mucscularis mucosa or superficial submucosa are considered a gray zone for endoscopic treatment19,20 These standards of therapy are based on the risk of lymph node metastasis (LNM).^21,22

Determining which patients have ESCC limited to the lamina propria can be challenging. In a recent retrospective study, specimens from patients that underwent ESD for flat ESCC, were examined.²⁰ The study showed that one third of patients that met clinical and endoscopic criteria for RFA had histologic criteria that were considered contraindications for RFA. The study concluded that determining which patients should receive RFA therapy is challenging. The challenge stems from inaccurate pre-therapy staging of ESCC.²³ High-frequency endoscopic ultrasound (HF- EUS) and EUS are limited in imaging superficial ESCC.²³ However, studies have shown that optical coherence tomography (OCT) can produce high- resolution images of staging ESCC. A prospective study compared OCT to HF-EUS in 123 patients with superficial ESCC and found that OCT had a higher accuracy (95% vs 81%; p<0.05).²³ The probe based first generation OCT, used in that study, is not commercially available.

There is limited experience on the use of VLE for staging superficial squamous cell cancer of the esophagus. In our experience we have found that VLE can be helpful for squamous dysplasia/SIN or superficial cancers involving up to the lamina propria. This staging is based on OCT signal penetration into a layer with preservation of the layers below it. In VLE staging of SIN, a surface hyperreflective (darker) signal from the neoplasm is visualized only involving the epithelium with preservation of the layers below it (Figure 5).²⁴ However with disease involving deeper layers, a surface hyperreflectivity is seen with effacement (loss of the traditional layering) below the darkened surface. The extent or depth of disease involvement is determined by which layers are preserved below it. If there is involvement of the muscularis mucosa or deeper, a surface hyperreflectivity is seen, with complete effacement of all layers below it. An example of a SIN lesion is seen in Figure 5. Studies are needed to confirm our findings. If studies confirm our findings, than it is conceivable that VLE can guide appropriate endoscopic therapy for SIN (RFA or resection) and superficial squamous cell esophageal cancer limited to the lamina propria (RFA or endoscopic resection). Disease determined to involve the muscularis mucosa based on EUS/ VLE could be candidates for endoscopic resection by endoscopic mucosal resection or endoscopic submucosal resection technique.

VLE Use in Peroral Endoscopic Myotomy

Peroral endoscopic myotomy (POEM) has emerged as a first line treatment for achalasia.²⁵ A POEM consists of creation of an esophageal submucosal tunnel, and subsequent myotomy of the distal esophageal circular and lower esophageal sphincter muscles. It is unclear if the tunnel and subsequent myotomy should be in the anterior versus posterior approach.²⁶ Desai and colleagues examined if pre-procedure VLE imaging could determine the optimal approach.²⁶ In this multi- center international registry, they compared outcomes of patients that underwent a VLE tailored POEM versus a traditional POEM. In a VLE tailored exam, if the pre-procedure VLE scan showed a thickened anterior muscle, then the patient underwent an anterior approach. On the other hand if the patient had a thickened posterior muscle (Figure 6) then they underwent a posterior approach. If they had a thickened circumferential muscle, then the approach was dictated by the presence of vasculature. If anterior vessels were noted, then a posterior approach was used. If posterior vessels were noted, then an anterior approach was used.

A total of 84 patients were included in the study by Desai et al. Fifty-one patients underwent pre-POEM VLE. Twenty-four and twenty-seven patients underwent an anterior and posterior approach respectively. Technical success was achieved in 96% of patients. Statistically significant less bleeding was observed in the VLE group versus the traditional group (8% vs 43%, p<0.0001). As a result procedural times was less in the VLE group compared to the traditional group, despite the time taken to perform the VLE (86 min vs 122 min, p=0.0001). This study is limited in that there are no validated scaled scoring systems in place to measure the muscle thickness, however the concept is promising. Further research is needed to show if VLE pre-POEM can indeed reduce peri-procedural bleeding and reduce procedure time.

CONCLUSION

VLE is a tool that can be used in the esophagus to help guide diagnosis of neoplasia and aid or guide the correct endoscopic therapy. The majority of procedures to date have been in Barrett’s esophagus. Not surprising, most of the literature supporting its use is in Barrett’s as well. Although further studies are needed showing the incremental yield of VLE in diagnosing dysplasia, the preliminary data being presented is encouraging. VLE?s potential for guiding staging and therapy in squamous cell esophageal cancer is also promising and may guide which therapy to perform. Finally, the use of pre- procedural POEM may improve outcomes during the procedure. Further studies using computerized measurements of muscle thickness of the VLE scans are needed to validate this approach.

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A Case Report

Acute Esophageal Necrosis Caused by Gallstone Pancreatitis

January 2018 • Volume XLII, Issue 1

Bradley M. Yamanaka,Brian J. Hanson

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INTRODUCTION

Acute esophageal necrosis is a serious, yet relatively rare clinical condition afflicting hospitalized patients. It is most often observed in medically ill elderly males and nearly always presents with upper gastrointestinal hemorrhage.^1,2,3,4 Endoscopy typically finds black, necrotic mucosa in the distal esophagus with abrupt termination at the gastroesophageal junction.¹ The pathogenesis is unknown, although tissue hypoperfusion and gastric reflux are commonly cited contributing factors.¹ It has been associated with hyperglycemia, hypoproteinemia, hypoxemia, underlying malignancies, dehydration, various infections and antibiotic use.^2,3,5 Treatment remains primarily supportive and overall mortality is heavily dependent on the underlying comorbid conditions.^1,4 While this condition remains uncommon, there are growing numbers of case reports and case series noting its presence. Here we discuss a case of acute esophageal necrosis following gallstone pancreatitis.

Case

A 50 year old man presented in the emergency department following the acute onset of severe, sharp epigastric pain radiating to his back. His symptoms were associated with nausea and non-bloody vomiting. Physical examination was notable for diffuse abdominal tenderness to palpation, worst in the epigastrium. Laboratory results revealed an elevated white blood cell count (25,000/cmm (Normal 4,000-11,000)), elevated lipase 8307 U/L (Nl 73-393), a slightly elevated total bilirubin (1.2 mg/dL (Nl 0.2-1)), and a normal triglyceride level. A computed tomography (CT) scan of his abdomen and pelvis with oral and intravenous contrast demonstrated diffuse enlargement of the pancreatic head and body with extensive peripancreatic fluid consistent with acute pancreatitis. Multiple hyperdense foci were noted within the gallbladder, suggestive of gallstones. No biliary dilation was noted.

The patient was admitted with the diagnosis of acute pancreatitis, thought to be secondary to gallstones, aggressively resuscitated and his pain was managed with hydromorphone.

Over the next two days, his bilirubin rose to 2.5 mg/dL, and an endoscopic retrograde cholangiopancreatography (ERCP) was performed. On examination, a short segment of the proximal esophagus was normal (Figure A), however the mucosa in the remainder of the esophagus was black and necrotic (Figure B). The gastric mucosa was uninvolved with a clear demarcation at the gastroesophageal junction (Figure C). The major papilla could not be located due to duodenal edema.

Repeat endoscopies over the following months demonstrated complete mucosal healing, though he did require an esophageal dilatation to treat a stricture. His course was complicated by the development of pancreatic necrosis initially managed with an endoscopic ultrasound (EUS) guided cystgastrostomy. Due to chronic abdominal pain and complete obstruction of the distal pancreatic duct, he later underwent a pancreaticojejunostomy to relieve the obstruction. His clinical condition improved significantly following this surgical procedure.

Discussion

Acute esophageal necrosis, also known as black esophagus or necrotizing esophagitis, is a relatively rare and often incidentally noted clinical entity. It is characterized by diffuse circumferential black esophageal mucosa that generally involves at least the distal esophagus with abrupt termination at the gastroesophageal junction.^1,4 It is rarely seen in clinical practice; Augusto et al. reported the condition in 29 of 10,295 patients who underwent an upper gastrointestinal endoscopy over a 5 year period (0.28%).³

Most commonly described in elderly hospitalized men, acute esophageal necrosis often presents with symptoms of upper gastrointestinal hemorrhage, though dysphagia and epigastric pain have been observed. It has been associated with diabetes mellitus, malignancy, and vascular diseases, as well as hypoalbuminemia, hypoxemia, and dehydration.^1,4 The pathogenesis has yet to be fully elucidated; the most commonly advanced explanation is transient tissue hypoperfusion leading to diminished esophageal mucosal defense, followed by severe gastric reflux and subsequent tissue injury.⁴

Endoscopy typically discovers diffuse, black, and necrotic mucosa in a circumferential pattern involving varying lengths of the esophagus with stark and abrupt termination at the gastroesophageal junction.^1,2,4,5 While it most often affects the distal third of the esophagus, the condition has been noted in the mid and upper esophagus as well.⁴ Histology usually demonstrates severe mucosal and submucosal necrosis along with muscle fiber inflammation and/or destruction.²

Management is primarily supportive and typically involves oral nutritional rest, intravenous proton pump inhibitor use, short term total parental nutrition, and treatment of the underlying disorders.^2,4 If co-morbid conditions show adequate improvement, case studies suggest that spontaneous mucosal healing can be expected.^1,3 Mortality may be as high as 32.5% due to severe underlying medical conditions.⁵ Esophageal rupture is the most severe immediate complication, occurring in approximately 6% of cases and is typically accompanied by mediastinitis, abscess formation, and an extremely high mortality rate.⁴ Esophageal strictures are commonly encountered during the recovery period and are seen in 10-25% of cases.¹

SUMMARY

Acute esophageal necrosis is a rare but serious medical condition that often presents in medically ill older men with symptoms consistent with upper gastrointestinal bleeding. Endoscopy typically discovers black and necrotic mucosa in the distal esophagus with abrupt termination at the gastroesophageal junction. Management is generally limited to supportive esophageal care and aggressive treatment of the underlying medical issues. While immediate and devastating acute complications can occur, the high mortality associated with this condition is attributed to the severity of the underlying medical issues. Should the medical issues improve, spontaneous esophageal healing can be reasonably expected

References

1. Gurvits G, Cherian K, Shami M, et al. Black esoph- agus: New Insights and Multicenter International Experience in 2014. Dig Dis Sci. 2015; 60: 444-453.

2. Day A, Sayegh M. Acute oesophageal necrosis: A case report and review of the literature. Int’l Journal of Surgery. 2010; 8: 6-14.

3. Moreto M, Ojembarrena M, Zaballa J, et al. Idiopathic Acute Esophageal Necrosis: Not Necessarily a Terminal Event. Endoscopy. 1993; 25: 534-538.

4. Gurvits G, Shapsis, A, Lau N, et al. Acute esophageal Necrosis: a rare syndrome. J Gastroenterology. 2007; 42: 29-38.

5. Augusto F, Fernandes V, Cremers M I, et al. Acute Necrotizing Esophagitis: a Large Retrospective Case Series. Endoscopy. 2004; 36: 411-415.

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The Microbiome And Disease, Series #2

The Microbiome and Inflammatory Bowel Disease

January 2018 • Volume XLII, Issue 1

Jessica Murray,

Daniel Frochtzwajg,

Sabine Hazan

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An IBD patient’s quality of life can be significantly diminished when treated with conventional therapies. However, like the trend of fecal microbiota transplantation (FMT) for the treatment of Clostridium difficile infection, there is promising evidence that a similar approach will prove efficacious in treating UC and Crohn’s, especially given the increasingly predictable intestinal microbiome perturbation.

Sabine Hazan Steinberg MD, Gastroenterology/ Hepatology/Internal Medicine Physician, CEO, Ventura Clinical Trials, CEO, Malibu Specialty Center Dr. Daniel Frochtzwajg DO, Research Assistant, Ventura Clinical Trials Jessica Murray BS, Research Assistant, Ventura Clinical Trials, Ventura, CA

Ulcerative colitis (UC) and Crohn’s disease are the two chronic and progressive inflammatory states that commonly define inflammatory bowel disease (IBD). UC is typically characterized by continuous mucosal inflammation that involves that rectum and colon and often presents as bloody diarrhea. In Crohn’s disease, inflammation is spotty, transmural and can be observed in any portion of the gastrointestinal tract. IBD affects roughly 1.4 million people in the United States and some 2.2 million in Europe.^5,6 The steadily increasing incidence and prevalence of IBD, as well as the association of IBD and urban living, suggests that environment plays a critical role in the development of these diseases.^8,13 This hypothesis, in conjunction with the documented variations in gut microbiome associated with industrialization and geography,3 has led researchers to pursue the intestinal microbiota as an avenue for diagnostic and therapeutic intervention.

It is thought that a shift in composition of the intestinal microbiome may contribute to the development of IBD in genetically susceptible individuals. Initially hinted at by studies demonstrating such things as a reduced risk of IBD in breastfed infants or increased risk in those with low vitamin D levels,^1,2,10 the new age of bioinformatics has enabled corroboration of this theory. One example of the complex genetic-microbe interplay is a study by Ijaz et al.. demonstrating that adult relatives of patients with Crohn’s disease had less diverse intestinal microbiota than healthy adults unrelated to IBD patients.4

While there is no singular microbe responsible for IBD, gut dysbiosis is clearly implicated.⁵ An overall reduction in microbial diversity has been observed as well as specific, relative increases and decreases in “good” and “bad” microbes.^5,9,12 In Sartor and Wu’s extensive 2017 review, Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Disease and Therapeutic Approaches, the authors distill the latest documented genetic compositional changes in the intestinal microbiome of IBD patients.¹² They identify the overarching theme of the associated dysbiosis as a decrease in known “protective”” bacteria such as Bifidobacterium species and an expansion of potentially inflammatory microbes like Proteobacteria, Fusobacterium species, and invasive E. coli.¹²

The common treatments for UC and Crohn’s, including immunosuppressive therapies, mesalamine, glucocorticoids, and tumor necrosis factor antagonists, rarely induce remission and colectomy is too often an undesirable endpoint. Furthermore, an IBD patient’s quality of life can be significantly diminished when treated with conventional therapies.¹⁷ However, like the trend of fecal microbiota transplantation (FMT) for the treatment of Clostridium difficile infection, there is promising evidence that a similar approach will prove efficacious in treating UC and Crohn’s, especially given the increasingly predictable intestinal microbiome perturbation. In one of the premier studies of alternative treatments for IBD, Moayyedi et al. demonstrate, in a randomized controlled trial, that FMT can induce remission in UC patients.⁷ Researchers used the Mayo score for UC, which includes scores for stool pattern, rectal bleeding, endoscopic findings, and physician assessment (scores ranges from 0-12, with higher scores correlating with increased disease severity) to assess patients. Eligible enrollees were adults 18 years or older with active UC determined by a Mayo score ≥4 (with an endoscopic score =1); remission was defined as a Mayo score <3 at seven weeks. FMT from healthy donors was completed via retention enemas administered once weekly for six weeks. Overall, 9 of the 38 patients in the FMT treatment arm achieved remission, compared to 2 of the 37 patients in the placebo arm. Moreover, there was no difference in serious adverse events between the two groups. In another promising prospective, uncontrolled study, by Uygun et al. response of UC patients to FMT was examined.¹⁴ Responders were defined as a decrease in Mayo score ≥30%. 21 patients in the study, 70% of the subjects, were ultimately classified as responders. While 9 patients were categorized as non-responders, there was still improvement in CRP and hemoglobin levels after FMT.

Despite the positive findings mentioned above, there is conflicting data, and in another RCT, Rossen et al.¹¹ did not demonstrate a difference in the remission rate of FMT vs. placebo. However, increased intestinal microbiome richness following FMT has been shown in patients with Crohn’s, and there is evidence to suggest that FMT donor species richness determines efficacy of FMT treatment for IBD.^15,16

Ultimately, while current data is cause for optimism, more foundational research is necessary to characterize the microbe-gene interaction and define a treatment paradigm.

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Gastrointestinal Motility And Functional Bowel Disorders, Series #23

Gastroesophageal Reflux can be an Explanation for Dysphagia of Otherwise Unknown Etiology

December 2017 • Volume XLI, Issue 12

Pratik Naik,

Yi Jia,

Richard W. McCallum

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Dysphagia and gastroesophageal reflux disease (GERD) are common entities in clinical practice. High- resolution manometry (HRM) of the esophagus is a diagnostic test to investigate dysphagia where other esophageal tests and evaluations had not disclosed an etiology. The goals of our study were to investigate the frequency of GERD in patients whose dysphagia cannot be explained by all prior studies, including HRM, and propose that GERD, by inducing esophageal hypersensitivity, could explain this sensation of dysphagia. A retrospective chart review of HRM studies that were performed from 2012-2016 in 167 patients with dysphagia was conducted. Results were categorized based on the Chicago Classifications as follows: achalasia 11%; nutcracker 7%; Jackhammer 2%; scleroderma 4%; diffuse esophageal spasm 1%; elevated integrated relaxation pressure 7%; presbyesophagus 4%; hypertensive LES pressure 3%. In addition, 80 (48 %) had normal and 24 (14%) had minor non-specific HRM findings. Medical records where available for review in 78 of those 104 patients with dysphagia who had normal or minor non-specific HRM findings. We identified Schatzki ring in two and eosinophilic esophagitis in three patients. 73% of the remaining 73 patients had evidence of GERD based on one or more of the following test results: EGD, esophageal biopsy, pH impedance, BRAVO test and barium swallow; while in the other 20 (27%) there was no objective evidence of GERD. 95% were receiving ongoing PPI therapy for symptoms consistent with GERD. In conclusion, when HRM findings are normal or minor non-specific in patients with unexplained dysphagia then evidence for concomitant GERD should be sought since the esophageal hypersensitivity induced by GERD can be one explanation for this dysphagia and can lead to further treatment approaches.

Pratik Naik, MD, GI Motility Fellow, TTUHSC Yi Jia, MD, GI Fellow, PGY-6, TTUHSC Richard W. McCallum, MD, FACP, FRACP (AUST), FACG, AGAF, Professor of Medicine and Founding Chair, Division of Gastroenterology, Director, Center for Neurogastroenterology and GI Motility, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX

INTRODUCTION

Patients with gastroesophageal reflux disease (GERD) may present with various symptoms including heartburn, regurgitation, dysphagia, chronic cough, laryngitis, aspiration and even asthma.¹ An etiology of dysphagia in patients with GERD is sometimes unknown and can be further investigated with High-resolution manometry (HRM) of the esophagus.

Prior to referral for HRM, patients often undergo evaluation including esophagogastroduodenoscopy (EGD) and/or barium swallow study to rule out mechanical causes of dysphagia and to exclude eosinophilic esophagitis (with esophageal biopsies). After undergoing HRM, the diagnosis of a motility disorder is made based on the Chicago Classifications; however, many patients who undergo this evaluation for dysphagia with HRM studies have no recognized abnormalities, being regarded as either normal or minor nonspecific findings. At our center, we have observed concomitant GERD in many patients who were referred for HRM to elucidate a suspected esophageal cause of dysphagia but in whom either normal or minor nonspecific abnormalities are found. Patients with GERD may continue to report dysphagia despite being treated with standard anti reflux medications. This sensation of dysphagia in patients with GERD could be secondary to visceral hypersensitivity of the esophagus. Among practicing clinicians there is limited acceptance and appreciation for the term “visceral hypersensitivity” as far as understanding its role in a patient’s symptoms. The concept of visceral hypersensitivity has been described in the literature in functional bowel disorders such as non-cardiac chest pain, non-ulcer dyspepsia and irritable bowel syndrome.²

Aims:

We investigated the frequency of objective evidence for GERD in patients whose dysphagia cannot be explained by all prior studies including HRM. Additionally, we propose that GERD, by inducing esophageal hypersensitivity, could explain this sensation of dysphagia.

Methods:

A retrospective chart review of high resolution manometry studies, performed for various indications, from 2012-2016 in patients referred to a University Motility Center was conducted. The standard technique described for HRM was utilized and a total of 16 wet swallows were employed. Those patients referred for the specific assessment of dysphagia were categorized according to underlying manometric etiologies for dysphagia as recognized in the current as well as the previous Chicago Classifications which overlapped our study years of 2012-16.^3,4 In patients with no recognized motility disorder on the HRM study, we identified two additional groups: 1) entirely normal manometric findings and 2) minor, non-specific motility findings. We defined the entity of a minor, nonspecific motility abnormalities as having one or more of the following: 1) a decreased resting lower esophageal sphincter (LES) pressure (< 10 mm Hg); low amplitude contractions defined as < 30 mm Hg in less than 30% of the contractions induced by 16 wet swallows at the level of 3 and 7 cm above the LES; a small percentage loss of peristalsis, < 50% of the sequences following wet swallows, where <30% non- peristalsis is regarded as normal.^5-7 Clinical chart reviews were conducted only in patients with dysphagia who had normal or minor non- specific HRM findings. The aim of the chart review was to identify all the diagnostic testing performed for both confirmatory evidence of GERD as well as excluding other causes of dysphagia. We reviewed EGD reports for evidence of esophagitis as per the Los Angeles classification, and/or Barrett’s esophagus and to identify other etiologies such as strictures, masses, rings and hiatal hernias.⁸ We also examined endoscopic esophageal biopsy reports to identify GERD related changes (basal cell hyperplasia, elongation of connective tissue papillae, infiltration by neutrophils and eosinophils) in patients with an endoscopically normal esophagus as well as to identify other etiologies such as eosinophilic esophagitis.⁹ Barium swallow reports were reviewed to identify mechanical obstruction (including strictures or rings), gastroesophageal reflux and hiatal hernia. BRAVO and 24-hour pH impedance tests were also evaluated where applicable.

Results:

319 patients were referred for HRM testing for all indications from 2012-2016. There were 167 (52.4%) patients that met the criteria of dysphagia. These 167 patients had the following manometric entities based on the definitions of the Chicago classifications (Figure 1): achalasia 18 (11%); high amplitude peristaltic contractions with distal contractile integral (DCI) >5000 but <8000 (nutcracker esophagus) 11 (7%); extremely elevated amplitude but peristaltic contractions with DCI > 8000 (Jackhammer esophagus) 4 (2%); scleroderma 6 (4%); diffuse esophageal spasm in 2 (1%); elevated integrated relaxation pressure in 11 (7%); presbyesophagus 6 (4%); and hypertensive LES pressure (> 40 mm Hg) 5 (3%). In addition, 80 (48 %) were judged as having an entirely normal manometry while there was a subgroup of 24 (14%) with non-specific minor motility abnormalities (the criteria for which we have previously defined) (Figure 1). Of those 104 (62%) patients who had either normal or minor non-specific HRM findings, the age range was 15-86 years and 71 (68%) were female. 90% were being managed by a proton pump inhibitor (PPI) for symptomatic GERD at the time of evaluation of dysphagia. Of those 104 patients, 78 had medical chart records available to review results of the diagnostic testing. Based on those studies, Schatzki rings (2 patients) and eosinophilic esophagitis (3 patients) were identified as causes of dysphagia. Fifty-three (73%) of the remaining 73 patients had objective evidence of GERD based on one or more of the following test results: EGD, esophageal biopsy, pH with impedance, BRAVO pH study and barium swallow (Table 1). EGD confirmed esophagitis in 15 patients (LA classification) as well as 4 with Barrett’s epithelial changes confirmed by biopsies. Esophageal biopsies in the patients with normal endoscopic findings were consistent with GERD in 25 patients. Six patients had acid reflux based on 24-hour pH impedance data and one had predominant non-acid reflux. One patient had a positive 48-hour BRAVO study. Barium swallow showed evidences of GE reflux in four patients. Hiatal hernias were observed in one or more of those studies in 16 (30%) patients. While 73% of the patients had confirmatory objective evidence of GERD, 20 (27%) of 73 patients whose charts were available for review had no objective evidence of GERD but 95% were receiving ongoing PPI therapy for symptoms. In this subset of negative GERD findings, the diagnostic testing was suboptimal in that in the setting of a negative EGD other tests were not routinely pursued for the evaluation of GERD.

Discussions:

Based on HRM classifications, there are well identified manometric disorders that can explain dysphagia. However, 104 (62%) of the patients referred for HRM to evaluate dysphagia at our motility center had a normal or minor nonspecific esophageal motility findings. These findings alone would not explain dysphagia without there being other underlying esophageal pathology. Indeed, 73% of our patients with normal or minor nonspecific findings whose medical records were accessible for review had objective evidence of GERD. Therefore, in the setting of either normal or nonspecific HRM findings the presence of GERD could provide evidence for underlying pathology and a possible explanation for their dysphagia.

One of the limitations of our data is that 27% of the patients with normal or non-specific motility findings did not have medical records available for review. This is because they were referred by gastroenterologists in private practice in our city and our access to their medical records was limited. Another limitation of our study is that in the 28% of patients whose medical records were available for review had no objective evidence of GERD and we observed that if their EGD was normal then pH studies and endoscopic esophageal biopsies were usually not pursued. Hence GERD could still have been present. In fact, they were being managed by PPI for symptoms consistent with GERD.

Our findings of esophageal pathology in the form of GERD poses the question of whether GERD related visceral hypersensitivity of esophagus could be an explanation for the sensation of dysphagia. Visceral hypersensitivity is present in other organs and is proposed to be mediated by peripheral, central and psychosocial factors.¹⁰ The sensation of stimuli chemical, mechanical, thermal etc – in contact with the esophageal mucosa is transmitted to the central nervous system (CNS) via either spinal nerves or vagal nerves (Figure 2).¹⁰ This sensation is thought to be physiologically important to help sense the passage of food or foreign material through the esophagus during swallowing.¹¹ In a hypersensitive esophagus, there is a heightened perception of stimuli, discomfort or pain and this could generate a visceral sensation interpreted by the patient as the symptom of dysphagia.¹²

In reflux esophagitis (RE), there is a break in the esophageal mucosa and noxious stimuli can penetrate and activate nociceptive receptors in deep layers of the mucosa resulting in signals, which then are transmitted to the CNS.¹³ Patients with nonerosive reflux disease (NERD) can have heartburn even though damage to the esophageal mucosa is not observed. Here, microscopic changes based on dilation of the intracellular space have been reported.¹⁴ Based on intra-esophageal acid infusion tests, pain response to acid reflux in patients with NERD has been shown to be stronger than in patients with erosive GERD.^15,16 Miwa and et al. suggested that patients with NERD can have increased mucosal permeability that could permit penetration of the mucosa by noxious stimuli such as gastric acid, bile acids, or pepsin.¹⁵ A symptom of heartburn is not specific to acid reflux into the esophagus and has been reported as a symptom response to mechanical stimuli including esophageal dilation and longitudinal contraction of esophageal smooth muscle.^17,18 It is conceivable that dysphagia could be perceived as an uncomfortable sensation accompanying swallowing, when there is esophageal mucosa sensitized by chronic GE reflux, in the absence of mechanical obstruction or a motility disorder. Patients with depression, anxiety, somatization disorders, and fibromyalgia tend to have a higher prevalence of esophageal hypersensitivity and this aspect could also be a contributing factor in sensing the symptom of dysphagia.¹⁹ Hypersensitive esophagus has also been investigated by a balloon distension method. Here, a small balloon is distended in the esophagus to assess which volume induces the first perception of symptoms and the degree of discomfort experienced.¹⁹ The implication from the balloon test results are that touching, stretching, or perturbing the esophagus induces a sensation e.g. heartburn, chest pain and non-specific discomfort. In the setting of eating where food is stretching the esophageal lumen, the resulting sensation could be interpreted as dysphagia by the patient. This balloon testing was not performed in our patients due to the retrospective nature of the study. However, 90% of patients with unexplained dysphagia were being treated with a PPI for symptomatic GERD at the time of evaluation of dysphagia and 73% patients with available medical records had objective evidence of GERD. In addition, 71% of our patients were females similar to the female dominance in such entities as irritable bowel syndrome and non-ulcer dyspepsia where visceral hypersensitivity is thought to be important in the mediation of the symptoms.

CONCLUSION

In conclusion, in patients with unexplained dysphagia when HRM is normal or only minor non-specific findings are present then evidence for concomitant GERD should be sought. We hypothesize that GERD could induce a hypersensitive state in the esophageal mucosa. This leads to a heightened awareness of esophageal movement and touching during swallowing, which is interpreted by the patient as the symptom of “trouble swallowing” or dysphagia. Our observations should be confirmed in more studies in this specific patient setting of unexplained dysphagia and accompanying GERD where testing for assessing visceral hypersensitivity of the esophagus as well as treatment trials to address this entity are included.

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Nutrition Issues In Gastroenterology, Series #170

Have PN (Parenteral Nutrition) – Will Travel

December 2017 • Volume XLI, Issue 12

Anna Patsy,

Adriana Panciu,

Nizar Senussi

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

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

INTRODUCTION

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

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

Case Presentation

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

Clinical Concerns

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

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

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

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

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

Monitoring

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

Infusion Pumps and Supplies

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

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

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

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

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

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

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

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

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

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

Swimming

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

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

Case Study Continued

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

CONCLUSION

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

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The Microbiome And Disease, Series #1

The Microbiome and Clostridium Difficile

December 2017 • Volume XLI, Issue 12

Sabine Hazan,

Daniel Frochtzwajg,

Jessica Murray

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

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

INTRODUCTION

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

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

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

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Introduction To A New Series: The Microbiome And Disease

The Microbiome and Disease

December 2017 • Volume XLI, Issue 12

Sabine Hazan

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INTRODUCTION

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

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

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

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

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

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

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Inflammatory Bowel Disease: A Practical Approach, Series #104

Management of the Ileal Pouch-Anal Anastomosis in the Elderly

December 2017 • Volume XLI, Issue 12

Irving Levine,

Shannon Chang

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

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

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

INTRODUCTION

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

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

Pouch Creation in the Elderly

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

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

Pouch Function Over Time

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

Pouchitis

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

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

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

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

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

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

Treatment of Pouchitis in the Elderly

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

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

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

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

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

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

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

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

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

Medical Management of Diarrhea with IPAA

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

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

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

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

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

Other Potential Concerns in the Elderly
Radiation and Pouch Function

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

Sphincter Dysfunction

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

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

Dysplasia Surveillance

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

CONCLUSION

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

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A Case Report

Complicated Metastatic Melanoma to the Gastrointestinal Tract

November 2017 • Volume XLI, Issue 11

Joseph P. Kingsbery,David M. Poppers

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

INTRODUCTION

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

Case

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

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

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

Discussion

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

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

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Frontiers In Endoscopy, Series #40

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

November 2017 • Volume XLI, Issue 11

Douglas G. Adler

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

CASE REPORT

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

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

Discussion

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

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

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

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

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

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

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

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

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

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INTRODUCTION

Normal VLE Images

VLE in Barrett’s Esophagus

VLE in Squamous Cell Dysplasia and Cancer

VLE Use in Peroral Endoscopic Myotomy

CONCLUSION

INTRODUCTION

Case

Discussion

SUMMARY

INTRODUCTION

Aims:

Methods:

Results:

Discussions:

CONCLUSION

INTRODUCTION

Case Presentation

Clinical Concerns

Monitoring

Infusion Pumps and Supplies

Swimming

Case Study Continued

CONCLUSION

INTRODUCTION

INTRODUCTION

INTRODUCTION

Pouch Creation in the Elderly

Pouch Function Over Time

Pouchitis

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

Treatment of Pouchitis in the Elderly

Medical Management of Diarrhea with IPAA

Other Potential Concerns in the Elderly Radiation and Pouch Function

Sphincter Dysfunction

Dysplasia Surveillance

CONCLUSION

INTRODUCTION

Case

Discussion

CASE REPORT

Discussion

Other Potential Concerns in the Elderly
Radiation and Pouch Function