Neuromuscular Disorders of the Gastrointestinal Tract

Introduction

Normal bowel motility depends on smooth muscle, interstitial cells of Cajal (ICC), the intrinsic and extrinsic nerve supply and their supporting cells, and various neuroendocrine peptides. Abnormalities in any one or more of these components may result in bowel dysmotility. In addition, other inflammatory cells such as lymphocytes, eosinophils, and mast cells may act directly, or indirectly, on the neuromuscular apparatus of the bowel wall. The clinical manifestations of motility disorders depend on the extent and specific site of the abnormality. Some of these disorders present with distinct clinical features (e.g., idiopathic hypertrophic pyloric stenosis, Hirschsprung’s disease, achalasia), whereas others have nonspecific manifestations. For example, patients with congenital idiopathic hypertrophic pyloric stenosis present with projectile vomiting in the first month of life, often associated with an olive-size abdominal mass. Patients with Hirschsprung’s disease manifest with delayed passage of meconium. The pathogenesis of many of these conditions is still poorly understood. In fact, many disorders have no specific pathological features and lack standardized diagnostic criteria. This has led to marked variability in the approach to a diagnostic workup among different laboratories. To address these issues, an international working group was formed in 2007. This group published a comprehensive guideline for handling of most specimens, including biopsies and resections, pertaining to GI motility disorders. The classification proposed by this group is recognized as the London classification of neuromuscular disorders of the GI tract. This classification has placed various primary neuropathies and myopathies into well-delineated categories. However, it includes only a short list of secondary disorders. A modified version of this classification is shown in Box 8.1 . It is expected that this will lead to application of uniform criteria, use of standardized terminology, and an improvement in our understanding of gastrointestinal (GI) motility disorders.

BOX 8.1

Classifications of Neuromuscular Disorders

A

Primary Neuropathy

Absent Neurons
- Aganglionosis (Hirschsprung’s disease)
Decreased number of neurons
- Hypoganglionosis
Increased number of neurons
- Intestinal neuronal dysplasia, type B
- Ganglioneuromatosis
Degenerative neuropathies
Inflammatory neuropathies
- Lymphocytic ganglionitis
- Eosinophilic ganglionitis
Abnormal content in neurons
- Intraneuronal inclusion disease
- Megamitochondria
Abnormal neuronal coding
Relative immaturity of neurons
Abnormal enteric glia
- Increased number of glia
- Decreased number of glia

B

Primary Myopathy

Muscularis propria malformations
- Focal absence of enteric muscle coats
- Segmental fusion of enteric muscle coats
- Presence of additional muscle coats
- Colonic desmosis (absent connective tissue scaffold)
Muscle cell degeneration
- Degenerative leiomyopathy
  - Sporadic
  - Familial
- Inflammatory myopathies
  - Lymphocytic leiomyositis
  - Eosinophilic leiomyositis
Muscle hyperplasia/hypertrophy
- Muscularis mucosae hyperplasia
Abnormal content in myocytes
- Filament protein abnormalities
  - Alpha actin myopathy
  - Desmin myopathy
- Inclusion bodies
  - Polyglucosan bodies
- Amphophilic “M” bodies
- Megamitochondria

C

Interstitial Cells of Cajal (ICC) Abnormalities (Mesenchymopathies)

Absent ICC
Increased ICC
Decreased ICC

D

Neurohormonal Abnormalities

E

Secondary Neuropathy

Systemic disorders
- Paraneoplastic inflammatory neuropathy
- Diabetic neuropathy
- Chagasic neuropathy
- Connective tissue disorder–associated neuropathy
- Storage disease
- Amyloidosis
Local disorders
- Crohn’s disease

F

Secondary Myopathy

Systemic disorders
- Desmin myopathy
- Muscular dystrophies
- Mitochondrial cytopathies
- Metabolic storage disorders
- Amyloidosis
- Progressive systemic sclerosis
- Other collagen vascular disorders
- Cystic fibrosis
Local disorders
- Obstructive/postirradiation muscle failure

Muscle Coats of the Bowel Wall

Knowledge of the basic organization of the neuromuscular apparatus of the bowel is essential to understand and diagnose GI motility disorders. The neuromuscular framework of the bowel is similar throughout the tract. However, there are some minor variations. The bowel smooth muscle is composed of a thin superficial layer that separates mucosa from submucosa (muscularis mucosae) and a thick outer layer (muscularis propria), which has an inner circular and outer longitudinal coat. The muscularis propria is organized into an inner circular and outer longitudinal layer, except for the esophagus, which has only a single longitudinal muscle coat. The proximal part of the muscularis propria of the esophagus is formed entirely of skeletal muscle. The skeletal muscle merges with the smooth muscle of the esophagus in the vicinity of the proximal half of the organ ( Fig 8.1 ). Thus esophageal motility is susceptible to the effects of systemic disorders of both smooth and skeletal muscle. In the stomach, an additional inner oblique muscle layer is also present. In contrast, the outer longitudinal layer in the colon forms thick localized bands of muscle termed taenia coli . The muscularis mucosae of the colon continues into the anal canal. The inner circular layer of muscularis propria of the rectum becomes thickened distally to form the internal anal sphincter. The external anal sphincter is formed of skeletal muscle and is connected to the skeletal muscle of the pelvic floor. The outer longitudinal muscle layer of the rectum continues in between the inner and outer anal sphincters and then separates caudally into multiple septa, which then diverge fanwise throughout the subcutaneous part of the external sphincter into the skin. These fibers are responsible for the characteristic corrugated appearance of the perianal skin. In addition, the muscle fibers from the outer longitudinal coat and the internal anal sphincter extend into the submucosa to form a meshwork of fibers surrounding the vascular plexuses (muscularis submucosae ani). The organization of the muscle layers in the appendix is similar to the colon, except that it lacks taenia coli .

FIGURE 8.1, A, Low-magnification view of a section obtained near the proximal margin from an esophagectomy specimen shows skeletal muscle fibers in the outer layer of muscularis propria of the proximal esophagus. B, Higher-magnification view of a section obtained from the mid-esophagus shows skeletal muscle fibers merging imperceptibly with smooth muscle fibers of muscularis propria.

Neural Network of the Bowel

The organization of the neural network in the bowel is quite complex. The extrinsic nerve supply of the bowel wall consists of both sympathetic and parasympathetic nerve fibers that penetrate the wall and become the intrinsic neural plexus. The sympathetic fibers originate in the prevertebral ganglia and parallel the superior and inferior mesenteric arteries. The parasympathetic fibers are located alongside the posterior branch of the vagus nerve. The intrinsic neural system of the bowel wall is organized into three plexuses: the submucosal plexus (Meissner’s plexus), the deep submucosal plexus (Henle’s plexus) and the myenteric plexus (Auerbach’s plexus) ( Fig. 8.2 ). The most easily identified, and prominent, is the myenteric plexus, which is composed of clusters of ganglion cells connected by an intricate network of nerves located in the space between the inner circular and outer longitudinal muscle layers. The ganglion cells are surrounded by glial cells. Although the ganglion cells and nerve bundles are easily identified within these plexuses ( Fig. 8.3A ), the intricacy of the neural meshwork of fibers is not easily detectable on hematoxylin and eosin (H&E)–stained tissue sections. Whole-mount specimens, silver stains, and/or immunostains are normally needed to visualize the complexity of the neural network ( Fig. 8.3B ). ^,

FIGURE 8.2, Section of normal colon shows the neural plexus: submucosal plexus (SP), deep submucosal plexus (DSP), and myenteric plexuses (MP) (S100 stain).

FIGURE 8.3, A, Normal ganglion cells (H&E stain). B, A tangential section of muscularis propria shows myenteric ganglia in the complex neural network, which is not evident in a well-oriented section (S100 stain).

In addition to muscle fibers and the neural network, a third population of mesenchymal cells, the ICC, are critical for bowel motility. These cells generate a slow wave of depolarization and represent the “pacemaker cells” of bowel peristalsis. ^, Their function is, in turn, modulated by both intrinsic and extrinsic neural inputs. These cells are difficult to detect on routine tissue sections, and most of our initial knowledge regarding the morphology and structural organization of these cells stems from ultrastructural studies. Ultrastructurally, these cells show a partial basal lamina, many intermediate filaments, darkly staining cytoplasm, abundant rough endoplasmic reticulum, sublamellar caveolae, oval indented nuclei, and lack of myosin filaments. Many of these features overlap with smooth muscle cells. It was soon realized that these cells express c-kit (CD117), a tyrosine kinase receptor. c-kit or DOG1 immunostains can be used to visualize these cells. It is now recognized that ICC are part of an intricate neural network and have a close association between smooth muscle cells and nerve endings. They are most easily identified surrounding the myenteric plexus, especially in the small bowel, where the network of cells extends into the inner and outer muscle coats ( Fig. 8.4A–D ). In addition, there is also a distinct ICC plexus in the submucosa. The distribution and organization of ICC in the appendix is similar to that in the colon. The structural organization of ICC has been described in the various segments of the GI tract (from esophagus to anus). Minor regional differences within each bowel segment do exist.

FIGURE 8.4, A, Section from a small intestine shows interstitial cells of Cajal (ICC) extending into the inner circular and outer longitudinal layers of the muscularis propria (KIT/CD117 stain). A dense collection of ICC is present around the myenteric plexus. B, Section of colon shows distribution of ICC (KIT stain). Compared with the small intestine, fewer KIT-positive ICC are present around the myenteric plexus, which may be difficult to appreciate on low magnification. C, High-power view of muscularis propria shows multiple processes of KIT-positive ICC. In well-oriented sections, this morphology is difficult to appreciate. D, Semi-thin resin-embedded section shows ICCs (arrows) around the myenteric ganglia (toluidine blue stain).

The neuromuscular organization of the appendix is similar to the colon and small bowel. However, the ganglia are sometimes embedded deeper into the circular or longitudinal layer ( Fig. 8.5A–B ). The neural and ICC networks in the appendix are similar to the colon, but with less aggregation of ICC surrounding the myenteric plexus ( Fig. 8.5B–C ). Understanding the neuromuscular organization of the appendix is helpful because it is sometimes examined intraoperatively to evaluate the extent of aganglionosis.

FIGURE 8.5, A, Muscularis propria of a normal appendix shows ganglia of the myenteric plexus in the deeper layers of circular and longitudinal muscle, instead of at the junction of the two (H&E stain). B, S100 stain highlights the neural plexus in the appendix and the location of the ganglia within the circular and longitudinal layers of muscularis propria. C, KIT stain shows the organization of interstitial cells of Cajal in the circular and longitudinal layers of muscularis propria, showing very few cells around the myenteric ganglia, similar to the colon.

Esophagus

Primary Achalasia

Achalasia is a motor disorder of the esophagus characterized by failure of the lower esophageal sphincter to relax in response to swallowing. ^, Clinically, achalasia is divided into three subtypes: type I, classic type; type II, achalasia with compression; and type III, spastic achalasia. It is uncommon, as the overall prevalence rate is less than 10/10 ⁵ population. Its incidence has been fairly stable over the past 50 years. It is a disease of adults mainly older than 60 years of age and affects both sexes equally. Achalasia is more frequent in North America, northwestern Europe, and Australia than in other regions, and it is more common in Caucasians.

Clinical Features

The major clinical manifestations of achalasia differ between children and adults. Younger children (<5 years of age) and infants typically present with a feeding aversion, failure to thrive, choking, recurrent pneumonia, nocturnal cough, aspiration, or nonspecific regurgitation. Older children and adults often manifest with vomiting, chest pain, and dysphagia for solids and liquids. Heartburn is a common symptom (50%), even in untreated patients. However, only a minority of patients have documented gastroesophageal reflux disease. The diagnosis is confirmed with imaging studies and manometry. Barium studies typically reveal reduced peristalsis, a characteristic beaklike deformity of the distal esophagus, and dilation of the proximal esophagus. Manometry studies reveal abnormal peristalsis, increased intraluminal pressure, and incomplete and delayed relaxation of the lower esophageal sphincter. Endoscopy and endoscopic ultrasonography are often performed to rule out coexisting mucosal pathology and to exclude secondary causes of achalasia (“pseudoachalasia”).

Pathogenesis

The most significant feature of achalasia is loss of myenteric ganglion cells. However, the cause of ganglion cell loss is unknown. Current data suggest that myenteric inflammation precedes loss of ganglion cells, but the initial inciting events that cause the disease remain unknown. Environmental factors, viral infection, autoimmune mechanisms, and genetic predisposition have all been proposed. In addition, there is some data to suggest familial aggregation. Rare familial forms associated with alacrimia (absence of tears) and adrenocorticotropic hormone (ACTH) insensitivity have been described (Allgrove’s syndrome, or “Triple A” syndrome). ^, Concordance in monozygotic twins and an association with Down’s syndrome has also been reported. A significant association has been found with class II human leukocyte antigen (HLA) DQw1 in Caucasian patients. The alleles identified, HLA DQB1∗0602, DQA1∗0101, and DRB1∗15, are the same ones that have been found to be associated with other autoimmune disorders, including multiple sclerosis and Goodpasture’s syndrome, Graves’ disease, myasthenia gravis, polymyositis, autoimmune polyglandular syndrome, Sjögren’s syndrome, and Sicca syndrome. Antimyenteric neuronal antibodies have been identified in some patients. It has been shown in an ex vivo model that on exposure to sera from achalasia patients, gastric corpus mucosa shows phenotypic and functional changes that mimic achalasia. A factor in the serum, other than an antineuronal antibody, may be responsible for this phenomenon. Varicella-zoster viral DNA has been identified in the myenteric plexus in rare cases by in situ hybridization. Lymphocytes taken from the lower esophageal sphincter area seem to respond to herpes simplex virus (HSV) exposure by producing gamma interferon and cytotoxic T-cell proliferation, suggesting a role for remote/latent HSV infection, although studies looking for a variety of neurotropic and non-neurotrophic viruses have failed to provide any conclusive evidence for a viral infection. ^, Polymorphisms in VIP receptor-1, c-kit, and interleukin 23 receptor (IL23R) genes may increase susceptibility to achalasia. VIP is responsible for relaxation of esophageal smooth muscle, whereas KIT plays an important role in the function of ICC. The IL23 pathway is important in immune activation and plays an important role in many chronic inflammatory disorders, including inflammatory bowel disease.

As noted previously, the pathogenesis of achalasia is poorly understood. However, progressive inflammatory destruction of myenteric ganglion cells is the most important underlying event. This results in failure of the lower esophageal sphincter to relax in response to swallowing. Esophageal peristalsis is decreased or completely absent. This results in esophageal dilatation, chronic stasis, and reactive hypertrophy of the muscularis propria. There also is a substantial decrease in VIP-containing neurons in the distal esophagus. ^, Subsequently, it has been shown that nitric oxide is a primary esophageal inhibitory neurotransmitter. It colocalizes with VIP in ganglion cells. In addition, intrinsic nitrergic ganglion cells are lost, or markedly decreased, in achalasia. In fact, loss of VIP-positive ganglion cells is synonymous with loss of nitrergic ganglion cells. ^, Unfortunately, most early studies evaluated specimens only at the time of autopsy or esophagectomy, which showed end-stage disease. However, study of esophagomyomectomy specimens has given some insight into the early sequence of events in this condition. These studies revealed that as the disease progresses, the inflammatory infiltrate decreases in intensity, whereas loss of ganglion cells and degeneration of the myenteric plexus become more prominent features.

Pathological Features

Pathologists often encounter esophagus specimens resulting from an esophagectomy for end-stage achalasia. Grossly, the esophagus shows dilation, and the extent depends on the severity and duration of disease ( Fig. 8.6A ). It often contains stagnant and foul-smelling partially digested food. The distal end is typically narrowed and stenotic.

FIGURE 8.6, A, Resection specimen of achalasia shows a dilated proximal segment and a narrow distal segment. B, Myenteric plexus in a patient with end-stage achalasia. There are no residual ganglion cells, and the chronic inflammatory cells are seen in and around a fibrotic nerve (H&E stain). C, Strong CD8 staining of lymphocytes within the myenteric plexus of a patient with end-stage achalasia.

The main histological abnormality in achalasia is related to the myenteric plexus, although numerous secondary changes are often present, presumably resulting from prolonged stasis and reflux. Widespread, often total, loss of myenteric ganglion cells is the cardinal feature of achalasia (see Fig. 8.6B; Fig. 8.7 ). Better preservation of the ganglion cells may be present in the more proximal portions of the esophagus. Some degree of neural hyperplasia may accompany neuronal loss (see Fig. 8.7 ). A variable amount of chronic inflammation often admixed with eosinophils and plasma cells is typical. Mast cells may be noted surrounding the myenteric nerves and residual ganglion cells (see Fig. 8.6B and Fig. 8.7 ). In end-stage disease, the degree of inflammation may become minimal or disappear completely. One ultrastructural study showed that numerous mast cells are also present within the inflammatory infiltrate closely associated with the nerve fibers. Occasionally, lymphocytes may infiltrate the cytoplasm of ganglion cells (ganglionitis). The majority of chronic inflammatory cells are CD3-positive T cells, most of which are CD8-positive (see Fig. 8.6C ), although the relative percentage of these cells decreases with progression of disease. ^, ^, A large subset of T cells represents either resting or activated cytotoxic cells.

FIGURE 8.7, Specimen from a patient with achalasia shows complete absence of ganglion cells in the myenteric plexus, which appears hyperplastic. There is perineural inflammation with eosinophils (H&E stain).

Other changes frequently present are related to distal esophageal obstruction and include muscularis propria hypertrophy, muscularis propria eosinophilia, and dystrophic calcification. Hypertrophied muscle may also show degenerative changes, including cytoplasmic vacuolation and liquefactive necrosis. The branches of the vagus nerve within the adventitia are unremarkable in most cases, although degenerative changes in the vagus nerve and in dorsal motor nuclei have been described as well. These changes may be caused by infection with a neurotrophic virus; however, no specific virus has been identified thus far. ^, The squamous mucosa also shows secondary changes, including diffuse hyperplasia, increased intraepithelial lymphocytes (“lymphocytic esophagitis”), papillomatosis, basal cell hyperplasia, and an increase in nonspecific lamina propria inflammation. Some of these changes mimic reflux esophagitis, although sustained lower esophageal pressure does not allow regurgitation of gastric contents in untreated cases. Increased intraepithelial eosinophils, sometimes raising a concern for eosinophilic esophagitis, are seen. Despite symptoms of dysphagia and presence of motor dysfunction, studies show that this is not likely to represent eosinophilic esophagitis, although few cases of eosinophilic esophagitis in achalasia that respond to steroids have also been reported. After esophagomyotomy, gastroesophageal reflux develops in up to 50% of patients and can lead to the development of Barrett’s esophagus in some cases. ^,

Differential Diagnosis

Biopsies are not performed to establish a diagnosis of achalasia. Pathologists encounter this condition when a resection is performed or at autopsy. The role of biopsy in patients with achalasia is largely to exclude Barrett’s esophagus (postmyotomy), dysplasia, and malignancy. The differential diagnosis of achalasia, both clinically and pathologically, is pseudo-achalasia, secondary to tumors or paraneoplastic syndrome. These are easily resolved with esophageal manometry and imaging, or with biopsies when a mass is present. Occasionally, strictures at the gastroesophageal junction secondary to reflux, prior surgery, or trauma can mimic achalasia ( Fig. 8.8A–B ). The esophagus may show muscular hypertrophy and neural hyperplasia similar to achalasia. However, on close examination, ganglion cells are easily identified in the neural plexus, and there is a lack of inflammatory or degenerative changes in the ganglion cells. In postinfectious or autoimmune-mediated ganglion cell loss, lymphocytic inflammation may be present in or around ganglion cells. Residual ganglion cells can often be identified ( Fig. 8.8C ). In para-neoplastic achalasia, the diagnosis of malignancy is often already known, and despite histological similarity with the idiopathic form, their differentiation is seldom a problem clinically. Chagas’ disease, which also causes massive dilation of the esophagus with ganglion cell loss, should be suspected in any patient from an endemic area. By the time achalasia-type features develop, the infectious organisms can no longer be demonstrated in the tissues, and thus one has to rely on serological evidence of infection. Patients with Chagas’ disease may also show dilatation of other hollow viscera with ganglion cell loss.

FIGURE 8.8, A, Stricture of the distal esophagus near the gastroesophageal junction developed after reflux surgery in this patient and led to proximal dilatation and muscular hypertrophy, mimicking achalasia (B). However, microscopy showed a normal population of ganglion cells in the myenteric plexus (H&E stain). C, Inflammatory infiltrate and degenerative changes in the ganglion cells can be seen in a wide variety of immune-mediated or postviral cases of ganglion cell loss (H&E stain).

Natural History and Treatment

Achalasia is a chronic disorder, and the treatment is largely palliative. Medications such as anticholinergics, nitrates, and calcium channel blockers are used in some circumstances but result in only partial benefit. Pneumatic dilatation and botulinum toxin injection into the lower esophageal sphincter show an initial response, but the results are usually short lasting. The best results are typically obtained with esophagomyotomy of the lower esophageal sphincter, either with or without pneumatic dilatation. Patients with type II achalasia have the most favorable outcome and show better response to treatment. Esophageal resection is usually reserved for end-stage cases. Patients have an increased long-term risk for developing squamous cell carcinoma of the esophagus. ^, The risk is about 33-fold higher than in the general population. Studies show that the risk for adenocarcinoma is also higher, although to a lower degree.

Secondary Achalasia

As discussed earlier, signs and symptoms indistinguishable from primary achalasia may be encountered with other conditions such as Chagas’ disease or in association with a neoplasm that directly invades the myenteric plexus. In some cases, a paraneoplastic phenomenon may cause secondary achalasia, such as paraneoplastic achalasia associated with small cell carcinoma. Rare associations have been described with other tumors, such as leiomyomatosis of the esophagus and sarcoidosis. In sarcoidosis, inflammation surrounding the myenteric plexus has been described, but without granulomas. One of these reported patients showed resolution of symptoms with steroid treatment.

Chagas’ disease results from infection with the protozoan Trypanosoma cruzi. ^, The infection is acquired from the bite of blood-sucking reduviid bugs. The geographical distribution of the disease is limited to certain parts of the world, such as South America, Central America, and Africa. Chagas’ disease is uncommon in the United States and occurs almost exclusively in immigrants from endemic countries, such as Brazil. Any part of the GI tract may be affected; however, the esophagus and the sigmoid colon are the most frequent sites. Infection results in dysmotility and often massive dilatation (e.g., megaesophagus, megacolon). In the esophagus, the symptoms closely resemble idiopathic achalasia. Colonic involvement results in constipation and intestinal pseudo-obstruction. These features are seen in the chronic phase of disease, and by the time symptoms are noted, the organisms are usually no longer present in the myenteric plexus.

Idiopathic Muscular Hypertrophy of the Esophagus

This is a poorly understood condition of uncertain etiology and clinical significance. Most of the reported cases with pathological descriptions have been diagnosed at the time of autopsy. The condition can be diagnosed clinically with imaging techniques and esophageal motility studies. New clinical diagnostic criteria have been proposed. ^, Some cases are symptomatic, presenting with symptoms such as dysphagia, chest pain, vomiting, and weight loss, whereas others are entirely asymptomatic. Some patients also develop gastroesophageal reflux. Esophageal spasm and increased intraluminal pressure are believed to be the cause of symptoms. The disorder occurs in adults, with no gender or race predilection. Many patients with this disorder also have diabetes. Some cases have shown autosomal dominant inheritance and association with bilateral cataracts and Alport-like nephropathy. Squamous cell carcinoma has also been described in some cases. Pathologically, the muscularis propria is markedly thickened, particularly toward the distal end ( Fig. 8.9 ). Some cases also show a mild degree of lymphocytic infiltration in the myenteric plexus. The vast majority of cases lack evidence of muscle fiber degeneration, fibrosis, ganglion cell abnormalities, or neural plexus abnormalities.

FIGURE 8.9, Idiopathic muscular hypertrophy of esophagus. A, Gross specimen shows marked thickening of the muscularis propria of the esophagus that is more prominent distally, toward the gastroesophageal junction (arrows). Compare this with the normal wall of the stomach and the lack of any gross mucosal abnormalities. B , A cross-section of hypertrophic muscle from the same case (top) compared with normal esophagus (bottom). C, Microscopy shows hypertrophied muscularis propria and a lack of any other associated histological changes, including inflammation, fibrosis, muscle degeneration, or myenteric plexus abnormalities (H&E stain).

Differential Diagnosis

A variable degree of muscular hypertrophy of the esophageal musculature may be seen in patients with distal obstruction of any cause, including achalasia. However, the cause of the obstruction is often obvious clinically (see Fig. 8.8A ). Histologically, the muscle fibers appear normal in idiopathic muscular hypertrophy, and ganglion cells and neural plexus are present. The key is to exclude distal obstruction in the presence of markedly hypertrophic muscularis propria.

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