Cancer is a major global cause of morbidity and mortality. Survivorship is increasing, bringing new challenges. Cancer treatment, including chemotherapeutic drugs, immunotherapy, and radiotherapy, can have severe and impactful gastrointestinal side effects occurring shortly after treatment (acute toxicity) or persisting for years after treatment ends (late/chronic toxicity).

The aim of this article is to review the neurotoxic effects of chemotherapy on the enteric nervous system (ENS) and the gut extrinsic innervation. These effects could contribute to the development of long-term gastrointestinal dysfunctions. Research, primarily conducted in animal models, indicates that antitumoral drugs can lead to chemotherapy-induced enteric neuropathy (CIEN). Studies, mainly performed in the myenteric plexus, show that CIEN is characterized by a reduced density of nerve cells and fibers, as well as an imbalanced representation of neuronal subpopulations or their markers, with enteric glial cells also affected. These alterations underlie changes in neuronal activity and gastrointestinal motor function. Although research on the submucosal plexus remains limited, evidence suggests that CIEN affects the entire ENS. Furthermore, scarce studies show that CIEN also occurs in humans. Moreover, emerging experimental data on chemotherapy-induced alterations in visceral sensitivity suggest that the extrinsic innervation of the gut is also affected, but this has received little attention thus far. Nevertheless, this could contribute to the development of chemotherapy-induced brain-gut axis (BGA) disorders in the long term. Cancer chemotherapy (and probably also immunotherapy and radiotherapy) seems to cause neuropathic effects on the intrinsic and extrinsic innervation of the gastrointestinal tract, with an important impact on gastrointestinal and BGA functions. This is a relatively neglected area deserving further investigation.

The latency of the swallowing reflex is an important factor causing dysphagia in head and neck cancer patients. Although there are many reports comparing voluntary swallowing function before and after treatment, few studies have focused on the latency of the swallowing reflex, which is a risk factor for pneumonia due to silent aspiration. The aim of this retrospective study was to clarify the changes in the latency of the swallowing reflex before and after treatment.

The latency of the swallowing reflex was quantified using the time from the injection of 1 ml of distilled water into the pharynx through a nasal catheter to the onset of swallowing.

The latency time of the swallowing reflex was significantly decreased 3 months after treatment compared to before treatment. A significant reduction was also observed in patients with pharyngeal cancer who underwent chemoradiation therapy.

This retrospective study showed that a delayed swallowing reflex improved with treatment in advanced head and neck cancer patients.

The Institutional Review Board of Tohoku University Hospital (Number 2014-1-274).

Radiotherapy has played a major role in both the curative and palliative treatment of cancer patients for decades. However, its toxic effect to the surrounding normal healthy tissue remains a major drawback. In cases of intra-abdominal and/or pelvic malignancy, healthy bowel is inevitably included in the radiation field, causing undesirable consequences that subsequently manifest as radiation-induced bowel injury, which is associated with significant morbidity and mortality. The pathophysiology of radiation-induced bowel injury is poorly understood, although we now know that it derives from a complex interplay of epithelial injury and alterations in the enteric immune, nervous, and vascular systems in genetically predisposed individuals. Furthermore, evidence supporting a pivotal role for the gut microbiota in the development of radiation-induced bowel injury has been growing. In this review, we aim to appraise our current understanding of radiation-induced bowel injury and the role of the microbiome in its pathogenesis as well as prevention and treatment. Greater understanding of the relationship between the disease mechanism of radiation-induced bowel injury and gut microbiome might shed light on potential future prevention and treatment strategies through the modification of a patient's gut microbiome.

Each year, millions of people worldwide are treated for primary or recurrent pelvic malignancies, involving radiotherapy in almost 50% of cases. Delayed development of visceral complications after radiotherapy is recognized in cancer survivors. Therapeutic doses of radiation may lead to the damage of healthy tissue around the tumor and abdominal pain. Because of the lack of experimental models, the underlying mechanisms of radiation-induced long-lasting visceral pain are still unknown. This makes managing radiation-induced pain difficult, and the therapeutic strategies proposed are mostly inefficient. The aim of our study was to develop an animal model of radiation-induced visceral hypersensitivity to (1) analyze some cellular and molecular mechanisms involved and (2) to test a therapeutic strategy using mesenchymal stromal cells (MSCs). Using a single 27-Grays colorectal irradiation in rats, we showed that such exposure induces a persistent visceral allodynia that is associated with an increased spinal sensitization (enhanced p-ERK neurons), colonic neuroplasticity (as increased density of substance P nerve fibers), and colonic mast cell hyperplasia and hypertrophy. Mast cell stabilization by ketotifen provided evidence of their functional involvement in radiation-induced allodynia. Finally, intravenous injection of 1.5 million MSCs, 4 weeks after irradiation, induced a time-dependent reversion of the visceral allodynia and a reduction of the number of anatomical interactions between mast cells and PGP9.5+ nerve fibers. Moreover, unlike ketotifen, MSC treatment has the key advantage to limit radiation-induced colonic ulceration. This work provides new insights into the potential use of MSCs as cellular therapy in the treatment of pelvic radiation disease.

Tachykinins (TKs) are a family of endogenous peptides widely expressed in the central and in the peripheral nervous systems as well as in the gastrointestinal (GI) tract. They act as full agonists at three different membrane receptors neurokinin (NK) 1, NK2, and NK3, which are G protein-coupled receptors and in the GI tract are expressed both on neurons and effector cells.

This article reviews the literature concerning the role of TKs in the GI tract function in physiological and pathological conditions and their potential relevance in the treatment of functional GI disorders with particular reference to irritable bowel syndrome (IBS). The efficacy of NK1 antagonists in chemotherapy-induced and postoperative nausea and vomiting is well established. While pharmacodynamic studies have reported conflicting and negative results concerning the effects of NK1 and of NK3 antagonists, respectively, on the GI tract function in humans, clinical studies applying the NK3 antagonist talnetant in IBS-D were negative. Pharmacodynamic studies applying NK2 antagonists have suggested a role for antagonism of NK2 receptors in modulation of GI chemical-induced altered motility and of stress-induced altered bowel habits. Clinical studies and in particular a recently completed Phase 2 study have reported that the NK2 antagonist ibodutant is effective and safe in treating symptoms of D-IBS, especially in females.

This investigation was aimed at immunohistochemical analysis of potential changes in the enteric nervous system caused by cancer of the large intestine. In this purpose, neurons and nerve fibers of intestinal plexuses containing neuropeptides: vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP) and neuropeptide Y (NPY), in pathologically changed part of the large intestine were microscpically observed and compared. Samples were taken from patients operated due to cancer of the sigmoid colon and rectum. The number of neurons and density of nerve fibres containing neuropeptides found in sections with cancer tissues were compared to those observed in sections from the uninvolved intestinal wall. Changes relating to reductions in the number of NPY-ergic neurons and density of nerve fibres in submucous and myenteric plexuses in the sections with cancer tissues (pathological sections) were statistically significant. A statistically similar presence of VIP-ergic and PACAP-ergic neurons in the submucosal and myenteric plexuses was observed in both the pathological and control sections. On the other hand, in the pathological sections, VIP-ergic nerve fibres in the myenteric plexuses and PACAP-ergic nerve fibres in the submucosal and myenteric plexuses were found to be less dense. Analysis revealed changes in pathologically affected part of the large intestine may caused disruption of proper intestinal function. Observed changes in the neural elements which are responsible for relaxation of the intestine may suggest dysfunction in the innervation of this part of the colon.

Since September 11, 2001, there has been the recognition of a plausible threat from acts of terrorism, including radiological or nuclear attacks. A network of Centers for Medical Countermeasures against Radiation (CMCRs) has been established across the U.S.; one of the missions of this network is to identify and develop mitigating agents that can be used to treat the civilian population after a radiological event. The development of such agents requires comparison of data from many sources and accumulation of information consistent with the "Animal Rule" from the Food and Drug Administration (FDA). Given the necessity for a consensus on appropriate animal model use across the network to allow for comparative studies to be performed across institutions, and to identify pivotal studies and facilitate FDA approval, in early 2008, investigators from each of the CMCRs organized and met for an Animal Models Workshop. Working groups deliberated and discussed the wide range of animal models available for assessing agent efficacy in a number of relevant tissues and organs, including the immune and hematopoietic systems, gastrointestinal tract, lung, kidney and skin. Discussions covered the most appropriate species and strains available as well as other factors that may affect differential findings between groups and institutions. This report provides the workshop findings.

Nerve signal substances, such as the tachykinin substance P (SP), may be involved in the changes that occur in response to tendinopathy (tendinosis). It is previously known that the level of SP innervation within tendon tissue is limited, but results of experimental studies have suggested that SP may have stimulatory, angiogenetic and healing effects in injured tendons. Therefore, it would be of interest to know if there is a local SP-supply in tendon tissue. In the present study, the patterns of expression of SP and its preferred receptor, the neurokinin-1 receptor (NK-1 R), in normal and tendinosis human Achilles tendons were analyzed by use of both immunohistochemistry and in situ hybridization. We found that there was expression of SP mRNA in tenocytes, and that tenocytes showed expression of NK-1 R at protein as well as mRNA levels. The observations concerning both SP and NK-1 R were most evident for tenocytes in tendinosis tendons. Our findings suggest that SP is produced in tendinosis tendons, and furthermore that SP has marked effects on the tenocytes via the NK-1 R. It cannot be excluded that the SP effects are of importance concerning the processes of reorganization and healing that occur for tendon tissue in tendinosis. In conclusion, it appears as if SPergic autocrine/paracrine effects occur in tendon tissue during the processes of tendinosis, hitherto unknown effects for human tendons.

Limited information is available concerning the existence of a cholinergic system in the human Achilles tendon. We have studied pain-free normal Achilles tendons and chronically painful Achilles tendinosis tendons with regard to immunohistochemical expression patterns of the M(2) muscarinic acetylcholine receptor (M(2)R), choline acetyltransferase (ChAT), and vesicular acetylcholine transporter (VAChT). M(2)R immunoreactivity was detected in the walls of blood vessels. As evidenced via parallel staining for CD31 and alpha-smooth muscle actin, most M(2)R immunoreactivity was present in the endothelium. M(2)R immunoreactivity also occured in tenocytes, which regularly immunoreact for vimentin. The degree of M(2)R immunoreactivity was highly variable, tendinosis tendons that exhibit hypercellularity and hypervascularity showing the highest levels of immunostaining. Immunoreaction for ChAT and VAChT was detected in tenocytes in tendinosis specimens, particularly in aberrant cells. In situ hybridization revealed that mRNA for ChAT is present in tenocytes in tendinosis specimens. Our results suggest that autocrine/paracrine effects occur concerning the tenocytes in tendinosis. Up-regulation/down-regulation in the levels of M(2)R immunoreactivity possibly take place in tenocytes and blood vessel cells during the various stages of tendinosis. The presumed local production of acetylcholine (ACh), as evidenced by immunoreactivity for ChAT and VAChT and the detection of ChAT mRNA, appears to evolve in response to tendinosis. These observations are of importance because of the well-known vasoactive, trophic, and pain-modulating effects that ACh is known to have and do unexpectedly establish the presence of a non-neuronal cholinergic system in the Achilles tendon.

The effectiveness of the cough reflex in patients who aspirated following radiation for head and neck cancer was evaluated in 89 patients (49 chemoradiation, 33 postoperative radiation, and 7 radiation alone). All patients had modified barium swallow because of dysphagia. The cough reflex was graded as present and effective, ineffective, intermittently effective, or absent. All patients were cancer-free at the time of the swallowing study. The cough reflex was present and effective in 46 patients (52%), ineffective in 17 patients (19%), and absent in 26 patients (29%) on initial investigation. Among the 43 patients who had ineffective or absent cough reflex, their treatment was chemoradiation (26), postoperative radiation (13), and radiation alone (4). In 30 patients who had sequential modified barium swallow, the cough reflex was constantly effective, ineffective, or intermittently effective in 12 (40%), 13 (43%), and 5 (17%) patients, respectively. The cough reflex was frequently ineffective or absent in patients who aspirated following radiation for head and neck cancer. Cough may also be intermittently ineffective to protect the airways following radiation.

Changes in the patterns of production and in the effects of signal substances may be involved in the development of tendinosis, a chronic condition of pain in human tendons. There is no previous information concerning the patterns of sympathetic innervation in the human patellar tendon. In this study, biopsies of normal and tendinosis patellar tendons were investigated with immunohistochemical methods, including the use of antibodies against tyrosine hydroxylase (TH) and neuropeptide Y, and against alpha1-, alpha2A-, and beta1-adrenoreceptors. It was noticed that most of the sympathetic innervation was detected in the walls of the blood vessels entering the tendon through the paratendinous tissue, and that the tendon tissue proper of the normal and tendinosis tendons was very scarcely innervated. Immunoreactions for adrenergic receptors were noticed in nerve fascicles containing both sensory and sympathetic nerve fibers. High levels of these receptors were also detected in the blood vessel walls; alpha1-adrenoreceptor immunoreactions being clearly more pronounced in the tendinosis tendons than in the tendons of controls. Interestingly, immunoreactions for adrenergic receptors and TH were noted for the tendon cells (tenocytes), especially in tendinosis tendons. The findings give a morphological correlate for the occurrence of sympathetically mediated effects in the patellar tendon and autocrine/paracrine catecholamine mechanisms for the tenocytes, particularly, in tendinosis. The observation of adrenergic receptors on tenocytes is interesting, as stimulation of these receptors can lead to cell proliferation, degeneration, and apoptosis, events which are all known to occur in tendinosis. Furthermore, the results imply that a possible source of catecholamine production might be the tenocytes themselves

Tachykinins (TKs), substance P (SP), neurokinin A (NKA) and B (NKB) are important peptide modulators of intestinal motility in animal species studied so far, including humans. Modulation of motility by TKs can occur at various levels, since these peptides are expressed in cholinergic excitatory motor neurons projecting to both circular and longitudinal muscle, interneurons, and intramural and extramural sensory neurons. The effects of SP, NKA and NKB are preferentially mediated through the stimulation of NK1, NK2 and NK3 receptors, respectively; however, the selectivity of natural TKs for their preferred receptors is relative. In addition, SP and NKA are expressed in similar quantities in the human intestine and adequate stimuli can release similar amount of these TKs from enteric nerves. Furthermore, a single anatomical substrate can express more than one TK receptor type, so that the blockade of a single receptor type may not reveal functional effects in integrated models of motility. In isolated human small intestine and colon circular muscle strips, both NK1 and NK2 receptors mediate contractile effects. Indeed, in the human small intestine, smooth muscle electrical and motor events induced by electrical field stimulation (EFS) can involve either or both NK1 and NK2 receptors or these latter receptors predominantly, depending on the experimental conditions. In contrast, in the human colonic smooth muscle, only the NK2 receptor-mediated component of the response to EFS is prominent and some evidence would suggest that this component is the main excitatory motor mechanism at this level. Furthermore, a NK2 receptor-mediated secretory component in the human colonic mucosa has been recently demonstrated. Thus, it could be speculated that the blockade of both NK1 and NK2 receptors will be necessary to antagonise motor effects induced by exogenous administration or endogenous release of TKs in the small intestine, whereas the blockade of the NK2 receptors would be sufficient to disrupt physiological motor and, possibly, secretory activity at the colonic level. Available evidence indicates that, in healthy volunteers, the infusion of NKA (25 pmol/kg/min i.v.) stimulated small intestine motility and precipitated a series of intestinal and non-intestinal adverse events. Nepadutant (8 mg i.v.), a selective NK2 receptor antagonist, antagonised small intestine motility induced by NKA and prevented associated intestinal adverse events. In another study, the same dose of nepadutant increased colo-rectal compliance during isobaric balloon distension in healthy volunteers pretreated with a glycerol enema, disclosing a NK2 receptor-mediated component in the regulation of colonic smooth muscle tone. However, the prolonged blockade of NK2 receptors by nepadutant (16 mg i.v. b.i.d. for 8 days) did not affect bowel habits, neither in term of movements nor of stool consistency. Altogether, these results indicate that, even when there is a significant redundance in the effects of TKs and in the role of their receptors, the selective blockade of tachykinin NK2 receptors can have functional consequences on human intestinal motility and perception, but this can occur without the disruption of the physiological functions.

Pain-free normal Achilles tendons and chronic painful Achilles tendons were examined by the use of antibodies against a general nerve marker (protein gene-product 9.5, PGP9.5), sensory markers (substance P, SP; calcitonin gene-related peptide, CGRP), and immunohistochemistry. In the normal tendons, immunoreactions against PGP9.5 and against SP/CGRP were encountered in the paratendinous loose connective tissue, being confined to nerve fascicles and to nerve fibers located in the vicinity of blood vessels. To some extent, these immunoreactions also occurred in the tendon tissue proper. Immunoreaction against PGP9.5 and against SP/CGRP was also observed in the tendinosis samples and included immunoreactive nerve fibers that were intimately associated with small blood vessels. In conclusion, Mechanoreceptors (sensory corpuscles) were occasionally observed, nerve-related components are present in association with blood vessels in both the normal and the tendinosis tendon.

Intestinal motility disorders are a common complication after surgery for neonatal intestinal atresia. Although intestinal atresia causes alterations in the enteric nervous system, especially in its inner structures (nervous fibers in the mucosa, submucous and deep muscular plexuses), how these alterations develop is unclear. The chick model is a useful research tool for investigating the ontogenesis of the enteric nervous system and the pathogenesis of congenital bowel diseases. More information is needed on the overlap between the developing enteric nervous system and intestinal atresia. Because vasoactive intestinal polypeptide and substance P are typical intestinal neuropeptides, and vasoactive intestinal polypeptide acts as a modulator in neurodevelopment and an inhibitor of smooth muscle cell proliferation, our aim in this study was to investigate the distribution of their immunoreactivity in the developing enteric nervous system of normal and experimental chick models. We studied gut specimens excised from normal chick embryos (aged 12-20 days) and experimental chick embryos (aged 15-20 days) that underwent surgical intervention on day 12 to induce intestinal atresia (atresic embryos) or simply to grasp the bowel loop (sham-operated embryos). In normal chick embryos we showed vasoactive intestinal polypeptide and substance P immunoreactivity from day 12 in the submucous and myenteric plexuses. The distribution of peptide immunoreactivity differed markedly in atresic and normal or sham-operated gut embryos. These differences especially affected the inner structures of the enteric nervous system of specimens proximal to atresia and were related to the severity of dilation. Because nerve structures in the gut wall mucosa and submucous and deep muscular plexuses play a role in motility control and stretch sensation in the intestinal wall, our findings in the chick embryo may help to explain how gut motility disorders develop after surgery for neonatal intestinal atresia.

The aim of this study was to assess the potential of gastrointestinal peptide plasma levels as biomarkers of radiation-induced digestive tract damage. To this end, plasma levels of substance P, GRP, motilin, PYY, somatostatin-28, gastrin, and neurotensin were followed for up to 5 days in pigs after a 16-Gy whole-body X-irradiation, completed by a histopathological study performed at 5 days. Each peptide gave a specific response to irradiation. The plasma levels of GRP and substance P were not modified by irradiation exposure; neither were those of motilin and PYY. Concerning gastrin, a 2-3-fold increase of plasma concentration was observed in pig, which presented the most important histological alterations of the stomach. The plasma levels of somatostatin, unchanged from 1 to 4 days after irradiation, was also increased by 130% at 5 days. In contrast, a diminution of neurotensin plasma levels was noted, firstly at 1 day (-88%), and from 3 days after exposure (-50%). The present study suggested that changes in gastrin and neurotensin plasma levels were associated with structural alterations of the stomach and ileum, respectively, indicating that they may be relevant biological indicators of radiation-induced digestive damage to these segments.