Functional megacolon in children

The author discusses a group of 21 children (15 boys and % girls aged between 4 and 16 years) with diagnosed syndrome of the functional megacolon. Possible causes of the chronic constipation which could lead to the functional megacolon have been analysed. The treatment--preceded by the detailed analysis of anamnesis and laboratory tests (rectoscopy and contrast medium enema)--included: enemas washing out the colon, emollient and laxative agents, fiber-rich diet, and instructions on the proper defecation. Excellent therapeutical results seem to result from the detailed explanation of causes of the functional megacolon. It has enabled to avoid surgical treatment which should be carried out in these cases in which long-term conservative treatment failed.     

Congenital aganglionic megacolon

Twenty-one pull-through procedures for congenital aganglionic megacolon (Hirschsprung's disease) have been performed at the Los Angeles Children's Hospital since the adoption of the etiological concept of a distal aganglionic segment in 1949. In 14 cases the Swenson procedure as modified by Hiatt was employed, with perineal excision of the colon segment. There were four postoperative deaths and three symptomatic recurrences in this group. Three patients were treated by transabdominal resection of colon and rectum with subsequent pull-through reconstruction (Swenson). Anterior resection (State) was carried out in two cases. Three children with recurrence of symptoms following primary operation were subjected to a secondary pull-through procedure with an eventual successful outcome. The major portion of the postoperative mortality (29 per cent) in this group occurred in infants less than six months of age in whom anastomotic disruption or proximal segment infarction occurred after operation.A study of 31 cases of congenital aganglionic megacolon in very young infants drew attention to the difficulty of establishing a diagnosis in this age group even at exploratory laparotomy. Among these infants the mortality rate was excessive, regardless of the form of therapy employed. Colostomy appeared to be the indicated surgical procedure if a conservative regimen failed to control intractable colonic obstruction during the first year of life.     

Partial colectomy for treating acquired megacolon in long-tailed macaques.

A syndrome presenting as gross abdominal distension and diagnosed as acquired megacolon was observed in five adult female long-tailed macaques. Gastrointestinal signs included diarrhea, mucus in the stool, anorexia, and failure to pass stool, with repeated episodes of extreme abdominal distension and accumulation of gas and feces in greatly enlarged colons. Medical management was unsuccessful. A partial colectomy with a standard end-to-end colonic anastomosis was performed to remove the section of distended colon in each animal. Histologically, affected colons had degeneration and fibrosis, primarily in the longitudinal layer of the lamina muscularis. Hemograms, serum chemistries, and histopathologic features were not diagnostic of a specific etiology for megacolon. Four of five animals had undergone at least one obstetrical surgery. Two of these had the first episode of colonic distension within 3 days postoperatively. Intra-abdominal adhesions were noted during exploratory surgery in all animals. Three of five had colonic volvulus observed during colectomy. Recovery post-colectomy was uneventful and animals remained free of clinical signs of megacolon.     

Treatment of Aganglionic Megacolon Mice via Neural Stem Cell Transplantation

To explore a potential methodology for treating aganglionic megacolon, neural stem cells (NSCs) expressing engineered endothelin receptor type B (EDNRB) and glial cell-derived neurotrophic factor (GDNF) genes were transplanted into the aganglionic megacolon mice. After transplantation, the regeneration of neurons in the colon tissue was observed, and expression levels of differentiation-related genes were determined. Primary culture of NSCs was obtained from the cortex of postnatal mouse brain and infected with recombinant adenovirus expressing EDNRB and GDNF genes. The mouse model of aganglionic megacolon was developed by treating the colon tissue with 0.5 % benzalkonium chloride (BAC) to selectively remove the myenteric nerve plexus that resembles the pathological changes in the human congenital megacolon. The NSCs stably expressing the EDNRB and GDNF genes were transplanted into the benzalkonium chloride-induced mouse aganglionic colon. Survival and differentiation of the implanted stem cells were assessed after transplantation. Results showed that the EDNRB and GDNF genes were able to be expressed in primary culture of NSCs by adenovirus infection. One week after implantation, grafted NSCs survived and differentiated into neurons. Compared to the controls, elevated expression of EDNRB and GDNF was determined in BAC-induced aganglionic megacolon mice with partially improved intestinal function. Those founding indicated that the genes transfected into NSCs were expressed in vivo after transplantation. Also, this study provided favorable support for the therapeutic potential of multiple gene-modified NSC transplantation to treat Hirschsprung’s disease, a congenital disorder of the colon in which ganglion cells are absent.     

Anatomic modifications in the enteric nervous system of piebald mice and physiological consequences to colonic motor activity

It has been assumed that in piebald lethal mice that develop megacolon, impaired colonic motor activity is restricted to the aganglionic distal colon. Peristaltic mechanical recordings, immunohistochemistry, and quantitative PCR were used to investigate whether regions of the colon, other than the aganglionic segment, may also show anatomical modifications and dysfunctional colonic motor activity. Contrary to expectations, colonic migrating motor complexes (MMCs) were absent along the whole colon of piebald lethal homozygote mice and severely impaired in heterozygote siblings. Aganglionosis was detected not only in the distal colon of piebald homozygote lethal mice (mean length: 20.4 +/- 2.1 mm) but also surprisingly in their heterozygote siblings (mean length: 12.4 +/- 1.1 mm). Unlike homozygote lethal mice, piebald heterozygotes showed no signs of megacolon. Interestingly, mRNA expression for PGP 9.5 was also dramatically reduced (by 71-99%) throughout the entire small and large bowel in both homozygote lethal and heterozygous littermates (by 67-87%). Histochemical staining confirmed a significant reduction in myenteric ganglia along the whole colon. In summary, the piebald mutation in homozygote lethal and heterozygote siblings is associated with dramatic reductions in myenteric ganglia throughout the entire colon and not limited to the distal colon as originally thought. Functionally, this results in an absence or severe impairment of colonic MMC activity in both piebald homozygote lethal and heterozygote siblings, respectively. The observation that piebald heterozygotes have an aganglionic distal colon (mean length: 12 mm) but live a normal murine life span without megacolon suggests that aganglionosis >12 mm and the complete absence of colonic MMCs may be required before any symptoms of megacolon arise.     

Trypanosomiasis-Induced Megacolon Illustrates How Myenteric Neurons Modulate the Risk for Colon Cancer in Rats and Humans

Background

Trypanosomiasis induces a remarkable myenteric neuronal degeneration leading to megacolon. Very little is known about the risk for colon cancer in chagasic megacolon patients. To clarify whether chagasic megacolon impacts on colon carcinogenesis, we investigated the risk for colon cancer in Trypanosoma cruzi (T. cruzi) infected patients and rats.

Methods

Colon samples from T. cruzi-infected and uninfected patients and rats were histopathologically investigated with colon cancer biomarkers. An experimental model for chemical myenteric denervation was also performed to verify the myenteric neuronal effects on colon carcinogenesis. All experiments complied the guidelines and approval of ethical institutional review boards.

Results

No colon tumors were found in chagasic megacolon samples. A significant myenteric neuronal denervation was observed. Epithelial cell proliferation and hyperplasia were found increased in chagasic megacolon. Analyzing the argyrophilic nucleolar organiser regions within the cryptal bottom revealed reduced risk for colon cancer in Chagas’ megacolon patients. T. cruzi-infected rats showed a significant myenteric neuronal denervation and decreased numbers of colon preneoplastic lesions. In chemical myenteric denervated rats preneoplastic lesions were reduced from the 2^nd wk onward, which ensued having the colon myenteric denervation significantly induced.

Conclusion/Significance

Our data suggest that the trypanosomiasis-related myenteric neuronal degeneration protects the colon tissue from carcinogenic events. Current findings highlight potential mechanisms in tropical diseases and cancer research.     

HIRSCHSPRUNG'S DISEASE AND CONGENITAL MEGACOLON

Hirschsprung''s disease and congenital megacolon are recognized as separate entities. They differ one from another in clinical, roentgenographic and histologic features.Conservative treatment of patients with Hirschsprung''s disease is ineffective; surgical therapy with a new technique is beneficial. In congenital megacolon, operation is futile and may be harmful, whereas patients may be benefited by conservative measures, and improvement may occur spontaneously after adolescence.     

In vivo destruction of tumor tissue by cryoablation can induce inhibition of secondary tumor growth: an experimental study

BACKGROUND: Cryoablation has been used successfully for the local treatment of several cancers. Besides local destruction, a systemic antitumor response has been postulated after cryoablation of tumor tissue. In this study we evaluate the possible systemic antitumor response induced by cryodestruction of tumor tissue in two mouse tumor models. METHODS: Mice received two subcutaneously placed tumor implants (thigh and flank) of the nonimmunogenic mouse colon tumor cell line, colon 26-B. After 7 days, the thigh implant was treated by cryoablation or excision and the effect on secondary tumor growth was determined by volume measurement of the nontreated flank tumor. Cytokine (IL-1alpha and TNF-alpha) levels in plasma were measured after treatment. Similar experiments were performed in nude mice using a human melanoma cell line (MV3). Moreover, in this model the effect of cryoablation on development of spontaneous lung metastases was evaluated. RESULTS: In the colon 26-B tumor model treatment of primary tumor implants by cryoablation resulted in a significant inhibition of secondary tumor growth compared to animals treated by surgical excision (P < 0.01). Six hours after treatment, plasma levels of IL-1alpha and TNF-alpha were higher after cryoablation than after excision (P < 0.01). Also in the nude mice model cryoablation resulted in inhibition of secondary tumor growth, though not significant. Mice treated by cryoablation showed significantly less lung metastases compared to those treated by excision (P = 0.03). CONCLUSIONS: Cryoablation of tumor tissue can result in inhibition of secondary and metastatic tumor growth. A cytokine response induced by cryoablation of tumor tissue may attribute to this feature.     

Murine Ileocolic Bowel Resection with Primary Anastomosis

Intestinal resections are frequently required for treatment of diseases involving the gastrointestinal tract, with Crohn’s disease and colon cancer being two common examples. Despite the frequency of these procedures, a significant knowledge gap remains in describing the inherent effects of intestinal resection on host physiology and disease pathophysiology. This article provides detailed instructions for an ileocolic resection with primary end-to-end anastomosis in mice, as well as essential aspects of peri-operative care to maximize post-operative success. When followed closely, this procedure yields a 95% long-term survival rate, no failure to thrive, and minimizes post-operative complications of bowel obstruction and anastomotic leak. The technical challenges of performing the procedure in mice are a barrier to its wide spread use in research. The skills described in this article can be acquired without previous surgical experience. Once mastered, the murine ileocolic resection procedure will provide a reproducible tool for studying the effects of intestinal resection in models of human disease.     

Subtotal maxillectomy for melanotic neuroectodermal tumor of infancy.

Melanotic neuroectodermal tumor of infancy is a rare pigmented neoplasm occurring in infants before 1 year of age. It is a rapidly growing tumor that most frequently affects the craniofacial skeleton. Although melanotic neuroectodermal tumor of infancy is benign in the vast majority of cases, inadequate excision, occasional multicentricity, and a small malignant potential result in a fairly high recurrence rate. On the basis of data obtained from the literature and our clinical experience, we advocate an aggressive surgical approach consisting of complete surgical excision when vital structures are not involved. Histopathologic confirmation of complete excision is mandatory to minimize the risk of recurrence and provide the patient with curative treatment and minimal morbidity.     

Outpatient treatment of pilonidal disease.

In pilonidal disease there are recurrent painful draining intergluteal abscesses that require surgical treatment. Many types of treatment have been suggested for this condition. On the basis of our experience, as described below, we propose that pilonidal disease can be successfully treated on an outpatient basis with local anesthesia, minimal excision, marsupialization and packing.     

Neuronal plasticity of the enteric nervous system is correlated with chagasic megacolon development

Chagas' disease is one of the few functional gastrointestinal disorders for which a causative agent has been identified. However, some pathological aspects of the chagasic megasyndromes are still incompletely understood. Chagasic megacolon is characterized by an inflammatory process, organ dilatation and neuronal reduction in both plexuses of the enteric nervous system (ENS). Although some studies on the ENS in Chagas' disease have been performed, the process of neuronal destruction and neuronal regeneration still remains unclear. Our hypothesis is that the regeneration process of the ENS may be involved with the mechanisms that prevent or retard organ dilatation and chagasic megacolon development. For that reason, we evaluated the neuronal regeneration with the marker GAP-43 in the colon's neuronal plexuses from chagasic patients with megacolon, and from non-infected individuals. Visual examination and quantitative analysis revealed an increased neuronal regeneration process in the dilated portion from chagasic patients when compared with the non-dilated portion and with non-infected individuals. We believe that this increased regeneration can be interpreted as an accentuated neuronal plasticity that may be a response of the ENS to avoid megacolon propagation to the entire organ and maintain the colon functional innervation.     

Treatment of Congenital Pseudarthrosis with Endomedullary Nail and Low Frequency Pulsing Electromagnetic Fields: A Controlled Study

We report our experience in the treatment of congenital pseudarthrosis with pulsing electromagnetic fields in a controlled study. Both the stimulated and control groups received the same surgical procedure: excision of the pseudarthrosis site, reduction and fixation by intramedullary nail. Stimulation with electromagnetic fields was begun within 3 days after surgery. The orthopaedic treatment was the same for all patients. The stimulation lasted up to 12 months. All patients were followed at least 24 months after the surgery. The data showed that the surgical approach in association with pulsing electromagnetic-field stimulation gave significantly better results than surgery alone.     

RESULTS OF MEDICAL AND SURGICAL MANAGEMENT IN TEN CASES OF CONGENITAL MEGACOLON

Of 20 patients under 15 years of age with proven diagnoses of megacolon, ten were treated surgically with either partial colectomy or resection of the entire colon down to the rectosigmoid junction after thorough trial of medical management. Follow-up shows five of these patients as 100 per cent relieved, one as 75 per cent relieved. Three were entirely well a few months after operation but have not been heard from since. One died of peritonitis on the 16th postoperative day.In four cases in which lumbar sympathectomy was done, the result was partial, temporary or no improvement.Of the patients not operated upon, several have been lost to follow-up, some are doing well on medical treatment, one died in early infancy, and resection is being considered for two.For children with congenital megacolon the authors recommend first a thorough trial of medical treatment consisting of diet, vitamins, drugs and enemas. This should be started as soon as possible after the diagnosis is made, in an attempt to prevent the distention and hypertrophy of the bowel from progressing. If distention remains after a reasonable trial period and the child is not gaining weight adequately, requires repeated hospitalization, and is three years of age or more, then resection of the affected portion of the colon is indicated. The risk of operation has been somewhat reduced with better supportive measures and chemotherapy now available. Since infants and extremely young children do not stand operation on the colon as well as older children, decision to operate should take into consideration the age of the patient. In the reported series, the patient who died following operation was the youngest—2½ years of age.     

Cutaneous leiomyosarcoma

Cutaneous leiomyosarcoma is a rare soft-tissue sarcoma with negligible metastatic potential, but local recurrence rates after surgical excision have ranged from 14 percent to 42 percent. Unlike other sarcomas, guidelines for the optimal surgical excision margin of cutaneous leiomyosarcoma are not clearly defined in the existing literature. A review of local experience with this condition revealed eight patients over 12 years, none of whom developed local recurrence or distant metastases. This is despite poor prognostic factors in seven patients and excision margins ranging from 1 to 27 mm. These findings are compared with previously published data, and conclusions are drawn based on analysis of the collective results. Complete surgical excision with a narrow margin is recommended, and patients should be observed for a minimum of 5 years after surgery.     

Targeting of endothelin receptor-B to the neural crest

Endothelin receptor B (Ednrb) plays a critical role in the development of melanocytes and neurons and glia of the enteric nervous system. These distinct neural crest-derived cell types express Ednrb and share the property of intercalating into tissues, such as the intestine whose muscle precursor cells also express Ednrb. Such widespread Ednrb expression has been a significant obstacle in establishing precise roles for Ednrb in development. We describe here the production of an Ednrb allele floxed at exon 3 and its use in excising the receptor from mouse neural crest cells by use of Cre-recombinase driven by the Wnt1 promoter. Mice born with neural crest-specific excision of Ednrb possess aganglionic colon, lack trunk pigmentation, and die within 5 weeks due to megacolon. Ednrb receptor expression in these animals is absent only in the neural crest but present in surrounding smooth muscle cells. The absence of Ednrb from crest cells also results in a compensatory upregulation of Ednrb expression in other cells within the gut. We conclude that Ednrb loss only in neural crest cells is sufficient to produce the Hirschsprungs disease phenotype observed with genomic Ednrb mutations.     

Managers for Medicine

For many years patients with chronic ulcerative colitis were subjected to operation as a last resort, but now, owing to improved surgical techniques and adequate preoperative preparation of the patient, mortality associated with operation has decreased and better-risk patients are being operated upon electively. The experience of the University of Alberta Hospital during the past 10 years in respect of the surgical management of chronic ulcerative colitis is reviewed, on the basis of 105 patients, 36 of whom underwent operation. The indications for surgery include obstruction, suspected carcinoma, hemorrhage, perforation, acute fulminating disease with toxic megacolon, and intractability. A variety of surgical procedures were used during this period, reflecting changing views in surgical management. Surgical complications include wound infections, bowel obstruction with ileostomy malfunction, skin excoriation, and electrolyte imbalance. In this series three of the 36 died, a mortality rate of 8%. One death was from liver failure and two were from peritonitis.     

Treatment of Peyronie's disease by dermal grafting.

We describe our experience with dermal grafting for the treatment of Peyronie's disease in 27 patients over a 3-year period. With the various nonsurgical treatments, a significant number of patients remain handicapped by the disease. For this unresponsive group, we recommend surgical excision of the penile plaque with dermal grafting. The proper selection of patients for this operation is of paramount importance, and this can be facilitated by a preoperative psychological evaluation in doubtful cases.     

The use of morphometric and fractal parameters to assess the effects of 5-fluorouracil, interferon and dexamethasone treatment on colonic anastomosis healing: an experimental study in rats

Adjuvant chemotherapy and steroid therapy have been demonstrated to interfere with the wound healing process. The aim of this study was to evaluate the effects of 5-fluorouracil, interferon, and dexamethasone, on the healing of colon anastomosis by assessing morphometric and fractal parameters of the colonic wall. An experimental anastomosis of the ascending colon was performed in 60 male Wistar rats, which were then randomly assigned to four groups. On the second to sixth post-operative days, the rats were administered 5-fluorouracil, interferon-α, dexamethasone, or 0.9% NaCl solution as a control. Macroscopic, histomorphometric and microbiological evaluation was performed in order to assess healing of the anastomosis. In three animals from the dexamethasone group, there was leakage of anastomosis; adhesion formation was highest in the interferon group, and significantly higher than in the control and 5-fluorouracil groups. Histomorphometric parameter alterations were most pronounced on the seventh and fourteenth post-operative days in all treatment groups, with submucosal thickness the most affected parameter. Connective tissue fractal dimension was significantly decreased in those animals treated with interferon and dexamethasone. All three pharmaceutical agents impaired healing of anastomosis, and promoted infection in the anastomosis and skin wound sites. As dexamethasone induced both morphometric and macroscopic alterations, it was considered the most detrimental in this study.     

Ruby laser treatment of congenital melanocytic nevi: a review of the literature and report of our own experience

The authors describe the possibilities and advantages of ruby laser treatment of large congenital nevi as an alternative to surgical excision. The literature (from 1980 to 2002) is reviewed and a case report is presented. Literature and the authors' experience show good cosmetic results after ruby laser treatment. Skin texture is improved and there is a considerable reduction in pigmentation and unsightly hair growth. Ruby laser treatment does not result in scarring, mutilation, or functional impairments, in contrast to surgical treatment. Only short outpatient sessions are required, recovery periods are extremely short, and no rehabilitation period is needed. No malignant changes have been reported after treatment with the ruby laser, even after 8 years of follow-up. The results imply that ruby laser treatment could be a valuable new treatment modality for large congenital nevi. It should be considered when patients refuse to undergo surgery, or when surgery would cause severe morbidity. More research should be initiated to assess possible risks and long-term results.