Subtotal colectomy and ileorectal anastomosis for slow transit constipation: clinical follow-up at median of 15 years.

BACKGROUND: Slow transit constipation is characterised by prolonged colonic transit and reliance on laxatives. The pathophysiology is poorly understood and in its most severe form, total colectomy with ileorectal anastomosis is the final treatment option. We present a follow-up study of the long-term function in patients who had surgery for laxative-resistant slow transit constipation. METHODS: A postal survey was sent to assess bowel frequency, abdominal pain, St Mark's continence score, satisfaction with procedure, likelihood to choose the procedure again, and long-term rates of small bowel obstruction and ileostomy. Longitudinal data from a subgroup studied 23 years previously are reported. RESULTS: Forty-two patients (male = 2) were available for follow-up out of an initial cohort of 102. Mean time since surgery was 15.9 years (range 1.7-29.7) years. Fifty percent had < 4 bowel motions per day, most commonly Bristol stool 6, mean St Mark's score 7.45. Twenty-one percent had severe incontinence. Satisfaction and likelihood to choose surgery were high (median 10/10). There was a high rate of small bowel obstruction, suggesting pan-intestinal dysmotility in some cases. Conversion to ileostomy occurred in 8 patients. In the longitudinal follow-up in 15 subjects, continence deteriorated (p < 0.01), stool consistency softened (p < 0.01), and stool frequency fell (p < 0.01). CONCLUSIONS: Satisfactory stool frequency was achieved in the long term, and although 21% had incontinence scores > 12, patient satisfaction was high. This is the longest reported follow-up of colectomy for slow transit constipation, with longitudinal outcomes reported. There was considerable attrition of patients, so larger, longitudinal studies are required to better ascertain the functional outcomes of these patients.

Relationships between the results of anorectal investigations and symptom severity in patients with faecal incontinence.

PURPOSE: Anorectal dysfunction is the focus of diagnostic investigations for faecal incontinence. However, severity of incontinence and anorectal investigation results can be discordant. The aim of this study was to define the relationships between anorectal investigation results and incontinence severity to determine which measures, if any, were predictive of incontinence severity. METHODS: Patients presenting for investigation of faecal incontinence completed a symptom questionnaire, anorectal manometry, rectal sensation, pudendal nerve terminal motor latency, and endoanal ultrasound. Bivariate analyses were conducted between the Jorge-Wexner score and investigation results. Subgroup analyses were performed for gender and symptom subtypes (urge, passive, mixed). A multiple regression analysis was performed. RESULTS: Five hundred and thirty-eight patients were included. There were weak correlations between the Jorge-Wexner score and maximal squeeze pressure [r = - 0.24, 95%CI(- 0.31, - 0.16), p < 0.001], and resting pressure [r = - 0.18, (95%CI(- 0.26, - 0.10), p < 0.001]. In men only, there were significant associations between the Jorge-Wexner score and endoanal sonography [IAS defects: t(113) = - 2.26, p = 0.03, d = 0.58, 95%CI(- 4.38, - 0.29)] and rectal sensation (MTV: rs = - 0.24, 95%CI(- 0.41, - 0.06), p = 0.01). No substantial differences were observed in the urge/passive/mixed subgroup analyses. Multiple regression analysis included three variables: age (ß = 0.02, p = 0.17), maximal resting pressure (ß = - 0.01, p = 0.28), and maximal squeeze pressure (ß = - 0.01, p < 0.01). The variance in the Jorge-Wexner score accounted for by this model was < 10%, (R2 = 0.07, p = < 0.01, adjusted R2 = 0.06). CONCLUSION: Anorectal investigations cannot predict the severity of faecal incontinence. This may be due to limitations of diagnostic modalities, the heterogeneity of anorectal dysfunction in these patients, or contributing factors which are extrinsic to the anorectum.

Colonic motor abnormalities in slow transit constipation defined by high resolution, fibre-optic manometry.

BACKGROUND: Slow transit constipation (STC) is associated with colonic motor abnormalities. The underlying cause(s) of the abnormalities remain poorly defined. In health, utilizing high resolution fiber-optic manometry, we have described a distal colonic propagating motor pattern with a slow wave frequency of 2-6 cycles per minute (cpm). A high calorie meal caused a rapid and significant increase in this activity, suggesting the intrinsic slow wave activity could be mediated by extrinsic neural input. Utilizing the same protocol our aim was to characterize colonic meal response STC patients. METHODS: A fiber-optic manometry catheter (72 sensors at 1 cm intervals) was colonoscopically placed with the tip clipped at the ascending or transverse colon, in 14 patients with scintigraphically confirmed STC. Manometric recordings were taken, for 2 h pre and post a 700 kCal meal. Data were compared to 12 healthy adults. KEY RESULTS: Prior to and/or after the meal the cyclic propagating motor pattern was identified in 13 of 14 patients. However, the meal, did not increase the cyclic motor pattern (preprandial 7.4 ± 7.6 vs postprandial 8.3 ± 4.5 per/2 h), this is in contrast to the dramatic increase observed in health (8.3 ± 13.3 vs 59.1 ± 89.0 per/2 h; p < 0.001). CONCLUSIONS & INFERENCES: In patients with STC a meal fails to induce the normal increase in the distal colonic cyclic propagating motor patterns. We propose that these data may indicate that the normal extrinsic parasympathetic inputs to the colon are attenuated in these patients.

Quantification of in vivo colonic motor patterns in healthy humans before and after a meal revealed by high-resolution fiber-optic manometry.

BACKGROUND: Until recently, investigations of the normal patterns of motility of the healthy human colon have been limited by the resolution of in vivo recording techniques. METHODS: We have used a new, high-resolution fiber-optic manometry system (72 sensors at 1-cm intervals) to record motor activity from colon in 10 healthy human subjects. KEY RESULTS: In the fasted colon, on the basis of rate and extent of propagation, four types of propagating motor pattern could be identified: (i) cyclic motor patterns (at 2-6/min); (ii) short single motor patterns; (iii) long single motor patterns; and (iv) occasional retrograde, slow motor patterns. For the most part, the cyclic and short single motor patterns propagated in a retrograde direction. Following a 700 kCal meal, a fifth motor pattern appeared; high-amplitude propagating sequences (HAPS) and there was large increase in retrograde cyclic motor patterns (5.6 ± 5.4/2 h vs 34.7 + 19.8/2 h; p < 0.001). The duration and amplitude of individual pressure events were significantly correlated. Discriminant and multivariate analysis of duration, gradient, and amplitude of the pressure events that made up propagating motor patterns distinguished clearly two types of pressure events: those belonging to HAPS and those belonging to all other propagating motor patterns. CONCLUSIONS & INFERENCES: This work provides the first comprehensive description of colonic motor patterns recorded by high-resolution manometry and demonstrates an abundance of retrograde propagating motor patterns. The propagating motor patterns appear to be generated by two independent sources, potentially indicating their neurogenic or myogenic origin.

Low-resolution colonic manometry leads to a gross misinterpretation of the frequency and polarity of propagating sequences: Initial results from fiber-optic high-resolution manometry studies.

BACKGROUND: High-resolution manometry catheters are now being used to record colonic motility. The aim of this study was to determine the influence of pressure sensor spacing on our ability to identify colonic propagating sequences (PS). METHODS: Fiber-optic catheters containing 72-90 sensors spaced at 1 cm intervals were placed colonoscopically to the cecum in 11 patients with proven slow transit constipation, 11 patients with neurogenic fecal incontinence and nine healthy subjects. A 2 h section of trace from each subject was analyzed. Using the 1 cm spaced data as the gold standard, each data set was then sub-sampled, by dropping channels from the data set to simulate sensor spacing of 10, 7, 5, 3, and 2 cm. In blinded fashion, antegrade and retrograde PS were quantified at each test sensor spacing. The data were compared to the PSs identified in the corresponding gold standard data set. KEY RESULTS: In all subject groups as sensor spacing increased; (i) the frequency of identified antegrade and retrograde PSs decreased (P < 0.0001); (ii) the ratio of antegrade to retrograde PSs increased (P < 0.0001); and (iii) the number of incorrectly labeled PSs increased (P < 0.003). CONCLUSIONS & INFERENCES: Doubling the sensor spacing from 1 to 2 cm nearly halves the number of PSs detected. Tripling the sensor spacing from 1 to 3 cm resulted in a 30% chance of incorrectly labeling PSs. Closely spaced pressure recording sites (<2 cm) are mandatory to avoid gross misrepresentation of the frequency, morphology, and directionality of colonic propagating sequences.

The effect of sacral nerve stimulation on distal colonic motility in patients with faecal incontinence.

BACKGROUND: Sacral nerve stimulation (SNS) is an effective treatment for neurogenic faecal incontinence (FI). However, the clinical improvement that patients experience cannot be explained adequately by changes in anorectal function. The aim of this study was to examine the effect of SNS on colonic propagating sequences (PSs) in patients with FI in whom urgency and incontinence was the predominant symptom. METHODS: In patients with FI a high-resolution fibre-optic manometry catheter, containing 90 sensors spaced at 1-cm intervals, was positioned colonoscopically and clipped to the caecum. A unipolar or quadripolar tined electrode was implanted into the S3 sacral nerve foramen. Colonic manometry was evaluated in a double-blind randomized crossover trial, using true suprasensory stimulation or sham stimulation. Each stimulation period, lasting 2 h, was preceded by a 2-h basal manometric recording. RESULTS: All 11 patients studied showed a colonic response to SNS. In ten patients there was a significant increase in the frequency of retrograde PSs throughout the colon during true stimulation compared with sham stimulation (P = 0·014). In one outlier, with baseline retrograde PS frequency nine times that of the nearest patient, a reduction in retrograde PS frequency was recorded. Compared with sham stimulation, SNS had no effect on the frequency of antegrade PSs or high-amplitude PSs. CONCLUSION: SNS modulates colonic motility in patients with faecal urge incontinence. These data suggest that SNS may improve continence and urgency through alteration of colonic motility, particularly by increasing retrograde PSs in the left colon.

Pancolonic motor response to subsensory and suprasensory sacral nerve stimulation in patients with slow-transit constipation.

BACKGROUND: Sacral nerve stimulation (SNS) is emerging as a potential treatment for patients with constipation. Although SNS can elicit an increase in colonic propagating sequences (PSs), the optimal stimulus parameters for this response remain unknown. This study evaluated the colonic motor response to subsensory and suprasensory SNS in patients with slow-transit constipation. METHODS: Patients with confirmed slow-transit constipation were studied. Either a water-perfused manometry catheter or a high-resolution fibre-optic manometry catheter was positioned colonoscopically to the caecum. A temporary electrode was implanted transcutaneously in the S3 sacral nerve foramen. In the fasted state, three conditions were evaluated in a double-blind randomized fashion: sham, subsensory and suprasensory stimulation. Each 2-h treatment period was preceded by a 2-h basal period. The delta (Δ) value was calculated as the frequency of the event during stimulation minus that during the basal period. RESULTS: Nine patients had readings taken with a water-perfused catheter and six with a fibre-optic catheter. Compared with sham stimulation, suprasensory stimulation caused a significant increase in the frequency of PSs (mean(s.d.) Δ value - 1·1(7·2) versus 6·1(4·0) PSs per 2 h; P = 0·004). No motor response was recorded in response to subsensory stimulation compared with sham stimulation. Compared with subsensory stimulation, stimulation at suprasensory levels caused a significant increase in the frequency of PSs (P = 0·006). CONCLUSION: In patients with slow-transit constipation, suprasensory SNS increased the frequency of colonic PSs, whereas subsensory SNS stimulation did not. This has implications for the design of therapeutic trials and the clinical application of the device.

Diagnostic exercise: sudden death in a mouse with experimentally induced acute myeloid leukemia.

A 22-week-old female 129/SvEv mouse suddenly died in the context of an experiment aimed at defining the efficacy of valproic acid in a mouse model of PML/RARalpha-induced acute myeloid leukemia. Histologic analysis confirmed the mouse as being affected by a progressive myeloid leukemia, with infiltration of the spleen, bone marrow, liver, kidneys, and lungs. Variably sized intravascular clumps (emboli) of dense basophilic material admixed with necrotic or lytic neoplastic cells were also observed in multiple organs. A positive reaction to Feulgen and Hoechst stain confirmed the high content in chromatin of these basophilic emboli. Cleaved caspase-3 activity was demonstrated both in the leukemic infiltrates and among the intravascular necrotic or lytic neoplastic cells accompanying the basophilic emboli. A diagnosis of acute tumor lysis syndrome related to therapy-induced massive necrosis and/or apoptosis of leukemic cells with subsequent dissemination of emboli of chromatin was proposed.

Immunohistopathological and neuroimaging characterization of murine orthotopic xenograft models of glioblastoma multiforme recapitulating the most salient features of human disease.

Tumorigenesis in human glioblastoma multiforme (GBM) is driven by several genetic abnormalities with disruption of important molecular pathways, such as p53/MDM2/p14ARF and EGFR/PTEN/Akt/mTOR. The malignant progression of human GBM is also primarily associated with a peculiar multistep pathophysiological process characterized by intratumoral ischemic necrosis (i.e. pseudopalisading necrosis) and activation of the hypoxia-inducible factor (HIF)-1alpha pathway with consequent peritumoral microvascular proliferation and infiltrative behaviour. Predictable preclinical animal models of GBM should recapitulate the main pathobiological hallmarks of the human disease. In this study we describe two murine orthotopic xenograft models using U87MG and U251 human cell lines. Ten Balb/c nude male mice were orthotopically implanted with either U87MG (5 mice) or U251 (5 mice) cell lines. Intracranial tumor growth was monitored through Magnetic Resonance Imaging (MRI). Immunohistopathological examination of the whole cranium was performed 30 days after implantation. U251 orthotopic xenografts recapitulated the salient pathobiological features described for human GBM, including invasive behaviour, wide areas of pseudopalisading necrosis, florid peripheral angiogenesis, GFAP and vimentin expression, nonfunctional p53 expression, striking active-caspase-3 and HIF-1alpha expression along pseudopalisades. U87MG orthotopic xenografts proved to be very dissimilar from human GBM, showing expansile growth, occasional necrotic foci without pseudopalisades, intratumoral lacunar pattern of angiogenesis, lack of GFAP expression, functional p53 expression and inconsistent HIF-1alpha expression. Expression of pAkt was upregulated in both models. The results obtained suggest that the U251 orthotopic model may be proposed as a predictive and reliable tool in preclinical studies since it recapitulates the most salient pathobiological features reported for human GBM.

The DOSIMAP, a high spatial resolution tissue equivalent 2D dosimeter for LINAC QA and IMRT verification.

The continual need for more accurate and effective techniques in radiation therapy makes it necessary to devise new control means combining high spatial resolution as well as high dose accuracy. Intensity modulated radio therapy (IMRT) allows highly conformed fields with high spatial gradient and therefore requires a precise monitoring of all the multileaf positions. In response to this need, the authors have developed a new 2D tissue equivalent dosimeter with high spatial resolution. A plastic scintillator sheet is sandwiched between two polystyrene blocks and the emitted light is captured by a high resolution camera. A newly developed procedure described herein allows efficient discrimination of the scintillation from the parasitic Cerenkov radiation. This processing is applied on the cumulated image from a sequence of images taken during an irradiation field at a rate of 10 images/s. It provides a high resolution mapping of the cumulated dose in quasireal time. The dosimeter is tissue equivalent (ICRU-44) and works both for electrons and photons without complex parameter adjustment since phantom and detector materials are identical. Instrument calibration is simple and independent of the irradiation conditions (energy, fluence, quality, ...). In this article, the authors present the principle of the dosimeter and its calibration procedure. They compare the results obtained for photons and electron beams with ionization chamber measurements in polystyrene. Technical specifications such as accuracy and repeatability are precisely evaluated and discussed. Finally, they present different IMRT field measurements and compare DOSIMAP measurements to TPS simulations and dosimetric film profiles. The results confirm the excellent spatial resolution of the instrument and its capacity to inspect the leaf positions for each segment of a given field.

DOSIMAP: a high-resolution 2-D tissue equivalent dosemeter for linac QA and IMRT verification.

New generation of radiation therapy accelerators requires highly accurate dose measurements with high spatial resolution patterns. IMRT is especially demanding since the positioning accuracy of all the multi-leafs should be verified for each applied field and at any incidence. A new 2-D tissue equivalent dosemeter is presented with high spatial resolution that can fulfil these tasks. A plastic scintillator sheet is sandwiched between two polystyrene cubes, and the emitted light is observed by a high-resolution camera. A patented procedure allows efficient discrimination of the scintillation proportional to the dose from the parasitic Cerenkov radiation. This extraction made on the cumulated images taken during an irradiation field at a rate of 10 images s(-1) provides high-resolution mapping of the dose rate and cumulated dose in quasi real time. The dosemeter is tissue equivalent (ICRU-44) and works both for electrons and photons without complex parameter adjustment, since phantom and detector materials are identical. The calibration is simple and independent of the irradiation conditions (energy, fluence, quality and so on). The principle of the dosemeter and its calibration procedure are discussed in this paper. The results and, in particular, the dose depth profiles are compared with standard ionisation chamber measurements in polystyrene for both photons and electrons. Finally, the detector specifications are summarised and one example of complex IMRT field is discussed.

Cytokeratin and vimentin expression in normal and neoplastic canine prostate.

Intermediate filament expression in the canine prostate, unlike that in human prostate, is represented in the literature by only a few reports. In this study, the expression of cytokeratin (CK) and vimentin was examined in three normal canine prostates and 11 canine prostatic carcinomas. Monoclonal antibodies directed against vimentin, CK AE1/AE3, CK 18-8 (for luminal epithelial cells), CK 5, CK clone 8.12 and CK 14 (for basal cells) were employed. As in man, normal canine prostatic luminal cells were positive for CK 8-18. Basal cells were positive for CK 5 and CK clone 8.12 but, in contrast to findings in man, were negative for CK 14. Luminal cells were vimentin-negative, whereas in man they have been reported as vimentin-positive. The majority of carcinomas showed an undifferentiated histological pattern and all were positive for CK AE1/AE3 and for vimentin. Ten tumours were positive for CK 8-12, but six of them showed many cells co-expressing CK 14. Moreover, in two of these six cases a large number of neoplastic cells also reacted with CK clone 8.12 antibody, and in one of them co-expression of CK 5 was detectable. This co-expression, of luminal and basal cytokeratins, suggests a possible origin of the tumours from prostatic epithelial stem cells. Vimentin expression is an inconstant finding in human prostatic carcinomas; its almost uniform occurrence in canine carcinomas suggests a lesser degree of differentiation than in the human neoplasm.

A study of the validity of the Hospital Activity Analysis information.

For a number of years the medical profession and its administrators have been using statistical tabulations from the Hospital Activity Analysis returns. The quality of this information has often been criticized and no attempt has been made to quantify the levels of 'errors' in England and Wales. This paper reports the findings of such a study in Nottingham, and concludes that the Hospital Activity Analysis system in that area is almost as good as the clinical notes from which it is derived.