Consequence of restaging after neoadjuvant treatment for locally advanced rectal cancer.

BACKGROUND: Locally advanced rectal cancer is customarily treated with neoadjuvant chemoradiotherapy (CRT) followed by a total mesorectal excision. During the course of CRT, previously non-detectable distant metastases can appear. Therefore, a restaging CT scan of the chest and abdomen was performed prior to surgery. The aim of this study was to determine the frequency of a change in treatment strategy after this restaging CT scan. METHODS: Patients treated with neoadjuvant CRT for locally advanced rectal cancer between January 2003 and July 2013 were included retrospectively. To determine the value of the restaging CT scan, the surgical treatment as planned before CRT was compared with the treatment ultimately received. RESULTS: A total of 153 patients (91 male) were eligible, and median age was 62 (32-82) years. The restaging CT scan revealed the presence of distant metastases in 19 patients (12.4, 95 % confidence interval [CI] 7.0-17.8). In 17 patients (11.1, 95 % CI 6.1-16.1), a change in treatment strategy occurred due to the detection of metastases with a restaging CT scan. CONCLUSION: A restaging CT scan after completion of neoadjuvant CRT may detect newly developed metastases and consequently alter the initial treatment strategy. This study demonstrated the added value of the restaging CT scan prior to surgery.

Intracerebral haemorrhage in neurofibromatosis type I.

Neurofibromatosis type I patients usually present themselves with multiple neurofibromas and cafe-au-lait spots. We report a case with an intracerebral haemorrhage as an uncommon feature of the disease. The clinical, radiological, neurosurgical and histological features of this case are discussed and a review of the literature on the broad spectrum of neurofibromatosis is presented. The etiological factors and clinical consequences of this and other cerebrovascular features are briefly discussed.

Rupture of the arterial wall causes deflection in pressure time course during ex vivo balloon angioplasty.

A relation between restenosis and arterial lesions resulting from balloon angioplasty has been suggested in literature. Nevertheless, it is unclear to what extent angioplasty-induced arterial wall lesions contribute to the occurrence of restenosis. One problem is that arterial ruptures cannot be detected during balloon inflation. This study describes a method to detect ruptures in the arterial wall, based on deflections observable in the development of the balloon pressure. We performed ex vivo angioplasty with constant strain rate on 28 human femoral artery segments, showing deflections in 21 cases. In 20 cases wall rupture was confirmed histologically. From seven cases not showing deflections, four showed intact wall at microscopy. These figures result in a selectivity of the proposed method of 87 +/- 7% and a predictive value of the positive test of 95 +/- 5%. We conclude that this method can enhance detection of arterial rupture during ex vivo angioplasty and may become important clinically.

Myocardial rupture after myocardial infarction is related to the perfusion status of the infarct-related coronary artery.

Acute or subacute myocardial rupture is a serious and often lethal complication of acute myocardial infarction. The role of an occluded or open culprit coronary artery on the occurrence of this complication is not clear. We therefore reviewed the perfusion status of the infarct-related coronary artery retrospectively in 57 patients who had an initially nonfatal rupture (group A) and 28 patients (including 9 patients from group A) with a postmortem diagnosis of myocardial rupture (group B). In 35 of the 57 patients in group A, a coronary angiogram was available. Complete occlusion or ineffective reperfusion was present in 30 (89%) of 35 patients. The remaining 22 patients of group A showed no clinical signs of reperfusion. All 28 patients of group B had inadequate reperfusion of the infarcted area on postmortem angiography and macroscopic examination of the coronary artery. Our observations suggest that myocardial rupture typically occurs in an infarcted area without reperfusion.

The alpha-smooth muscle actin-positive cells in healing human myocardial scars.

Interstitial cells in the scars of human myocardial infarctions of different postinfarction times (6 hours to 17 years old) were characterized by antibodies to alpha-smooth muscle actin (ASMA), vimentin, and desmin. Basal lamina deposition was studied with antibodies to the basal lamina protein type IV collagen. Nonvascular spindle-shaped cells expressing ASMA were present within 4 to 6 days after infarction. These cells co-expressed vimentin but no desmin and showed discontinuous basal lamina deposition. In electron microscopy these cells showed features characteristic of myofibroblasts. The spindle-shaped cells persisted for a long period of time and could even be identified 17 years postinfarction. In transmural infarctions they were orientated parallel to the endocardium and epicardium. In nontransmural patchy infarctions they showed an orientation adjacent to the cardiomyocytes and appeared to be less dense than in the transmural infarctions. In conclusion, myofibroblasts expressing ASMA persist within human myocardial scars and show a preferential alignment that may be the result of the continuous mechanical stress caused by the ongoing contraction and relaxation of the surrounding viable myocardium.

Structural alterations in heart valves during left ventricular pressure overload in the rat.

BACKGROUND: Heart valves are an important denominator of the function of the heart but detailed studies of structural alterations of heart valves after hemodynamic changes are lacking. EXPERIMENTAL DESIGN: Structural alterations of heart valves, including DNA synthesis, collagen mRNA, and protein concentration were measured in heart valves of Wistar Kyoto (WKY) rats with acute left ventricular pressure overload, created by intrarenal aortic ligation (AL, N = 18) as well as in heart valves of age-matched spontaneously hypertensive rats, a model of chronic hypertension (N = 18). SHAM aortic ligation and normal WKYs (N = 17 and N = 17) served as controls. All animals received 5'bromo-2' deoxyuridine, during the last 7 days of the experiment, in a dose of 2.4 mg/kg.day. RESULTS: The cumulative labeling fraction (LF) in the mitral valve of AL animals was 47.8 +/- 5.2% as compared with 9.4 +/- 2.6% in SHAM animals (mean +/- SEM, p < 0.01). The LF in the aortic valve of AL animals was 33.3 +/- 2.9% as compared with 7.7 +/- 0.7% in SHAM animals (p < 0.01). The LF in the tricuspid valve was also significantly increased: 11.3 +/- 1.4% in AL versus 5.8 +/- 0.7% in SHAM (p < 0.01). Labeling fractions of heart valves in SHR were not increased as compared with normal WKY. The total collagen concentration in the three heart valves, measured by the hydroxyproline assay, did not change. The mRNA amounts of both collagen type I and III, detected by in situ hybridization, were increased in the heart valves of AL and spontaneously hypertensive animals as compared with the two control groups (SHAM and WKY). In all 3 heart valves, interstitial cells were vimentin-positive, but desmin-negative. A fraction of interstitial cells showed alpha-smooth muscle actin positivity. This immunophenotype did not change during pressure overload. CONCLUSIONS: Heart valves have the capacity to adapt to acute pressure overload, by means of DNA synthesis and increased collagen turnover. The increase in LF in the normotensive tricuspid valve suggests a role for an additional circulating factor. A constant fraction of the interstitial heart valve cells consists of myofibroblasts.

Histopathologic validation of intracoronary ultrasound imaging.

The purpose of this study was to validate intracoronary ultrasound imaging by correlation with histologic examination. In this in-vitro study of pressure-perfused human coronary arteries, 104 matching intracoronary ultrasound imaging images and histologic cross-sections from 12 hearts were compared to determine the diagnostic accuracy of 30 MHz commercially available intracoronary ultrasound imaging. For lipid deposits, sensitivity was 46% and specificity 97%. The smallest lipid deposit that was visualized measured 0.25 mm in axial diameter on histologic study. For calcific deposits, sensitivity was 77% and specificity 100%. The smallest calcific deposit that was visualized measured 0.25 mm in axial diameter on histologic examination. Atherosclerotic intimal thickening could not be distinguished qualitatively or quantitatively from nonatherosclerotic intimal thickening unless there were localized deposits of lipids or calcium. Intracoronary ultrasound imaging is accurate in detecting lipid and calcium deposits. Intimal thickening in intracoronary ultrasound imaging images does not prove the presence of atherosclerosis.

Canine model for treatment of faecal incontinence using transposed and electrically stimulated sartorius muscle.

A neosphincter was successfully created around each end of a Thiry-Vella loop in five dogs using transposed sartorius muscle to study new treatments for faecal incontinence. One of these dynamic neosphincters in each dog was electrically trained for 8 weeks while the other served as a control. Muscle biopsies demonstrated an increase in type 1 fatigue-resistant fibres from a median of 49 (range 37-54) per cent before electrical stimulation to 78 (range 53-99) per cent 8 weeks later in the stimulated sartorius neosphincters (P < 0.05), whereas the percentage of type 1 fibres in control neosphincters increased only slightly. Retention times of saline increased from a median of 10 (range 5-50)s before to 340 (range 100-470)s after electrical stimulation (P < 0.05) but also increased in control neosphincters (to 370 (range 330-1200)s); this may indicate that electrical stimulation immediately increases acute retention times. It is concluded that construction of a neosphincter is technically feasible with preservation of muscle morphology and that stimulation induces morphological and functional changes towards the characteristics of the external anal sphincter.

Interstitial collagen is increased in the non-infarcted human myocardium after myocardial infarction.

In this study we report the changes of interstitial collagen in the human non-infarcted interventricular septum after a myocardial infarction as well as in hypertrophic human hearts with or without hypertension. The collagen amount was determined with the Sirius Red morphometry technique, which enabled us to perform these studies on routinely processed, paraffin embedded sections. The collagen amount was significantly increased in the septum of infarct patients as compared to non-infarcted controls (P < 0.001). The collagen amount in the septum of the hypertensive hypertrophy group (HH) was significantly increased as compared to the non-hypertensive hypertrophy group (NHH) (P < 0.01). The collagen content in the NHH was not significantly different from the controls in the infarct group, while the collagen amount in the HH showed no significant difference to the collagen content in the infarct group. The results indicate that collagen deposition is increased in the non-infarcted myocardium after a myocardial infarction, as well as in the hypertensive hypertrophied myocardium. The data suggest that the appearance of excessive collagen is not mediated by cardiac hypertrophy per se, but that the underlying cause, infarction or hypertension, is the significant factor.

Morphology of dynamic graciloplasty compared with the anal sphincter.

Dynamic graciloplasty for fecal incontinence includes gracilis muscle transposition around the anal canal as a new sphincter and subsequent electrical stimulation. The aim of electrical stimulation is to transform the gracilis fast-twitch, "fatigue-prone" fibers into slow-twitch, "fatigue-resistant" fibers to achieve a sustained tonic contraction. The latter is considered essential for sphincter function. Therefore, the following features of transposed gracilis muscle morphology were studied in nine patients before and after electrical stimulation: 1) the percentage of Type I fibers, 2) the lesser diameter of these fibers, and 3) the positive collagen staining area. Furthermore, the external and sphincter and gracilis muscle histology was investigated in six autopsy cases. The mean percentage of Type I, slow-twitch, fatigue-resistant fibers in transposed gracilis muscle increased from 46 percent before electrical stimulation to 64 percent (P < 0.01, paired Student's t-test) after electrical stimulation. The mean lesser diameter of these fibers did not change significantly (from 32 to 29 microns), and the mean percentage of collagen increased from 4 percent before electrical stimulation to 7 percent (P < 0.01) afterward. The external sphincter in cadavers demonstrated a predominance of Type I fibers (80 percent) with a lesser diameter of 23 microns and a high percentage (12 percent) of collagen. Gracilis muscle histology was uniform at six different sample sites in these cadaver dissections. We conclude that electrical stimulation induces histologic changes in transposed gracilis muscle, allowing this muscle to function as an external anal sphincter.

Follow-up of anal dynamic graciloplasty for fecal continence.

The feasibility of anal dynamic graciloplasty (transposition of the gracilis muscle and subsequent implantation of a stimulation device) to restore continence, was assessed in a case-control study of 26 patients with severe fecal incontinence. It was shown that anal dynamic graciloplasty is capable of achieving the sphincter tone of healthy persons, as stimulated graciloplasty increased anal pressure from 46 mmHg without stimulation to 65 mmHg with stimulation (mean increase 19 mmHg; 95% confidence interval 13, 25; n = 25; p < 0.01). Time to retain a 250-ml phosphate enema increased from 52 seconds before to 204 seconds after 8 weeks of electrical stimulation (mean increase 151 seconds; 95% confidence interval 61, 241; n = 25; p < 0.01). Complete fecal continence was achieved in 17 patients (65%); two of these patients developed a wound infection, but one of the two realized continence without stimulation and the other patient became continent after reimplantation. Three other patients improved after anal dynamic graciloplasty, but infection necessitated removal of the stimulation device. One patient developed a fistula. Failures were encountered in five patients. Although our long-term follow-up results suggest a learning curve, it is concluded that electrical stimulation improves the results of conventional graciloplasty and avoids construction of a colostomy.

Evaluation of gracilis muscle transposition for fecal incontinence with magnetic resonance imaging.

Ten consecutive patients with incapacitating fecal incontinence were treated with 'anal dynamic graciloplasty' (transposition of the gracilis muscle around the anal canal and implantation of intramuscular electrodes connected with an implanted pulse generator, 6 weeks later) to achieve continence. We measured the gracilis muscle diameter immediately after transposition and before implantation of the stimulation device. It was found that gracilis diameter decreased from 12 (5 days after transposition) to 8 mm, 6 weeks later (mean decrease: 4 mm (95% confidence interval 3.6), n = 10, P < 0.05). In addition, morphology demonstrated a decrease of both Type I and Type II muscle fiber diameter and an increase in endomysial collagen. Despite this decrease in muscle (and muscle fiber) diameter, electrical stimulation of the transposed gracilis muscle increased the pressure into the anal canal from 37 to 55 mmHg (mean increase: 17 mmHg (95% confidence interval 6.29), P < 0.05). Fecal continence was achieved in seven (70%) of these patients. Further analysis revealed no correlations between reduction of the gracilis muscle diameter before implantation of the stimulation device and clinical outcome in terms of achieved continence and/or anal canal pressures. MRI is an excellent method to demonstrate the shape of gracilis muscle after transposition. However, the size of transposed gracilis muscle is not associated with the functional outcome.

Feasibility of stoma continence, using electrically stimulated rectus abdominis muscle in pigs.

To develop surgical techniques to obtain stoma continence with a muscular sphincter, the anatomy (especially innervation and vascularization patterns) of the human abdominal wall muscles was studied in three cadaver dissections. It was found that transposed rectus abdominis muscle might be positioned as a new sphincter (sphincteroplasty). Next, the feasibility was assessed in six pigs, and the rectus muscle was positioned as a sphincter around a Thiry Vella loop. The use of three different surgical procedures has been assessed: 1) a muscular ring of the proximal rectus was constructed and partly denervated the muscle; 2) the distal end of the Thiry Vella loop was pulled through the middle of the rectus muscle, thereby also introducing partial muscle denervation; and 3) a sling was constructed using the distal muscle part. In four of these six pigs, identical procedures were performed also at the left side. These new sphincters were electrically stimulated (with implanted stimulation devices) to study the feasibility of prolonged sphincter contraction independent of will. Stimulation with a frequency of 25 Hz was used at the right and 2 Hz was used at the left sphincters. It was found that electrical stimulation with a frequency of 25 Hz as well as 2 Hz increased the percentage of Type I (relatively fatigue-resistant) muscle fibers significantly from 42 to 65 percent (n = 6) in the right and from 50 to 67 percent (n = 4) in the left rectus muscle into innervated muscle areas of the sphincters. This increase is considered essential for sustained sphincter function. Stoma continence was not achieved because constructing muscular rings (as a sphincter) caused partial atrophy. Construction of a sling using the distal part of the rectus did not cause substantial atrophy, but continence was not achieved because the dorsal side of the Thiry Vella loop was not completely covered with muscle fibers.

Immunohistochemical detection of very recent myocardial infarctions in humans with antibodies against heart-type fatty acid-binding protein.

Depletion of human heart-type fatty acid-binding protein (H-FABP) from cardiomyocytes in infarcted areas with varying postinfarction intervals was studied in 25 autopsy cases. In 23 autopsy cases myocardial infarction was the clinical diagnosis; 2 cases were noncardiac deaths and served as controls. Formaldehyde-fixed and paraffin-embedded myocardial tissue sections were stained immunohistochemically with antibodies to human H-FABP. H-FABP immunohistochemical findings were compared with those from conventional nitroblue tetrazolium (NBT) macroenzyme staining and conventional histochemical hematoxylin-eosin staining of sections of the same infarctions. In all cases of infarction confirmed by NBT staining, decreased or absent H-FABP immunostaining was observed. In 12 cases of clinically diagnosed infarction, H-FABP depletion could be demonstrated in areas that showed normal NBT staining. These findings strongly suggest that immunohistochemical staining with antibodies to H-FABP can confirm the clinical diagnosis or suspicion of early myocardial infarction. In both control cases no depletion of H-FABP was observed in cardiomyocytes in different myocardial tissue sections, and macroenzyme staining with NBT was normal. We conclude that H-FABP immunostaining may detect very recent ischemia/ infarction in human myocardium and can be applied in routine autopsy pathology.

[Anal dynamic plastic surgery of the gracilis muscle; a new surgical technique for the treatment of fecal incontinence]. / Anale dynamische M. gracilis-plastiek; een nieuwe chirurgische techniek voor de behandeling van fecale incontinentie.

OBJECTIVE: To study the clinical outcome of anal dynamic graciloplasty (gracilis muscle transposition and implantation of electric stimulation device) in a consecutive series of 12 patients. DESIGN: Prospective study. SETTING: Maastricht University Hospital. PATIENTS AND METHODS: Twelve patients with incapacitating faecal incontinence were treated using anal dynamic graciloplasty because they were not amenable to other medical management. The data were analysed with emphasis on the clinical outcome, anal manometry, and gracilis muscle composition before and after electric stimulation. Results were considered significant if p < or = 0.05, using the paired Student's t-test. RESULTS: Eight patients achieved complete faecal continence, one patient still has a previously constructed colostomy and in three patients no faecal incontinence could be achieved, due to infections. Median follow-up is now over 18 months (range 16 weeks-5 years). Anal manometry demonstrated an anal pressure increased from 39 mmHg (without stimulation) to 66 mmHg with electric stimulation (mean increase 27 mmHg (CI: 19-35; n = 12, p < 0.01). Gracilis muscle composition showed an increase of type I relatively fatigue-resistant fibres, capable of prolonged contractions, from 45% before stimulation to 64% afterwards (mean increase 19% (CI: 14-21; n = 8, p < 0.01). CONCLUSION: Dynamic graciloplasty is capable of replacing the function of damaged or absent anal sphincters. The construction of a colostomy in patients with incapacitating faecal incontinence can be avoided.

Recurrent adult nephroblastoma. Long-term remission after surgery plus adjuvant high-dose chemotherapy, radiation therapy, and allogeneic bone marrow transplantation.

The authors report a case of Stage IV, unfavorable histologic type adult nephroblastoma. The patient was treated with multimodal therapy: combination chemotherapy consisting of cyclophosphamide, doxorubicin, cisplatin, and etoposide succeeded by nephrectomy and radiation therapy. After a disease-free period of 27 months, a pararectal relapse was treated by surgery, high-dose chemotherapy, and allogeneic bone marrow transplantation (BMT). The patient is alive and disease-free 3.5 years after BMT.

Changes in canine latissimus dorsi muscle during 24 wk of continuous electrical stimulation.

To study functional, structural, and biochemical adaptations to electrical stimulation of striated muscle in a large animal, the canine latissimus dorsi (LD) muscle was conditioned continuously for 24 wk with an increasing number of pulse bursts (burst duration 250 ms, burst frequency 30 Hz). Force measurements in vivo after 12 wk showed a significant decrease in the ripple, the ratio of interstimulus to peak force amplitude, from 0.94 +/- 0.03 to 0.13 +/- 0.08 (SE; n = 8, P less than 0.05), indicating reduction in contractile speed. Also the steep part of the force-frequency relation shifted to lower frequencies. A significant change in fiber-type composition was seen with both enzyme- and immunohistochemistry, manifested by an increase of type I fibers from 29.5 +/- 2.9 to 83 +/- 8% (SE; n = 8, P less than 0.05). During this period a transient rise in the number of type IIc/Ic fibers (from 3 to 10%) was seen. In the stimulated muscle, capillary-to-fiber ratio increased from 1.9 +/- 0.4 to 2.7 +/- 0.1 (P less than 0.05). A significant increase in mitochondrial volume was also seen, especially in the peripheral part of the fiber. Both creatine kinase and lactate dehydrogenase revealed a significant decline in activity within 12 wk. At the same time a shift in lactate dehydrogenase-isozyme pattern was observed toward the cardiac composition. No additional changes occurred after 12 wk of stimulation, indicating that conversion of the canine LD muscle was complete within this period.

Programmed electrical stimulation and drugs identify two subgroups of ventricular tachycardias occurring 16-24 hours after occlusion of the left anterior descending artery.

BACKGROUND: Spontaneous sustained ventricular tachycardia (VT) occurring 16-24 hours after left anterior descending (LAD) coronary artery occlusion in the canine heart is most likely based on abnormal automaticity. In vitro, it has been demonstrated that the rate of the arrhythmia and the effect of overdrive pacing depends on the maximal diastolic potential (MDP). The MDP is also of importance in understanding the effect of antiarrhythmic drugs. To study 1) the possible presence of different responses to overdrive pacing and 2) the relation between the response to overdrive pacing and the effect of different antiarrhythmic drugs in the intact heart, we investigated the effect of 1) (prolonged) pacing and 2) lidocaine (3 mg/kg), verapamil (0.4-1.0 mg/kg), or flunarizine (2 mg/kg) during VT. METHODS AND RESULTS: In 21 conscious dogs with chronic atrioventricular block, 60 sustained VTs were observed 1 day after LAD occlusion. During VT, pacing with interstimulus intervals of 400, 300, and 200 msec for 15, 60, and 120 seconds was done on 40 VTs. Based on their response to pacing, VTs were divided into a pacing-suppressible (PS group) and a pacing-nonsuppressible group (PNS group). The mean cycle length in the PS group was significantly longer (410 +/- 50 msec) than in the PNS group (360 +/- 35 msec, p less than or equal to 0.01). Suppression was directly related to the rate and duration of pacing. Spontaneous recurrence of VTs was observed after 26 +/- 45 seconds. Lidocaine and verapamil increased cycle length of the suppressible VTs and terminated them, whereas flunarizine had no effect. Except for verapamil, which increased cycle length of the VTs, no effects were seen in the PNS group. CONCLUSIONS: In conscious dogs showing sustained VTs 16-24 hours after LAD occlusion, 1) the slower VTs can be suppressed by pacing, verapamil, and lidocaine but not by flunarizine, and 2) the faster VTs are not affected by pacing, lidocaine, and flunarizine, and are only slowed by verapamil. These findings are compatible with in vitro findings of abnormal automaticity, with the slower VTs originating from a higher MDP than the faster VTs.