Andrew K. Williams

Evidence of a common pathogenesis for foregut duplications and esophageal atresia with tracheo‐esophageal fistula

The pathogenesis of the alimentary tract duplications, including foregut duplications (FgD) remains speculative. The accidental finding of FgD in fetal rats with esophageal atresia and tracheoesophageal fistula (EA‐TEF) induced by Adriamycin provided an animal model to investigate a possible relationship between these two entities. Timed‐pregnant rats were intraperitoneally injected with Adriamycin (1.75 mg/kg) on gestational Days 6 to 9. Their embryos were harvested by Caesarean section from gestational Days 14 to 21. Forty‐six of embryos were processed and serially sectioned in the transverse or sagittal planes. EA‐TEF occurred in 43/46 (93%) embryos of which 11 (24%) were found to have an associated FgD located at the level where the esophagus was absent. Six FgDs communicated with the foregut or the trachea. Five noncommunicating FgDs were located between the foregut and the vertebral column. In the control embryo, the notochord was located in the centre of the vertebral column from Day 11 of the gestation. In Day 14, 15 and 16, however, embryos exposed to Adriamycin, an abnormal notochord or branch frequently was located within the mesenchyme of the maldeveloped foregut or attached to the duplication cyst. In some, it appeared that the notochord was drawing the cyst‐like structure away from the foregut. The present study confirms that duplications adjacent to the esophagus arise from the foregut and that failure of the foregut to detach from the notochord at the normal time may contribute to the development of foregut duplications. Anat Rec 264:93–100, 2001.

Demonstration of abnormal notochord development by three-dimensional reconstructive imaging in the rat model of esophageal atresia.

Abstract The notochord (Nt) is believed to have a role in the development of axial organs. This study was undertaken to reconstruct in three dimensions (3D) the relationship of the Nt to abnormal development of the foregut (Fg) in the adriamycin-induced rat model of esophageal atresia (EA). Pregnant Sprague-Dawley rats were given 1.75 mg/kg adriamycin intraperitoneally on gestational days 6–9 inclusive; control rats received i.p. saline of equal volume, or no injection. Rats were killed between days 11 and 14 and their embryos harvested, histologically sectioned serially, and stained with hematoxylin and eosin. Digitized photographs were taken of serial transverse sections; these photos were traced and used as the basis for 3D reconstruction. From day 11 the normal Nt is no longer in contact with the respiratory or Fg mesenchyme. In adriamycin-treated embryos the Nt branches abnormally as it enters the Fg mesenchyme. Adherence of the Nt to the mesenchyme of the Fg exerts mechanical traction pulling the upper Fg dorsally. The severity of the Fg abnormalities correlates with the length of the ventral extension of the Nt within the Fg mesenchyme: the embryo develops atresia of the esophagus or trachea when the Nt is grossly abnormal. The Nt undergoes reactive thickening in the absence of Fg structures ventral to it. Thus, structural lesions of the Fg (e.g., atresias) are associated with abnormalities of the Nt. The relationship of the Nt to the Fg mesenchyme determines the severity of the abnormality induced by adriamycin: extensive adherence produces tracheal agenesis and EA.

Does the urorectal septum fuse with the cloacal membrane

PURPOSE Traditional theories of cloacal embryogenesis assume that the urorectal septum fuses with the cloacal membrane before the anal membrane disintegrates. However, recent observations in humans and other species raise doubt about this assumption. We determined whether urorectal septum fusion occurs in rats. MATERIALS AND METHODS Rat embryos were harvested at specific times between days 11 and 16 of gestation. We evaluated the morphology, growth and relationship of the urorectal septum to the cloacal membrane on serial histological sections. RESULTS The urorectal septum consistently fused with the cloacal membrane on day 15 of gestation before the cloacal membrane began to disintegrate. CONCLUSIONS In rats the urorectal septum fuses with the cloacal membrane, after which the urogenital membrane and anal membrane disintegrate by a process of apoptosis.

Multifocality rather than tumor location is a prognostic factor in upper tract urothelial carcinoma

OBJECTIVES Whether a patient has urothelial carcinoma located within the renal pelvis or ureter remains a controversial prognostic indicator in clinical urology. We wished to evaluate whether tumor location is associated with recurrence in patients undergoing nephroureterectomy for upper tract urothelial cancer in a large volume patient cohort. SUBJECTS AND METHODS We created a retrospective database of patients from 7 academic centers throughout Canada who underwent nephroureterectomy for upper tract urothelial carcinoma. Patient demographics as well as pathologic and surgical factors were analyzed to evaluate any statistical association between tumor location and overall survival, disease-free survival, and disease-specific survival. RESULTS A total of 1,029 patients had data available for analysis with a mean follow up of 3.2 years. Kaplan Meier 5-year disease-free survivals (DFS) were 46%, 37%, and 19% for renal pelvis tumors, ureteric tumors, and multifocal tumors respectively. There was no association between the location of the tumor and the DFS, however, disease involving both the ureter and renal pelvis was associated with lower DFS and overall survival (OS) (P < 0.001). CONCLUSIONS Tumor location does not appear to have any influence on the risk of recurrence of disease following nephroureterectomy in this large patient cohort. However, multifocal tumors involving both the ureter and renal pelvis had a significantly worse prognosis and should be considered for more aggressive management.

Development of the bones and synovial joints in the rat model of the VATER association

Abstract The adriamycin-induced rat model of the Vertebral, Anorectal, Tracheo-Esophageal, Radial and Renal (VATER) association produces a variety of vertebral, rib, and limb abnormalities. This study was designed to document accurately the nature of these abnormalities and to determine whether synovial joints are affected. Fetuses from pregnant Sprague Dawley rats that had received intraperitoneal injections of 1.75 mg/kg of adriamycin on days 6–9 or 10–13 of gestation were harvested. Double-stained skeletal preparations and histological sections were examined for vertebral, rib, and limb anomalies. The incidence of anomalies was high in the group treated on gestational days (GD) 6–9, while it was low in the GD 10–13 group. The length and thickness of the long bones were reduced, with bowing and reduction in their endochondral ossification. Sirenomelia occurred in the group treated on GD 6–9, and was often associated with a short tail and anal atresia. The joint cavities, and intra-articular structures such as menisci and the cruciate ligaments developed normally from the mesenchymal interzone. These data indicate that adriamycin inhibits skeletal growth and differentiation without any interference in the differentiation of the mesenchymal interzone, thus producing normal synovial joints.

The development of the proximal oesophageal pouch in the adriamycin rat model of oesophageal atresia with tracheo-oesophageal fistula

Abstract. This study examined the morphological development of the proximal oesophagus in the Adriamycin-induced rat model of oesophageal atresia. The proximal oesophageal segment in oesophageal atresia with tracheo-oesophageal fistula (OA\TOF) has been assumed to be of similar embryological origin to the distal oesophagus. However, recent research using the Adriamycin model of OA\TOF has indicated that these structures may have a different origin. Time-mated Sprague-Dawley rats were administered either Adriamycin intraperitoneally or saline of an equivalent volume between days 6–9 of gestation. The rats were sacrificed between days 11–19 of gestation, their embryos removed and histologically sectioned. These sections were analysed to observe the morphological changes occurring in the proximal foregut. The proximal oesophageal pouch first appeared on day 15.25 as a dorsal outpouching of the proximal foregut immediately cranial to an area of apoptosis in the dorsal epithelium of the distal pharynx. It elongated through a process of cellular proliferation until it was clearly formed on day 16. Relatively little growth occurred from days 17–19. In the rat developing oesophageal atresia, the proximal oesophageal pouch has an origin different to that of the distal oesophagus. This study may explain the difference in immunohistological properties and intrinsic nervous supply between the proximal and distal oesophageal segments in oesophageal atresia.