Adriamycin induces notochord hypertrophy with conservation of sonic hedgehog expression in abnormal ectopic notochord in the adriamycin rat model

Background/purpose

The Adriamycin rat model (ARM) is a well-established model of the Vertebral, Anorectal, Cardiac, Tracheoesophageal, Renal, Limb (VACTERL) association. The notochord, which expresses Sonic Hedgehog (Shh), has been found to be grossly malformed with ventral ectopic branches in the foregut region of embryos in the ARM. The authors designed this study to test the hypothesis that Shh-expressing ectopic notochord could contribute to an increased volume of notochord relative to total embryo volume, resulting in an increased concentration of Shh in the notochord of affected embryos.

Methods

Adriamycin was administered intraperitoneally to rats on days 7 (E7), E8, and E9 of gestation and saline to control animals. Embryos recovered at E12 and E14 were examined immunohistochemically for Shh expression. Quantitative morphology using the Cavalieri technique was performed to determine embryo and notochord volume.

Results

Embryos in both Adriamycin and control groups at E12 and E14 showed comparable levels of Shh expression in notochord at all locations. The percentage of notochord per embryo was significantly increased in Adriamycin embryos at E12 and E14 compared with equivalent controls.

Conclusions

These data suggest that Adriamycin induces notochord hypertrophy. With all regions of the notochord secreting Shh, this could result in a higher concentration gradient of Shh in close abnormal proximity to the foregut, possibly contributing to the malformations found in the VACTERL association.     

The optimal dose of Adriamycin to create a viable rat model potentially applicable to congenital obstructive uropathy

Purpose

The Adriamycin rat model is an established model for different organ anomalies including congenital obstructive uropathy. In the current study, we carried out a dose-response analysis to find out the optimal dose of Adriamycin to create a viable rat model of obstructive uropathy.

Methods

Thirty time-mated Sprague-Dawley rats were divided into 5 groups including 1 control group and 4 different treatment groups. The 4 Adriamycin dosage regimens investigated in this study were 1.25, 1.5, 1.75, and 2 mg/(kg d). Experimental rats (n = 24) were injected intraperitoneally with different doses of Adriamycin on gestational days 7 to 9 (6 rats in each group). Control rats (n = 6) were injected with an equivalent volume of saline on the same days. Viable term fetuses were harvested on gestational day 21 by cesarean delivery and dissected under a dissecting microscope. Serial transverse sections from urinary tract system were obtained for histological examination.

Results

One hundred thirty-three viable fetuses were recovered from Adriamycin-treated rats, and 50 were from rats in the control group. There were no resorptions in the control group; however, 52 resorptions were recorded in Adriamycin groups. The rates of hydronephrosis and resorptions were 60% and 0%, 80.5% and 5.8%, 100% and 17.3%, and 100% and 76.9% at doses of 1.25, 1.50, 1.75, and 2 mg/(kg d), respectively. Histologic examination of the kidneys in the treated groups showed a significant decrease in renal parenchyma compared with the control group.

Conclusions

The dosage of 1.5 mg/(kg d) of Adriamycin yielded the highest number of viable hydronephrotic fetuses. At this dose, urinary abnormalities are milder; but the highest number of viable fetuses is provided, which is necessary to create a reproducible and viable animal model.     

Surgical treatment in Paget's disease of the breast

Background

The aim of this study was to evaluate the outcomes of surgical treatment of Paget's disease of the breast, with special emphasis on magnetic resonance imaging (MRI) and sentinel node biopsy (SNB).

Methods

The study included 58 consecutive patients with Paget's disease treated from 1995 to 2006.

Results

Twenty-five patients had ductal carcinoma in situ, and 31 had invasive carcinoma. MRI was performed in 14 patients, with positive findings in 7 patients, 5 of whom had negative findings on conventional imaging. The overall mastectomy rate was 76%. Eighteen patients underwent SNB, and 26 patients underwent full or partial axillary clearance. Fourteen patients had no axillary surgery. One patient had local recurrence after breast conservation, and another had axillary recurrence after negative results on SNB. Six patients had distant metastases. Four patients died of breast cancer.

Conclusions

Paget's disease is frequently associated with peripheral or multicentric cancer. MRI may be helpful when considering breast conservation or omitting axillary nodal staging.     

Notable sequential alterations in notochord volume during development in the Adriamycin rat model

Background/Purpose

The Adriamycin rat model (ARM) is a well-established model of the vertebral, anorectal, cardiac, tracheoesophageal, renal, and limb association. An important finding in the ARM is that Adriamycin induces abnormal notochord morphology in the region of the foregut. Having recently demonstrated notochord hypertrophy in ARM embryos, the authors designed this study to assess notochord volume sequentially from gestational days 10 to 14 (E10-E14) to test the hypothesis that notochord hypertrophy occurs maximally soon after Adriamycin administration.

Methods

Adriamycin (1.75 mg/kg) was administered intraperitoneally to pregnant rats on E7, E8, and E9. Control animals were given saline. Embryos were recovered at E10, E11, E12, E13, and E14 and embedded in paraffin. Quantitative morphology using the Cavalieri technique was performed on hematoxylin and eosin-stained transverse serial sections to determine total embryo and total notochord volume.

Results

The percentage volume of notochord per embryo was significantly increased (P < .05) in Adriamycin-treated embryos at all gestational time frames from E10 to E14 when compared with equivalent controls. This increased volume of notochord was found to be maximal at E11.

Conclusions

These data support the authors' previous finding that Adriamycin induces notochord hypertrophy and suggest that notochord volume is increased relative to embryo volume soon after Adriamycin administration and is maximal on E11. The abnormal increase in notochord volume during the critical phase of development may interfere with organogenesis, resulting in the vertebral, anorectal, cardiac, tracheoesophageal, renal, and limb association.     

Experience in treating congenital esophageal atresia in China

Purpose

The aim of the study was to evaluate our recent experience in treating esophageal atresia (EA) and the outcomes observed at a single center for pediatric surgery.

Materials and Methods

The records of infants with EA from 2006 to 2009 were reviewed. Birth weight, associated anomalies, details of management, complications, and outcomes were examined.

Results

Forty-eight consecutive infants with EA were identified from 2006 to 2009, of which 33 (69%) were boys. Mean birth weight was 2668 g (range, 1700-3800 g). Common associated malformations (35%) were cardiac anomalies, imperforate anus, limb anomalies, and chromosomal anomalies. Forty-seven were Gross type C, and one was Gross type A. Forty-five infants underwent ligation of the tracheoesophageal fistula and end-to-side primary anastomosis, and one received a colonic interposition. Six patients died (12.5% mortality). Three died before or during operation because of severe pneumonia and complex cardiac anomalies, and 3 died during recovery (within 1 month after repair) because of aspiration and severe pneumonia (early postoperative mortality was 6.67%). Complications included pneumonia, anastomotic leakage (16%, all recovered after conservative treatment), wound sepsis (11%), recurrent tracheoesophageal fistula (9%) (3/4 recovered after conservative treatment), anastomotic stricture (10%), and gastroesophageal reflux in about 2 of 3 patients. Preoperative computed tomographic imaging and 3-dimensional graphic reconstruction used in 15 patients were useful.

Conclusions

Most patients with EA have excellent short- to midterm surgical outcomes. The main factors for mortality are complex cardiac anomalies, aspiration, and pneumonia. Computed tomographic imaging and 3-dimensional graphic reconstruction can provide surgeons with excellent preoperative reference about the anatomy of the defect. Most anastomotic related complications resolve with conservative treatment. Patients of low-risk prognosis group with type A and long gap EA can be managed with a primary colonic interposition with good results. The main midterm complications are gastroesophageal reflux and stricture.     

Faulty bone morphogenetic protein signaling in esophageal atresia with tracheoesophageal fistula

Background

The organogenesis of esophageal atresia with tracheoesophageal fistula remains unclear. We have previously demonstrated that the fistula tract develops from a trifurcation of the embryonic lung bud and displays pulmonary lineage traits. Unlike the lung, the fistula grows without branching. Bone morphogenetic proteins (BMPs) are known to be important in lung branching. We studied possible BMP signaling defects as a potential cause for the absence of branching in the fistula tract.

Methods

Adriamycin was administered to pregnant rats on days 6-9 of gestation to induce tracheoesophageal fistula. Microdissection was performed at E13 and E17 isolating the foregut. Tissues were analyzed using immunohistochemistry for BMP ligand (BMP2, BMP4, BMP7) and receptor (BMPRIA, BMPRIB, BMPRII) expression.

Results

Immunohistochemistry revealed the presence of all 3 BMP ligands at E13, localized specifically to the esophageal mucosa but absent in the fistula and lung. At E17, the ligands were again present in the esophageal mucosa, and additionally in the fistula tract mucosa, but remained absent in the lung. At E17, all of the BMP receptors were also localized to the luminal surface of esophagus and fistula. However, in the lung epithelium, only BMPRII was found, whereas BMPRIA and BMPRIB remained absent.

Conclusions

The normal expression pattern of BMP4 was increased at the branch tips and low between branches. Among other results, we show here a constant expression level of BMP ligands throughout the entire epithelium of the fistula tract. This diffuse expression suggests defective BMP signaling in the fistula tract and explains its nonbranching phenotype.     

Perception and use of minimal access surgery simulators in pediatric surgery training programs

Background/Purpose

In the current time-restricted training environment, simulator use in surgical teaching is receiving increasing attention. A large body of literature addresses simulators' effectiveness in surgical education. No prior studies assess how widely simulators are actually being used or attitudes about their effectiveness of those involved in training.

Methods

Surveys were e-mailed to all current pediatric surgery trainees and training directors. Queries examined respondents' perceptions about surgical simulators' usefulness and to what extent they are used in their programs. Other questions assessed obstacles to simulator use.

Results

Response rates were high (47% of program directors and 67% of current fellows). Nearly all respondents felt laparoscopic simulators improve training efficiency (88%). About half (55%) report regular simulator availability to trainees. Only 21% of programs have current or planned simulation curricula. Less than half of the training directors (32%) and about half of the fellows (55%) felt they have actually significantly improved trainees' skills.

Conclusions

Trainees and training directors placed significant importance on simulator use in pediatric surgery training. However, most did not feel that simulators had actually improved the trainees' laparoscopic skills. Wider availability of simulation laboratories and protected time for using them would enhance the impact of simulators on pediatric surgery training.     

Use of transanastomotic feeding tubes during esophageal atresia repair

Purpose

Esophageal atresia (EA) with tracheoesophageal fistula (TEF) type C accounts for 85% of all EA. In our center, patients were previously started on total parenteral nutrition (TPN) postoperatively and oral feedings initiated only after a contrast esophagogram. Our aim is to assess the benefit of intraoperatively placed transanastomotic feeding tubes (TAFTs).

Methods

A 7-year retrospective review analyzed the outcomes of children with EATEF type C as they relate to the use of TAFT. Demographics, associated anomalies, operative findings, complications, duration of TPN, resumption of oral feeding, length of stay, and follow-up were examined.

Results

Twenty-one patients had EATEF type C. Eleven (55%) and 9 (45%) patients were identified as nonfeeding tube (NFT) and TAFT groups, respectively. There were no differences in gestational age, birth weight, associated anomalies, and interval to operative intervention or operative time. Excluding one patient with a severe cardiac malformation in the NFT group, there were no significant differences in anastomotic leak (8% vs 22%), stenosis (36% vs 22%), TPN duration (20 days vs 12 days), and cholestasis (36% vs 11%).

Conclusion

Transanastomotic feeding tube may lead to shorter TPN duration and decreased cholestasis, but a larger prospective study would be required to prove these benefits and ensure that it does not increase anastomotic leaks. This could be done through an expanded Canadian Pediatric Surgery Network study.     

Four-year clinical update from the American Society of Breast Surgeons MammoSite brachytherapy trial

Background

We present a 4-year update on the efficacy, cosmetic results, and complications of MammoSite breast brachytherapy in patients enrolled in the American Society of Breast Surgeons registry trial.

Methods

A total of 1,449 breasts in 1,440 patients with early stage breast cancer undergoing breast-conserving therapy were treated with adjuvant, accelerated partial breast irradiation (APBI) (34 Gy in 3.4-Gy fractions) delivered with the MammoSite device. The median follow-up period for the entire group was 36.1 months.

Results

The 3-year actuarial rate of ipsilateral breast tumor recurrence was 2.15%. The 3-year actuarial rate of axillary recurrence was .36%. Complication rates were as follows: infection, 9.5%; seroma, 26.8% (symptomatic seroma, 12.7%); and fat necrosis, 2.0%. The percentages of breasts with good or excellent cosmetic results were as follows: 12 months, 95%; 24 months, 94%; 36 months, 94%; and 48 months, 91%.

Conclusions

Locoregional control, complications, and cosmetic outcomes from MammoSite APBI at the 4-year update are acceptable and similar to results seen with other forms of APBI.     

Impact of omphalocele size on associated conditions

Purpose

Omphalocele is often associated with the presence of other congenital anomalies. Case reports have demonstrated nonclassical associations occurring in smaller omphaloceles. The aim of this study was to determine if omphalocele defect size correlates with the type of anomalies found.

Methods

Patient records at a pediatric hospital were retrospectively reviewed for an 8-year period. Data were collected on patient demographics, omphalocele size, and congenital anomalies identified. Size of the abdominal wall defect was determined by either physical examination or operative record of repair. Patient cohorts were designated as those with small (4 cm and less) or large (greater than 4 cm) omphaloceles.

Results

Fifty-three cases of omphalocele were observed. Twenty-seven cases were classified as small, with 26 classified as large. A predominance of males was noted in the small omphalocele group (78% vs 42%; P = .01). Intestinal anomalies, including Meckel's diverticulum and intestinal atresia, were only seen in patients with small omphaloceles. Most cardiac anomalies were associated with large omphaloceles (34.6% vs 3.7%; P = .01).

Conclusion

Small omphalocele size correlates with an increased prevalence of associated gastrointestinal anomalies, a lower prevalence of cardiac anomalies, and a higher predominance of male sex.     

Differences in the outcome of surgically placed long-term central venous catheters in neonates: neck vs groin placement

Background/Purpose

Long-term tunneled central venous catheters (CVC) are frequently used in the neonatal intensive care unit (NICU) babies. They are placed either in the neck or groin based primarily upon the surgeon's preference. There is meager published information available about the relative risks of these lines.

Methods

This is a retrospective analysis of all the tunneled central venous catheters placed in NICU babies at a children's hospital over a nearly 5-year period. Single lumen Broviac catheters were used in all cases.

Results

A total of 137 catheters were placed in 126 patients. There were 88 neck lines and 49 groin lines. Age, gestational maturity, and body weight were significantly lower for babies who underwent groin line placement. There was no significant difference in the number of days the catheters were live between the 2 groups. Total complication rates and catheter infection rates were significantly higher with neck lines. The accidental removal rate was higher with neck lines but did not reach statistical significance.

Conclusions

Broviac catheters placed in the groin of NICU babies are associated with significantly fewer complications compared with those placed in the neck.     

Long-term analysis of children with esophageal atresia and tracheoesophageal fistula

Background/purpose

For children with esophageal atresia (EA) or tracheoesophageal fistula (TEF), the first years of life can be associated with many problems. Little is known about the long-term function of children who underwent repair as neonates. This study evaluates outcome and late sequelae of children with EA/TEF.

Methods

Medical records of infants with esophageal anomalies (May 1972 through December 1990) were reviewed. Study parameters included demographics, dysphagia, frequent respiratory infections (> 3/yr), gastroesophageal reflux disease (GERD), frequent choking, leak, stricture, and developmental delays (weight, height < 25%, < 5%, respectively).

Results

Over 224 months, 69 infants (37 boys, 32 girls) were identified: type A, 10 infants; type B, 1; type C, 53; type D, 4; type E, 1. Mean follow-up was 125 months. During the first 5 years of follow-up, dysphagia (45%), respiratory infections (29%), and GERD (48%) were common as were growth delays. These problems improved as the children matured.

Conclusions

Children with esophageal anomalies face many difficulties during initial repair and frequently encounter problems years later. Support groups can foster child development and alleviate parent isolationism. Despite growth retardation, esophageal motility disorders, and frequent respiratory infections, children with EA/TEF continue to have a favorable long-term outcome.     

Conjoined twins--past, present, and future

Background/Purpose

Conjoined twins are rare and complex anomalies of the newborn. They require a highly experienced team and a center equipped to deal with such challenging anatomy.

Method

A review of 31 sets of conjoined twins was managed by one team over a 15-year period. The spectrum of the anomalies, management strategies, and outcomes will be analyzed with future recommendations.

Results

Ten sets of complete conjoined twins and two sets of parasitic conjoined twins were successfully separated. Tissue expanders and prosthetic meshes were not required. A separation of one set of craniopagus parasiticus conjoined twins was attempted, but abandoned owing to major vascular and brain sharing. The remaining 18 sets were not separable owing to major cardiac anomalies and/or sharing, and all died within several weeks of birth.

Conclusion

Careful planning, a multidisciplinary approach, rehearsal, and experience are important factors in dealing with conjoined twins. Tissue expanders and prosthetic meshes are not required in most cases. Selective abortion or fetal intervention may play a role in the future.     

Infants with repaired esophageal atresia and distal tracheoesophageal fistula with severe respiratory distress: is it tracheomalacia, reflux, or both?

Aim of Study

Infants with repaired esophageal atresia and distal tracheoesophageal fistula (EA/TEF) are at risk for severe respiratory distress, which is related to tracheomalacia (TM), gastroesophageal reflux, or both. This usually mandates an operation for TM and/or a fundoplication procedure (FP).

Methods

We retrospectively performed a 26-year review of 288 patients with repaired EA/TEF. Research Ethic Board approval was obtained.

Results

Postoperatively, 22 (7.6%) infants with EA/TEF developed severe respiratory distress. Thirteen infants had an initial TM procedure and symptoms improved in 7 (54%). The 6 (46%) remaining patients with ongoing respiratory symptoms required an FP. Nine infants had an initial FP and the symptoms improved in 6 (67%). The remaining 3 (33%) patients with ongoing respiratory symptoms required a TM procedure. All patients improved with the second procedure. Several clinical parameters were assessed among the 4 patient groups (FP only, FP followed by TM procedure, TM procedure only, and TM procedure followed by FP); there were no significant differences noted.

Conclusions

Whereas 54% to 67% of infants improved with a TM procedure or FP, 33% to 46% required both surgical procedures. No clinical parameters were identified that could predict which procedure should be performed first.     

The bispectral index, a useful adjunct for the timely diagnosis of brain death in the comatose trauma patient

Background

The bispectral index (BIS) is a processed electroencephalographic value (awake = 100, isoelectric = 0). The relationship of BIS and brain death (BD) is assessed.

Methods

BIS was evaluated in GCS 3 head-injured patients with BD (no brain function including apnea) or near BD (no apnea or negative ancillary test [cerebral perfusion and electroencephalogram]).

Results

In 27 patients, there were 37 BD evaluations (apnea assessment or ancillary test). BD was confirmed in 62% (n = 23). However, 38% (n = 14) showed near BD. BD BIS is 3 ± 5 and near BD BIS is 36 ± 31 (P = .002). In the 23 BD patients, BIS was <20 for 7 hours ± 6 hours before a BD evaluation was performed. Of 14 near BD evaluations, 9 (64%) had BIS ≥20. BIS <20 for predicting BD had a sensitivity of 100% (23/23), a positive predictive value of 84% (23/28), and a negative predictive value of 100% (9/9).

Conclusions

Distinguishing brain death and near brain death in severely comatose trauma patients is complex. By indicating the likelihood of brain death, BIS is an adjunct for efficient evaluation.     

Congenital anomalies are commonly associated with exomphalos minor

Aim

The objective of this study is to define the incidence of chromosomal and congenital anomalies in neonates with exomphalos major and minor.

Background

Incidence of major congenital anomalies varies from 35% to 81% in exomphalos. It is unclear whether these malformations are more common with exomphalos major.

Material and Methods

The case notes of 82 antenatal diagnoses of exomphalos, made between January 1998 and December 2004, were retrospectively reviewed. Exomphalos major was defined as a defect 5 cm or greater and exomphalos minor a defect less than 5 cm in diameter.

Results

There were 72 live births, 6 still births, and 4 terminations of pregnancy. There was no statistical significance between exomphalos major and minor regarding mode of delivery, gestational age at birth, birth weight, major cardiac anomalies (21% vs 23%), and renal and external genitalia abnormalities (11% vs 18%). Chromosomal anomalies, syndromes, and dysmorphism were common in exomphalos minor 17 (39%, P = .0001). Congenital malformations of the gastrointestinal tract (14% vs 27%), central nervous system (0 vs 21%), and Wilms' tumor (0 vs 5%) occurred commonly in exomphalos minor. Limb abnormalities (25% vs 5%), ectopia cordis (11% vs 0), and bladder exstrophy (7% vs 0) occurred predominantly in exomphalos major. Mean follow-up was 34 months. Three neonates with exomphalos major died. Overall mortality was 4%.

Conclusions

Chromosomal anomalies and syndromes occur more commonly in exomphalos minor. Exomphalos minor and major seem to have a predilection for associated anomalies of specific organ systems. This predisposition may help in counseling parents, planning investigations, and organization of multidisciplinary management strategy.     

Long-term outcomes of kidney transplants with multiple renal arteries: a retrospective study

Objective

The aim of this study was to investigate whether kidney transplantations performed using grafts with multiple arteries negatively affected renal function or increased the risk of vascular or urologic complications.

Methods

Among 249 kidney transplant patient followed for at least 1 year between 2000 and 2005, we retrospectively evaluated their donor renal artery anatomy to compare postoperative vascular and urologic complications: creatinine clearance at 1, 2, and 5 years, as well as graft survival at 3 and 5 years.

Results

While 214 (85.9%) displayed a single artery (group 1), 35 (14.1%) showed multiple renal arteries (group 2). Thirty-one of the group 2 allografts had two, three donors had three, and one had four arteries. The postoperative vascular and urologic complications and the creatinine clearance values at 1, 2, and 5 years of both groups were similar. The 3- and 5-year graft survivals among group 1 were 95% and 90%, whereas those of group 2 were 94% and 91% respectively (P < .05).

Conclusion

Our study indicated that multiple renal arteries did not adversely affect postoperative urologic or vascular complications or kidney allograft or patient survival compared with single renal artery cases.     

Supplementation of retrobulbar block with clonidine in vitreoretinal surgery: effect on postoperative pain

Study Objective

To evaluate the effect of clonidine when added to local anesthetics on duration of postoperative analgesia during retrobulbar block.

Design

Prospective, randomized controlled trial.

Setting

Operating room and Postanesthesia Care Unit of a university-affiliated hospital.

Subjects

80 ASA physical status 1, 2, and 3 patients undergoing vitreoretinal surgery with or without scleral buckling.

Interventions

Patients in the control group (n = 40) received a retrobulbar block with 4.5 mL of lidocaine-bupivacaine and 0.5 mL of saline. Clonidine group patients (n = 40) received 4.5 mL of lidocaine-bupivacaine and 0.5 μg/kg of clonidine in a 0.5 mL volume.

Measurements

The time to first analgesic request, frequency of postoperative pain, and number of postoperative analgesic requests per patient were assessed.

Main Results

37 patients in the control group (92.5%) versus 24 patients (60%) in the clonidine group reported pain postoperatively (P = 0.001), with a shorter time to first analgesic request noted in the control group (4.9 ± 3 vs 11.9 ± 5.3 hrs; P < 0.001). The median number of postoperative analgesic requests per patient during the first 24 hours was higher in the control group than the clonidine group [2 (0-3) vs. 1 (0-3); P < 0.001].

Conclusions

The addition of clonidine 0.5 μg/kg to the local anesthetics of a retrobulbar block for vitreoretinal surgery decreases the frequency of postoperative pain and prolongs the time of analgesia.