Biomedical subjects
Publications and source records attributed to Timothy M Crombleholme.
A patent urachus, which is typically diagnosed as leakage from the umbilicus postnatally, can present as an allantoic cyst in the umbilical cord antenatally. We report a case of a patent urachus with an allantoic cyst diagnosed via fetal MR imaging at 24 weeks' gestation. Early detection allowed for appropriate counseling and prompt corrective surgery after birth.
Tendon injuries account for a significant number of musculoskeletal afflictions each year. While new surgical techniques and rehabilitation protocols have led to improved clinical outcomes, postsurgical scarring remains the most problematic aspect of tendon repair. In contrast to this typical pattern of fibrosis, recent studies have shown that fetal tendon is capable of healing without scar. However, whether this regenerative healing pattern is intrinsic to the fetal tissue itself or the result of its environment is not known. Thus, the objective of this study is to examine the influence of an adult environment on healing in adult and fetal tendons. We hypothesized that injured fetal tendon tissue transplanted into an adult environment would retain a regenerative healing pattern after injury, demonstrating normal histological and mechanical properties. Our results support this hypothesis. Histological analyses revealed considerable alterations in adult tendon transplants after injury while fetal transplants showed no abnormalities. The injured adult tendons also demonstrated elevated levels of TGF-beta1, bFGF, and CD44 at the wound site, whereas the fetal specimens showed little or no such changes in response to injury. The data from our biomechanical studies further corroborate these observations, with significant decreases in the stiffness, modulus, and almost all viscoelastic properties in wounded versus unwounded adult tendons, and fetal specimens showing no differences in mechanical properties between the wounded and unwounded groups. Thus, the results of our investigation demonstrate that the adult environment is not an impediment to scarless repair and that this capability is intrinsic to the fetal tendon itself. Our study also begins to provide insight into the mechanisms controlling this regenerative response.
BACKGROUND: The use of the ex utero intrapartum treatment (EXIT) procedure has salvaged many fetuses with giant neck masses. Despite an adequate airway, a subset of these patients die from an inability to achieve adequate gas exchange. METHODS: We reviewed our experience with the EXIT procedure from 1996 to 2004. The EXIT was used to deliver 23 fetuses with giant neck masses. RESULTS: Three fetuses with giant cervical teratomas died of severe pulmonary hypoplasia. On postmortem, these patients had severe airway distortion by the mass. The carina was retracted superiorly to the first or second rib resulting in compression of the lungs in the apices of the chest and pulmonary hypoplasia. Hypoplasia was reflected in the lung weights of 24 vs 38 g and 17 vs 34 g for age-matched normal lung. CONCLUSIONS: Unsuspected obstructive fetal neck masses can be fatal because of an inability to secure an airway. Prenatal ultrasonography can identify fetuses at risk, allowing the fetus to be salvaged using the EXIT procedure. Despite obtaining airway control, a subset of these patients will die because of pulmonary hypoplasia. When counseling patients with large cervical masses it is important to discuss potential pulmonary hypoplasia in these patients.
Although performing procedures on a fetus before severing the umbilical cord has previously been reported, the principles of the ex utero intrapartum treatment (EXIT) procedure were first fully developed for reversing tracheal occlusion in fetuses with severe congenital diaphragmatic hernia. The EXIT procedure offers the advantage of insuring uteroplacental gas exchange while on placental support. The lessons learned in the development of the principles that underlie the EXIT procedure have improved outcomes when applied in other conditions, most notably in cases of airway obstruction. The range of indications for the EXIT procedure has expanded and currently includes giant fetal neck masses, lung or mediastinal tumors, congenital high airway obstruction syndrome, and EXIT to ECMO (extracorporeal membrane oxygenation), among others. This review summarizes the underlying principles of the EXIT procedure, the expanding indications for its use, the pitfalls of management, and the progress that has been made in its successful application.
Mesenchymal hamartoma of the chest wall is an unusual lesion remarkable for its occurrence in early infancy and alarming clinical presentation, which often suggests malignancy. Despite its aggressive appearance and propensity to attain massive size, the lesion behaves biologically in a benign fashion, and may be treated conservatively, provided that there is no respiratory compromise secondary to mass effect. The case of an incompletely resected mesenchymal hamartoma that has behaved in a benign fashion after more than 4 years of follow-up is discussed here. We present this case to provide insight and raise clinicians' awareness of the behavior of an extremely rare tumor.
BACKGROUND/PURPOSE: Mediastinal teratomas are rare congenital germ cell tumors that prenatally can compress mediastinal structures and cause hydrops. Two possible presentations of massive fetal mediastinal teratoma include hydrops leading to fetal demise, or fetal esophageal and airway compression causing late-gestation polyhydramnios and preterm labor. The authors present 2 cases of fetal mediastinal teratoma that illustrate successful strategies for either of these presentations. METHODS: A 37-year-old woman carrying a fetus with a mediastinal mass and secondary hydrops at 23 weeks of gestation underwent in utero resection of the mass. Delivery was by cesarean delivery at 25 weeks because of preterm labor. A 24-year-old mother carrying a fetus with a mediastinal mass and severe polyhydramnios at 36 weeks of gestation underwent an ex utero intrapartum therapy procedure for establishment of an airway and tumor resection on uteroplacental support. RESULTS: These strategies resulted in physiologic improvement in the first case and controlled resection and resuscitation in the second. The first patient had significant sequelae of prematurity including bronchopulmonary dysplasia but is currently well at 9 months of age. The second patient is well at 1 year of age. CONCLUSIONS: Massive fetal mediastinal teratoma can result in fetal or neonatal mortality by a variety of mechanisms. Optimal prenatal and perinatal management is required to salvage fetuses compromised by this lesion.
BACKGROUND: Indications for the ex utero intrapartum therapy (EXIT) procedure have expanded to include any fetal anomaly in which resuscitation of the neonate may be compromised. METHODS: We reviewed the medical records of 9 patients after resection of lung lesions during the EXIT procedure. RESULTS: The mean gestational age at EXIT procedure was 35.4 weeks. All lung masses maintained large sizes late into gestation with mean mass volume/head circumference ratio of 2.5 at presentation and 2.2 at EXIT. Seven of 9 fetuses demonstrated hydropic changes (n = 6) and/or polyhydramnios (n = 5), and underwent prenatal intervention including thoracentesis, thoracoamniotic shunt placement, amnioreduction, and/or betamethasone administration. Overall survival after EXIT for lung mass resection was 89%. The average time on placental bypass was 65 minutes. Postnatal complications included reoperation for air leak (n = 1), reoperation for bleeding (n = 1), and death from sepsis and prematurity (n = 1). Venoarterial extracorporeal membrane oxygenation was used in 4 neonates for persistent pulmonary hypertension. Maternal prenatal complications included polyhydramnios (n = 5), preterm labor (n = 4), and chorioamnionitis (n = 1). One mother required perioperative blood transfusion. CONCLUSION: The EXIT procedure allows for controlled resection of large fetal lung lesions at delivery, avoiding acute respiratory decompensation related to mediastinal shift, air trapping, and compression of normal lung.
Management of Twin-Twin Transfusion Syndrome (TTTS) is one of the most challenging clinical problems concerning multiple gestations. The pathophysiology of TTTS and Quintero staging system are described. The importance of fetal echocardiograms in assessing prognosis and response to therapy is highlighted. Treatment modalities, particularly amnioreduction, microseptostomy, and fetoscopic laser photocoagulation, are discussed. Questions still remain as to how various treatment options affect short- and long-term cardiac and neurodevelopmental outcomes and which patients will benefit most from selective laser photocoagulation therapy.
BACKGROUND: Prenatal surgery for congenital anomalies can prevent fetal demise or alter the course of organ development, resulting in a more favorable condition at birth. The indications for fetal surgery continue to expand, yet little is known about the acute sequelae of fetal surgery on the human cardiovascular system. METHODS AND RESULTS: Echocardiography was used to evaluate the heart before, during, and early after fetal surgery for congenital anomalies, including repair of myelomeningocele (MMC, n=51), resection of intrathoracic masses (ITM, n=15), tracheal occlusion for congenital diaphragmatic hernia (CDH, n=13), and resection of sacrococcygeal teratoma (SCT, n=4). Fetuses with MMC all had normal cardiovascular systems entering into fetal surgery, whereas those with ITM, CDH, and SCT all exhibited secondary cardiovascular sequelae of the anomaly present. At fetal surgery, heart rate increased acutely, and combined cardiac output diminished at the time of fetal incision for all groups including those with MMC, which suggests diminished stroke volume. Ventricular dysfunction and valvular dysfunction were identified in all groups, as was acute constriction of the ductus arteriosus. Fetuses with ITM and SCT had the most significant changes at surgery. CONCLUSIONS: Acute cardiovascular changes take place during fetal surgery that are likely a consequence of the physiology of the anomaly and the general effects of surgical stress, tocolytic agents, and anesthesia. Echocardiographic monitoring during fetal surgery is an important adjunct in the management of these patients.
OBJECTIVES: To review prenatal findings, short- and long-term outcomes of giant omphaloceles (GO) managed at a single institution (1996-2001). METHODS: Prenatal findings and early postnatal outcomes were retrospectively reviewed. Clinical short- and long-term outcomes were analyzed in eight and five children respectively. Parents and physicians of the children were surveyed by written questionnaires about the children's subsequent health issues. (IRB 2002-2-2683). RESULTS: Seventeen pregnancies with GO were identified: Eight fetuses were live born, four ended in (terminations), two died in utero and three were lost to follow-up. Live-born fetuses had prenatal ascites, extreme levocardia and were delivered by cesarean section at a mean of 37 weeks' gestation with a mean birth weight of 2903 g. All neonates required intubation. Two infants (2/8) died within one year. Four of the six survivors had respiratory insufficiency with a mean ventilation time of 76 days. Respiratory and feeding problems complicated the early neonatal course. Long-term follow-up was available for five patients (mean age of 33.2 months). Asthma, recurrent pulmonary infections, feeding problems, gastroesophageal reflux and failure to thrive were the major problems. CONCLUSIONS: Respiratory and feeding problems were the most common neonatal and long-term medical management issues. Parents need to be counseled prenatally about the probability of multiple surgeries and long hospitalization following birth.
OBJECTIVE: The reproductive outcomes for women after the pregnancy complicated by maternal-fetal surgery were evaluated to obtain evidence-based information for prenatal risk counseling. STUDY DESIGN: The retrospective review identified 83 women with maternal-fetal surgery from a single institution (1996-2002). These women were sent a consent form and a questionnaire to document postoperative problems, fertility, obstetric outcomes, and psychosocial concerns in pregnancy after the index fetal therapy. Institutional Review Board approval was obtained from Committee for Protection of Human Subjects. RESULTS: The total return rate was 55 (66%). The pregnancy rate was 62% (18% spontaneous abortion, 24% preterm delivery, and 58% term delivery). Complications were reported in 12 of 34 pregnancies (35%), including uterine dehiscence/rupture (12%/6%), cesarean hysterectomy (3%), and antepartum hemorrhage requiring transfusion (9%). CONCLUSION: The reproductive outcome of uterine dehiscence, rupture, and hysterectomy was 12%, 6%, and 3%, respectively, after a pregnancy complicated by maternal-fetal surgery. The uterine rupture rate is similar to the rupture rate after "classical" cesarean section (4%-9%).
PURPOSE: To understand the natural history and define indications for fetal intervention in sacrococcygeal teratoma (SCT), the authors reviewed all cases of fetal SCT presenting for evaluation. METHODS: Prenatal diagnostic studies including ultrasound scan, magnetic resonance imaging (MRI), echocardiography and pre- and postnatal outcomes were reviewed in 30 cases of SCT that presented between September 1995 and January 2003. RESULTS: The mean gestational age (GA) at presentation was 23.9 weeks (range, 19 to 38.5) with 3 sets of twins (10%). Overall outcomes included 4 terminations, 5 fetal demises, 7 neonatal deaths, and 14 survivors. Significant obstetric complications occurred in 81% of the 26 continuing pregnancies: polyhydramnios (n = 7), oligohydramnios (n = 4), preterm labor (n = 13), preeclampsia (n = 4), gestational diabetes (n = 1), HELLP syndrome (n = 1), and hyperemesis (n = 1). Fetal intervention included cyst aspiration (n = 6), amnioreduction (n = 3), amnioinfusion (n = 1), and open fetal surgical resection (n = 4). Indications for cyst aspiration and amnioreduction were maternal discomfort, preterm labor, and prevention of tumor rupture at delivery. Although 15 SCTs were solid causing risk for cardiac failure, only 4 fetuses met criteria for fetal debulking based on ultrasonographic and echocardiographic evidence of impending high output failure and favorable anatomy at 21, 23.6, 25, and 26 weeks' gestation. Intraoperative events included maternal blood transfusion (n = 1), fetal blood transfusion (n = 2), chorioamniotic membrane separation (n = 2), and fetal arrest requiring successful cardiopulmonary resuscitation (CPR) (n = 1). In the fetal resection group, 3 of 4 survived with mean GA at delivery of 29 weeks (range, 27.6 to 31.7 weeks), mean birth weight of 1.3 kg, hospital stay ranging from 16 to 34 weeks, and follow-up ranging from 20 months to 6 years. Postnatal complications in the fetal surgery group included neonatal death (n = 1, secondary to premature closure of ductus arteriosus with cardiac failure), embolic event (n = 1, resulting in unilateral renal agenesis, jejunal atresia), chronic lung disease (n = 1), and tumor recurrence (n = 1). CONCLUSIONS: For fetal SCT, the rapidity at which cardiac compromise can develop and the high incidence of obstetric complications warrant close prenatal surveillance. Amnioreduction, cyst aspiration, and surgical debulking are potentially life-saving interventions.
PURPOSE: To understand the natural history of right congenital diaphragmatic hernia (CDH), the authors retrospectively reviewed 27 cases of right CDH that presented for prenatal evaluation or postnatal treatment. METHODS: Between 1995 and September 2002, a total of 194 cases of fetal CDH were evaluated and included 22 right-sided defects. The authors reviewed prenatal diagnostic studies (ultrasound scan, magnetic resonance imaging [MRI] echocardiography) and pre- and postnatal outcomes in these 22 cases of right CDH. Five additional cases of right CDH without a prenatal diagnosis were reviewed. RESULTS: The mean gestational age at evaluation was 26.1 weeks. The lung area to head circumference ratio (LHR) ranged from 0.32 to 2.5. In all cases, the fetal liver was herniated into the right chest. Associated anomalies were common. There were no karyotype abnormalities (17 of 22 tested). There were 4 terminations. Nine of the 18 (50%) continuing pregnancies had polyhydramnios, premature rupture of membranes, or preterm labor. The mean gestational age at birth was 36.8 weeks. One patient underwent tracheal occlusion at 27 weeks, and 2 patients died before postnatal repair. Overall survival rate (22 prenatal plus 5 postnatal diagnoses) was 19 of 27 (70%). Postnatal survival rate was 19 of 23 (83%). A Gore-tex (W. L. Gore and Associates, Flagstaff, AZ) patch was utilized in 14 of 21 neonates undergoing surgery. Twelve of 23 (52%) required extracorporeal membrane oxygenation (ECMO) with a 75% survival rate. Significant morbidity occurred in 10 of 19 survivors and included neurologic sequelae in 6 of 19 (32%). CONCLUSIONS: MRI was helpful in the determination of liver position and confirmation of diagnosis. The high incidence of preterm complications, frequent need for ECMO, and high prevalence of comorbidities are indicative of the severity of this CDH population and warrant close prenatal surveillance and delivery at a tertiary care center with ECMO capability.
A 6-year-old girl sustained an unusual constellation of injuries after blunt trauma sustained in a motor vehicle accident. Transection of the trachea and esophagus were managed successfully by repair through a median sternotomy while the patient was on cardiopulmonary bypass. A cervical spinal injury was fixated with halo traction and a femur fracture with internal fixation.
Gene transfer to the tracheobronchial tree has been an active area of investigation since the discovery of the genetic defect in the cystic fibrosis transmembrane conductance regulator over two decades ago. Cystic fibrosis (CF) is the most common lethal monogeneic disorder for which there is no cure short of lung transplantation. The ultimate goal of gene therapy in CF is to achieve efficient gene transfer at a level and distribution in target tracheobronchial epithelial cells and submucosal gland cells, which results in the genotypic and phenotypic correction of CF. This article reviews the current challenges and limitations of postnatal gene therapy to the tracheobronchial tree, and the potential advantages of fetal gene therapy for CF. We review recent work with novel viral vectors to achieve extremely efficient gene transfer in target cells in the respiratory epithelium and submucosal glands in models that are representative of the developing human fetal trachea. Finally, we will examine the prospects for, limitations of, and regulatory challenges facing the translation of fetal gene therapy from research to clinical application.
These experiments evaluate the efficacy of a demineralized bone matrix putty engineered as a hybrid construct for sustained, site-directed gene transfer using an adenoviral vector. In vitro experiments were performed to evaluate the optimal dosing for gene transfer to fetal calvarial osteoblasts and dural cells and for the sustainability of gene transfer from the hybrid constructs. In the dosing experiments, hybrid constructs were created by combining 0.5 mL of demineralized bone matrix putty (DBX; SYNTHES Maxillofacial, Monument, CO) with 1 x 10(8), 1 x 10(7), or 1 x 10(6) particle-forming units (PFU) of an adenoviral vector carrying the gene encoding green fluorescent protein (AdGFP). These constructs were then placed in direct contact, or in transwell coculture, with fetal murine calvarial osteoblasts or dural cells at a multiplicity of infection (MOI = viral particle/cell ratio) of 1000, 100, and 10. The sustainability of gene transfer was tested through transfer of the hybrid construct to wells containing untransfected cells every 24 hours for 30 days. In both experiments, gene transfer was determined through the visualization of GFP using fluorescence light microscopy 24 hours after the onset of transfection. Optimal dosing for gene transfer occurred at an MOI of 10 for calvarial osteoblasts and 100 for dural cells. At greater concentrations, toxicity was observed in the majority of samples. Gene transfer to fetal dural cells and calvarial osteoblasts was sustained throughout the 30-day period. These experiments suggest that adenoviral vectors could be successfully incorporated within demineralized bone matrix to provide effective, sustained, site-directed gene transfer.
BACKGROUND/PURPOSE: Postnatal gene transfer in respiratory epithelium has been inefficient, particularly in submucosal gland cells, the target cells for cystic fibrosis transmembrane regulator (CFTR) gene transfer in cystic fibrosis. The authors hypothesized that fetal tracheobronchial epithelium may be more receptive to gene transfer in that precursor cells of the respiratory epithelium may be more accessible. METHODS: Vesicular stomatitis virus-G (VSV-G) pseudotyped lentiviral vector was first tested in human fetal tracheal organ culture then validated in a human fetal tracheal xenograft model in severe combined immunodeficiency (SCID) mice. Between 7 x 10(7) and 1.6 x 10(8) transducing units of lentiviral vector encoding the transgene LacZ under the control of the human CMV promoter were administered onto the lumenal surface of the xenografts (n = 6). Biopsy specimens were taken from the xenografts at one month (n = 1), 2 months (n = 2), 3 months (n = 1), 6 months (n = 4), and 9 months (n = 1) after vector administration. Analysis of transgene expression was performed on X-gal stained sections. RESULTS: Transgene expression was observed in 20.2% to 99% of the surface epithelial cells (mean, 70.8 +/- 32.3% SD) and in 28.4% to 99% of the submucosal gland cells (mean, 68.5 +/- 26.2% SD) out to 9 months after vector administration in the tracheal xenografts, equivalent to 63 weeks postconceptual age. No staining was seen in the controls. CONCLUSIONS: Excellent gene transfer in human fetal tracheal xenografts after VSV-G pseudotyped lentiviral vector administration, which may result from more accessible target precursor cells during development, suggests the feasibility of fetal gene therapy for the treatment of congenital airway disease such as cystic fibrosis.
The natural history of extremity amniotic band syndrome (ABS) is a progression to deformity or amputation. Fetoscopic laser release of amniotic bands in extremity ABS offers the potential to prevent limb amputation. The authors report on 2 patients with isolated extremity ABS who underwent fetoscopic release. Both patients had isolated extremity ABS with compromised extremity perfusion and no other significant structural abnormality diagnosed sonographically. The first patient underwent fetoscopic release of bands of the left wrist, and the second patient underwent lysis of bands around the right wrist and an unsuspected band around the right lower extremity. Both patients had restoration of blood flow by color Doppler to the affected extremity. There were no perioperative complications. In select patients with isolated extremity ABS, early fetoscopic release may prevent amputation and allow improved limb development.