Aligning tumor mutational burden (TMB) quantification across diagnostic platforms: phase II of the Friends of Cancer Research TMB Harmonization Project.

BACKGROUND: Tumor mutational burden (TMB) measurements aid in identifying patients who are likely to benefit from immunotherapy; however, there is empirical variability across panel assays and factors contributing to this variability have not been comprehensively investigated. Identifying sources of variability can help facilitate comparability across different panel assays, which may aid in broader adoption of panel assays and development of clinical applications. MATERIALS AND METHODS: Twenty-nine tumor samples and 10 human-derived cell lines were processed and distributed to 16 laboratories; each used their own bioinformatics pipelines to calculate TMB and compare to whole exome results. Additionally, theoretical positive percent agreement (PPA) and negative percent agreement (NPA) of TMB were estimated. The impact of filtering pathogenic and germline variants on TMB estimates was assessed. Calibration curves specific to each panel assay were developed to facilitate translation of panel TMB values to whole exome sequencing (WES) TMB values. RESULTS: Panel sizes >667 Kb are necessary to maintain adequate PPA and NPA for calling TMB high versus TMB low across the range of cut-offs used in practice. Failure to filter out pathogenic variants when estimating panel TMB resulted in overestimating TMB relative to WES for all assays. Filtering out potential germline variants at >0% population minor allele frequency resulted in the strongest correlation to WES TMB. Application of a calibration approach derived from The Cancer Genome Atlas data, tailored to each panel assay, reduced the spread of panel TMB values around the WES TMB as reflected in lower root mean squared error (RMSE) for 26/29 (90%) of the clinical samples. CONCLUSIONS: Estimation of TMB varies across different panels, with panel size, gene content, and bioinformatics pipelines contributing to empirical variability. Statistical calibration can achieve more consistent results across panels and allows for comparison of TMB values across various panel assays. To promote reproducibility and comparability across assays, a software tool was developed and made publicly available.

The roles of HOXD10 in the development and progression of head and neck squamous cell carcinoma (HNSCC).

BACKGROUND: HOX gene expression is altered in many cancers; previous microarray revealed changes in HOX gene expression in head and neck squamous cell carcinoma (HNSCC), particularly HOXD10. METHODS: HOXD10 expression was assessed by qPCR and immunoblotting in vitro and by immunohistochemistry (IHC) in tissues. Low-expressing cells were stably transfected with HOXD10 and the phenotype assessed with MTS, migration and adhesion assays and compared with the effects of siRNA knockdown in high-HOXD10-expressing cells. Novel HOXD10 targets were identified using expression microarrays, confirmed by reporter assay, and validated in tissues using IHC. RESULTS: HOXD10 expression was low in NOKs, high in most primary tumour cells, and low in lymph node metastasis cells, a pattern confirmed using IHC in tissues. Overexpression of HOXD10 decreased cell invasion but increased proliferation, adhesion and migration, with knockdown causing reciprocal effects. There was no consistent effect on apoptosis. Microarray analysis identified several putative HOXD10-responsive genes, including angiomotin (AMOT-p80) and miR-146a. These were confirmed as HOXD10 targets by reporter assay. Manipulation of AMOT-p80 expression resulted in phenotypic changes similar to those on manipulation of HOXD10 expression. CONCLUSIONS: HOXD10 expression varies by stage of disease and produces differential effects: high expression giving cancer cells a proliferative and migratory advantage, and low expression may support invasion/metastasis, in part, by modulating AMOT-p80 levels.

Gingipain-dependent degradation of mammalian target of rapamycin pathway proteins by the periodontal pathogen Porphyromonas gingivalis during invasion.

Porphyromonas gingivalis and Tannerella forsythia are gram-negative pathogens strongly associated with periodontitis. Their abilities to interact, invade and persist within host cells are considered crucial to their pathogenicity, but the mechanisms by which they subvert host defences are not well understood. In this study, we set out to investigate whether P. gingivalis and T. forsythia directly target key signalling molecules that may modulate the host cell phenotype to favour invasion and persistence. Our data identify, for the first time, that P. gingivalis, but not T. forsythia, reduces levels of intracellular mammalian target of rapamycin (mTOR) in oral epithelial cells following invasion over a 4-h time course, via the action of gingipains. The ability of cytochalasin D to abrogate P. gingivalis-mediated mTOR degradation suggests that this effect is dependent upon cellular invasion. We also show that levels of several other proteins in the mTOR signalling pathway are modulated by gingipains, either directly or as a consequence of mTOR degradation including p-4E-BP1. Taken together, our data suggest that P. gingivalis manipulates the mTOR pathway, providing evidence for a potentially novel mechanism by which P. gingivalis mediates its effects on host cell responses to infection.

Effects of plate location and selection on the stability of midshaft clavicle osteotomies: a biomechanical study.

Operative fixation of midshaft clavicle fractures is controversial with few biomechanical data to assist surgical decision making. The purpose of this 2-phase biomechanical investigation is to report on the effects of plate location and selection on the stability of midshaft clavicle fractures. Thirty matched pairs of human adult formalin-fixed clavicles were used. In the first phase, in which a 3.5-mm reconstruction plate and simulated midshaft transverse clavicle osteotomies were used, we observed the effect of superior plate placement compared with anterior placement on fracture rigidity, construct stiffness, and strength. In the second phase, in which simulated midshaft oblique clavicle osteotomies were repaired on the superior aspect, we compared the fracture rigidity, construct stiffness, and strength of the 3.5-mm reconstruction, 3.5-mm limited contact dynamic compression (LCDC), and 2.7-mm dynamic compression (DC) plates. Intact clavicles were prepared, potted, and tested for axial and torsional stiffness in an Instron test frame equipped with gimbaled fixtures. Clavicles were band-sawed to simulate an osteotomy, repaired, re-mounted on the test frame with shear and opening extensometers placed across the osteotomy site, and then tested to observe axial and torsional fracture rigidity and stiffness. Constructs were then loaded to failure in compression. First-order regressions were used to estimate fracture rigidity (in kilonewtons per millimeter)and retained construct stiffness (in kilonewtons per millimeter), whereas the maximum applied compressive load at collapse or gross deformation determined the failure load. Values for the comparisongroups were tested for significance at the 95% confidence level. In the first phase we found that constructs plated at the superior aspect of the clavicle exhibited significantly greater fracture rigidity and mean retained stiffness than the anterior location (P <.05). In the second phase we found that the torsional fracture rigidity of LCDC-plated constructs significantly exceeded that of the reconstruction and DC plates (P <.05), whereas the axial fracture rigidity of the LCDC-plated constructs significantly exceeded that of the reconstruction plate (P <.05). In retained stiffness the performance of the LCDC-plated constructs significantly exceeded that of the DC plate in torsion (P <.05), whereas in load to failure the LCDC plate withstood significantly more compressive load than the reconstruction plate (P <.05). We concluded that clavicles plated at the superior aspect exhibit significantly greater biomechanical stability than those plated at the anterior aspect. Furthermore, we concluded that the LCDC plate offers significantly greater biomechanical stability than the reconstruction and DC plates.

Recovery of locomotion correlated with axonal regeneration after a complete spinal transection in the eel.

This research has examined the relationship between axonal regeneration and the return of normal movement following complete transection of the spinal cord. We made measurements of tail beat frequency and amplitude of the caudal body wave from video recordings of eels (Anguilla anguilla) swimming in a water tunnel at several speeds. Each eel was then anaesthetised and the spinal cord cut caudal to the anus; in some animals the resulting gap was filled with a rubber block. All animals were kept at 25 degrees C for recovery periods ranging from 7 to 128 days, during which their swimming performance was monitored regularly. Each fish was then re-anaesthetised and perfused with fixative and the regrowing descending axons labelled with 1,1'-diotadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate. For all animals and at all speeds after surgery, tail beat frequency increased, while amplitude decreased. In non-blocked animals, an improvement in performance was first seen from 8 days following transection and thereafter tail beat frequency decreased progressively until it had returned to normal after 35 to 45 days, while amplitude remained below baseline until at least 45 days. In these animals, few axonal growth cones had penetrated the caudal stump by 7 days, but some had extended as much as 3 mm by 15 days. Many had reached as far as 6 mm between 25 and 36 days, while by 128 days they had progressed up to 10.5 mm. Contralateral crossing was never observed. Functional recovery was never witnessed in animals in which the cord had been blocked and these eels swam at all times with elevated tail beat frequency and reduced caudal amplitude. No labelled axons could be traced into the caudal spinal cord at any recovery stage in such animals. We conclude that re-innervation of only 1-2 segments caudal to the injury is necessary for functional recovery, although continued axonal growth may be important for the refinement of some aspects of movement.

Severe blunt hepatic trauma in children.

BACKGROUND: Severe blunt hepatic injury in children is associated with a high mortality rate. Although nonoperative management has become the treatment of choice for mild to moderate liver trauma, there is no consensus as to the optimal treatment for the most severe hepatic injuries in children. METHODS: A statewide trauma registry was reviewed to identify children (age 18 years or less) treated for a severe blunt liver injury for the period 1993 to 1998. Only children with an American Association for the Surgery of Trauma grade V (AIS code 541828.5) liver injury were included. Database records were reviewed for demographic information, associated injuries, survival rate, length of stay (LOS), intensive care days (ICUD), and treatment rendered after resuscitation in the emergency department. RESULTS: Thirty children with a grade V liver injury were identified. The mean age was 11.2 years (range, 1 to 18), and the overall survival rate was 56%. Data for 5 patients were excluded (4 patients died in the emergency department, and 1 patient was transferred to another institution after arrival). Survivors had a trend toward a lower injury severity score (ISS) (36.1 v 44.6; P <.1) and a significantly higher Glasgow Coma Scale (GCS), 12.5 v 6.6; P <.007). Patients with a decreased GCS had a lower overall survival rate (GCS < 8, 30% v GCS > 8, 76%). In the subset of 14 patients taken directly to the operating room, there was no difference between survivors (n = 6, 43%) and nonsurvivors (n = 8, 57%) in ISS (43 v 43; P value, not significant) or GCS (8.6 v 8.0; P value, not significant). Of the 11 patients treated nonoperatively, 10 (91%) survived with an average ISS of 33 and GCS of 13.8. Nonsurvivors more often had identified associated injuries to other abdominal and retroperitoneal organs. CONCLUSIONS: Severe hepatic injury is associated with a very high overall mortality rate in children. A low GCS is associated with a significant decrease in survival rate and may be the most important factor in outcome. Patients taken directly to the operating room have a slightly greater injury severity and a decreased survival rate compared with those treated nonoperatively. Thresholds and indications for laparotomy in these patients are not clear, and the need for operative management should be guided by the child's physiologic response to resuscitation. For those patients whose physiologic response to resuscitation permitted nonoperative management, a good outcome was achieved.

Predicting hollow visceral injury in the pediatric blunt trauma patient with solid visceral injury.

BACKGROUND: Nonoperative management of a solid organ injury (SVI) is accepted in the stable pediatric trauma patient. A concern with nonoperative management is missing a hollow visceral injury (HVI). Factors that may help predict HVI have not been well documented. METHODS: The National Pediatric Trauma Registry was reviewed for the period October 1988 through September 1998 for all blunt injured, hemodynamically stable pediatric patients (age < or =12 years) with an SVI (kidney, liver, pancreas, spleen) of Abbreviated Injury Scale (AIS) score > or =2. HVIs included AIS > or =2 gastrointestinal tract injuries. RESULTS: For the decade of review, 2,977 pediatric patients sustained an SVI, including 96 with an HVI (3.2%). The mean age was 6.6 years, with a mean Injury Severity Score of 12.4. An occupant in a motor vehicle accident was the most common injury mechanism (30.4%), but assault was the most likely to result in an HVI (11.5%). The liver was the most common SVI (n = 1,400), the spleen the least likely to have an associated HVI (2.5%). Pancreatic injuries had a higher rate of HVI (P < .001). The majority of patients had a single SVI (n = 2,507) with 71 associated HVIs (2.8%). The risk of associated HVI increased as the number of solid organs injured increased: 4.7% with 2 organs, 13.5% if 3 organs were injured (P< .001). In patients with a single SVI, the rate of HVI did not differ as AIS increased (range, 2.7% to 6.5%, Pvalue not significant). CONCLUSIONS: The overall rate of HVI was low (3.2%). Higher rates of HVI were found in assaulted patients and patients with multiple SVIs or pancreatic injuries. The risk of associated HVI was dependent more on number of SVIs than severity of the individual organ injury. This data suggest that nonoperative management is justified in the patient with a single SVI but should be used cautiously in the patient with multiple SVI or a pancreatic injury.

Sequence and phylogenetic analysis of squid myosin-V: a vesicle motor in nerve cells.

We have shown that vesicles in the axoplasm of the squid giant axon move on actin filaments and that movement is inhibited by myosin V-specific antibodies [Tabb et al., 1998]. In the study reported in this article, experiments were performed to clone and sequence the cDNA for squid brain myosin V. Five proteolytic fragments of purified squid brain myosin V were analyzed by direct protein sequencing [Tabb et al., 1998]. Based on this sequence information, degenerate primers were constructed and used to isolate cDNA clones by PCR. Five clones, representing overlapping segments of the gene, were sequenced. The sequence data and the previous biochemical characterization of the molecule support the classification of this vesicle-associated myosin as a member of the class V myosins. Motif analysis of the head, neck, and tail domains revealed that squid MyoV has consensus sequences for all the motifs found in vertebrate members of the myosin V family of motor proteins. A phylogenetic tree was constructed from a sequence alignment by the neighbor-joining method, using Megalign (DNAStar, Madison, WI); the resulting phylogenetic tree showed that squid MyoV is more closely related to vertebrate MyoV (mouse dilute, chicken dilute, rat myr6, and human myo5a) than Drosophila and yeast (myo2, and myo4) myosins V. These new data on the phylogenetic relationships of squid myosin V to vertebrate myosin V strengthens the argument that myosin V functions as a vesicle motor in vertebrate neurons.

Rat8p/Dbp5p is a shuttling transport factor that interacts with Rat7p/Nup159p and Gle1p and suppresses the mRNA export defect of xpo1-1 cells.

In a screen for temperature-sensitive mutants of Saccharomyces cerevisiae defective for mRNA export, we previously identified the essential DEAD-box protein Dbp5p/Rat8p and the nucleoporin Rat7p/Nup159p. Both are essential for mRNA export. Here we report that Dbp5p and Rat7p interact through their Nterminal domains. Deletion of this portion of Rat7p (Rat7pDeltaN) results in strong defects in mRNA export and eliminates association of Dbp5p with nuclear pores. Overexpression of Dbp5p completely suppressed the growth and mRNA export defects of rat7DeltaN cells and resulted in weaker suppression in cells carrying rat7-1 or the rss1-37 allele of GLE1. Dbp5p interacts with Gle1p independently of the N-terminus of Dbp5p. Dbp5p shuttles between nucleus and cytoplasm in an Xpo1p-dependent manner. It accumulates in nuclei of xpo1-1 cells and in cells with mutations affecting Mex67p (mex67-5), Gsp1p (Ran) or Ran effectors. Overexpression of Dbp5p prevents nuclear accumulation of mRNA in xpo1-1 cells, but does not restore growth, suggesting that the RNA export defect of xpo1-1 cells may be indirect. In a screen for high-copy suppressors of the rat8-2 allele of DBP5, we identified YMR255w, now called GFD1. Gfd1p is not essential, interacts with Gle1p and Rip1p/Nup42p, and is found in the cytoplasm and at the nuclear rim.

Pediatric splenic injury: pathway to play?

BACKGROUND: Nonoperative management of blunt splenic injury (BSI) remains a "gold standard" in pediatric trauma care. Controversy exists regarding the minimal hospital stay necessary for the care of these patients and the appropriate duration of reduced activity required after discharge. METHODS: A clinical pathway was developed in an attempt to standardize the hospital and outpatient management of children with BSI cared for at the Children's Hospital of Philadelphia. From July 1, 1996 to September 30, 1997, all children with BSI were treated using this pathway (pathway group). To better evaluate outcome, data were compared with an historical control of consecutive children treated at our institution during the previous 2 years (control group). RESULTS: Twenty-eight children in the control group and 21 children in the pathway group comprise the study population. Average age, injury mechanism, grade of splenic injury, injury severity score, length of intensive care unit stay, and number of transfusions were not significantly different between the two groups (P<.05). As expected, there was a significant decrease in the length of stay on the general care units (5.3+/-1.2 v 2.9+/-0.9 days, control v pathway, P<.05), which, in turn, resulted in a significant decrease in the total length of hospitalization (6.7+/-1.4 v 3.9+/-1.2 days, P<.05) and estimated hospital charges. During follow-up, no complications or missed injuries were identified at a standard 3-week and the 3-month office visit. CONCLUSION: Hemodynamically stable children with isolated blunt splenic injuries may be treated safely with a 4-day hospital stay followed by 3 weeks of quiet activities at home and 3 months of light activity before return to full, unrestricted activity.

Ovarian masses in the pediatric patient.

Ovarian masses in the pediatric patient are uncommon. Children with ovarian tumors, however, pose diagnostic and therapeutic challenges because their presentation can mimic other more common intraabdominal disorders and their tumor histology varies widely. The refinement of surgical techniques and the advent of more effective chemotherapy in the past 25 years has increased overall survival rates from approximately 20% to 70%, thus improving the outcome for girls with malignant tumors. This article summarizes the current evaluation and management of ovarian masses in childhood and reviews pertinent pathology.

Firearm injury among urban youth during the last decade: an escalation in violence.

PURPOSE: To better characterize firearm violence in urban youth, the authors investigated the circumstances and outcome of shootings among youths under 17 years of age. METHODS: A retrospective case review was undertaken of all patients under 17 years of age treated for a gunshot wound at two adjoining level I Trauma Centers (adult and pediatric) administering to a predominantly lower socioeconomic population from January 1986 to December 1995. Demographics, injury severity, circumstances, and outcome of injury were analyzed. RESULTS: 323 youths were wounded by firearms. The mean age was 12.8 years, and 82.3% were boys. There was a 110% increase in frequency of wounding noted during the second half of study (219 v 104), predominantly in the adolescent subset (160% increase for age greater than 12 years v 30% increase for age 12 years and under). The mean injury severity score and trauma score were 9.3 and 14.4, respectively. Violent circumstances (assault, crossfire, drive-by shooting, suicide) accounted for 60.4% of injuries and more than doubled over the study period (26.7% of total in the first 2 years [n = 4], 68.8% in the last 2 years [n = 55]). Unintentional injuries (self nonsuicide, family, friend) accounted for 26.3% of the injuries and declined in relative frequency over the study period (46.7% of total in the first 2 years [n = 7], 20.0% in the last 2 years [n = 16]). Black boys had the highest wounding incidence (9.2/1,000 population), were most commonly injured by assault (29.0%), and had a higher mean number of wounds (1.8). White boys had a lower wounding incidence (3.1/1,000 population), were more often injured unintentionally by a friend (41.2%), and had a lower mean number of wounds (1.3), none as a result of violence. Girls had a wounding incidence of less than 2/1,000 and were most commonly injured in crossfire (40.7%). Ten percent of shootings were fatal. The assailant was known to the victim in 52.8% of children less than 6 years of age, but only 24.7% of children over 12 years of age. CONCLUSIONS: The incidence of gunshot wounds in the youth of this urban population has increased substantially over the past decade. Adolescent black boys were the most frequent victims of these shootings. There has been a disproportionate growth in violent circumstances surrounding the shootings.

Cystic lung lesions with systemic arterial blood supply: a hybrid of congenital cystic adenomatoid malformation and bronchopulmonary sequestration.

Congenital cystic adenomatoid malformation and bronchopulmonary sequestration are congenital lung tumors that are classically described as having distinct embryology, pathology, and natural history. The authors treated six patients who had prenatally diagnosed lung masses that displayed clinicopathologic features of both lesion types. At prenatal diagnosis (19 to 30 weeks' gestation), all six lesions were classified sonographically as congenital cystic adenomatoid malformation, and none of the masses appeared to have a systemic arterial blood supply as seen by color flow Doppler study. Two of the six masses showed size regression antenatally. At the time of surgery, all six lesions had a systemic vessel directly from the aorta--five cases were consistent grossly with an intralobular bronchopulmonary sequestration, and one case was consistent with an extralobular bronchopulmonary sequestration. However, all six lesions displayed congenital cystic adenomatoid malformation histology. Hydrops developed in one fetus with a huge mass, and that fetus underwent successful fetal surgical resection (left lower lobectomy) at 22 weeks' gestation with delivery at 35 weeks' gestation. One neonate with a large extralobular bronchopulmonary sequestration was treated with resection and extracorporeal membrane oxygenation (ECMO) but died of pulmonary hypoplasia. Four other patients who had much smaller masses underwent elective lower lobectomy after birth. These findings emphasize the importance of seeking an anomalous blood supply in patients who have congenital lung lesions. These "hybrid" cases suggest a similar embryological origin for congenital cystic adenomatoid malformation and bronchopulmonary sequestration.

Conservative management of pancreatic trauma in children.

Many adults and most children with a solid-organ abdominal injury can be managed nonoperatively. To date, however, little is known about the outcome of nonoperative management of pancreatic injury. To analyze current treatment patterns of pancreatic injury in children, all children (age < 19 years) identified in the National Pediatric Trauma Registry (49,540 patients) and admitted to two level I pediatric trauma centers with a diagnosis of injury to the pancreas (International Classification of Disease-9 codes 863.81-863.84 and 863.91-863.94) were reviewed. Over a 7-year period, 154 children were identified with pancreatic injury. Thirty-one (20%) sustained severe injuries (grades III, IV, or V) and 123 (80%) sustained lower-grade injuries (grades I and II). Sixteen (52%) of the children sustaining grades III, IV, or V injury required pancreatic procedures (9 distal resections, 3 simple repairs, 2 enteric anastomoses, 2 others). Only 26 (21%) of the grades I and II injuries required surgical intervention specific to the pancreas (11 resections, 9 catheter drainage of pseudocysts, 2 enteric anastomoses, 4 others). Ninety-seven (79%) grades I and II injuries were successfully managed conservatively. Overall, 15 (10%) children required drainage procedures for pseudocyst. The frequency of operative intervention decreased during the last 4 years of the study (18 vs. 26%, p > 0.05), coinciding with a decrease in the frequency of drainage procedures for pseudocysts. The need for surgical intervention was not influenced by age, Injury Severity Score, or Pediatric Trauma Score (p > 0.05). Associated abdominal injuries were common but did not influence operations on the pancreas (p > 0.05). No deaths were attributed to the pancreatic injury. These data indicate that early intervention for pancreatic injury, in the absence of clinical deterioration or major ductal injury (grades III, IV, or V), is unwarranted, and careful observation may supplant the conventional surgical therapy recommended for adults.

Signal averaged P wave compared with standard electrocardiography or echocardiography for prediction of atrial fibrillation after coronary bypass grafting.

OBJECTIVE: To define the clinical value of the signal averaged P wave (SAPW) and to compare it with the standard electrocardiogram (ECG), echocardiogram, and clinical assessment for the prediction of atrial fibrillation after coronary bypass grafting (CABG). DESIGN: Prospective validation cohort study. SETTING: Regional cardiothoracic centre. PATIENTS: 201 unselected patients undergoing first elective CABG were recruited over six months. Patients requiring concomitant valve surgery were excluded. MAIN OUTCOME MEASURES: Age, sex, cardiothoracic ratio, and cardioactive drugs were noted. P wave specific SAPW recordings, ECG, and M mode echocardiograms from which left atrial diameter was measured were performed within 24 hours of surgery. Filtered P wave duration (SAPWD), spatial velocity, and energy were calculated from the SAPW. From the ECG, lead II P wave duration, P terminal force in lead V1, total P wave duration, and isoelectric interval were measured. Patients had Holter monitoring for 48 hours postoperatively and daily ECGs until discharge. RESULTS: Two patients died (1%) and 10 were unsuitable for analysis (5%). Of the remaining 189, 51 (27%) had atrial fibrillation (AF) lasting > 1 hour at a mean of 2 (0.5 to 7) days after CABG. Of the variables examined, only SAPWD (AF group 148 (SD 12), v 142 (14) ms, P = 0.008) and male sex (AF group 96%, v 78%, P < 0.01) were significantly different. A prospectively defined SAPWD of > 141 ms predicted atrial fibrillation with positive and negative predictive accuracies of 34% and 83%. Logistic regression analysis identified both male sex and SAPWD as significant independent predictors of postoperative atrial fibrillation. CONCLUSIONS: Signal averaged P wave duration was a better predictor of atrial fibrillation after coronary bypass grafting than standard electrocardiographic or echocardiographic criteria. The predictive value of this test is such that it is likely to be useful in the design of prospective trials of prophylactic antiarrhythmic treatment but is of limited use using current techniques in the clinical management of individual patients.

Esophageal replacement using the colon: is it a good choice?

Thirty-eight children (2 months to 26 years of age) underwent esophageal replacement at our institution between 1962 and 1993. Twenty-four patients had esophageal atresia, with the replacement performed at a mean age of 17 months. The remaining patients (37%) had strictures and were older (mean, 7.4 years). Replacement procedures involved the right colon in 61% of cases and the transverse left colon in the others (39%). Sixty-three percent were placed substernally and 37% were done in transthoracic fashion. The average length of stay in the hospital was 34 days (range, 11 to 256 days.) Early complications (within 30 days) included cervical anastomotic leaks (11 patients; 29%) pneumonia (4), would infection (2), pneumothorax/hemothorax (3), wound dehiscence (1), prolonged ventilation (2), vocal cord paralysis (1), Horner's syndrome (1), pancreatitis (1), and perforated graft (1). Despite the incidence of early leaks, only two persisted long-term (more than 3 months). Other late complications included significant proximal strictures (5), and cologastric strictures developed in five patients. Seven cases were considered graft failures (18%), and all of these eventually require graft replacement. Additional problems included redundant graft requiring revision (4) and dumping syndrome (2). There were six cases of intestinal obstruction caused by adhesions. Four of these involved intrathoracic obstruction of the graft and two involved small bowel obstruction. There was only one death, which occurred late and was not related to the primary disease or procedure. Long-term follow-up data were available for 20 patients (53%). The follow-up period ranged from 1 to 33 years (mean, 12 years). Fourteen had excellent results after the initial interposition, being able to eat and function well without any further intervention. Seven patients (18%) have had poor results and 17 (45%) required additional procedures to obtain good functional results. In our experience, the colon continues to be a good option for esophageal replacement, but additional procedures frequently are necessary to optimize the functional outcome. Good results can be expected in the majority of cases, but late problems (ie, redundant colon and poor emptying) are not unusual, and careful follow-up is essential in the management of such patients.