Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications.

More than one million patients will manifest colorectal cancer (CRC) this year of which, conservatively, approximately 3% (approximately 30,700 cases) will have Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome. Each case belongs to a family with clinical needs that require genetic counseling, DNA testing for mismatch repair genes (most frequently MLH1 or MSH2) and screening for CRC. Colonoscopy is mandated, given CRC's proximal occurrence (70-80% proximal to the splenic flexure). Due to its early age of onset (average 45 years of age), colonoscopy needs to start by age 25, and because of its accelerated carcinogenesis, it should be repeated every 1 to 2 years through age 40 and then annually thereafter. Should CRC occur, subtotal colectomy may be necessary, given the marked frequency of synchronous and metachronous CRC. Because 40-60% of female patients will manifest endometrial cancer, tailored management is essential. Additional extracolonic cancers include ovary, stomach, small bowel, pancreas, hepatobiliary tract, upper uroepithelial tract, brain (Turcot variant) and sebaceous adenomas/carcinomas (Muir-Torre variant). LS explains only 10-25% of familial CRC.

Carrier risk status changes resulting from mutation testing in hereditary non-polyposis colorectal cancer and hereditary breast-ovarian cancer.

CONTEXT: In hereditary cancer syndrome families with an identified cancer associated mutation, mutation testing changes the carrier risk status of the tested person and may change the carrier risk status of relatives. OBJECTIVE: This study aimed to describe the change in the distribution of carrier risk status resulting from testing in hereditary breast-ovarian cancer (HBOC) and hereditary non-polyposis colorectal cancer (HNPCC) families. DESIGN: This was an observational cohort study. PATIENTS: The cohort included members of 75 HBOC and 47 HNPCC families. Of the 10 910 cohort members, 1408 were tested for a mutation and learned their test results. OUTCOME MEASURE: Carrier risk for all cohort members was assessed before and after mutation testing. RESULTS: There was a change in carrier risk status in 2906 subjects after testing of 1408 family members. The most common type of carrier risk change, from at risk to non-carrier status, accounted for 77% of the risk changes; 12% were a change to known carrier status from a lower risk. Sixty percent of persons with a carrier risk status change were not themselves tested; their risk status changed because of a relative's test result. CONCLUSIONS: Carrier risk status changes from uncertainty to certainty (that is, to carrier or to non-carrier) account for 89% of risk changes resulting from testing. These risk changes affect cancer prevention recommendations, most commonly reducing their burden. Current practices do not ensure that untested family members are informed about changes in their carrier risk status which result from mutation testing of their relatives.

Axon terminals immunolabeled for dopamine or tyrosine hydroxylase synapse on GABA-immunoreactive dendrites in rat and monkey cortex.

Dopamine afferents to the cortex regulate the excitability of pyramidal neurons via a direct synaptic input. However, it has not been established whether dopamine also modulates pyramidal cell activity indirectly through synapses on gamma-aminobutyric acid (GABA) interneurons, and whether such inputs differ across cortical regions and species. We sought to address these issues by an immunocytochemical electron microscopic approach that combined peroxidase staining for dopamine or tyrosine hydroxylase (TH) with a pre-embedding gold-silver marker for GABA. In the deep layers of the rat prefrontal cortex and in the superficial layers of the monkey prefrontal and primary motor cortices, terminal varicosities immunoreactive for dopamine or TH formed primarily thin, symmetric synapses on distal dendrites. Both GABA-immunoreactive dendrites as well as unlabeled spines and dendrites were contacted by dopamine- or TH-immunoreactive terminals. Synaptic specializations were detected at some, but not all of these contacts. The relative frequency of these appositional and synaptic contacts did not appear to differ between the rat and monkey prefrontal cortex, or between the monkey prefrontal and motor cortices. Across regions and species, labeled and unlabeled targets of dopamine- or TH-positive terminals received additional synaptic input from unlabeled, and occasionally GABA-immunoreactive terminals. Close appositions between dopamine- or TH-immunoreactive and GABA-positive terminals were observed only rarely. These findings indicate that dopamine afferents provide direct synaptic inputs to GABA local circuit neurons in a consistent fashion across cortical regions and species. Thus, dopamine's cellular actions involve direct as well as modulatory effects on both GABA interneurons and pyramidal projection neurons.

Cellular and subcellular localization of syntaxin-like immunoreactivity in the rat striatum and cortex.

Syntaxin is a synapse-specific protein previously localized to the plasma membrane of axon terminals. Biochemical and molecular biological studies indicate a prominent role for syntaxin 1A and 1B in synaptic vesicle docking and/or fusion, suggesting that these proteins are localized to active zone regions of most terminal varicosities in the central nervous system. We sought to test this hypothesis by examining the cellular and subcellular immunocytochemical localization of syntaxin 1 proteins in the striatum and frontal cortex of rats. Using either a polyclonal anti-syntaxin antibody, or a monoclonal antibody directed against the identical protein, HPC-1, immunoperoxidase reaction product was localized to preterminal axons and terminal varicosities that made almost exclusively Type I (asymmetric) synapses on dendritic spines or distal shafts. Immunoreactive terminals forming Type II (symmetric) synapses were observed rarely and only in tissue that was pretreated by rapid freeze-thaw to enhance antibody penetration. From a semi-quantitative analysis, it was estimated that at least 48-62% of all vesicle-filled varicosities and 67-69% of all terminals forming Type I synapses were immunoreactive for syntaxin or HPC-1, respectively. Using a pre-embedding immunogold-silver technique to provide a non-diffusible marker for subcellular localization, gold-silver particles for syntaxin or HPC-1 were localized to the cytoplasmic surface of non-synaptic portions of the plasma membrane of preterminal axons and terminal varicosities. Enrichment of presynaptic active zone regions was not observed with immunogold-silver staining. These findings suggest that syntaxin is primarily contained in a subpopulation of terminals that are associated with excitatory amino acid transmitters, but appears not to be ubiquitously expressed in all terminal classes. The results further indicate that syntaxin is localized to non-synaptic regions of axon and terminal membranes, but may not be enriched in presynaptic active zones. The apparent inconsistency between the subcellular localization of syntaxin and its proposed role in vesicle exocytosis is discussed in terms of possible technical limitations and alternative functions for syntaxin.

Cuff-occluded rate of rise of peripheral venous pressure: a new, highly sensitive technique for monitoring blood volume status during hemorrhage and resuscitation.

We investigated the cuff-occluded rate of rise of peripheral venous pressure (CORRP)--a new, nearly noninvasive peripheral hemodynamic monitoring parameter--in dogs subjected to hemorrhage and resuscitation. Twelve adult mongrel dogs under general anesthesia were subjected to hemorrhage of 30% of their estimated total blood volume (TBV) for 30 minutes; after this time the extracted blood was reinfused. Arterial pressure (AP), central venous pressure (CVP), pulmonary arterial pressure (PAP), cardiac output (CO), pulmonary venous pressure (PWP), heart rate, and CORRP were continuously monitored. A "clinically significant change" (CSC) in CORRP and CO was defined as a change that exceeded two standard deviations from the mean of five baseline measurements made before the onset of hemorrhage, whereas a CSC in PWP or CVP was conservatively defined as a change that exceeded 2 mm Hg from the average of five baseline measurements, and a CSC in PAP and AP was defined as a change that exceeded 3 mm Hg and 5 mm Hg, respectively from the average of the baseline measurements. There was no consistent change in heart rate during hemorrhage. Thus defined, a CSC in CORRP occurred after an average extraction of 9.2% +/- 4.7% TBV, whereas a CSC was not seen until an average loss of 16.5% +/- 8.1% TBV for AP, 21% +/- 13% TBV for PWP, 15.5% +/- 7% TBV for PAP, and 35% +/- 3% TBV for CVP. These average blood losses are all significantly different from the average blood loss required to effect a CSC in CORRP. The blood loss required to effect a CSC in CO averaged 9.7% +/- 6%. We conclude that in these anesthetized dogs, CORRP detected blood loss earlier than other commonly used hemodynamic parameters, including several invasive parameters such as CVP, PAP, and PWP; CORRP and CO were equivalent in their ability to detect early stages of blood loss.

Minimally invasive repair of pectus excavatum: a single institution's experience.

BACKGROUND: The Nuss repair of pectus excavatum is a relatively new, minimally invasive surgical (MIS) alternative to the traditional open "Ravitch-type" operation. We have one of the larger single-center experiences to date, and we conducted this clinical study to evaluate our early experience, emphasizing initial outcome and technical modifications designed to minimize complications. METHODS: A retrospective chart review was performed on 112 patients who underwent 116 pectus excavatum repairs between January 1995 and January 2001. The Nuss procedure was performed in 80 patients, and open repair was performed in 32 patients. Information about demographics, deformity, operative course, complications, and early outcome was recorded. RESULTS: Operative duration was 143 minutes for the open group and 53 minutes for the Nuss MIS group (P <.001). Blood loss was 6 mL/kg for the open group and 0.5 mL/kg for the MIS group (P <.001). Postoperative hospitalization was 3.2 days for the open group versus 3.7 days for the MIS group (P<.05). CONCLUSIONS: The MIS pectus repair can be performed safely with minimal blood loss and reduced operative time. Short-term analysis of the quality of repair, including absence of preoperative symptoms, patient satisfaction, and cosmetic appearance are encouraging.

Vascular anomalies and tracheoesophageal compression: a single institution's 25-year experience.

BACKGROUND: Vascular rings are uncommon anomalies in which preferred strategies for diagnosis and treatment may vary among institutions. In this report, we offer a description of our approach and a review of our 25-year experience. METHODS: A retrospective review was conducted of all pediatric patients with symptomatic tracheoesophageal compression secondary to anomalies of the aortic arch and great vessels diagnosed from 1974 to 2000. RESULTS: Thirty-one patients (38%) of eighty-two patients (mean age, 1.7 years), were identified with double aortic arch, 22 patients (27%) with right arch left ligamentum, and 20 patients (24%) with innominate artery compression. Our diagnostic approach emphasized barium esophagram, along with echocardiography. This regimen was found to be reliable for all cases except those with innominate artery compression for which bronchoscopy was preferred, and except those with pulmonary artery sling for which computed tomography or magnetic resonance imaging, in addition to bronchoscopy, were preferred. Left thoracotomy was the most common operative approach (70 of 82; 85%). Ten patients (12%) had associated heart anomalies, and 6 (7%) patients underwent repair. Complications occurred in 9 (11%) patients and led to death in 3 (4%) patients. CONCLUSIONS: In our practice, barium swallow and echocardiography are sufficient in diagnosing and planning the operative strategy in the majority of cases, with notable exceptions. Definitive intraoperative delineation of arch anatomy minimizes the risk of misdiagnosis or inadequate treatment.

Glans approximation procedure urethroplasty for the wide, deep meatus.

OBJECTIVES: To assess the reliability, cosmesis, and complication rate of the glans approximation procedure (GAP). METHODS: We reviewed 37 consecutive GAP urethroplasties performed at the Children's Mercy Hospital in Kansas City, Missouri over a 5-year period, performed by three different pediatric surgeons. All patients selected had a large, deep ventral groove, typically with a wide open urethral meatus. RESULTS: The mean age was 18 months, with a mean follow-up of 28 months. Of the 37, there was one urethrocutaneous fistula that has since been easily repaired with good results. The parents have been very pleased with the results in all cases, with a straight and strong urinary stream. There was one episode of transient erythema, possibly representing an infection, which resolved after 3 days of oral antibiotics. CONCLUSIONS: The GAP is technically easy, reliable, and offers a relatively low complication rate for the repair of a very select group of patients with hypospadias with a deep ventral glanular groove and wide-mouthed meatus.

A combined hospital experience with fundoplication and gastric emptying procedure for gastroesophageal reflux in children.

BACKGROUND: Operative treatment of symptomatic gastroesophageal reflux (GER), often together with neurologic feeding disorders, is very common in infancy and childhood. Delayed gastric emptying (DGE) has been observed frequently in association with GER in children. STUDY DESIGN: A retrospective review was performed on 1,200 consecutive patients 18 years of age and younger operated upon for symptomatic GER or neurologic feeding disorders, or both, at two pediatric surgery centers in widely separated geographic areas in the United States of America, to compare the results after fundoplication with or without a gastric emptying procedure (GEP). RESULTS: Operations included gastroesophageal fundoplication (GEF) alone (871 patients), GEF plus GEP (286 patients), reoperative GEF plus GEP (30 patients), and GEP alone (13 patients). Thus, 27 percent of the total and 40 percent of the last 494 children with reflux had a GEP. Delayed gastric emptying with retention of more than 60 percent of an isotope meal appropriate for age at 90 minutes was present in 241 of the 451 children with reflux studied. Major neurologic disorders were present in 219 (25 percent) of 871 children who underwent GEF alone and in 247 (75 percent) of 329 children who had a GEP. All patients operated upon from both hospitals were relieved of recurrent emesis, and those with failure to thrive showed significant weight gain; pulmonary symptoms were relieved in 94 percent. Recurrent GER developed in 47 (5.2 percent) of 901 children who had GEF alone, but in only four (1.2 percent) of 329 patients who had a GEP. CONCLUSIONS: The excellent clinical results with low morbidity in this largest reported clinical experience with GEP in childhood suggest that a GEP should be combined with GEF for symptomatic children who have both GER and DGE. Minimal investigative studies are necessary for most neurologically impaired children who require a feeding gastrostomy.

Operative therapy of gallbladder disease in patients with cystic fibrosis.

We retrospectively studied 20 patients with cystic fibrosis who underwent surgery for gallbladder disease from 1973 to 1986. A long delay between the onset of symptoms and the diagnosis was noted (mean 7.4 months). This delay was attributed to masking of the symptoms of biliary disease by the malabsorption and pulmonary symptoms seen in this patient population. There was a notable lack of common bile duct disease in our patients as well as in those reported in the literature. This may have been due to a combination of factors: the increased viscosity of the mucus, the small caliber of the gallbladder and ductal system, and the hypotonicity of the gallbladder. We do not recommend routine intraoperative cholangiography in patients with cystic fibrosis and gallbladder disease. Cystic fibrosis is a disease with progressive pulmonary deterioration. Cholecystectomy can be performed in these patients with relative safety if careful preoperative and postoperative care is provided. We recommend early operative intervention in the patient with gallbladder disease and cystic fibrosis.

Aggressive metastasectomy for pulmonic sarcomatous metastases: a follow-up study.

Pulmonary metastases are the primary cause of death due to bone and soft tissue sarcomas. We have previously shown that an aggressive approach and a new technique of multiple pulmonary metastasectomies have resulted in improved survival for patients with pulmonary metastases. In this follow-up study, an expanded database of patients was retrospectively analyzed to determine survivability as well as to evaluate potential prognostic indicators. Forty-nine patients, 26 of whom had osteogenic sarcoma (OGS), were evaluated. A number of patients had been referred from other institutions where their disease had been considered inoperable because it was extensive or recurrent. Using lateral thoracotomies exclusively, employment of a laser technique, and excision of minimal pulmonary parenchymal tissue, we performed aggressive metastasectomy. A mean of 3.0 thoracotomies was performed, in which an average of 10.2 nodules per thoracotomy were excised. Operative morbidity and mortality were minimal. The disease-free interval, the number of nodules resected, the number of thoracotomies performed, and the size of the nodules were evaluated as potential prognostic indicators. Statistically significant correlation could be established only for the size of the nodules resected. The 5-year survival rate for all patients was 39%; it was 24% for patients with OGS and 71% for those without OGS. Aggressive surgical resection of pulmonary metastases from bone and soft tissue sarcoma should be considered when there is control of local disease, no evidence of extrapulmonary metastasis, and adequate post-resection pulmonary reserve. The presence of bilateral, extensive, or recurrent disease is not a contraindication to thoracotomy. Aggressive resection of multiple nodules and improved chemotherapy appear to prolong survival of these patients when compared with survival rates of historical control subjects.

Nonoperative management of small-bowel obstruction with endoscopic long intestinal tube placement.

Intestinal obstruction remains a major cause of morbidity and mortality in surgical patients. We reviewed the records of 77 patients with mechanical small-bowel obstruction who were treated with endoscopically and fluoroscopically placed Leonard long intestinal tube decompression. Most patients (59%) had failed a trial of nasogastric tube or Miller-Abbott tube decompression. Overall, 29 per cent of patients were able to resolve their obstruction with Leonard tube decompression alone. Subdivision of patients on the basis of the etiology of their obstruction demonstrated a much higher rate of success for tube decompression in adhesive obstruction (37%) versus malignant obstruction (12%) or inflammatory obstruction (no successes). Patients with radiographic and clinical evidence of complete intestinal obstruction were significantly less likely to respond to long intestinal tube treatment (13%). The long intestinal tube was easily passed in all patients. There were no complications of the intubation procedure in our series, and the incidence of tube-related complications was four per cent. We conclude that an initial period of long intestinal tube decompression allows a significant percentage of patients with mechanical small-bowel obstruction to be treated nonoperatively, particularly if a partial obstruction from postoperative adhesions is present. Patients who have failed a trial of nasogastric tube decompression and are poor operative risks should also be considered for long intestinal tube placement.

Outcome analysis for gastroschisis.

BACKGROUND/PURPOSE: Several factors are reportedly associated with an adverse outcome in gastroschisis, including mode of delivery, in utero diagnosis, type of closure, concurrent anomalies, intestinal atresia, and necrotizing enterocolitis (NEC). Since 1969, the authors have treated 185 patients who had gastroschisis. The authors analyzed their database to identify variables associated with increased morbidity and mortality. METHODS: A retrospective study of all patients with gastroschisis treated at our institution in the last 30 years was performed. The characteristics of survivors and nonsurvivors were compared. A logistic regression analysis was performed, with survival as the dependent variable, and the following parameters as independent variables: in utero diagnosis, mode of delivery, gestational age and birth weight, era of repair, type of closure, presence of other associated anomalies, intestinal atresia, and development of necrotizing enterocolitis. Further logistic regression analysis was performed, with various indicators of morbidity as dependent variables. These included development of sepsis, bowel obstruction, and complications related to the closure or to the silo. No attempt at long-term follow-up was made. RESULTS: A total of 185 infants with gastroschisis were treated at our institution from 1969 to 1999. Mean gestational age was 36.6 weeks, and the mean birth weight was 2,501 g. A total of 21 infants had intestinal atresia. NEC developed in 8 infants. Six infants had other serious anomalies. The overall survival rate was 91%. Survival improved in last 2 decades (94%). There were no differences in gestational age, birth weight and mode of delivery, method of closure, or presence of intestinal atresia between survivors and nonsurvivors. Only the era of repair (P = .002), presence of necrotizing enterocolitis (P = .044), and presence of other major anomalies (P < .001) correlated with mortality in the logistic regression analysis. Sepsis, bowel obstruction, and closure complications accounted for most of the morbidity. Analysis of these three morbidity factors identified low gestational age (P = .038) and development of necrotizing enterocolitis (P = .020) as independent predictors of sepsis. Closure complications were only associated with lower birth weight (P = .006). No predictors of bowel obstruction were identified. CONCLUSIONS: Mode of delivery, method of closure, birth weight and gestational age, and the presence of intestinal atresia do not appear to correlate with survival in infants with gastroschisis. Only the presence of another major anomaly, the era of repair, and the development of necrotizing enterocolitis were associated with increased mortality. Degree of prematurity and development of enterocolitis were associated with an increased incidence of septic complications. Low birth weight was a marker for closure complications. Type of delivery (vaginal or cesarean section) had no influence on either morbidity or mortality.

The 're-do' chest wall deformity correction.

BACKGROUND: A small percentage of patients who undergo surgical correction of a chest wall deformity will have results so unsatisfactory that a second procedure, the so-called "re-do," will be required. CONCLUSIONS: The literature contains very little information regarding the technique and results of these procedures. Based on experience with 18 "re-do" procedures, the authors believe that recurrent deformities should be surgically corrected. Although this is a somewhat diverse group based on age at the first and second procedure, type of original operative procedure, and interval between the procedures, the operative approach is standard, and the results are predictable.

An absent right and persistent left superior vena cava in an infant requiring extracorporeal membrane oxygenation therapy.

A persistent left superior vena cava (PLSVC) is the most common anomaly of the major veins. However, an absent right superior vena cava and PLSVC is much less common; fewer than 100 cases have been reported in the world literature in patients with situs solitus. This rare variation was encountered in a newborn requiring extracorporeal membrane oxygenation (ECMO) for meconium aspiration and interfered with venous cannulation. The anomaly was not suspected before an unusual cannula position was observed on the chest radiograph, and it was confirmed by bedside venography. Adequate venous cannulation was obtained through the anomalous vessel using a flexible catheter, allowing for an uneventful ECMO course. The epidemiology and embryology of this incidental anomaly are reviewed, and the methods used to circumvent the difficulties it presented in this case are described.

Giant inguinal hernia in a 5-year-old boy with hydrocephalus: a case report.

A case of giant left inguinal hernia in a 5-year-old boy is presented. The patient had multiple neurosurgical procedures performed in the neonatal period for spina bifida and hydrocephalus, including the placement of a ventriculoperitoneal shunt. The hernia was first noted during this period but was not repaired, and the child was lost to follow-up until age 5. The hernia underwent progressive enlargement over this interval, and the eventual development of gastrointestinal symptoms prompted the "rediscovery" of the defect. The majority of the child's intestines were within the hernia, with at least partial loss of domain. The unique preoperative and postoperative management of this difficult problem is described.

Inferior vena caval obstruction from a horseshoe kidney: report of a case with operative decompression.

Horseshoe kidney is a common anomaly with frequent associated anomalies. The confluence of the lower poles of the kidneys lies anterior to the inferior vena cava. The authors were unable to find any reports in the world's literature of a vena caval obstruction caused by the presence of a horseshoe kidney. The authors report such a case presenting as bilateral lower leg swelling.

Diagnostic open-lung biopsy after bone marrow transplantation.

The development of pulmonary infiltrates is an ominous sign in the immunocompromised host (ICH). Selection of the best diagnostic and therapeutic approach is often difficult, and in part depends on the risk-to-benefit ratio of various diagnostic modalities, such as bronchoscopy, bronchioalveolar lavage, percutaneous needle biopsy, and open-lung biopsy (OLB). We reviewed our experience with OLB and bronchoscopy in a predominantly pediatric bone marrow transplantation population, and attempted to assess the frequency with which OLB results directed a therapeutic change, as well as the clinical results of any such therapeutic alteration. A retrospective chart review was conducted of 87 bone marrow transplantation recipients undergoing diagnostic OLB from 1975 to 1986. Bronchoscopic and OLB cultures, histopathologic studies, serological data, and autopsy results were all carefully examined. An assessment of therapeutic alteration as a result of OLB was made, and clinical changes attributable to an OLB-directed therapeutic alteration were sought. Ninety-four OLBs and 37 bronchoscopic examinations were performed in 87 patients. All patients had undergone bone marrow transplantation, most often for leukemia (58/87) or aplastic anemia (13/87). The mean interval from bone marrow transplantation to OLB was 106 days. There were no intraoperative complications, but minor postoperative surgical complications were frequent (incidence, 21%). Postoperative mortality, defined as a death occurring within 30 days of surgery, was 45% (39/87). Seventy-four percent of the patients (64/87) died during the course of the study, at a mean of 43 days after OLB. Most OLBs (60%) yielded a specific diagnosis, defined as the establishment of a precise cause for the infiltrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Esophageal duplication cyst with esophageal web and tracheoesophageal fistula.

The authors report the case of lower cervical/upper thoracic esophageal duplication associated with an obstructing esophageal web. This presented in the newborn period as an esophageal atresia. Initial resection of the web and closure of the fistula were performed. The duplication was excised electively at 2 months of age. Persistent symptomatic tracheomalacia required aortopexy, after which the child recovered uneventfully. There are only three other reports (four cases) in the literature of esophageal atresia (or variants) associated with esophageal duplication.

Nonoperative management of newborn splenic injury: a case report.

Traumatic injury of the spleen is rare in newborns. Nonoperative management of pediatric splenic injuries is now recognized as the treatment of choice, but there is scant experience with the problem in neonates. The authors report their experience with a neonatal splenic rupture, managed nonoperatively.