Inhibition of phospholipase C-gamma1 activation blocks glioma cell motility and invasion of fetal rat brain aggregates.

OBJECTIVE: Phospholipase C (PLC)-gamma is a cytosolic enzyme activated by several growth factor (GF) receptors (epidermal GF receptor [EGFR], platelet-derived GF receptor, and insulin-like GF 1 receptor), and its activation is associated with increased cell motility (but not cell proliferation) in nonglioma cell lines. Because up-regulated activation of EGFR has been consistently linked to poor patient survival in patients with glioblastoma multiforme (GBM) and because inhibition of EGFR activation by tyrosine kinase inhibitors prevents glioma infiltration in vitro, we hypothesized that inhibition of PLC-gamma activation would inhibit glioma cell invasiveness. METHODS: Our experimental model assesses tumor spheroid invasion of fetal rat brain spheroids by confocal microscopy. We treated U87 GBM spheroids, and those derived from a single patient, with the PLC inhibitor U73122. We also transfected rat C6 glioma cells with the PLCz complementary deoxyribonucleic acid coding for a dominant negative PLC-gamma1 src-homology-2/src-homology-3 peptide fragment, which blocks binding and activation of PLC-gamma1 by GF receptors. Two clones (C6F and C6E) were grown into spheroids and were tested for invasiveness in the spheroid model and for responsiveness to GFs in a standard in vitro motility assay. RESULTS: The infiltration rate of the patient GBM cell line overexpressing wild-type EGFR was reduced by 2 micromol/L U73122 from a slope (percent invasion/h) of 0.74+/-0.08 (with the inactive congener U73343) to 0.04+/-0.053 (P = 8 x 10(-7) by two-tailed t test, 92% reduction); the integral rate, another measure of invasion, was reduced from 49.7+/-13 percent-hours per hour to 13.6+/-12 (P = 0.002, 72% reduction). The U87 spheroid invasion rate was reduced by 0.5 micromol/L U73122 from 46.7+/-8.5 percent-hours per hour to 11.2+/-4.6 (P = 3 x 10(-5)); the slope decreased from 1.7+/-0.41 percent per hour to 0.35+/-0.14 (P = 0.0001). The C6F and C6E clones demonstrated attachment to and "surrounding" of the fetal rat brain aggregate but no true invasion by confocal or light microscopy. PLCz blocked the motility response to epidermal GF, platelet-derived GF, and insulin-like GF. There was a significant decrease in PLC-gamma1-associated tyrosine phosphorylation. CONCLUSION: These results support a key role for PLC-gamma activation as a common postreceptor pathway for GF-induced tumor infiltration and further identify PLC-gamma1 as a possible target for anti-invasive therapy for GBMs.

Möbius syndrome: classification and grading system.

Möbius syndrome is characterized by facial abnormalities, but the limbs, chest wall, spine, and soft tissues also can be involved. There is no system for categorizing the various anomalies, grading phenotypic severity, designing treatment protocols, or assessing therapeutic results. This is a retrospective analysis of 27 patients with Möbius syndrome seen in our craniofacial unit from 1980 to 1994. We categorized and graded the cranial nerve deficits and diverse musculoskeletal abnormalities of the face, upper and lower limbs, and trunk. The first letter for each of five potentially involved structures, i.e., cranial nerve, lower limb, upper limb, face, and thorax, formed the acronym CLUFT. The structural and/or functional deficits for each component were graded on a scale of 0 to 3. Complete facial nerve paralysis was documented in 11 patients and paresis in 16. Facial nerve paralysis was bilaterally symmetric in 17 of 26 patients. Sixth nerve paralysis was present in 23 of 27 patients; other cranial nerves were affected in 8 of 27 patients. Lower limbs were involved in 10 of 27 patients and upper limbs in 7 of 27 patients. Facial structures were affected in 17 of 27 patients (e.g., microtia, micrognathia, and microphthalmia), and chest wall deformities were found in 8 of 27 patients (e.g., scoliosis, hypoplasia of the breast, pectoral muscles, and scapula). We noted that microtia primarily involved second pharyngeal arch-derived structures. The CLUFT system permits categorization and comparison of Möbius patients for phenotypic and management outcome studies. Documentation of the widespread structural anomalies suggests that pathogenesis involves vascular disruption; a detailed prenatal history is indicated.

The use of free tissue transfer in burn reconstruction.

Patients that sustain extensive burns commonly present the reconstructive surgeon with problems caused by exposed tendons, scar contractures, and loss of digits. Frequently there is inadequate local tissue available to solve these reconstructive problems. To solve these complex postburn defects, we have used free tissue transfer in addition to more traditional therapy. From 1987 thru 1994, we have used free tissue transfer as an adjunct to our reconstructive armamentarium in 35 patients who have undergone a total of 45 free tissue transfers for the correction of postburn deformities. There have been two failures (96% flap survival). There were 27 males and 9 females. Twelve free flaps were performed during the initial hospitalization, and 33 were performed during subsequent hospitalizations. Sites of reconstruction included the hand (n = 17), neck (n = 12), face (n = 8), leg (n = 4), penis (n = 2), arm and axilla, 1 each. Flap origin included anterolateral thigh (n = 16), parascapular (n = 10), digital transfer (n = 4), rectus abdominus (n = 3), radial forearm (n = 3), groin, fibula, and foot, two each. Nine flaps underwent prefabrication or prelamination before transfer. In summary, free tissue transfer is a valuable tool in burn reconstruction and it can be used safely and effectively with minimal morbidity to the patient.

Increasing projection in patients undergoing free nipple graft reduction mammoplasty.

Reduction mammoplasty in patients with gigantomastia has traditionally been performed by a technique involving free nipple grafting. These patients usually have only a small amount of breast tissue above the inframammary fold and therefore this type of procedure has often left patients with an insufficient amount of superior pole projection. I have performed free nipple grafting in three patients with gigantomastia using a technique that utilizes two deepithelialized pedicles to increase projection. This technique is simple to perform, does not significantly lengthen the operative time, and results in a breast that provides significant projection.

Tumescent abdominoplasty: an ambulatory office procedure.

Abdominoplasty has traditionally been a procedure that has been performed in a hospital setting, usually with an overnight stay, particularly when full rectus plication has been part of the operative procedure. With the development of office-based operating rooms and improved office anesthesia, the ability to perform more extensive surgery outside the hospital is now possible. Additionally, the cost savings of office-based surgery compared with noncontrolled hospital charges makes it much easier for patients to plan the exact charges that they will encounter. Experience with the tumescent technique for liposuction has demonstrated to the plastic surgeon that extensive surgery can be performed with minimal postoperative discomfort. The tumescent technique has also been used to perform miniabdominoplasty [1]. By using this technique in patients undergoing full abdominoplasty, this procedure can be performed in the office with minimal blood loss and almost no need for pain management in the early postoperative period, and the patients can be discharged home within 3 h of the completion of the procedure.

Robin sequence: obstructive sleep apnea following pharyngeal flap.

OBJECTIVE: We reviewed 24 children with Robin sequence who underwent cleft palate repair. METHOD: All patients were 5 years of age or older at the time of review, allowing for accurate assessment of speech in relation to velopharyngeal function. All infants had palatal closure between 9 and 14 months of age, either V-Y repair (n = 16) or von Langenbeck repair (n = 8). RESULTS: Only 1 of 16 children who had V-Y repair had borderline velopharyngeal dysfunction (VPD). For reasons that are unclear, in the von Langenbeck repair group, six of eight children had VPD, and four of six underwent pharyngeal flap. Three additional patients with nonsyndromic Robin sequence had palatoplasty and subsequent pharyngeal flap. Six of the combined total of seven children with nonsyndromic Robin sequence developed obstructive sleep apnea and require flap take-down. CONCLUSION: Since conventional pharyngeal flap for VPD in nonsyndromic Robin sequence children resulted in a high incidence of obstructive sleep apnea, alternative management should be considered: modification of the standard pharyngeal flap, palatal lengthening (V-Y or double-opposing Z-plasty), or construction of a speech bulb.

Inverted deepithelialized latissimus dorsi flap for the correction of lumpectomy defects in the irradiated breast.

Deformities following lumpectomy and radiation can provide reconstructive challenges for the plastic surgeon. With the increasing incidence of breast conservation therapy, these problems are likely to become more frequent in the future. The use of autologous tissue, particularly the latissimus dorsi, provides an excellent option for correcting these tissue deformities. We propose using an inverted latissimus with a deepithelialized skin paddle to correct these defects when there is no shortage of overlying skin. Additionally, this technique provides a softer texture to the entire radiated breast.

Abnormalities of the cranial base in synostotic frontal plagiocephaly.

Skeletal abnormalities of the cranial base in various craniosynostoses are well known. Cranial base angulation has been documented in synostotic frontal plagiocephaly--"unilateral coronal synostoses." We analyzed four infants with synostotic frontal plagiocephaly, focusing on computed tomographic images through the cranial base. The scans were performed on a GE advantage spiral with 1.5-mm images. The anatomical structures examined were length of the foramina ovale, length of the eustachian tubes, and sphenotemporal angles. Ratios for these measures were calculated comparing the normal and synostotic sides. The foramen ovale was 21% longer on the synostotic side; the eustachian canal was 11% shorter on the synostotic side. The average sphenotemporal angle on the synotic side was 121 degrees compared with 149 degrees on the nonsynostotic side. Deformities of the cranial base (i.e., elongation of structures anterior to the synostosis and shortening of the structures posterior to the synostosis) can be documented before surgical correction of synostotic frontal plagiocephaly. Follow-up computed tomographic studies will permit study of the effect of fronto-orbital advancement and modeling on these basilar abnormalities.

An inexpensive method of intraoperative skin stretching for closure of large cutaneous wounds.

A simple and inexpensive method for closure of large wounds is presented. A rib approximator and two spinal needles, which are readily available in most operating rooms, have been utilized to close large cutaneous wounds of the chest and thigh after flap harvest.

Laser-assisted venous anastomosis: a comparison study.

A low-powered carbon dioxide laser was used to perform 25 vein grafts (50 anastomoses) on the femoral veins of Sprague-Dawley rats. The patency rate, clamp time, and bleeding time were compared with 50 conventional microvascular vein grafts (100 anastomoses). The patency of the laser-assisted anastomoses (LAVA) was 84 percent, while the conventional vein grafts yielded a 94 percent patency rate. The average clamp time and bleeding time for the LAVA were 47.2 min and 4.88 sec, respectively, while the conventional anastomoses required 57.6 min and had an average bleeding time of 9.44 sec. Histologically, both specimens healed at the same rate, but the laser-assisted anastomoses produced less inflammation and granulation tissue. These results suggest that the laser has potential as a tool for clinical application in microsurgery. In addition, the 94 percent patency rate achieved with the vein interposition graft would suggest that a decrease in the tension across the anastomosis can improve patency.

Crack-related perforated gastropyloric ulcer.

Cocaine is a potent topical vasoconstrictor that causes nasal mucosal and dermal ulceration. Use of the purified cocaine derivative "crack" has reached epidemic proportions in large cities. In 18 months we operated on 24 patients with perforated peptic ulcers. Five of the patients were young (27-38 years) male crack users without prior history of gastric symptoms who presented with a perforated gastric ulcer related to smoking crack. Three had had symptoms for only 1-5 days before admission. All five were afebrile, had a rigid abdomen, normal leukocyte count, and free intraabdominal air upon radiography. Five other age-matched, non-crack-using patients served as case controls. Their duration of symptoms was 1-24 months, they had elevated leukocyte counts on admission, and, in contrast to the crack users, four of these patients had duodenal perforations. The clinical presentation of the crack smokers and the unusual localization of the perforations imply different pathogenetic mechanisms than are commonly seen in perforated ulcer disease. With increasing abuse of crack, greater numbers of patients with this new complication may be expected to present to emergency services in urban areas.

Molding therapy for infants with deformational auricular anomalies.

Congenital auricular anomalies can be categorized as either malformed or deformational. Auricular deformations most commonly affect the helix and antehelix. Surgical correction involves sutural modeling, wedge excision, reshaping and reversing cartilage segments, and morselization. Since neonatal auricular cartilage is extremely pliable, we used early splinting to correct deformational ear anomalies. Splints were constructed of leadfree, soft soldering wire threaded into polyethylene tubing and held in place with Steri-Strips. From August 1995 through February 1996 we treated 19 infants with 32 deformed auricles: 10 infants were male and 9 were female, ranging in age from 1 day to 10 weeks. Thirteen infants had both ears affected. There were 8 prominent ears, 23 lop ears, 2 Stahl's ears, and 1 infant with an inverted concha. For prominent ears, the helical-mastoid distance decreased from an average of 16.8 to 12.2 mm, after an average of 13 weeks of splinting. Fourteen corrected lop ears had a normal appearance, and 9 were improved with minor residual deformity. There was only one complication: skin irritation requiring adjustment of the prosthesis. Five children had molding started after 3 months of age and all had no significant improvement. In addition, the parents of 5 children refused therapy and 12 children had either poor compliance to therapy or were lost to follow-up. Our experience with auricular molding confirmed that it is easy, effective, and inexpensive. If molded sufficiently early, most auricular deformations should not need surgical correction in childhood.

Traumatic avulsion and reconstruction of the midface.

Traumatic loss of midface soft tissue and supporting structures may result in communication between the oral and nasal cavities. Reconstruction requires both oral and nasal lining, as well as supporting structures. The need for multilaminar tissue, as well as the paucity of local tissue, creates a reconstructive challenge. This case report describes the reconstruction of a traumatic defect of the alveolus, hard palate, inferior orbits, and local soft tissues. An intraoperative alginate mold facilitated a three-dimensional understanding of the wound, and allowed translation of an osseomyocutaneous groin flap to reconstruct the defect in one stage.

Musculofascial flaps based on the dorsalis pedis vascular pedicle for coverage of the foot and ankle.

Soft-tissue reconstruction of the foot and ankle has long presented challenging problems for the plastic surgeon. Limitations of available local tissue, the need for specialized tissue, and donor site morbidity restrict the options available to the reconstructive surgeon. In an effort to solve these difficult problems, we have begun to use musculofascial flaps based on the branches of the dorsalis pedis artery. We present our early experience of 5 patients treated with an extensor digitorum brevis muscle flap with fascial extensions often containing the contents of the first web space. Our patients ranged from 6 to 60 years in age and included 4 males and 1 female. The etiologies of the wounds were secondary to trauma (N = 2), complications of surgery for rheumatoid arthritis (N = 2), and were secondary to a defect following resection of an arteriovenous malformation (N = 1). The flaps had antegrade blood flow in 3 patients and reverse flow in 2 patients. The flaps were covered with a split-thickness skin graft and the donor site was closed primarily. The donor sites healed without the need for further surgery. One patient required additional procedures. This flap proved to be both versatile and effective for closure of difficult wounds of the foot and ankle.

Single-stage, multimodality treatment of soft-tissue sarcoma of the extremity.

The present study describes the techniques available for single-stage sarcoma resection, soft-tissue reconstruction, and radiotherapy for limb preservation in patients who are unable to undergo primary wound closure after a complete soft-tissue resection of their primary sarcoma. From 1989 to 1994, 19 patients (age range, 18-79 years; mean, 51.2 years) underwent radical resection of extremity sarcomas followed by immediate reconstruction. Seven patients had tumors in the upper extremity and 12 patients had tumors in the lower extremity. There were 13 primary tumors and 6 recurrent tumors. Fifteen patients (79%) received radiation therapy, 7 patients by external beam and 8 patients by brachytherapy. Reconstruction included 16 regional flaps in 13 patients and 7 free tissue transfers in 6 patients. Commonly used flaps included the rectus abdominis (N = 5), the latissimus dorsi (N = 4), the anterolateral thigh (N = 4), the reverse-flow radial forearm (N = 2), and the gastrocnemius (N = 2) flaps. Complications included wound breakdown (N = 2), partial skin graft failure (N = 1), hematoma requiring operative evacuation (N = 1), and partial flap necrosis (N = 1). There were no operative mortalities. Eight patients underwent wide local excision, flap closure, and brachytherapy. Mean length of hospital stay for this group was 12.3 days compared with 13.8 days for the remaining 11 patients. There was one complication (13%) in this group and four complications in the remaining patients (4 of 11; 36%). Our study confirms the utility of soft-tissue reconstruction to permit wide local excision with clear margins as well as the delivery of postoperative radiotherapy. It demonstrates the ability of pedicled flaps and free tissue transfers to remain viable and provide sufficient wound coverage in the setting of early postoperative brachytherapy. In addition, this series illustrates the efficacy of a team approach and one-stage therapy for extremity soft-tissue sarcomas that includes excision, reconstruction, and early postoperative brachytherapy in a single hospitalization.

Genetic mapping of cleidocranial dysplasia and evidence of a microdeletion in one family.

Cleidocranial dysplasia (CCD) is an autosomal, dominantly inherited disorder of high penetrance affecting skeletal ossification and tooth development. Typically, affected individuals have hypoplastic/aplastic clavicles, patent fontanelles and sutures, supernumerary teeth, and short stature. We have used a candidate locus approach to map the responsible gene in two families with typical features of CCD. Linkage was established between CCD and four loci (D6S426, D6S451, D6S459, TCTE1) that span a region of 10 cM on chromosome 6p. A maximum lod score, Zmax, of 4.1 at a recombination fraction of zero was obtained at D6S451. One highly polymorphic microsatellite from this region (D6S459) showed allelic loss in all affected members of one family with two different sets of primers. The presence of a deletion in this area was confirmed by Southern blot analysis using a probe derived from the amplification product of the D6S459 marker. The data assign a gene for CCD to chromosome 6p21 and suggest that a microdeletion within an area of tight linkage to the CCD-phenotype has been identified.

Tissue expansion in children: a retrospective study of complications.

We retrospectively reviewed 105 consecutive children in whom 191 tissue expanders were placed by the Plastic Surgical Service at The Children's Hospital from 1987 to 1995. The age range was 1 month to 28 years. The series included 68 females and 37 males. The indications for tissue expansion were congenital pigmented nevus (N = 55), craniofacial anomaly (N = 13), aplasia cutis congenita (N = 7), meningomyelocele (N = 7), posttumor resection (N = 5), unstable scar (N = 4), burn scar (N = 3), and miscellaneous disorders. The expanders were located in the scalp (N = 59), cervicofacial area (N = 23), back (N = 18), chest (N = 6), and extremities (N = 6). A single expander was used in 47 patients and the mean number of expanders per patient was 1.8. All patients were given preoperative intravenous antibiotics. There were 25 complications in 20 patients (19%), which comprised 13% of all expanders. The most common complications were infection (6%, N = 11), deflation (3%, N = 6), and exposure (2%, N = 5). These complication rates were not related to either the gender, site of implantation, number of expanders, use of closed suction drains, or the indication for expansion. The complications were related to age, being higher in children (age 1-12 years) compared with infants and adolescents. Tissue expanders can be successfully used in children to construct and reconstruct a variety of cutaneous defects, but there is an irreducible minimum for the three major complications.