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Biomedical subjects

J Bostwick

Publications and source records attributed to J Bostwick.

At least 19 recordsLinked to original sources

Design and structure-activity relationships of potent and selective inhibitors of blood coagulation factor Xa.

The discovery of a series of non-peptide factor Xa (FXa) inhibitors incorporating 3-(S)-amino-2-pyrrolidinone as a central template is described. After identifying compound 4, improvements in in vitro potency involved modifications of the liphophilic group and optimizing the angle of presentation of the amidine group to the S1 pocket of FXa. These studies ultimately led to compound RPR120844, a potent inhibitor of FXa (K(i) = 7 nM) which shows selectivity for FXa over trypsin, thrombin, and several fibrinolytic serine proteinases. RPR120844 is an effective anticoagulant in both the rat model of FeCl(2)-induced carotid artery thrombosis and the rabbit model of jugular vein thrombus formation.

Animals

Restenosis following angioplasty in the swine coronary artery is inhibited by an orally active PDGF-receptor tyrosine kinase inhibitor, RPR101511A.

BACKGROUND: Platelet-derived growth factor (PDGF), a purported mediator of arterial response to injury, stimulates proliferation, chemotaxis, and matrix production by activation of its membrane receptor tyrosine kinase. Because these activities underlie restenosis, inhibition of the PDGF-receptor tyrosine kinase (PDGFr-TK) is postulated to decrease restenosis. METHODS AND RESULTS: RPR101511A is a novel compound which selectively and potently inhibits the cell-free and in situ PDGFr-TK and PDGFr-dependent proliferation and chemotaxis in vascular smooth muscle cells (VSMC). To evaluate the effect of RPR101511A (30 mg. kg-1. d-1 BID for 28 days following PTCA) on coronary restenosis, PTCA was performed in hypercholesterolemic minipigs whose left anterior descending (LAD) coronary artery had been injured by overdilation and denudation, yielding a previously existing lesion. Angiographically determined prePTCA minimal lumen diameters (MLD) were similar in vehicle and RPR101511A-treated pigs (1.98+/-0.09 versus 2.01+/-0.08 mm) and increased to the same extent in the 2 groups following successful PTCA (2.30+/-0.06 versus 2.52+/-0.13). At termination, there was an average 50% loss of gain in the vehicle-treated group but no loss of gain with RPR101511A (2.16+/-0. 05 versus 2.59+/-0.11, P<0.001). Morphometric analysis of the LAD showed that RPR101511A caused a significant decrease in total intimal/medial ratio (0.96+/-0.58 versus 0.67+/-0.09, P<0.05). CONCLUSIONS: RPR101511A, which acts by inhibition of the PDGFr-TK, completely prevented angiographic loss of gain following PTCA and significantly reduced histological intimal hyperplasia.

Administration, Oral

A comparison of morbidity from bilateral, unipedicled and unilateral, unipedicled TRAM flap breast reconstructions.

A large series of women who had undergone bilateral, pedicled TRAM flap reconstructions were compared with women who had had unilateral, unipedicled TRAM flap procedures to determine whether a bilateral TRAM flap breast reconstruction had significant additional morbidity. The records of all women who underwent either a bilateral or unilateral pedicled TRAM flap breast reconstruction through the Emory Clinic from 1987 to 1994 (n = 257) were retrospectively analyzed with respect to general, breast (fat necrosis, flap loss, and cellulitis), and abdominal (hernia, skin loss, and cellulitis) complications. By using logistic regression, risk factors for these complications were determined. The incidence of fat necrosis and partial flap loss was not significantly different among bilateral patients compared with patients with unilateral TRAM reconstructions (10.0 percent versus 12.6 percent, p = 0.64 and 3.8 percent versus 5.5 percent, p = 0.74, respectively). The rate of hernia formation in the bilateral TRAM flap patients (5.4 percent) was similar to that of unilateral patients (3.9 percent, p = 0.80). Significant factors for any complication in both patient populations included obesity, smoking, and prior irradiation. The type of breast reconstruction was not a significant factor for any breast or donor-site complication. A bilateral TRAM reconstruction showed a weak association with general complications. Review of the Emory Clinic experience with unilateral and bilateral pedicled TRAM flap reconstructions from 1987 to 1994 was able to detect no significant additional rate of complications for bilateral pedicled TRAM flap breast reconstructions compared with unilateral unipedicled TRAM flap procedures.

Age Factors

The delayed TRAM flap.

As surgeons gain increased clinical experience with the transverse rectus abdominis myocutaneous (TRAM) flap, or autologous breast reconstruction, technical modifications aimed at improving flap reliability continue to evolve. These modifications have allowed the TRAM flap to be performed safely in a higher-risk patient population. The delayed TRAM flap appears to have an augmented arterial supply and a lesser degree of venous congestion following division of the deep inferior epigastric vessels 2 weeks prior to reconstruction. Ischemia-related complications have been reduced in high-risk patients with the use of the delayed TRAM.

Female

Skin-sparing mastectomy. Oncologic and reconstructive considerations.

OBJECTIVE: The authors compared skin-sparing mastectomy and traditional mastectomy both followed by immediate reconstruction in the treatment of breast cancer. SUMMARY BACKGROUND DATA: Skin-sparing mastectomy is used increasingly in the treatment of breast cancer to improve the aesthetic results of immediate reconstruction. The oncologic and reconstructive outcomes of this procedure have never been analyzed closely. METHODS: Institutional experience with 435 consecutive patients who underwent total mastectomy and immediate reconstruction from January 1989 through December 1994 was examined. Mastectomies were stratified into skin-sparing (SSM) and non-skin-sparing (non-SSM) types. RESULTS: Three hundred twenty-seven SSMs and 188 non-SSMs were performed. The mean follow-up was 41.3 months (SSM, 37.5 months, non-SSM, 48.2 months). Local recurrences from invasive cancer occurred after 4.8% of SSMs versus 9.5% of non-SSMs. Sixty-five percent of patients who underwent SSMs had nothing performed on the opposite breast versus 45% in the group of patients who underwent non-SSM (p = 0.0002). Native skin flap necrosis occurred in 10.7% of patients who underwent SSMs versus 11.2% of patients who underwent non-SSMs. CONCLUSIONS: Skin-sparing mastectomy facilitates immediate breast reconstruction by reducing remedial surgery on the opposite breast. Native skin flap necrosis is not increased over that seen with non-SSM. Skin-sparing mastectomies can be used in the treatment of invasive cancer without compromising local control.

Adolescent

Management of the infected median sternotomy wound with muscle flaps. The Emory 20-year experience.

OBJECTIVE: The purpose of the study is to define those patient variables that contribute to morbidity and mortality of median sternotomy wound infection and the results of treatment by debridement and closure by muscle flaps. BACKGROUND: Infection of the median sternotomy wound after open heart surgery is a devastating complication associated with significant mortality. Twenty years ago, these wounds were treated with either open packing or antibiotic irrigation, with a mortality approaching 50% in some series. In 1975, the authors began treating these wounds with radical sternal debridement followed by closure using muscle or omental flaps. The mortality of sternal wound infection has dropped to < 10%. METHODS: The authors' total experience with 409 patients treated over 20 years is described in relation to flap choices, hospital days after sternal wound closure, and incidence rates of morbidity and mortality. One hundred eighty-six patients treated since January 1988 were studied to determine which patient variables had impact on rates of flap closure complications, recurrent sternal wound infection, or death. Variables included obesity, history of smoking, hypertension, diabetes, poststernotomy septicemia, internal mammary artery harvest, use of intra-aortic balloon pump, and perioperative myocardial infarction and were analyzed using chi square tests. Fisher's exact tests, and multivariable logistic regression analysis. RESULTS: The mortality rate over 20 years was 8.1% (33/49). Additional procedures for recurrent sternal wound infection were necessary in 5.1% of patients. Thirty-one patients (7.6%) required treatment for hematoma, and 11 patients (2.7%) required hernia repair. Among patients treated since 1988, variables strongly associated with mortality were septicemia (p < 0.00001), perioperative myocardial infarction (p = 0.006), and intra-aortic balloon pump (p = 0.0168). Factors associated with wound closure complications were intra-aortic balloon pump (p = 0.0287), hypertension (p = 0.0335), and history of smoking (p = 0.0741). Factors associated with recurrent infection were history of sternotomy (p = 0.008) and patients treated for sternal wound infection from 1988 to 1992 (p = 0.024). Mean hospital stay after sternal wound reconstruction declined from 18.6 days (1988-1992) to 12.4 days (1993-1996) (p = 0.005). To clarify management decisions of these difficult cases, a classification of sternal wound infection is presented. CONCLUSIONS: Using the principles of sternal wound debridement and early flap coverage, the authors have achieved a significant reduction in mortality after sternal wound infection and have reduced the mean hospital stay after sternal wound closure of these critically ill patients. Further reductions in mortality will depend on earlier detection of mediastinitis, before onset of septicemia, and ongoing improvements in the critical care of patients with multisystem organ failure.

Debridement

Mammography of the postreconstruction breast.

Experience with mammographic examination of the reconstructed breast after mastectomy is limited. Typical mammographic changes associated with breast reconstruction are described. When these changes are identified on mammography, they can prevent patients from having unnecessary biopsies and can alleviate patient anxiety. A retrospective review of all mammograms performed in our breast center was made to identify typical as well as unusual findings on the postreconstruction mammogram. The findings were correlated with the type of reconstruction and the physical examination findings. Mammography after mastectomy and breast reconstruction was performed in patients with palpable abnormalities, a suspicion for implant failure, or for patient anxiety. In the postreconstruction patient with a palpable mass, features characteristic of fat necrosis were the most frequent abnormal findings on mammography. Unusually placed implants or focal implant ruptures may explain a mass discovered on breast physical examination. Imaging of the reconstructed breast after mastectomy yields typical mammographic findings. Fat necrosis can be identified on mammography and may explain a new palpable mass on physical examination. Mammography continues to be useful to identify a postoperative complication or implant failure and to differentiate it from tumor recurrence.

Adult

The effects of radiation treatment after TRAM flap breast reconstruction.

A subgroup of mastectomy patients receives adjuvant radiation therapy after autogenous breast reconstruction for locoregional control of cancer. The effects of radiation therapy on pedicled transverse rectus abdominis musculocutaneous (TRAM) flaps were determined to evaluate complication rates and aesthetic results. Nineteen patients from 1981 to 1994 receiving radiation therapy after a pedicled TRAM flap reconstruction were compared with 108 patients who received radiation prior to reconstruction and 572 patients who underwent breast reconstruction without radiation. Retrospective reviews of patient charts were completed. Adjuvant radiation therapy was given for chest-wall recurrence in 13 of 19 patients. With a mean follow-up of 47.6 months from the time of reconstruction, 10 patients (52.6 percent) demonstrated postradiation changes in the TRAM flap reconstruction, and 6 required surgical intervention (31.6 percent). Overall complication rates were increased but were not found to be statistically significant between the radiated TRAM flap group and patients with preoperative radiation followed by TRAM flap reconstruction (31 versus 25 percent). Fibrosis was not found in patients with pre-TRAM flap radiation or in patients without radiation but was seen in 31.6 percent of patients who received radiation after the reconstruction. Fat necrosis was not significantly increased between the two groups of radiated patients. The complication rate does not change whether a patient receives radiation before or after her reconstruction; only the nature of the complication changes (fat necrosis to fibrosis).

Breast Neoplasms

Reconstruction of the breast.

The options for breast reconstruction include implant and expander, latissimus dorsi flap, TRAM flap, and free flaps. The moratorium on silicone gel implants has increased the use of TRAM and free flap breast reconstruction. Immediate reconstruction after preoperative planning with the surgical oncologist has improved the aesthetic results. Morbidity has been reduced through refinement in surgical technique and careful patient selection.

Breast Neoplasms

[Breast reconstruction after mastectomy and breast implants. Current status in the USA].

The author review breast reconstruction after mastectomy for cancer, taking account the technical progress and problems raised by breast implants over the last twenty years. Immediate breast reconstruction has become a routine clinical practice. The principle, indications and complications of reconstruction techniques are presented: temporary expansion prosthesis, permanent expansion prosthesis, latissimus dorsi myocutaneous flap associated with an implant, rectus abdominis myocutaneous pedicle flap, free flaps.

Breast Implantation

Immediate breast reconstruction for stage III breast cancer using transverse rectus abdominis musculocutaneous (TRAM) flap.

BACKGROUND: The management of state III breast cancer is challenging; it often includes multimodal treatment with systemic therapy and/or radiation therapy and surgery. Immediate breast reconstruction has not traditionally been performed in these patients. We review the results of immediate transverse rectus abdominis musculocutaneous (TRAM) flap in 21 patients treated for stage III breast cancer. METHODS: Data have been collected retrospectively on 21 patients diagnosed with stage III breast cancer between 1987 and 1994. All patients had mastectomy and immediate TRAM reconstruction. Thirteen patients received primary systemic therapy, 10 patients received postoperative consolidation radiotherapy to the operative site, and 3 patients received preoperative radiation. RESULTS: Mean follow-up for the group was 26 months. Two patients died with disseminated disease: neither of them developed local disease recurrence in the operative site; 82% of the patients followed for at least two years are free of disease. Sixty-two percent of the patients received preoperative chemotherapy, the remaining patients received postoperative multiagent chemotherapy and/or radiation therapy. Two of the patients received autologous bone marrow transplants after their adjuvant therapy. Ten patients had postoperative radiotherapy for consolidation; three patients received preoperative radiation. CONCLUSIONS: Immediate TRAM reconstruction for stage III breast cancer is not associated with a delay in adjuvant therapy or an increased risk of local relapse. It facilitates wide resection of involved skin without skin grafting. Radiation therapy can be delivered to the reconstructed breast when indicated without difficulty. Breast reconstruction facilitates surgical resection of stage III breast cancer with primary closure and should be considered if the patient desires immediate breast reconstruction.

Breast Neoplasms

Autologous breast reconstruction with endoscopic latissimus dorsi musculosubcutaneous flaps in patients choosing breast-conserving therapy: mammographic appearance.

OBJECTIVE: The objective of this study was to define and evaluate mammographic changes in patients treated with breast-conserving therapy and a new reconstructive technique that uses autologous tissue from a latissimus dorsi musculosubcutaneous flap. MATERIALS AND METHODS: Of 20 patients who underwent either immediate or delayed endoscopic latissimus dorsi muscle flap reconstruction after lumpectomy, 13 also had postsurgery mammograms available for review. Radiographic findings assessed included skin thickening, density or radiolucency at the reconstruction site, density around the flap, fat necrosis, calcifications, and the presence of surgical clips. RESULTS: Mammograms for three patients (23%) revealed thickening that we believed was attributable to radiation therapy. No patient had increased density in the flap itself; all flaps were relatively radiolucent centrally (13/13; 100%). Mammograms revealed density around the rim of the flap in four patients (31%). This density was most likely secondary to latissimus dorsi muscle fibers and did not limit radiographic evaluation. One patient had calcifications, probably secondary to fat necrosis. No oil cysts were seen. In the majority of patients (11/13; 85%), surgical clips were visible. CONCLUSION: Endoscopic latissimus dorsi muscle flap reconstruction, previously used only for mastectomy patients, is now being used for improved esthetic outcome in selected patients who desire breast conservation. Our results indicate that the mammographic findings are predictable. The most common findings are relative radiolucency centrally, with or without density from muscle fibers around the edges of the area of tissue transfer. The transplanted musculosubcutaneous flap does not interfere with mammographic evaluation.

Adult

Endoscopic abdominoplasty and endoscopically assisted miniabdominoplasty.

Recent developments in abdominal contouring procedures have included the extensive use of liposuction and the use of modified or limited scars, producing in effect a "downsizing" of the operative procedures for many patients. The use of minimally invasive techniques based on endoscopic technology and instrumentation represents a logical extension of this trend. Endoscopic visualization and dissection facilitate musculofascial repair through a very small incision and, combined with liposuction, allows significant improvement in abdominal recontouring in selected patients. Patient selection parameters, instrumentation, operative techniques, and complications of this developing procedure are described.

Abdomen

TRAM flap breast reconstruction after radiation treatment.

OBJECTIVE: Patients with and without radiation treatment before their breast reconstruction were compared to study the relationship of radiation to flap-related complications. SUMMARY BACKGROUND DATA: The transverse rectus abdominis muscle (TRAM) flap for breast reconstruction involves a a vascular pedicle and recipient bed, both included in the radiated field of patients undergoing adjunctive therapy. Detailed reviews of flap-related complications in this subgroup of patients have been limited. METHODS: One hundred eight patients with radiation treatment who subsequently underwent a TRAM flap breast reconstruction were compared with 572 patients with no radiation treatment before similar reconstruction. Flap-related complications, radiation dosage, time, fields, relationships between risk factors, and complications were studied. RESULTS: Overall complication rates were comparable between the two groups. Only fat necrosis (> 10% of total reconstruction) was found to be statistically significant (17.6% vs. 10.1%, p = 0.03228). No difference was found for fat necrosis in unipedicled vs. bipedicled flaps controlled for radiation (17.7% vs. 17.4%). Obesity and radiation therapy were associated with fat necrosis and major infection in a logistic regression. Significant abdominal scarring was also associated with major infection (p = 0.0044). CONCLUSIONS: In this, the largest reported series, radiation therapy was associated with increased fat necrosis and major infection. The use of the TRAM flap was not found to be prohibitive in radiated patients and should still be the first choice in this subgroup of patients.

Breast Neoplasms

TRAM flap anatomy correlated with a 10-year clinical experience with 556 patients.

This study examines the vascular anatomy of the TRAM flap and evaluates risk factors associated with complications among 556 women who had TRAM flap breast reconstruction. Fifty-nine patients (10.6 percent) developed fat necrosis involving 10 percent or more of their breast. Risk factors associated with fat necrosis were a history of chest-wall irradiation (p = 0.001), significant abdominal scar (p < 0.01), and obesity (p < 0.02). Among unipedicle reconstructions, patients with multiple risk factors had three times the incidence of fat necrosis (24.7 versus 8.3 percent) compared with patients with one or no risk factors (p < 0.002). Patients with multiple risk factors who had bipedicled TRAM flap reconstruction had no associated increased incidence of fat necrosis (p > 0.18). Forty-nine patients (8.8 percent) developed abdominal hernias. Risk factors associated with hernia formation included smoking at the time of surgery (p = 0.00001) and abdominal-wall repair with interposed mesh (p < 0.00001). The overall complication rate for this series was 23.7 percent (132 of 556). Risk factors associated with any complication included smoking (p < 0.002), history of chest-wall irradiation (p < 0.002), significant abdominal scar (p < 0.005), and obesity (p < 0.02). Patient selection is a fundamental determinant of successful TRAM flap breast reconstruction. Among patients with multiple risk factors, the risk of tissue loss in the reconstructed breast may be diminished by use of a bipedicled TRAM flap.

Breast Neoplasms