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Biomedical subjects

D M Cromeens

Publications and source records attributed to D M Cromeens.

At least 19 recordsLinked to original sources

Preclinical analysis of radiolabeled anti-GD2 immunoglobulin G.

BACKGROUND: Unlabeled murine monoclonal anti-GD2 immunoglobulin (Ig)G (14G2a) reactive with nervous system diganglioside and neuroblastoma, melanoma, and small cell lung carcinoma produces tumor regression. However, serious acute abdominal pain, paresthesia, hypotension and hypertension, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and occasional motor weakness occur. Studies in preclinical animal models can elucidate the mechanism of the observed neurotoxicity and lead to anti-GD2 antibody treatment with a higher therapeutic ratio. METHODS: One mg of 14G2a or control IgG was labeled with 1-2 mCi of indium-111 and administered intravenously to beagles (n = 8). In 2 dogs, additional high dose (200 mg) unlabeled 14G2a was given over 5 days. Whole body gamma camera images and SPECT scans were obtained repeatedly over 7 days. On Day 7, sciatic nerve conduction studies were performed, and after euthanasia radioactivity was determined in major organs. RESULTS: Unlabeled high dose 14G2a administered to mice, rats, or rabbits did not cause neurotoxicity within 3 weeks. GD2 antigens were shown by immunochemistry to be present in brain and peripheral nerve tissues of rodents and beagles. After in vivo administration of radiolabeled 14G2a, canine lymph nodes showed specific uptake, but only minimal radioactivity was found in the nervous system. Dogs that received additional high dose unlabeled 14G2a showed much higher lymph node uptake and follicular lymph node hyperplasia. Low motor response amplitudes on nerve conduction studies were noted. CONCLUSIONS: A radioisotope label on IgG and its visualization in a large series of animal models indicate that a low protein dose of anti-GD2 IgG will not cause neurologic side effects in patients. High protein dose anti-GD2 IgG may enhance antineoplastic effects and contribute to neurotoxicity through stimulation of normal lymphocytes with subsequent release of cytokines.

Animals

Drug-induced vasodilation in an in vitro and in vivo study: the effects of nicardipine, papaverine, and lidocaine on the rabbit carotid artery.

Extreme arterial vasoconstriction (vasospasm) is a common problem encountered in microvascular surgery. An ideal pharmacologic tool able to counteract ischemia during microsurgery should be easy to apply and exert its action both locally and distally in the microcirculation of the flap. We have compared in vitro and in vivo vascular properties of nicardipine, papaverine, and lidocaine in the rabbit carotid artery. In vitro, rings from the rabbit carotid artery (n = 7) were bathed in Krebs-Ringers solution and stretched progressively to an optimal tension of 3.7 to 4.2 g. The specimens were contracted with norepinephrine (1 microM), and a cumulative dose response curve was established. In vivo, microvascular anastomoses were performed bilaterally in the rabbit carotid artery in 35 animals using 9-0 nylon suture and standard microsurgical techniques. During and after the anastomoses, nicardipine (0.1, 0.01 mg topical, or 0.1 mg/hour IV), papaverine (30 mg/cc topical), and lidocaine (2% with and without epinephrine) were applied (blinded) at the anastomotic site in five rabbits each. Heparinized sodium chloride was used as topical irrigation for control and to clean the anastomosis. Blood flow changes were monitored continuously with the transonic Doppler for 30 minutes after the procedure. The systemic blood pressure was also monitored in a group of pilot experiments. A documented decrease in blood flow was noted in all animals after the microvascular anastomosis. Nicardipine and papaverine evoked a concentration-dependent relaxation to precontracted rings to norepinephrine. Nicardipine was greater than papaverine in inducing relaxation. Lidocaine demonstrated a biphasic response with low concentrations potentiating contraction. Systemic nicardipine and papaverine significantly increased the blood flow in the rabbit carotid artery. Topical application of nicardipine and lidocaine did not significantly alter the blood flow; however, the application of nicardipine demonstrates a trend toward increased flow. Lidocaine with epinephrine significantly decreased the blood flow. No drug was found to alter the blood pressure of the animals. Our results demonstrate that nicardipine and papaverine seem to be pharmacologic tools able to increase the blood flow in anastomotic arteries. In contrast, the use of 2% lidocaine as a spasmolytic agent should be re-evaluated, since this substance may act as a partial agonist.

Administration, Topical

Stenosing colonic adenocarcinoma in a female rhesus monkey.

Laparoscopic surgery was performed on a 16 year-old female rhesus monkey presenting with chronic lethargy and inappetence. The procedure revealed a "napkin-ring" stricture located in the ascending large colon. Histologic evaluation of the colonic lesion exhibited large numbers of irregular acini lined by a single layer of well-differentiated neoplastic epithelial cells. Based on the gross and histopathologic findings a diagnosis of adenocarcinoma of the proximal colon was made.

Adenocarcinoma

Visual laser ablation of the canine prostate with a diffusing fiber and an 805-nanometer diode laser.

BACKGROUND AND OBJECTIVE: Although the popularity of visual laser ablation of the prostate (VLAP) as a treatment for symptomatic, benign prostatic hyperplasia (BPH) is increasing, the perceived advantages of VLAP over conventional transurethral electroresection of the prostate (TURP) is being debated because optimal technique and dosimetry for surgical lasers are still being refined. At this time, the 1.06 neodymium:yttrium-aluminum-garnet (Nd:YAG) laser and a laterally deflecting delivery system is the hardware combination most widely used for VLAP. STUDY DESIGN/MATERIALS AND METHODS: Reported here is a study of an alternate system, a 805-nm diode laser (Diomed 25 Diomedics, The Woodlands, TX) with a cylindrically diffusing fiber (Surgimedics Inc., The Woodlands, TX). Eight mongrel dogs were prostatectomized by transurethral irradiation of the prostate with 15,000 J of diode laser energy delivered via a fiber that diffuses the energy in a 1.5-cm-long cylindrical pattern. The dogs were sacrificed and prostates harvested at 3 hours and 1,4,7,14,21,35, and 49 days after the procedure, fixed with 10% buffered formalin, and examined histologically. RESULTS/CONCLUSIONS: It was found that this laser/fiber combination created volumes of tissue coagulation similar to those encountered in our previous work with the Nd:YAG laser in combination with both laterally deflecting and diffuser fibers, while offering the distinct advantages of simplified technique, lower cost hardware, and fewer postoperative complications in the dog model.

Animals

Alternative methods of exposure minimize cardiopulmonary risk in experimental animals during minimally invasive surgery.

BACKGROUND: Alternative methods of exposure are needed for minimally invasive surgery to avoid hypercarbia and acidosis associated with carbon dioxide (CO2) abdominal insufflation. The goals of this study were to determine the pulmonary and hemodynamic effects of both helium (HE) abdominal insufflation and placement of a mechanical abdominal wall-lifting device (lifter) during laparoscopy. METHODS: Sixteen adult domestic pigs under general endotracheal anesthesia underwent baseline measurements of pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and arterial blood gas. Six pigs underwent standard CO2 abdominal insufflation, five pigs underwent abdominal insufflation with HE, and a lifter was used for exposure in five other animals. Sequential readings of PCWP, CO, and arterial blood gas were recorded at 20-min intervals for 60 min in all 16 animals. RESULTS: No significant changes from baseline values were noted in arterial pCO2 or pH in animals who underwent placement of the lifter at any time point. After undergoing HE insufflation, animals experienced modest but significant acidosis and little change in pCO2. There was a significant rise in arterial pCO2 and decrease in pH from baseline values at all time points in animals undergoing CO2 insufflation. CONCLUSIONS: This study shows that neither HE abdominal insufflation or the lifter have significant deleterious pulmonary or hemodynamic effects on experimental animals during laparoscopy. Gasless laparoscopy or HE insufflation may provide a safer alternative method of exposure for minimally invasive surgery in patients with pre-existing pulmonary or cardiac dysfunction. By minimizing risk in these patients, costly invasive monitoring may be avoided.

Animals

Proposal for translational analysis and development of clinical radiolabeled immunoglobulin therapy.

BACKGROUND AND PURPOSE: Radiolabeled immunoglobulin therapy (RIT) can be a selective, effective, low-toxicity outpatient cancer therapy. A consensus on the best approach for the preclinical and clinical development of RIT reagents needs to be developed. We report the M.D. Anderson Cancer Center prior experience in translating RIT from laboratory to clinic for the treatment of Hodgkin's disease and propose a flow diagram for the development of RIT for other malignancies. MATERIAL AND METHODS: Three different animal models are described: nude mice bearing human tumor xenografts, normal beagle dogs, and normal rhesus monkeys. We produced and purified antibodies and prepared chelate-immunoconjugates reactive with six different human tumor-associated antigens. The Igs used were derived from rabbits, mice, and humans (human-derived RIT reagents being less immunogenic in human patients). Eighty patients with refractory Hodgkin's disease were treated with radiolabeled antiferritin. RESULTS: We recommend a two-injection scheme using, (1) an indium-111-labeled radioimmunoconjugate for diagnosis, pharmacokinetic studies, and dosimetry, and (2) a yttrium-90-labeled radioimmunoconjugate for therapy. The animal models provide useful data on tumor targeting, radiotoxicology, and undesirable biodistributions. A 70% response rate is obtained in patients with advanced recurrent Hodgkin's disease. More extensive preclinical testing allows for safer and more effective clinical RIT studies. CONCLUSIONS: We recommend, (1) preclinical optimization of chelation chemistry, Ig size, Ig origin, route of administration, and fractionation, (2) new clinical Phase I-III studies more appropriate for RIT development than the classical Phase I-III studies used for the development of chemotherapeutic agents, and (3) more extensive preclinical testing of RIT reagents.

Animals

Thrombosis in an ischemia-reperfusion injury flap model: is vessel anastomosis a factor?

This study was undertaken to elucidate the possible contribution of vessel anastomosis to the incidence of vessel thrombosis in an ischemia- reperfusion injury flap model in rabbits. Bilateral groin flaps were elevated on isolated vascular pedicles and rendered ischemic for 6 (n = 11), 8 (n = 5), 15.5 (n = 5), or 24 hr (n = 8). After the ischemic episode, an arterial anastomosis was performed on one side, and then perfusion was reestablished on both sides. Although the incidence of thrombosis increased with the interval of ischemia, there was no statistically significant difference in thrombosis rate between the two sides for any of the ischemia intervals studied. The authors conclude that the presence of an arterial anastomosis does not increase the rate of vessel thrombosis in flaps after primary ischemia-reperfusion injury in the rabbit model.

Anastomosis, Surgical

Collagen matrix cisplatin prevents local tumor growth after margin-positive resection.

The extent of a tumor, sometimes combined with its anatomic location, can compromise the surgeon's ability to obtain clear margins of resection. Regional recurrence of a tumor in the resection bed frequently produces significant local morbidity and limits patient survival time and quality of life. A positive margin resection model was created by induction of perinephric VX-2 tumors in New Zealand white rabbits followed by unilateral nephrectomy with grossly positive margins in the retroperitoneum. Resection bed injection of a novel collagen matrix with cisplatin (CDDP) and epinephrine prevented tumor recurrence in all treated animals. In contrast, control animals treated with CDDP alone, CDDP and epinephrine alone, or the collagen matrix with epinephrine had bulky tumor recurrence in the resection bed. Resection bed tissue levels of platinum were determined by flameless absorption spectrophotometry at 1, 4, and 7 days following nephrectomy and injection of the collagen matrix, CDDP, and epinephrine or CDDP and epinephrine without the collagen matrix. Significantly higher resection bed drug levels of platinum were achieved through the use of the novel collagen matrix than through the use of CDDP and epinephrine alone (P < 0.05). The results of this study indicate that tumor bed treatment with CDDP and a unique collagen matrix drug-delivery vehicle produces prolonged high resection bed levels of platinum and prevents local tumor recurrence.

Animals

Interstitial laser prostatectomy.

Serial gross and histopathologic examinations of the prostate following interstitial laser prostatectomy in the canine model demonstrated distinct zonal thermal changes around the entire active area of the interstitial thermal therapy (ITT) fiber. A large, well-demarcated area of acute coagulative necrosis immediately surrounded each fiber tract; beyond that were a prominent narrow peripheral zone of marked tissue disruption and an outer zone of hemorrhage. Liquefaction within these coagulative areas was evident within 24 hours, and by 4 days, each lobe of the prostate contained an irregular cavity that became lined by normal-appearing transitional epithelium and that, by 5 weeks, communicated with the prostatic urethra. These postmortem pathologic observations, similar to findings previously reported following transurethral laser prostatectomy, suggest that interstitial laser thermal therapy may provide an additional means for treating benign prostatic hyperplasia in men.

Animals

Pathologic changes following transurethral canine prostatectomy with a cylindrically diffusing fiber.

Transurethral laser prostatectomy was performed on eight mongrel dogs employing a cylindrically diffusing fiber delivery system and a 1.06 mu Nd:YAG laser. Each dog received 15,000 joules of laser energy delivered to the prostate in one continuous dose of 25 watts for 10 minutes. Gross and histopathologic examinations of serial sections of the prostate were performed postoperatively after intervals of 2 hours to 7 weeks. Grossly, a spherical zone of destruction averaging 2.8 cm in diameter was present in dogs except one. Histopathologic changes in the prostate consisted of acute coagulative necrosis with interstitial edema at 2 hours, becoming hemorrhagic by 24 hours. A prominent circular area of acute coagulative necrosis with progressively larger areas of liquefaction and hemorrhage was present in prostates harvested from 4 days to 1 week after lasing. Initial re-epithelization of the resulting cavity was observed at 3 weeks with nearly complete epithelialization 7 weeks after laser treatment. The simplified fiber placement and lack of postoperative complications in this small group of dogs suggest that the cylindrically diffusing fiber could offer significant advantages over laterally deflecting fibers for transurethral prostatectomies in the dog model.

Animals

Hepatic arterial infusion of verapamil and doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration: pharmacological evaluation of reduction in systemic drug exposure and assessment of hepatic toxicity.

Tumour resistance to chemotherapeutic drugs through expression of the multidrug resistance phenotype is a major impediment in the treatment of hepatic malignancies. We performed hepatic arterial infusion of verapamil (at a dose known to block P-glycoprotein activity) and doxorubicin combined with complete hepatic venous isolation and extracorporeal chemofiltration in non-tumour-bearing pigs with normal livers to evaluate the pharmacology and toxicology of this drug combination. The complete hepatic venous isolation-chemofiltration system significantly reduced system exposure to both verapamil and doxorubicin (P < 0.01). Hepatic arterial infusion of verapamil (2 mg/kg) alone did not result in hepatocellular toxicity. However, the combination of verapamil and doxorubicin (3 mg/kg or 5 mg/kg) produced significant elevations in liver enzymes (P < 0.01), and gross histological evidence of liver damage in 90% of the treated animals. The results of this study indicate that hepatic arterial infusion of verapamil and doxorubicin, in an attempt to improve treatment response in unresectable liver tumours expressing the multidrug resistance phenotype, may not be tolerated by patients with limited hepatic reserve.

Animals

NG-methyl-L-arginine, an inhibitor of nitric oxide formation, reverses IL-2-mediated hypotension in dogs.

The effects of NG-methyl-L-arginine (L-NMA), an inhibitor of nitric oxide formation, were studied in dogs treated with interleukin-2 (IL-2). The administration of IL-2 to dogs resulted in hypotension within 3 days of treatment. The development of hypotension correlated with accumulation in the serum of nitrate, which is a stable breakdown product of nitric oxide. Administration of L-NMA decreased serum nitrate levels and increased the mean arterial pressure. The antihypotensive effect was dose dependent with a maximum effect observed at a dose of 20 mg/kg. Administration of a continuous infusion of L-NMA (5 mg.kg-1.h-1) maintained the mean arterial pressure for 48 h with concurrent administration of IL-2. Evaluation of IL-2-induced lymphokine-activated killer cell proliferation and tumoricidal activity toward a canine glioblastoma target cell line was unaffected by L-NMA. These studies imply that L-NMA may effectively ameliorate the dose-limiting hypotension associated with administration of IL-2 without adversely affecting the antitumor effects.

Animals

NG-methyl-L-arginine, an inhibitor of nitric oxide formation, acts synergistically with dobutamine to improve cardiovascular performance in endotoxemic dogs.

OBJECTIVE: To evaluate the hemodynamic effects of the nitric oxide inhibitor, NG-methyl-L-arginine, and dobutamine during experimental endotoxemia. DESIGN: Prospective, randomized, controlled animal study. SETTING: University research laboratory. SUBJECTS: Adult, male mongrel dogs. INTERVENTIONS: After catheterization with a flow-directed, thermal-dilution pulmonary artery flotation catheter and arterial catheter, awake dogs received either NG-methyl-L-arginine or dobutamine alone or in combination (controls; n = 5). Other animals were administered endotoxin (50 micrograms/kg), then received either NG-methyl-L-arginine alone or in combination with dobutamine after the onset of hypotension (endotoxin-treated; n = 5). MEASUREMENTS AND MAIN RESULTS: Both dobutamine and NG-methyl-L-arginine alone had a small, but significant vasopressor effect on control animals. In contrast, administration of the combination of NG-methyl-L-arginine and dobutamine resulted in a 48.6% increase in mean arterial pressure, an effect which was dose-dependent with respect to NG-methyl-L-arginine. In dogs treated with 50 micrograms/kg of endotoxin, hypotension could be only partially reversed by NG-methyl-L-arginine, mainly due to a decline in cardiac output. Co-infusion of dobutamine reversed this depression of cardiac output and resulted in a complete restoration of blood pressure. CONCLUSIONS: Later stages of septic shock are characterized by hypotension and decreased myocardial performance. A major mediator of hypotension is nitric oxide, a vasodilatory agent derived from L-arginine. Administration of the arginine derivative, NG-methyl-L-arginine, improved systemic vascular resistance but not myocardial performance. The addition of an inotropic agent to NG-methyl-L-arginine, a nitric oxide synthase inhibitor, resulted in an enhancement of the antihypotensive action of NG-methyl-L-arginine through the restoration of cardiac output. The synergistic action between dobutamine and NG-methyl-L-arginine may be of therapeutic value in the treatment of septic shock.

Animals

Amiprilose in the prevention of restenosis after coronary intervention in a swine model.

BACKGROUND: Amiprilose hydrochloride is a synthetic carbohydrate with anti-inflammatory and antiproliferative properties. This study tested the potential benefit of amiprilose in preventing coronary artery restenosis in a swine model. METHODS: The swine restenosis model was prepared using Hanford miniature swine made atherosclerotic with coronary abrasion, high-fat and high-cholesterol feeding, and intracoronary stenting. Eighteen animals were randomized to receive amiprilose, 100 mg/kg body weight orally twice per day (n = 9), or no amiprilose (n = 9) beginning 5 days before stenting and continuing through 4 weeks until sacrifice. Presacrifice quantitative coronary angiography and postsacrifice histologic examination revealed the degree of intimal proliferation. RESULTS: Coronary angiography revealed no difference in percentage-diameter stenosis between the amiprilose and control groups (left anterior descending artery [LAD], 46% +/- 10% vs 44% +/- 17%; circumflex artery [CFX], 43% +/- 21% vs 42% +/- 15%; right coronary artery [RCA], 37% +/- 11% vs 34% +/- 9%; P = not significant [NS]), respectively, or in change in lumen diameter from poststenting to presacrifice (LAD, -1.0 +/- 0.4 mm vs -1.1 +/- 0.7 mm; CFX, -1.2 +/- 0.8 mm vs -1.0 +/- 0.7 mm; RCA, -1.1 +/- 0.4 mm vs -1.0 +/- 0.4 mm; P = NS). Morphometric histologic analysis likewise showed no difference in percentage-area stenosis (LAD, 55% +/- 14% vs 55% +/- 15%; CFX, 53% +/- 15% vs 54% +/- 12%; RCA, 39% +/- 17% vs 39% +/- 20%; P = NS) or in maximal intimal thickness. CONCLUSION: Amiprilose hydrochloride did not prevent coronary intimal proliferation in this swine model of restenosis.

Angioplasty, Balloon, Coronary

Pathologic changes occurring in the prostate following transurethral laser prostatectomy.

Serial gross and histopathologic examinations of the prostate following transurethral laser prostatectomy in the canine model demonstrated an immediate well-demarcated sphere of thermal necrosis measuring 2.7 cm in diameter, which, within 24 hours, had begun liquefaction and was showing multiple areas of cavitation. By the end of the 1st week, the areas of cavitation had coalesced to form a central cavity lined by a narrow layer of necrotic tissue clinging to the thin surviving peripheral belt of prostatic glandular parenchyma. At 3 weeks, the bluish-black discoloration resulting from breakdown of blood in the necrotic tissue had subsided, leaving masses of coagulonecrotic tissue within the central cavity. Within 5 weeks, the ectatic central cavity was lined by transitional epithelium. These postmortem pathologic observations confirm our surgical and clinical impressions of being able to satisfactorily perform an effective transurethral prostatectomy using neodymium:YAG (Nd:YAG) laser photoirradiation.

Animals

Use of the holmium:YAG laser in urology.

The tissue effects of a holmium:YAG (Ho:YAG) laser operating at a wavelength of 2.1 mu with a maximum power of 15 watts (W) and 10 different energy-pulse settings was systematically evaluated on kidney, bladder, prostate, ureteral, and vasal tissue in the dog. In addition, various urologic surgical procedures (partial nephrectomy, transurethral laser incision of the prostate, and laser-assisted vasovasostomy) were performed in the dog, and a laparoscopic pelvic lymph node dissection was carried out in a pig. Although the Ho:YAG laser has a strong affinity for water, precise tissue ablation was achieved in both the contact and non-contact mode when used endoscopically in a fluid medium to ablate prostatic and vesical tissue. Using the usual parameters for tissue destruction (blanching without charring), the depth of thermal injury in the bladder and ureter was kept superficial. In performing partial nephrectomies, a 2-fold reduction in the zone of coagulative necrosis was demonstrated compared to the use of the continuous wave Neodymium:YAG laser (Nd:YAG). When used through the laparoscope, the Ho:YAG laser provided precise cutting and, combined with electrocautery, allowed the dissection to proceed quickly and smoothly. Hemostatic control was adequate in all surgical procedures. Although the results of these investigations are preliminary, our initial experience with the Ho:YAG laser has been favorable and warrants further investigations.

Aluminum Silicates

Transurethral incision of the prostate using the holmium:YAG laser.

Transurethral incisions of the prostate were made endoscopically in 5 dogs under a fluid medium using a holmium:YAG (Ho:YAG) laser operating at a wavelength of 2.1 microns and with delivery of 1.0 J/pulse in 15 Hz (15 W). Histopathologic examination of tissues collected immediately after surgery revealed irregular crevices outlined by a narrow zone of coagulative necrosis. Ulcerated fissures persisted at 5 and 7 days with the initial stages of epithelial regeneration partially re-epithelializing the ulcerated surfaces. A modest inflammatory response characterized by edema, hemorrhage, and a mixed inflammatory cell infiltrate was also associated with the laser incision sites at 5 and 7 days. Three weeks postlasing, the ulcerated surfaces of the fissures were completely re-epithelialized. At 5 weeks only a slight indentation persisted at the incision sites with minimal changes in the subjacent submucosa and prostatic glandular architecture. Although the results of these investigations are preliminary, we believe that the Ho:YAG laser warrants further clinical evaluation for treating patients with benign prostatic hyperplasia (BPH), urethral strictures, bladder neck contractures, and constrictions of the upper urinary tracts.

Aluminum Silicates

Sutureless end-to-end bowel anastomosis using Nd:YAG and water-soluble intraluminal stent.

Sutureless end-to-end intestinal anastomoses were successfully constructed in 20 rabbits. A water-soluble intraluminal stent was used to approximate the tissue edges, and the anastomotic seam was lased with 1.06 microns neodymium:YAG (Nd:YAG) laser energy supplied through a hand-held 600-microns gas-cooled noncontact optical fiber. A continuous 5-watt wave of power was applied over periods ranging from 46 to 92 seconds to produce the tissue blanching and shrinkage that indicated a satisfactory tissue weld. Integrity, degree of tissue reaction, and bursting pressures of the anastomoses were compared to those of anastomoses constructed using standard sutured techniques. The results of the two methods were equivalent at 1 to 3 days, but the laser-fused enteric anastomoses showed less inflammatory reaction and greater bursting pressures at 7 and 14 days. Application of a variety of proteinaceous solutions including extracellular matrix materials and epidermal growth factors prior to lasing failed to augment wound healing. We conclude that lasers show promise as reconstructive, in addition to ablative, surgical instruments.

Anastomosis, Surgical