A Multicentre Retrospective Review of Clinical Characteristics of Uterine Sarcoma.

OBJECTIVE: Professional societies have recently urged gynaecologists to counsel patients about the risks of encountering uterine sarcoma at fibroid surgery especially when morcellation is used. Our objective was to learn the preoperative and postoperative characteristics of patients with uterine sarcoma to better counsel patients undergoing surgery for presumably benign fibroids. METHODS: This is a multicentre, retrospective cohort study. Three academic tertiary cancer centres in Southern Ontario over a 13-year period (2001-2014). Patients diagnosed with leiomyosarcoma or endometrial stromal sarcoma were included after identification using pathology databases. A retrospective chart review was conducted to determine clinical characteristics and survival data. RESULTS: The study included 302 patients with uterine sarcomas (221 leiomyosarcomas, 81 endometrial stromal sarcomas). Mean age at diagnosis was 55 years, and 59% were postmenopausal. Sarcoma diagnosis was made following endometrial sampling (25%), hysterectomy (69% laparotomy, 2.7% laparoscopic/vaginal), and myomectomy (3.3%). Of all the patients who underwent endometrial sampling, 65% were diagnosed with a uterine sarcoma in this manner. A general gynaecologist performed the primary surgical procedure in 166 of 302 patients (55%). Tumour disruption at the time of primary surgery occurred in 57 of 295 patients (19%): subtotal hysterectomy (21), myomectomy (10), dissection of adherent tumour (17), and morcellation (9). Morcellation, to facilitate a minimally invasive approach, was performed with scalpel (2 at laparotomy, 5 vaginally) and with a laparoscopic electro-mechanical morcellator (2). At a median follow-up of 2.9 years, there was no significant difference in survival for stage I and II patients with tumour disruption (n = 32) compared with those without tumour disruption (n = 143), regardless of sarcoma type (P = 0.6). CONCLUSION: The majority of patients with uterine sarcomas were postmenopausal. Many can be diagnosed preoperatively with endometrial sampling. Forty-one percent of patients with uterine sarcomas had a high preoperative index of suspicion, resulting in intervention by an oncologist. Morcellation with laparoscopic electro-mechanical morcellator was rare.

Tacrolimus preserves vasomotor function and maintains vascular homeostasis.

BACKGROUND: Post-transplant immunosuppression is associated with endothelial dysfunction that may lead to vasculopathy. We have previously demonstrated that cyclosporine causes vascular dysfunction. In this we study examined the effect of tacrolimus (Tac) in an identical model. METHODS: Lewis rats (n = 8 per group) were injected with Tac (low, medium or high dose) or saline (Con) daily for 2 weeks. Segments of thoracic aorta (TAo) were assessed for endothelium-dependent (Edep) and -independent (Eind) vasorelaxation (E(max)) and sensitivity to endothelin (ET)-induced vasoconstriction (C(max)). ET(A) and ET(B) receptor (Rc) expression levels were determined in TAo. Tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-ß) expression were determined in myocardial (LV) tissue. Plasma ET levels and tissue oxidative injury were quantified by enzyme-linked immunoassay. RESULTS: Tac did not impair Edep relaxation when compared with Con (p = 0.69). Impairment of sodium nitroprusside-mediated Eind vasorelaxation was noted with Tac (E(max): Con 69 ± 2%, Tac high 54 ± 2%; p = 0.0001), whereas no such impairment was seen with diltiazem-mediated Eind vasorelaxation (p = 0.06). Tac decreased sensitivity to ET (C(max): Con 222 ± 19%, Tac high 162 ± 11%; p = 0.0002) and ET levels (Con 0.8 ± 0.1 fmol/ml, Tac 0.4 ± 0.1 fmol/ml; p = 0.02). Tac did not alter ET(A) Rc expression (p = 0.28), but increased ET(B) Rc levels (p = 0.02). Oxidative injury was similar in both LV (p = 0.43) and Ao (p = 0.73) tissue. Similarly, TNF-α expression (p = 0.16) was not different between groups, whereas expression of TGF-ß demonstrated a significant decrease with Tac treatment (p = 0.02). CONCLUSION: Our findings suggests that tacrolimus has beneficial effects with respect to endothelial function.

Endothelin-1 antagonism and nitric oxide augmentation prevents cyclosporine-induced vasomotor impairment.

BACKGROUND: We previously demonstrated that cyclosporine (CyA) impairs endothelial function as a result of alterations in nitric oxide (NO) and endothelin-1 (ET-1) regulation. Bosentan (BOS), an ET-1 antagonist, and tetrahydrobiopterin (BH4), an eNOS cofactor, may reduce endothelial dysfunction by improving ET-1/NO homeostasis. METHODS: Lewis rats received intraperitoneal injections of CyA with BOS or with BOS+BH4 daily for 2 weeks. Control (Con) animals received saline injections. Thoracic aortic segments were assessed for endothelial-dependent (E(dep)) and -independent (E(ind)) relaxation (E(max%)) after exposure to acetylcholine and sodium nitroprusside. Vessel sensitivity to ET-1-induced vasospasm was evaluated. RESULTS: CyA use resulted in impaired E(dep) vasorelaxation when compared with Con, whereas BOS and BH4 treatment preserved E(dep) vasorelaxation. CyA significantly altered E(ind) vasorelaxation, whereas BOS and BH4 therapy attenuated CyA-induced effects. Compared with Con, CyA and BH4 exposure demonstrated increased sensitivity to ET-1 vasospasm. BOS therapy abrogated the CyA and BH4-induced sensitivity to vasospasm. CyA treatment resulted in higher 8-isoprostane levels compared with Con. CyA-mediated vascular dysfunction is characterized by impaired NO and ET-1 homeostasis. CONCLUSIONS: Our study suggests potential therapeutic strategies to prevent endothelial dysfunction as combined therapy with ET-1 antagonism and NO augmentation completely abrogated CyA-induced vascular injury.

Donor pretreatment with hypertonic saline attenuates primary allograft dysfunction: a pilot study in a porcine model.

BACKGROUND: Hypertonic saline (HTS) has been previously demonstrated to have immune modulatory and vascular protective effects. We assessed the effect of donor pretreatment with HTS on allograft preservation in a porcine model of orthotopic heart transplantation. METHODS AND RESULTS: Orthotopic transplants were performed after 6 hours of cold static allograft storage. Donor pigs were randomly assigned to pretreatment with (n=7) or without (n=6) HTS (4.5 mL/kg of 7.5% NaCl) administered 1 hour before donor heart arrest. Administration of HTS increased serum sodium level from 138+/-2 mmol/L to 154+/-4 mmol/L, which normalized to 144+/-3 mmol/L 1 hour after infusion. Successful weaning from cardiopulmonary bypass was significantly greater in HTS-treated hearts (6/7 vs 1/6; P=0.029). Preload recruitable stroke work after transplantation was improved compared to control (88+/-21% vs 35+/-8% of baseline; P=0.0001). Similarly, end-systolic elastance was improved compared to control (85+/-17% vs 42+/-12% of baseline; P=0.0002). Posttransplantation systolic blood pressure was significantly higher in the donor HTS group (60+/-9 mm Hg vs 35+/-6 mm Hg; P=0.04). Donor HTS treatment improved coronary artery endothelial-dependent vasorelaxation compared with control (Emax: HTS, 59+/-4%; control, 47+/-3%; P=0.04). HTS also resulted in improved endothelial-independent vasorelaxation compared with control (Emax: HTS, 71+/-3%; control, 59+/-4%; P=0.03; ED-50: HTS, 0.56x10 to 6+/-0.23 mol/L; control, 2.5x10 to 6+/-1.0 mol/L; P=0.04). Sensitivity to endothelin-1-induced vasospasm was reduced with HTS pretreatment (% maximum contraction [Cmax]: HTS, 338+/-15%; control, 419+/-40%; P=0.01). CONCLUSIONS: Donor HTS pretreatment attenuates posttransplantation cardiac allograft myocardial dysfunction, improves posttransplantation systemic hemodynamic function, and preserves posttransplantation cardiac allograft vascular function. HTS may be a novel organ donor intervention to prevent primary graft dysfunction.

Dual immunosuppression enhances vasomotor injury: interactive effect between endothelin-1 and nitric oxide bioavailability.

OBJECTIVE: Cyclosporine A and corticosteroids are associated with many side effects, such as endothelial dysfunction and transplant vasculopathy. We examined the effects of cyclosporine A and hydrocortisone exposure on endothelial function of the rat thoracic aorta. METHODS: Lewis rats were injected with cyclosporine A, hydrocortisone, cyclosporine A + hydrocortisone, or intraperitoneal saline daily for 2 weeks. Endothelial-dependent and independent vascular relaxation were assessed in isolated segments of thoracic aorta, as well as endothelin-1-induced vasoreactivity. Protein expression of endothelial nitric oxide synthase, endothelin(A), and endothelin(B) receptors were also determined in the thoracic aorta. RESULTS: Exposure to cyclosporine A and cyclosporine A + hydrocortisone resulted in a reduction in endothelial-dependent vasorelaxation compared with control and hydrocortisone (P = .001). Cyclosporine A and hydrocortisone-treated rats demonstrated increased vasoreactivity to endothelin-1 compared with control, whereas cyclosporine A + hydrocortisone treatment resulted in a synergistic increase (P = .04). All treatment groups displayed a significant reduction in endothelial nitric oxide synthase expression compared with control (P = .001). Endothelin(A) receptor expression was increased in all treatment groups with a synergistic effect seen after cyclosporine A + hydrocortisone treatment. No differences were seen in endothelin(B) receptor expression. CONCLUSION: Cyclosporine A and hydrocortisone induce vasomotor dysfunction with a synergistic impairment observed after concomitant exposure. Our findings suggest that the resultant vasomotor dysfunction is the result of alterations in both nitric oxide and endothelin-1 regulation.