Laparoscopic-Assisted Myomectomy with Bilateral Uterine Artery Occlusion/Ligation.

STUDY OBJECTIVE: Conventional laparoscopic myomectomy (CLM) and robotic-assisted myomectomy (RAM) are limited in the number and size of myomas that can be removed, whereas abdominal myomectomy (AM) is associated with increased complications and morbidity. Here we evaluated the surgical outcomes of these myomectomy techniques compared with those of laparoscopic-assisted myomectomy (LAM), a hybrid approach that combines laparoscopy and minilaparotomy with bilateral uterine artery occlusion or ligation to control blood loss. DESIGN: Retrospective chart review (Canadian Task Force classification II-1). SETTING: Suburban community hospital. PATIENTS: Women age ≥18 years with nonmalignant indications. INTERVENTION: A total of 1313 consecutive CLMs, RAMs, AMs, and LAMs performed between January 2011 and December 2013. MEASUREMENTS AND MAIN RESULTS: Our review included 163 CLMs (12%), 156 RAMs (12%), 686 AMs (52%), and 308 LAMs (23%). Although the average number, size, and total weight of leiomyomas removed were comparable in the LAM and AM groups (9.1, 8.13 cm, and 391 g, respectively, vs 9.0, 7.5 cm, and 424 g; p < .0001), the number and weight of myomas were significantly greater in those 2 groups compared with the CLM and RAM groups (2.9 and 217 g, respectively, and 2.9 and 269 g; p < .0001). The intraoperative complication rate was highest in the RAM group, and the postoperative complication rate was highest in the AM group, both of which were approximately 3 times greater than the rates in the LAM group. There was no statistically significant difference in postoperative complication rates between the CLM and LAM groups. CONCLUSION: LAM with uterine artery occlusion/ligation is a viable approach for removing large tumor loads while minimizing blood loss and precluding the need for power morcellation.

Value-based assessment of hysterectomy approaches.

AIM: By evaluating operative outcomes relative to cost, we compared the value of minimally invasive hysterectomy approaches, including a technique discussed less often in the literature, laparoscopic retroperitoneal hysterectomy (LRH), which incorporates retroperitoneal dissection and ligation of the uterine arteries at their vascular origin. METHODS: Retrospective chart review of all women (N = 2689) aged greater than or equal to 18 years who underwent hysterectomy for benign conditions from 2011 to 2013 at a high-volume hospital in Maryland, USA. Procedures included: laparoscopic supracervical hysterectomy, robotic-assisted laparoscopic hysterectomy (RALH), total laparoscopic hysterectomy, laparoscopic-assisted vaginal hysterectomy, total vaginal hysterectomy (TVH), and LRH. RESULTS: Total vaginal hysterectomy had the highest intraoperative complication rate (9.6%; P < 0.0001) but the lowest postoperative complication rate (1.8%; P < 0.0001). Robotics had the highest postoperative complication rate (11.4%; P < 0.0001). LRH had the shortest operative time (71.2 min; P < 0.0001) and the lowest intraoperative complication rates (2.1%; P < 0.0001). LRH and TVH were the least costly (averaging $4061 and $6416, respectively), while RALH was the most costly ($9354). Taking both operative outcomes and cost into account, LRH, TVH and laparoscopic-assisted vaginal hysterectomy yielded the highest value scores; total laparoscopic hysterectomy, RALH, and laparoscopic supracervical hysterectomy yielded the lowest. CONCLUSION: Understanding the value of surgical interventions requires an evaluation of both operative outcomes and direct hospital costs. Using a quality-cost framework, the LRH approach as performed by high-volume laparoscopic specialists emerged as having the highest calculated value.

Laparoscopic-assisted myomectomy with uterine artery occlusion at a freestanding ambulatory surgery center: a case series.

BACKGROUND: Non-hysteroscopic myomectomy is infrequently performed in a freestanding ambulatory setting, in part due to risks of intraoperative hemorrhage. There are also concerns about increased surgical risks for morbidly obese patients in this setting. The purpose of this study is to report the surgical outcomes of a series of laparoscopic-assisted myomectomy (LAM) cases at a freestanding ambulatory surgery center (ASC), including a comparative analysis of outcomes in morbidly obese patients (BMI > 40 kg/m2). METHODS: A retrospective comparative analysis was performed of 969 women, age 18 years or older, non-pregnant, who underwent LAM by one of two high volume, laparoscopic gynecologic surgical specialists at a freestanding ambulatory surgery center serving the Washington, DC area, between October 2013 and February 2019. Reversible occlusion was performed laparoscopically by placing a latex-based rubber catheter as a tourniquet around the isthmus of the uterus, causing a temporary occlusion of the bilateral uterine arteries. Permanent occlusion was performed laparoscopically via retroperitoneal dissection and uterine artery ligation at the origin of the anterior branch of the internal iliac artery. Minilaparotomy was performed for specimen removal in all cases. No power morcellation was used. Postoperative complications were graded using the Clavien-Dindo Classification system. Outcomes were compared across BMI categories using Pearson Chi-Square. RESULTS: Average myoma weight and size were 422.7 g and 8.3 cm, respectively. Average estimated blood loss (EBL) was 192.1 mL; intraoperative and grade 3 postoperative complication rates were 1.4% and 1.6%, respectively. While EBL was significantly higher in obese and morbidly obese patients, this difference was not clinically meaningful, with no significant difference in blood transfusion rates. There were no statistically significant intraoperative or postoperative complication rates across BMI categories. There was a low rate of hospital transfers (0.7%) for all patients. CONCLUSION: Laparoscopic-assisted myomectomy can be performed safely in a freestanding ambulatory surgery setting, including morbidly obese patients. This is especially important in the age of COVID-19, as elective surgeries have been postponed due to the 2020 pandemic, which may lead to a dramatic and permanent shift of outpatient surgery from the hospital to the ASC setting.

Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4.

PURPOSE: Previously, we reported our experience treating 14 patients with metastatic melanoma using a fully human antibody to cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) in conjunction with peptide vaccination. We have now treated 56 patients to evaluate two different dose schedules of anti-CTLA-4 and to explore the relationship between autoimmunity and tumor regression. PATIENTS AND METHODS: A total of 56 patients with progressive stage IV melanoma were enrolled onto the study. All had Karnofsky performance status > or = 60% with no prior history of autoimmunity. Twenty-nine patients received 3 mg/kg anti-CTLA-4 every 3 weeks, whereas 27 received 3 mg/kg as their initial dose with subsequent doses reduced to 1 mg/kg every 3 weeks. In both cohorts patients received concomitant vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). RESULTS: Two patients achieved a complete response (ongoing at 30 and 31 months, respectively) and five patients achieved a partial response (durations of 4, 6, 25+, 26+, and 34+ months, respectively), for an overall objective response rate of 13%. Tumor regression was seen in lung, liver, brain, lymph nodes, and subcutaneous sites. Of 14 patients with grade 3/4 autoimmune toxicity, five (36%) experienced a clinical response compared with only two responses in the 42 patients (5%) with no autoimmune toxicity (P = .008). There were no significant differences in response rate or toxicity between the two dose schedules. CONCLUSION: Administration of anti-CTLA-4 monoclonal antibody plus peptide vaccination can cause durable objective responses, which correlate with the induction of autoimmunity, in patients with metastatic melanoma.

Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a single agent.

OBJECTIVE: To describe the clinical and histologic manifestations of skin reactions incidentally noted in patients with stage IV melanoma who were treated with up to 9 mg/kg of a humanized monoclonal antibody reactive against human cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) as a single agent every 3 weeks. SETTING: Single-institution prospective study. DESIGN: Patients treated with anti-CTLA-4 as a sole agent were prospectively referred for clinicopathologic characterization of skin reactions occurring during treatment. MAIN OUTCOME MEASURES: Specific clinicopathologic features were determined by means of a detailed history, a physical examination, conventional histologic analysis, antibody staining, and complete blood cell counts. RESULTS: Nine (14%) of 63 consecutive patients treated with anti-CTLA-4 as a sole agent developed skin eruptions that were attributed to anti-CTLA-4 in 8 of them. Skin lesions consisted primarily of discrete, pruritic, erythematous, minimally scaly papules that typically coalesced into thin plaques on the trunk and extensor surfaces of the extremities. Extensive alopecia was also noted in 1 patient. Histologically, a superficial, perivascular CD4+-predominant T-cell infiltrate with eosinophils in the dermis, rare dyskeratotic cells, and mild epidermal spongiosis were present. An increase (compared with pretreatment values) in the peripheral blood eosinophil frequency was observed in patients at the time of skin eruptions (P = .006). CONCLUSIONS: Specific features of the skin eruption dermatitis with increased tissue and peripheral blood eosinophil levels in a subset of treated patients. Specific features of skin eruption associated with anti-CTLA-4 resemble those described for maculopapular reactions to medications.

Inability to immunize patients with metastatic melanoma using plasmid DNA encoding the gp100 melanoma-melanocyte antigen.

Immunization with plasmid DNA represents a theoretically attractive method for increasing T cell responses against cancer antigens. We administered plasmid DNA encoding the gp100 melanoma-melanocyte differentiation antigen to 22 patients with metastatic melanoma and evaluated immunologic and clinical responses. Patients were randomized to receive plasmid DNA either intradermally (n = 10) or intramuscularly (n = 12). One patient (4.5%) exhibited a partial response of several subcentimeter cutaneous nodules. All other patients had progressive disease. Of 13 patients with cells available before and after immunization, no patient exhibited evidence of the development of anti-gp100 cell responses using in vitro boost assays. The same assays were capable of demonstrating immunologic precursors after immunization with fowl poxvirus encoding gp100 or with gp100 peptides. We were thus unable to demonstrate significant clinical or immunologic responses to plasmid DNA encoding the "self" nonmutated gp100 tumor antigen.

Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma.

We previously reported our experience in treating 56 patients with metastatic melanoma using a human anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody. Durable tumor regressions were seen that correlated with the induction of autoimmune toxicities. In this study, we treated 46 additional patients using an intrapatient dose escalation schema to test whether higher doses of anti-CTLA-4 antibody would induce increased autoimmunity and concomitant tumor regression. Twenty-three patients started anti-CTLA-4 antibody administration at 3 mg/kg and 23 patients started treatment at 5 mg/kg, receiving doses every 3 weeks. Patients were dose-escalated every other dose to a maximum of 9 mg/kg or until objective clinical responses or grade III/IV autoimmune toxicity were seen. Escalating doses of antibody resulted in proportionally higher plasma concentrations. Sixteen patients (35%) experienced a grade III/IV autoimmune toxicity. Five patients (11%) achieved an objective clinical response. Two of the responses are ongoing at 13 and 16 months, respectively. Flow cytometric analysis of peripheral blood revealed significant increases in both T-cell surface markers of activation and memory phenotype. Thus, higher serum levels and prolonged administration of anti-CTLA-4 antibody resulted in a trend toward a greater incidence of grade III/IV autoimmune toxicity than previously reported, but did not seem to increase objective response rates.

Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma.

Elimination of regulatory T lymphocytes may provide a way to break self-tolerance and unleash the anti-tumor properties of circulating lymphocytes. The use of fusion proteins, which link cytotoxic molecules to receptor targets, provides one approach to this problem. This study examined the ability of a fusion protein of interleukin-2 (IL-2) and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes based on their expression of high-affinity IL-2 receptors. Thirteen patients (12 with metastatic melanoma, 1 with metastatic renal cell carcinoma) were treated at one of the two Food and Drug Administration-approved doses of Denileukin Diftitox (seven patients at 9 microg/kg, six patients at 18 microg/kg). None of the patients experienced an objective clinical response. Foxp3 expression did not decrease significantly overall, although it did decrease minimally among patients receiving 18 microg/kg (-2.01+/-0.618 copies of Foxp3/10(3) copies of beta-actin; P=0.031). Denileukin Diftitox did not decrease the suppressive ability of CD4CD25 cells as quantified by an in vitro co-culture suppression assay. Furthermore, the increased numbers of lymphocytes in patients resulting from treatment with IL-2 were not susceptible to Denileukin Diftitox. Administration of Denileukin Diftitox does not appear to eliminate regulatory T lymphocytes or cause regression of metastatic melanoma.

Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study.

BACKGROUND: Cytotoxic T lymphocyte-associated antigen (CTLA)-4 can inhibit T-cell responses and is involved in tolerance against self antigens. We previously reported autoimmune manifestations and objective cancer regressions in patients with metastatic melanoma treated with CTLA-4 blockade. The possibility of activating tumor-reactive T cells while removing inhibitory activity with CTLA-4 blockade has stimulated interest in using anti-CTLA-4 antibodies in combination with other cancer immunotherapies to improve clinical outcomes. In this study, we assessed the antitumor activity and autoimmune toxicity of CTLA-4 blockade in combination with an immune-activating stimulus, interleukin (IL)-2, in patients with metastatic melanoma. METHODS: Thirty-six patients received anti-CTLA-4 antibody every 3 weeks. Three patients per cohort received doses of .1, .3, 1.0, and 2.0 mg/kg. Twenty-four patients received 3.0 mg/kg. All patients received IL-2 therapy (720,000 IU/kg every 8 hours to a maximum of 15 doses). RESULTS: Eight patients (22%) experienced objective tumor responses (three complete and five partial), including metastases in the lungs, lymph nodes, mediastinum, and subcutaneous tissues. Six of the eight patients have ongoing objective responses at 11 to 19 months. Five patients (14%) developed grade III/IV autoimmune toxicities secondary to anti-CTLA-4 administration, including four patients with enterocolitis and one with arthritis and uveitis. CONCLUSIONS: There is not evidence to support a synergistic effect of CTLA-4 blockade plus IL-2 administration, because the 22% objective response rate is that expected from the sum of these two agents administered alone. Durable cancer regressions were seen in patients treated with this combination.

Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer.

Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an immunoregulatory molecule expressed by activated T cells and resting CD4CD25 T cells. In patients with advanced melanoma, our group reported that administration of anti-CTLA-4 antibody mediated objective cancer regression in 13% of patients. This study also established that the blockade of CTLA-4 was associated with grade III/IV autoimmune manifestations that included dermatitis, enterocolitis, hepatitis, uveitis, and a single case of hypophysitis. Since this initial report, 7 additional patients with anti-CTLA-4 antibody-induced autoimmune hypophysitis have been accumulated. The characteristics, clinical course, laboratory values, radiographic findings, and treatment of these 8 patients are the focus of this report.

Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c. vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). This blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients (43%), including dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated objective cancer regression in three patients (21%; two complete and one partial responses). This study establishes CTLA-4 as an important molecule regulating tolerance to "self" antigens in humans and suggests a role for CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer immunotherapy.