Kristina A. Butler

Tumorgrafts as In Vivo Surrogates for Women with Ovarian Cancer

Purpose: Ovarian cancer has a high recurrence and mortality rate. A barrier to improved outcomes includes a lack of accurate models for preclinical testing of novel therapeutics. Experimental Design: Clinically relevant, patient-derived tumorgraft models were generated from sequential patients and the first 168 engrafted models are described. Fresh ovarian, primary peritoneal, and fallopian tube carcinomas were collected at the time of debulking surgery and injected intraperitoneally into severe combined immunodeficient mice. Results: Tumorgrafts demonstrated a 74% engraftment rate with microscopic fidelity of primary tumor characteristics. Low-passage tumorgrafts also showed comparable genomic aberrations with the corresponding primary tumor and exhibit gene set enrichment of multiple ovarian cancer molecular subtypes, similar to patient tumors. Importantly, each of these tumorgraft models is annotated with clinical data and for those that have been tested, response to platinum chemotherapy correlates with the source patient. Conclusions: Presented herein is the largest known living tumor bank of patient-derived, ovarian tumorgraft models that can be applied to the development of personalized cancer treatment. Clin Cancer Res; 20(5); 1288–97. ©2014 AACR.

The role of sexuality symptoms in myeloproliferative neoplasm symptom burden and quality of life: An analysis by the MPN QOL International Study Group.

Patients with myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and myelofibrosis, are faced with oppressive symptom profiles that compromise daily functioning and quality of life. Among these symptoms, sexuality‐related symptoms have emerged as particularly prominent and largely unaddressed. In the current study, the authors evaluated how sexuality symptoms from MPN relate to other patient characteristics, disease features, treatments, and symptoms.

Surgeon fatigue and postural stability: is robotic better than laparoscopic surgery?

OBJECTIVE To compare muscular fatigue and postural stability of surgeons before and after laparoscopic and robotic surgery. SUBJECTS AND METHODS The design of this study is Class II. A consecutive cohort of patients presenting at an academic tertiary-care center for scheduled gynecologic surgery was used. Routine surgical care was examined with testing of surgeon fatigue and postural measures before and after the procedure. Motor fatigue was measured using a quantitative grip dynamometer, and postural stability was measured using a nondominant, single-leg stance. A subjective fatigue score was recorded following surgery. RESULTS Primary surgeons completed testing before and after 56 surgeries. A trend toward decline in postural stability was observed more in the laparoscopy group than in the robotic group (P=.29). The fatigue index and subjective fatigue scores were not significantly different. CONCLUSIONS Similar changes in postural stability and muscular strength were observed following laparoscopic and robotic surgery. The optimal measurement tool to capture surgical fatigue remains elusive. Fatigue differences may have been more pronounced if surgical procedure degree of difficulty had been more consistent between groups.

Prevention of Human Lymphoproliferative Tumor Formation in Ovarian Cancer Patient-Derived Xenografts

Interest in preclinical drug development for ovarian cancer has stimulated development of patient-derived xenograft (PDX) or tumorgraft models. However, the unintended formation of human lymphoma in severe combined immunodeficiency (SCID) mice from Epstein-Barr virus (EBV)–infected human lymphocytes can be problematic. In this study, we have characterized ovarian cancer PDXs which developed human lymphomas and explore methods to suppress lymphoproliferative growth. Fresh human ovarian tumors from 568 patients were transplanted intraperitoneally in SCID mice. A subset of PDX models demonstrated atypical patterns of dissemination with mediastinal masses, hepatosplenomegaly, and CD45-positive lymphoblastic atypia without ovarian tumor engraftment. Expression of human CD20 but not CD3 supported a B-cell lineage, and EBV genomes were detected in all lymphoproliferative tumors. Immunophenotyping confirmed monoclonal gene rearrangements consistent with B-cell lymphoma, and global gene expression patterns correlated well with other human lymphomas. The ability of rituximab, an anti-CD20 antibody, to suppress human lymphoproliferation from a patients ovarian tumor in SCID mice and prevent growth of an established lymphoma led to a practice change with a goal to reduce the incidence of lymphomas. A single dose of rituximab during the primary tumor heterotransplantation process reduced the incidence of CD45-positive cells in subsequent PDX lines from 86.3% (n = 117 without rituximab) to 5.6% (n = 160 with rituximab), and the lymphoma rate declined from 11.1% to 1.88%. Taken together, investigators utilizing PDX models for research should routinely monitor for lymphoproliferative tumors and consider implementing methods to suppress their growth.

Randomized controlled trial of postoperative belladonna and opium rectal suppositories in vaginal surgery

BACKGROUND: After vaginal surgery, oral and parenteral narcotics are used commonly for pain relief, and their use may exacerbate the incidence of sedation, nausea, and vomiting, which ultimately delays convalescence. Previous studies have demonstrated that rectal analgesia after surgery results in lower pain scores and less intravenous morphine consumption. Belladonna and opium rectal suppositories may be used to relieve pain and minimize side effects; however, their efficacy has not been confirmed. OBJECTIVE: We aimed to evaluate the use of belladonna and opium suppositories for pain reduction in vaginal surgery. MATERIALS AND METHODS: A prospective, randomized, double‐blind, placebo‐controlled trial that used belladonna and opium suppositories after inpatient or outpatient vaginal surgery was conducted. Vaginal surgery was defined as (1) vaginal hysterectomy with uterosacral ligament suspension or (2) posthysterectomy prolapse repair that included uterosacral ligament suspension and/or colporrhaphy. Belladonna and opium 16A (16.2/60 mg) or placebo suppositories were administered rectally immediately after surgery and every 8 hours for a total of 3 doses. Patient‐reported pain data were collected with the use of a visual analog scale (at 2, 4, 12, and 20 hours postoperatively. Opiate use was measured and converted into parenteral morphine equivalents. The primary outcome was pain, and secondary outcomes included pain medication, antiemetic medication, and a quality of recovery questionnaire. Adverse effects were surveyed at 24 hours and 7 days. Concomitant procedures for urinary incontinence or pelvic organ prolapse did not preclude enrollment. RESULTS: Ninety women were randomly assigned consecutively at a single institution under the care of a fellowship‐trained surgeon group. Demographics did not differ among the groups with mean age of 55 years, procedure time of 97 minutes, and prolapse at 51%. Postoperative pain scores were equivalent among both groups at each time interval. The belladonna and opium group used a mean of 57 mg morphine compared with 66 mg for placebo (P=.43) in 24 hours. Patient satisfaction with recovery was similar (P=.59). Antiemetic and ketorolac use were comparable among groups. Subgroup analyses of patients with prolapse and patients <50 years old did not reveal differences in pain scores. The use of belladonna and opium suppositories was uncomplicated, and adverse effects, which included constipation and urinary retention, were similar among groups. CONCLUSION: Belladonna and opium suppositories are safe for use after vaginal surgery. Belladonna and opium suppositories did not reveal lower pain or substantially lower narcotic use. Further investigation may be warranted to identify a population that may benefit optimally from belladonna and opium use.

Prognostic Factors for Morcellation During Vaginal Hysterectomy

OBJECTIVE: To determine prognostic factors associated with cold-knife morcellation during vaginal hysterectomy. METHODS: We conducted a retrospective cohort study evaluating all consecutive patients undergoing a vaginal hysterectomy between January 1, 2009, and August 31, 2014. The primary outcome was the utilization of uncontained vaginal morcellation performed using cold-knife wedge resection at the time of vaginal hysterectomy. Secondary outcomes included perioperative data. Significant factors were included in a multivariate logistic regression model to the binary variable vaginal morcellation at the time of vaginal hysterectomy. RESULTS: A total of 743 women met study inclusion criteria and underwent vaginal hysterectomy with intact uterine removal (n=383) or with uterine morcellation (n=360) with and without other vaginal procedures. A nonparametric Wilcoxon-rank-sum test and &khgr;2 test were used to compare the cohorts of patients with and without morcellation. Characteristics associated with significantly increased likelihood of morcellation included younger age, non-Caucasian race, American Society of Anesthesiologists class 1 or 2, lower parity, lower number of prior vaginal deliveries, absence of prolapse, presence of leiomyoma, and an enlarged uterus. A multivariate logistic model utilizing factors most likely associated with morcellation revealed lack of prolapse (adjusted odds ratio [OR] 3.87, P<.001), leiomyoma (adjusted OR 2.77, P=.035), and larger uterine weight (adjusted OR 7.25, P<.001) increased the likelihood of morcellation. Prior vaginal delivery was associated with a decreased likelihood of morcellation (adjusted OR 0.79, P=.005). CONCLUSION: Vaginal hysterectomy with morcellation is associated with the following factors: absence of prior vaginal delivery, absence of prolapse, presence of leiomyoma, and a uterus larger than normal size.

Oral Progestogens Versus Levonorgestrel-Releasing Intrauterine System for Treatment of Endometrial Intraepithelial Neoplasia

BACKGROUND Limited therapeutic guidelines exist regarding medical therapy, ideal dosing, duration of therapy, or recommendations for timing of endometrial reassessment for women with endometrial intraepithelial neoplasia (EIN) who desire fertility preservation or who are not optimal surgical candidates. We aimed to determine the effectiveness of oral progestogens (OP) versus the levonorgestrel-releasing intrauterine system (LNG IUS) in the medical treatment of EIN. METHODS We retrospectively identified women with EIN at our institution from 2007 through 2014 and compared the outcomes of those treated with OP versus LNG IUS. RESULTS Among 390 women, 296 were initially treated with OP and 94 with LNG IUS. Baseline characteristics of the patient groups were comparable, except for higher median body mass index in the LNG IUS group versus the OP group (37 kg/m2 vs. 31 kg/m2; p < 0.001). Among 332 women with follow-up endometrial biopsies (263 OP and 69 LNG IUS), EIN subcategory 1 (benign endometrial hyperplasia) resolved in 83% and 87% of patients, respectively (p = 0.31). Rates of resolution of EIN subcategory 2 (endometrial intraepithelial neoplasia) were also similar between groups (68% vs. 62%; p = 0.82). In women with EIN subcategory 3 (endometrial adenocarcinoma), 22% of those using LNG IUS and one of two women treated with OP had resolution of disease as of last follow-up. CONCLUSIONS OP and LNG IUS offer similar endometrial protection for women with EIN. LNG IUS offers convenience, minimal adverse effects, reversibility, and long-term endometrial protection.

Fine needle aspiration cytology of cervical lymph node involvement by ovarian serous borderline tumor

Serous borderline tumor (SBT) involving a cervical lymph node is extremely rare. In addition, fine needle aspiration (FNA) cytology of the involved cervical lymph node shares tremendous morphologic similarity with other low-grade papillary carcinomas. Thus, it can be easily misdiagnosed as metastatic carcinoma. A 42-year-old female had a history of bilateral SBT and postbilateral salpingo-oophorectomy. She presented with left cervical lymphadenopathy 6 months later. FNA cytology showed a low-grade papillary neoplasm with psammoma bodies. Needle core biopsy along with immunostains was diagnostic of cervical lymph node involvement (LNI) of SBT. although extremely rare, cervical LNI can be found in patients with SBTs. FNA cytology, sometimes, is indistinguishable from metastatic papillary adenocarcinoma. Cell block or needle core biopsy is essential to make the correct diagnosis.

7: Randomized clinical trial of postoperative belladonna and opium (B&O) suppositories in vaginal surgery

7 Randomized clinical trial of postoperative belladonna and opium (B&O) suppositories in vaginal surgery K. A. Butler, J. Yi, J. Klauschie, D. L. Ryan, J. G. Hentz, J. L. Cornella, P. Magtibay, R. Kho Gynecology, Mayo Clinic Arizona, Phoenix, AZ, Clinical Studies, Mayo Clinic Arizona, Phoenix, AZ, Columbia University Medical Center, New York, NY OBJECTIVES: Following vaginal surgery oral and parenteral narcotics are commonly used for pain relief and their use may exacerbate the incidence of sedation, nausea, and vomiting; ultimately delaying convalescence. Previous studies have demonstrated that rectal analgesia following surgery results in lower pain scores and less intravenous morphine consumption (1-2). Belladonna and opium (B&O) rectal suppositories may be used to relieve pain and minimize side effects; however their efficacy has not been confirmed. We aimed to evaluate the use of B&O suppositories for pain reduction in vaginal surgery. MATERIALS AND METHODS: A prospective, randomized, double-blind, placebo-controlled trial using B&O suppositories following inpatient or outpatient vaginal surgery was conducted. Vaginal surgery was defined as: (1) vaginal hysterectomy with uterosacral suspension or (2) post-hysterectomy prolapse repair including uterosacral suspension and/or colporrhaphy. B&O 16A (16.2/60 mg) or placebo suppositories were administered rectally immediately following surgery and every 8 hours for a total of 3 doses. Patient reported pain was collected using a visual analog scale (VAS) at 2, 4, 12, and 20 h postoperatively. Opiate use was measured and converted into IV morphine equivalents. The primary outcome was pain and secondary outcomes included pain medication, antiemetics, and a quality of recovery questionnaire. A priori power analysis aimed for 80% power (a .05) to detect a difference of 2 points. Adverse effects were surveyed at 24 hours and 7 days. Concomitant procedures for urinary incontinence or pelvic organ prolapse did not preclude enrollment. RESULTS: Ninety women were randomized consecutively at a single institution under the care of a fellowship trained surgeon group. Demographics did not differ between the groups with mean age 55, procedure time 97 minutes, and prolapse 51%. Postoperative pain scores were equivalent among both groups at each time interval. The B&O group used a mean of 57 mg morphine compared to 66mg for placebo (p1⁄40.43) in 24 hours. Patient satisfaction with recovery was similar (p1⁄40.59). Antiemetic and ketorolac use were comparable among groups. A subgroup analysis of patients with prolapse did not reveal differences in pain scores. The use of B&O suppositories was uncomplicated and adverse effects were similar among groups including constipation and urinary retention. CONCLUSION: B&O suppositories are safe for use following vaginal surgery. B&O suppositories did not reveal a statistically significant reduction in narcotic use compared to placebo; however the treatment group used fewer narcotics with similar recovery satisfaction which may offer clinical significance and/or reduced healthcare cost. Further investigation is warranted to identify a population that may optimally benefit from B&O use.

Lymphadenectomy in Endometrial Cancer: The Controversy Rages Unabated

The role of lymphadenectomy in endometrial cancer continues to provoke debate. The Mayo School advocates its use for the appropriate classification and treatment of those at risk of recurrent disease. The Manchester School argues that its use cannot be justified without clear evidence for a survival benefit. In this chapter, both sides of the debate are presented alongside a mutually agreeable trial design that has the potential to provide conclusive evidence, once and for all, for how early-stage endometrial cancer should be managed.