Faculty Bibliography

BACKGROUND:Timely genetic testing at ovarian cancer diagnosis is essential as results impact front line treatment decisions. Our objective was to determine rates of genetic counseling and testing with an expedited genetics referral pathway wherein women with newly-diagnosed ovarian cancer are contacted by a genetics navigator to facilitate genetic counseling. METHODS:Patients were referred for genetic counseling by their gynecologic oncologist, contacted by a genetics navigator and offered appointments for genetic counseling. Patients completed quality of life (QoL) surveys immediately pre- and post-genetic assessment and 6 months later. The primary outcome was feasibility of this pathway defined by presentation for genetic counseling. RESULTS:From 2015 to 2018, 100 patients were enrolled. Seventy-eight had genetic counseling and 73 testing. Median time from diagnosis to genetic counseling was 34 days (range 10-189). Among patients who underwent testing, 12 (16%) had pathogenic germline mutations (BRCA1-7, BRCA2-4, MSH2-1). Sixty-five patients completed QoL assessments demonstrating stress and anxiety at time of testing, however, scores improved at 6 months. Despite the pathway leveling financial and logistical barriers, patients receiving care at a public hospital were less likely to present for genetic counseling compared to private hospital patients (56% versus 84%, P = 0.021). CONCLUSIONS:Facilitated referral to genetic counselors at time of ovarian cancer diagnosis is effective, resulting in high uptake of genetic counseling and testing, and does not demonstrate a long term psychologic toll. Concern about causing additional emotional distress should not deter clinicians from early genetics referral as genetic testing can yield important prognostic and therapeutic information.

Objectives: The use of power morcellation has been restricted in many centers due to concerns for inadvertent spread of an undiagnosed leiomyosarcoma. Our institution implemented a preoperative protocol to avoid power morcellation in high risk cases. In this retrospective cohort study, we report the impact of this protocol on institutional surgical practice patterns, and the influence of MRI and LDH results on surgical route.
Material(s) and Method(s): An institutional protocol requiring preoperative MRI with diffusion-weighted imaging and serum LDH levels was implemented on 4/23/2014 at a single academic hospital. A retrospective chart review was performed including all women who underwent intra-abdominal surgery for symptomatic fibroids from 4/23/2013 to 4/23/2015. Statistical analyses included univariate comparisons between the cohorts pre- and post-protocol, as well as overall adherence to protocol, trends in surgical patterns, and incidence of uterine pathology.
Result(s): A total of 1085 patients were included, 479 before and 606 after implementation of the MRI/LDH protocol. The pre-protocol group had more post-menopausal women (4% vs. 2%, p=0.022) and women using tamoxifen (2% vs. 0%, p=0.022) than those in the post-protocol group, but baseline patient characteristics were otherwise similar between groups. Incidence of malignant pathological diagnoses did not change significantly over the time period in relation to protocol implementation. The rate of minimally invasive surgery (MIS) for both hysterectomy and myomectomy remained the same in the year preceding and the year following initiation of the protocol (81% vs. 84% and 90% vs. 91%, respectively). There was a significant decrease in the use of power morcellation (66% in pre- and 50% in post-protocol cohorts, p<0.001) and an increased use of containment bags when specimens were removed abdominally (1% in pre- and 19% in post-protocol cohort). When analyzing the subset of patients who had abnormal MRI and LDH results, abnormal MRI results alone resulted in higher rates of open approach (65% for abnormal vs. 35% for normal). Similarly, a combination of abnormal MRI and LDH tests resulted in higher rates of open approach (70% for abnormal and 17% for normal). Abnormal LDH results alone did not influence route.
Conclusion(s): Though earlier studies have suggested an overall decrease in minimally invasive hysterectomies in response to the FDA warning on power morcellation, there was no change in rates of minimally invasive hysterectomies and myomectomies at our institution during a similar time period. Changes in surgical techniques, such as decreased use of power morcellation and increased use of contained tissue extraction, were seen. Decreased rates of MIS were seen for patients with abnormal preoperative MRI.
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Objective: Surgery for leiomyomas is common; yet, no reliable test can help distinguish a benign leiomyoma and malignant leiomyosarcoma (LMS).
Material(s) and Method(s): This retrospective observational cohort study evaluated patients before and after implementation of a protocol to identify LMS, which included magnetic resonance imaging (MRI) with diffusion-weighted imaging.
Result(s): This study revealed the incidence of uterine pathology, as well as MRI, lactate dehydrogenase (LDH), and pathology results, in 1085 patients - 479 before and 606 after implementation of the protocol. Two cases of LMS were identified in the postprotocol cohort, and 70% of the patients underwent MRI. Test statistics for MRI to detect LMS in this cohort were: sensitivity of 100%; specificity of 67%; positive predictive value of 1%; negative predictive value of 100%; false-positive rate of 33%; and false-negative rate of 0%. For patients with both MRI and LDH results (358/606, 59%), 56.7% had normal MRI and LDH, 9.8% had negative MRI but high LDH, 6.4% had abnormal MRI and high LDH, and 27.1% had abnormal MRI and normal LDH.
Conclusion(s): Preoperative MRI for detecting LMS had high a sensitivity and a high false-positive rate, which warrants caution in interpreting MRI results, particularly in women of childbearing age.

OBJECTIVES/OBJECTIVE:Cystadenofibromas (CAFs) are rare benign ovarian tumors without a widely accepted ultrasound (US) pattern. They are usually described by as thin-walled, unilocular or multilocular, and at times septated cysts with scant blood flow and no solid components. We describe a unique US feature, the "shadow sign," seen in prospectively diagnosed benign CAFs. We also provide the histopathologic basis for this typical US appearance. METHODS:Ultrasound (US) examinations were performed in our obstetric and gynecologic US unit. Pathologic examinations were performed by a dedicated gynecologic pathology team. The US and pathology department's database was searched for the diagnosis of a CAF between 2010 and 2017. RESULTS:We identified 20 patients who underwent transvaginal US examinations with a sole US diagnosis of a CAF, and the tumors were surgically removed. The common US feature across the 20 cases was the presence of hyperechoic avascular shadowing nodules. The correlating histologic features were unilocular or multilocular cysts with a smooth internal wall surface lined by a simple epithelium and occasional robust polypoid fibrous stroma. CONCLUSIONS:This US marker helps in differentiating CAFs from borderline ovarian tumors, which do not show this US feature. We hope that recognizing the suggested shadow sign as an additional descriptor of CAFs will lead to minimizing their unnecessary removal and eliminating additional and unnecessary imaging by computed tomography and magnetic resonance imaging.

OBJECTIVE:Accurate diagnosis of borderline ovarian tumors (BOTs) is important to ensure timely and appropriate management, especially in women desiring to preserve fertility. Transvaginal ultrasound (TVUS) is considered the best modality to diagnose adnexal tumors. Sonographic features of BOTs described in the literature include septa, solid components, mural nodules (papillae) and blood vessels within these structures. However, there is no single signature that differentiates BOTs from other adnexal masses. We have identified a microcystic pattern on ultrasound of BOTs. The objective of our study was to evaluate the utility of a new sonographic pattern to describe a novel, yet typical, microcystic pattern of papillary projections, solid components and/or septa as a new ultrasound marker of BOTs and present their histologic confirmation. MATERIAL AND METHODS/METHODS:In this retrospective study, we identified women with a histologic diagnosis of BOT following surgical resection who underwent pre-operative transvaginal ultrasound (TVUS) examination. All images were reviewed for presence or absence of thin-walled, fluid-filled cluster(s) of 1-3-mm cystic formations associated with solid components, papillary projections, and/or septa. Case-matched histopathologic slides of each BOT were examined for the presence of the above-described microcystic features identified on TVUS. To confirm that the microcystic TVUS pattern is unique to BOTs, we randomly selected 20 cases of epithelial cancer and 20 cases of benign cystadenomas from our ultrasound and surgical database. These were also reviewed by the same pathologists. To confirm the novelty of our findings, we searched PubMed for literature published in the English language between 2010 and 2018 to learn if the above described microcystic tissue pattern was previously described. RESULTS:Sixty-seven cases with pre-operative ultrasound that had surgically confirmed BOT on pathologic examination were included in the final analysis. Median age at surgery was 39.8 years. Average size of the BOTs was 60.7mm. Of the 67 BOTs, 47 (70.14%) were serous, 15 (22.38%) were mucinous, and 5 (7.46%) were seromucinous. Sixty (89.7%) of 67 BOTs demonstrated the microcystic pattern in the papillary projections, solid components and/or septa. On ultrasound imaging, 46 of the 47 (97.9%) serous type BOTs had a microcystic pattern compared to 11 of the 15 (73.3%) mucinous and 3 of the 5 (60.0%) seromucinous BOTs. On microscopic evaluation, 60 (89.7%) of 67 samples had characteristic 1-3-mm fluid-filled cysts like those seen on transvaginal ultrasound. Only 7 cases revealed discrepancies between the sonographic and histologic identification of a microcystic pattern. The cystadenomas (we submitted 4 of the 20 pairs we studied for comparison for this article) were mostly unilocular and/or multilocular and largely avascular. None of the 20 cystadenomas or 20 epithelial ovarian malignancies case-matched to histology displayed microcystic characteristics on ultrasound. On review of 23 published articles in the English medical literature containing 163 sonographic pictures of BOT, no description of the microcystic tissue pattern was found. CONCLUSION/CONCLUSIONS:In conclusion, we report a novel sonographic marker of BOTs termed "microcystic pattern" of their papillary projections, solid components and/or septa. This was seen in the majority of both the serous and the mucinous BOT cases. Importantly, based on comparison of sonographic images and histopathology of both benign entities and malignancies, the microcystic appearance appears to be unique to BOTs. No such or similar description was previously provided. We feel utilization of this new marker will help to correctly identify BOTs, discriminating them from ovarian cancers and benign ovarian pathologies, and ensure their appropriate clinical and surgical management.

Introduction : We have recently reported that both CD80 upregulation and the degradation of SMPDL-3b on glomerular podocytes are involved in the development of post kidney xenotransplant (XKTx) proteinuria in a pig-to-baboon model. In this study, we assessed (1) if the incompatibility of porcine CD47 and baboon macrophages (CD47/SIRPalpha pathway) was involved in the development of post XKTx proteinuria, and (2) if transgenic (Tg) expression of human CD47 (hCD47) caused negative effects via a CD47/TSP-1 pathway following pig-to-baboon K+VT Tx. Methods : Study 1 : Phagocytosis of porcine endothelial cells (EC) as well as podocytes with/without hCD47 was assessed in co-culture assays with baboon macrophages. Study 2 (to assess the effect of hCD47 Tg in vivo) : Five baboons received porcine Kidney plus vascularized thymus (K+VT) in which hCD47 was expressed at high levels. All 5 received ATG and rituximab followed by anti-CD40 or CD40L mab +MMF. One of the 5 additionally received anti-IL6 receptor ab weekly from the 3rd week. Graft renal function, immunologic assays as well as graft expression of hCD47 and TSP-1 were assessed. Results : Co-culture phagocytosis assays : Statistically significant reductions of phagocytosis of both porcine EC and podocytes were observed when hCD47 was expressed on porcine ECs or podocytes. Expression of hCD47 and TSP-1 : One animal expressed hCD47 only on glomerular cells while the others (n = 4) expressed hCD47 on glomerular cells as well as vascular ECs and arterial median layers (widespread hCD47). Widespread hCD47-expressing kidneys also expressed TSP1, although weakly, in vascular median layers while no TSP1-expression was observed on kidneys with glomerular hCD47 or naive pig or baboon kidneys. Following XK+VT Tx : Historic controls of GalTKO K+VT without hCD47Tg uniformly developed proteinuria 2+ within 14 days (n > 10), while all recipients of hCD47Tg GalTKO K+VT displayed minimal (1+ or 0) Uprot. However, although the recipient of a kidney graft in which hCD47 was expressed only in the glomeruli maintained function >4 months, three of 4 animals that received widespread hCD47 K+V were euthanized due to systemic edema with evidence of up-regulation of TSP-1 in grafts, without evidence of immunologic rejection within 8 weeks. These had circulating pig CD3+ T thymic emigrants >5% following Tx with increased serum levels of IL6. One animal that received weekly anti-IL6r ab maintains stable renal function without systemic edema (Cr <1 mg/dl currently on POD 86). Conclusions : These results demonstrate that (1) high expression of hCD47 on porcine glomerular cells prevented the development of proteinuria; however, (2) widespread expression of hCD47 upregulates TSP-1 which might play a role in increased vascular permeability leading to systemic edema. These effects may be inhibited by anti-IL6r treatment

Background and Aims of the study : We have achieved >6 months survival of a life-supporting kidney with a vascularized thymus (VT) in a pig-to-baboon model. While improved survival has been achieved with GalT KO pig xenografts in primates, non-Gal natural antibody determinants, including beta1,4 N-acetylgalactosaminyl transferase (B4) and N-glycolylneuraminic acid (NeuGc) are recognized by human sera on GalT KO pig cells. In this study, we compared preformed anti-pig natural antibodies (nAb) against GalTKO alone (GalTKO) and triple knockout (TKO) pigs that were GalT, B4, and CMAH (NeuGc) KO, in baboons to test: (1) if TKO induced new antigens that are recognized by baboon preformed nAb; and then (2) assessed if these new antigens were immunogenic in vivo. Methods : Preformed nAb against GalTKO or TKO PBMC in 10 naive baboon sera were assessed by FCM Ab binding assays using anti-human IgM or IgG ab. Among these baboons, five received pig kidneys and VT grafts from porcine CMV negative TKO pigs. All baboons received anti-CD40 mAb, ATG and Rituximab. Graft renal function (sCre and histology), thymic emigrants from pig thymus (chimerism) as well as immunologic assays (anti-pig ab and cellular assays) were performed. Results : Among 10 naive baboon sera, two had less Ab binding against TKO than GalTKO cells. Four baboon sera had similar binding to TKO and GalTKO cells. Notably, 4 baboon sera had higher ab binding to TKO than GalTKO cells, suggesting that new antigens were revealed in association with the additional KO. Although all baboons (n = 5) had stable renal function in the first 11 days (Cre < 1.5 mg/dl), two baboons with higher non-Gal preformed IgG against TKO than GalTKO (high preformed nAb against TKO) rejected their kidney plus VT grafts at POD 20. Immunohistology showed predominant IgG binding in the excised rejected kidneys. In contrast, three baboons, including one that had similarly high preformed non-Gal IgG binding against both GalTKO and TKO equally, did not reject kidneys in the early period. One that had high IgG binding against both GalTKO and TKO maintained renal function but was euthanized due to tracheal edema at POD 53 (Cre 1.2 mg/dl). Others that had low IgG binding against TKO also maintained renal function without evidence of rejection. One was euthanized at POD 154 due to graft growth and the other at POD 43 due to an anesthetic complication. Conclusions : These data indicate that TKO pigs may express new antigenic specificities that led to delayed vascular xenograft rejection in a pig-to-baboon kidney plus VT model. Prescreening for preformed IgM and IgG nAb using both GalTKO and TKO PBMC is essential to avoid early loss of pig xenografts

OBJECTIVES/OBJECTIVE:Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is a treatment strategy for ovarian cancer patients with unresectable disease or poor performance status (PS). This strategy has been used in the treatment of advanced endometrial cancer and a survival benefit has been shown in patients who are subsequently able to undergo interval cytoreduction. This study sought to review our single institution experience with NACT for advanced endometrial cancer. METHODS:We conducted a retrospective review of all patients who received NACT for advanced endometrial cancer at two institutions in New York City between 2002 and 2016. RESULTS:We identified 39 patients (median age 61, range 35-89). The histologic subtype distribution was: serous (44%), endometrioid (28%), carcinosarcoma (10%), clear cell (8%), mixed (8%), neuroendocrine (3%). Contraindications to primary surgery included: unresectable disease (72%), poor PS (15%), unresectable disease and poor PS (13%). Twenty-three patients (59%) did not undergo IDS due to: progression of disease (70%), medical ineligibility (4%), unresectable disease (17%), lost to follow-up (4%), death (4%). Sixteen patients (41%) underwent IDS, 81% had an optimal cytoreduction. Disease status at NACT completion was: partial response (56%), stable disease (3%) and progression of disease (41%). There were no complete responses. Patients who responded to NACT had a significantly longer overall survival than those who did not (15 vs. 5 months. P = 0.015). IDS was also associated with an improvement in overall survival versus no surgery (16 vs. 6 months, P = 0.04). CONCLUSIONS:Unlike ovarian cancer, less than half of the patients undergoing NACT for endometrial cancer underwent IDS, none had a complete response, and 41% had disease progression during NACT. However, endometrial cancer patients who underwent IDS had a high rate of optimal cytoreduction. Both response to NACT and IDS were associated with improved survival.