Faculty Bibliography

Objective: We aimed to explore the disparities associated with the delay of initiating chemoradiation therapy (CRT) and brachytherapy (BT) beyond the recommended 8 weeks for patients with cervical cancer and the effect on outcomes.
Method(s): Patients with FIGO stage IB2-IVA cervical cancer treated at an academic medical center and an urban public hospital by the same team of gynecologic and radiation oncologists with definitive CRT and BT from July 2009 to September 2017 were included. Patients received CRT followed by BT (7 Gy x 4 fractions) delivered via 2 insertions 1 week apart with image-guided CT/MR delineation. Patients who initiated CRT within 8 weeks from diagnosis as recommended (rCRT) were compared across demographic and cancer outcomes to patients who received delayed CRT after 8 weeks (dCRT). Disease-free survival (DFS) and overall survival (OS) were analyzed using adjusted Cox regression analysis (P < 0.05).
Result(s): In our cohort of 97 patients, 72 (75.0%) had rCRT and 24 (25.0%) had dCRT. At a median follow-up of 31.5 months, overall local control was achieved in 94.8% of patients. Patients with dCRT were more likely to be African-American (37.5% vs 17.8%, P = 0.046) and be uninsured or on Medicaid (87.5% vs 61.6%, P = 0.023). There were no differences in stage and grade. Patients with dCRT were more likely to recur or progress (OR = 2.65, 95% CI 1.02-6.86). Of those who recurred, 35.0% of rCRT patients had locoregional recurrence versus 66.7% of dCRT patients (P = 0.144). When controlling for age, race, insurance, referring hospital, and stage, patients with dCRT had lower DFS than patients with rCRT (50.6 vs 63.2 months, aHR = 6.11, 95% CI 2.00-18.62). However, there were no differences in OS.
Conclusion(s): Patients receiving delayed CRT tended to have worse recurrence and DFS than those initiating CRT by 8 weeks from diagnosis. African-American and uninsured patients were more likely to experience a delay in care. Navigator and social work services may help improve access to treatments for these patients.
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Introduction: We have achieved greater than 6-month survivals in baboons that received vascularized thymus plus kidney xenotransplants (VT+KTx). We assessed the thymic function and recipient immune responses >4 months post-transplant.
Method(s): Six baboon recipients that survived >4 months after VT+KTx were studied. All animals underwent thymectomy and bilateral nephrectomy prior to Tx. Two received anti-CD154 mAb-based (129 and 193 days survivals) and the other four received anti-CD40 mAb-based immunosuppression (126, 154, 174 and 187 survivals). Three of the animals received grafts from GalTKO donors, without other transgenes, and three received grafts from hCD47+GalTKO pigs Tg for additional human complement +/-coagulation regulatory proteins. In vitro T cell responses as well as anti-donor antibodies were assessed using recipient PBMCs and kidney grafts. Graft cell infiltrates were examined with anti-CD3 and anti-FoxP3 Abs. Newly developed baboon T cells in peripheral blood were determined using anti-human CD3/ CD4/CD31/CD45RA mAbs.
Result(s): All animals had stable renal function for the first 4 months. Some exhibited eventual increased serum creatinine (Cre) due to organ growth. No grafts showed signs of acute or chronic rejection histologically. All animals showed pig-specific hyporesponsiveness at all time points tested, including the day of euthanasia. Only one baboon, which was euthanized at POD187 due to SVC syndrome associated with MMF toxicity, developed anti-donor IgG after POD60 (PODs 90, 120 and 187), with no rise in Cre (0.6-0.9mg/ dL) and no histologic evidence of rejection (Figure), suggesting accommodation. The remaining five did not develop anti-pig Abs. One kidney displayed cell infiltrates around vessels without tubulitis or endothelialitis (biopsy at POD144) that were FoxP3+, consistent with Treg-rich organized lymphoid structures (TOLs). Three baboons (174, 187 and 193 day survivors), all of whose native thymi had been removed prior to VT+K Tx, showed peripheral naive recipient T cells, which gradually increased after POD60 post-VT+KTx, suggesting recipient thymopoiesis in the donor pig thymus.
Conclusion(s): Life-supporting porcine VT+KTx in thymectomized baboon recipients led to new host T cell development and specific hyporesponsiveness to pig antigens, accompanied by development of FoxP3+ TOLs in the donor kidneys, without evidence of acute rejection

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.

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