Transdifferentiation of diffuse large B-cell lymphoma to a poorly differentiated neoplasm following CAR T-cell therapy.

Chimeric antigen receptor T-cell (CAR-T) therapy is a recent advancement in precision medicine with promising results for patients with relapsed or refractory B-cell malignancies. However, rare post-therapy morphologic, immunophenotypic, and genomic alterations can occur. This study is to present a case of a patient with diffuse large B-cell lymphoma (DLBCL) who underwent anti-CD19 CAR-T therapy with disease in the uterus that showed transdifferentiation to a poorly differentiated malignant neoplasm that failed to express any lineage specific markers. In immunohistochemistry, fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (NGS) were utilized to fully characterize the diagnostic DLBCL sample in comparison to the poorly differentiated neoplasm of the uterus. Analysis of the diagnostic DLBCL and the poorly differentiated neoplasm demonstrated evidence of a clonal relationship as well as revealing acquisition of mutations associated with CAR-T resistance. Furthermore, downregulation of B-cell associated antigens was observed, underscoring a mechanistic link to CAR-T evasion as well as demonstrating diagnostic confusion. This case illustrates the utility of employing multiple diagnostic modalities in elucidating a pathologic link between a B-cell lymphoma and poorly differentiated neoplasm following targeted therapy.

Participation in global health delivery: Survey results from the Society of Gynecologic Oncology.

•Gynecologic oncologists face multiple barriers in participating in global health.•Several barriers may be addressed at the institutional level.•Most global health experiences involved direct patient care, while only a small proportion involved research.•Gynecologic oncologists receive little structured training in global health.

Influence of a novel histone deacetylase inhibitor panobinostat (LBH589) on the growth of ovarian cancer.

BACKGROUND: Pre-clinical studies have demonstrated that natural and synthetic histone deacetylase (HDAC) inhibitors can impede the in vitro and in vivo growth of cell lines from a variety of gynecologic and other malignancies. We investigated the anti-tumor activity of panobinostat (LBH589) both in vitro and in vivo as either a single agent or in combination with conventional cytotoxic chemotherapy using patient-derived xenograft (PDX) models of primary serous ovarian tumors. METHODS: The ovarian cancer cell lines OVCAR8, SKOV3 and their paclitaxel-resistant derivatives OVCAR8-TR and SKOV3-TR were treated with increasing doses of LBH589. The effect of LBH589 on cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Serially transplanted primary human high-grade serous ovarian adenocarcinoma tissue was utilized to generate xenografts in 6-week old female NOD/SCID mice. The mice were then randomized into one of 4 treatment groups: (1) vehicle control; (2) paclitaxel and carboplatin (P/C); (3) LBH589; or (4) P/C + LBH589. Mice were treated for 21 days and tumor volumes and mouse weights were obtained every 3 days. These experiments were performed in triplicate with three different patient derived tumors. Wilcoxan rank-sum testing was utilized to assess tumor volume differences. RESULTS: In vitro treatment with LBH589 significantly reduced the viability of both taxol-sensitive and taxol-resistant ovarian cancer cell lines (p < 0.01). In vivo treatment with LBH589 alone appeared tumorstatic and reduced tumor growth when compared to vehicle treatment (p < 0.007) after 21 days. This single agent activity was confirmed in two additional experiments with other PDX tumors (p < 0.03, p < 0.05). A potential additive effect of LBH589 and P/C, manifested as enhanced tumor regression with the addition of LBH589 compared to vehicle (p < 0.02), in one of the three analyzed serous PDX models. CONCLUSIONS: Our findings suggest that pan-HDAC inhibition with panobinostat precludes the growth of ovarian cancer cell lines in vitro and PDXs in vivo. Added benefit of LBH589 to standard P/C therapy was observed in one of three PDX models suggesting improved response in a subset of serous ovarian cancers.

The role of radical surgery in the management of acquired uterine arteriovenous malformation.

BACKGROUND: Acquired arteriovenous malformations (AVMs) can develop after uterine instrumentation. The increased risks of vascular changes, including abnormal placentation, after repeated cesarean sections are well studied. Herein, we describe a patient with delayed hemorrhage from a uterine AVM, following dilation and curettage for a cesarean scar pregnancy. CASE: A 32-year-old G3P2 presented with a cesarean scar ectopic pregnancy managed with dilation and curettage, which incurred a 1,500-ml blood loss. Within 6 weeks, she returned with 2 episodes of vaginal bleeding. Initial angiography demonstrated a high-flow arteriovenous fistula, which was coiled. Vaginal hemorrhage recurred; repeat angiography demonstrated a large AVM. Gelfoam embolization of the bilateral internal iliac arteries reduced the vascularity of the AVM. The AVM's location, starting at the left lateral apex of the cesarean scar and extending into the parametrium, necessitated a radical hysterectomy. Pathologic examination revealed a placenta percreta extending into the parametrium. CONCLUSION: The prevalence of uterine AVMs has increased with the rise in surgical obstetrics. In patients with a failed prior interventional procedure, surgical management is necessary to prevent life-threatening hemorrhage. The location of the AVM within the abnormal uterine scar tissue requires familiarity with radical pelvic surgical techniques that are normally used in cancer surgery in order to definitively treat this delayed obstetrical complication.

Abnormal cytology in 2012: management of atypical squamous cells, low-grade intraepithelial neoplasia, and high-grade intraepithelial neoplasia.

Cervical cancer and human papillomavirus-related diseases continue to cause significant morbidity and mortality in the United States and worldwide. As we begin to understand the natural course of human papillomavirus infection, and the consequences of both its detection and treatment, changes have been made to our clinical approaches. The purpose of this review is to outline the management guidelines for the management of abnormal cytology. Successful triage of abnormal cytology in 2012 will allow for continued detection of precancerous lesions reducing the incidence of cervical cancer and increasing the detection of early stage disease.

Endometriosis-associated ovarian malignancy: a retrospective analysis of presentation, treatment, and outcome.

OBJECTIVE: To investigate the relationship of age and tumors associated with endometriosis and outcome of different histologies of epithelial ovarian cancer arising from endometriosis. STUDY DESIGN: We identified cases of epithelial ovarian cancers with clear cell, endometrioid, or mixed clear cell and endometrioid histologies from January 2001 to March 2009. Tumors were classified as either "arising in" endometriosis, "associated with" endometriosis or "controls" (not associated with endometriosis). We collected information regarding patient demographics, past medical history, presentation at diagnosis, treatment, and outcome. RESULTS: Of 140 patients identified, 42 (30.0%) had clear cell, 92 (65.7%) had endometrioid, and 6 (4.3%) had mixed. Of those, 28.6% of tumors were associated with endometriosis (n = 40), 37.1% were arising in endometriosis (n = 52), and 34.3% were controls (n = 48). Premenopausal women had tumors that were more likely arising from or associated with endometriosis as compared to tumors in postmenopausal women (p = 0.005). Premenopausal patients were also more likely to present with early stage disease as compared to postmenopausal women (80.4% vs. 63.6%, p = 0.04) and better overall survival (p < 0.008). Survival analyses of the entire cohort showed that improved survival was associated with stage (p < 0.001), grade (p < 0.001), endometrioid histology (p < 0.005), and with tumors associated with or arising in endometriosis (p < 0.04). Multivariate analysis controlling for menopausal status showed the presence of endometriosis was no longer associated with a survival advantage (p = 0.08). CONCLUSION: The association with endometriosis does appear, at least in endometrioid tumors, to provide a survival benefit. Overall, menopausal status, stage, and grade are more powerful variables associated with improved survival.

Laparoendoscopic single-site radical hysterectomy: the first report of LESS type III hysterectomy involves a woman with cervical cancer.

Laparoendoscopic single-site surgery is a logical advance in the evolution of minimally invasive surgery and is being utilized to perform increasingly complex procedures. We report its use for completion of radical hysterectomy as treatment for cervical cancer.

Management of a skin metastasis in a patient with advanced ovarian cancer.

► Skin metastasis of ovarian cancer is rare, often nodular in appearance, and conveys a poor prognosis. ► This patient developed an unusual maculo-papular rash which was biopsy-proven to be metastatic endometrioid adenocarcinoma. ► Pruritic symptoms from skin metastases should be palliated; SSRIs, local radiation, and topical creams all may play a role.

Cytoreductive surgery for advanced ovarian cancer: quo vadis?

Two-thirds of women who are newly diagnosed with invasive epithelial ovarian cancer present with stage III or IV disease.The preferred initial treatment has traditionally consisted of primary surgical debulking followed by platinum-based chemotherapy. However, recent data suggesting comparable efficacy for neoadjuvant chemotherapy and interval debulking have challenged this conventional dogma. Most patients with advanced ovarian cancer will achieve remission regardless of initial treatment, but 80% to 90% of patients will ultimately relapse. The timing and clinical benefit of a second debulking operation for recurrent disease is even more contentious. This article focuses on the recent debate regarding when--or whether--patients with ovarian cancer should undergo aggressive surgical resection.

Evolution of surgical management of early-stage endometrial cancer.

OBJECTIVE: We sought to examine the evolution of surgical care for early-stage endometrial cancers and factors affecting use of laparoscopy. STUDY DESIGN: Women with surgically managed early-stage endometrial cancer were divided into 2 groups corresponding to before and after addition of faculty with formal fellowship training in laparoscopic staging and access to a robotic surgery platform. RESULTS: In all, 502 women were identified. Laparoscopic management increased from 24-69% between time periods (P < .0001). Performance of comprehensive surgical staging, and lymph node counts, increased (P < .0001) despite an increase in median body mass index (P = .001). A traditional "straight stick" technique was performed in 72% of laparoscopic cases during the later period. Laparoscopy patients had lower estimated blood losses and shorter hospital stays (each P < .0001) compared to laparotomy patients. CONCLUSION: Addition of faculty with formal fellowship training in laparoscopic staging and access to a robotic surgery platform shifted management of early-stage endometrial cancer toward laparoscopy.

Evidence for cancer stem cells contributing to the pathogenesis of ovarian cancer.

Ovarian cancer represents the most lethal gynecologic malignancy, primarily due to a lack of early detection, which results in most patients being diagnosed at an advanced stage of disease. Though the ovarian surface epithelium is thought to provide the primary site of tumorigenesis, the exact etiology of the various tumor types associated with this disease remain undefined. Recent evidence suggests that ovarian tumors, like other solid tumors, contain distinct populations of cells that are responsible for tumor initiation, maintenance and growth. These specialized cells, termed cancer stem cells, display some of the hallmarks of normal stem cells and are thought to evade current chemotherapeutic strategies, resulting in an increased risk of recurrence. Here we review evidence for the existence of cancer stem cells in ovarian malignancies and their contribution to the pathology of this disease, critically evaluate the methods used for ovarian cancer stem cell definition and isolation, and discuss their clinical relevance.

Epidemiologic correlates of ovarian cortical inclusion cysts (CICs) support a dual precursor pathway to pelvic epithelial cancer.

OBJECTIVE: Many ovarian carcinomas are presumed to arise within ovarian cortical inclusion cysts (CICs). This study examined the frequency of ovarian CICs in relation to epidemiologic risk factors in women with BRCA1 and BRCA2 (BRCA+) mutations. METHODS: BRCA+ women who underwent risk-reducing bilateral salpingo-oophorectomy were studied (n=74). Fifteen demographic variables (e.g., age at time of surgery, age at first birth, age at menopause, body mass index (BMI), gravidity) from a review of the medical records and three pathologic variables (cystic and atretic follicles, corpora lutea) were recorded. Statistical associations were made using T-test or Chi Square analysis and logistic regression analysis for p-trend. RESULTS: Women whose ovaries contained 7 for more CICs were older at first birth (p=0.034), surgery (p=0.059), menopause (p=0.046) and had a higher BMI (p=0.034) than those with <7 CICs. Regression analysis revealed a significant association between CICs and increasing BMI (p=0.01). CONCLUSIONS: CICs correlate with greater body mass index, similar to low-grade serous and endometrioid tumors and in contrast to high-grade serous carcinoma and its putative precursor in the fallopian tube. A model is presented for ovarian and tubal pathways to pelvic cancer that are linked to different microscopic precursors with distinct epidemiologic correlates.

Subsequent pregnancy outcomes in patients with molar pregnancy and persistent gestational trophoblastic neoplasia.

OBJECTIVE: To evaluate the subsequent reproductive outcomes in patients with complete and partial molar pregnancy and gestational trophoblastic neoplasia (GTN) at the New England trophoblastic Disease Center between June 1, 1965, and December 31, 2007. STUDY DESIGN: Questionnaires regarding subsequent pregnancies were mailed to all patients with current mailing addresses at the New England Trophoblastic Disease Center. RESULTS: The subsequent reproductive outcomes in patients with complete and partial molar pregnancies and persistent GTN were in general the same as those in the general population. However, after an episode of molar pregnancy the incidence of molar pregnancy in a later gestation was approximately 1%. Additionally, after successful chemotherapy for GTN, the incidence of stillbirth was 1.4% in later pregnancies. CONCLUSION: Patients with molar pregnancies and GTN should be reassured that they can in general expect a normal future reproductive outcome.

Does the fimbria have an embryologic origin distinct from that of the rest of the fallopian tube?

OBJECTIVE: To propose a new theory describing the development of the fallopian tube fimbria. DESIGN: Case series report. SETTING: Metropolitan tertiary care children's hospital. PATIENT(S): Two girls, aged 12 and 20 years, who presented with pelvic pain. INTERVENTION(S): Magnetic resonance imaging, laparoscopy with salpingectomy, and pathologic analysis. MAIN OUTCOME MEASURE(S): Description of a novel theory regarding the embryologic development of the fallopian tube and its fimbria. RESULT(S): In two non-sexually active girls the cause of their pelvic pain was found to be a hydrosalpinx associated with a discontinuous fallopian tube in which the fimbriated end did not directly communicate with the remainder of the fallopian tube. CONCLUSION(S): The two cases of pure congenital fallopian tube atresia, the presence of fimbriae in patients with müllerian (uterine, cervical, and vaginal) agenesis, and the role of the fimbria in ovarian-like and peritoneal cancers, support a novel hypothesis that the fimbria of the fallopian tube may arise separately from the rest of the tube.

Atorvastatin restores endothelial function in normocholesterolemic smokers independent of changes in low-density lipoprotein.

Cigarette smoking impairs endothelial function. Hydroxymethylglutaryl (HMG) CoA reductase inhibitors (statins) may favorably affect endothelial function via nonlipid mechanisms. We tested the hypothesis that statins would improve endothelial function independent of changes in lipids in cigarette smokers. Twenty normocholesterolemic cigarette smokers and 20 matched healthy control subjects were randomized to atorvastatin 40 mg daily or placebo for 4 weeks, washed out for 4 weeks, and then crossed-over to the other treatment. Baseline low-density lipoprotein (LDL) levels were similar in smokers and healthy subjects, 103+/-22 versus 95+/-27 mg/dL, respectively (P=NS) and were reduced similarly in smokers and control subjects by atorvastatin, to 55+/-30 and 58+/-20 mg/dL, respectively (P=NS). Vascular ultrasonography was used to determine brachial artery, flow-mediated, endothelium-dependent, and nitroglycerin-mediated, endothelium-independent vasodilation. To elucidate potential molecular mechanisms that may account for changes in endothelial function, skin biopsy specimens were assayed for eNOS mRNA, eNOS activity, and nitrotyrosine. Endothelium-dependent vasodilation was less in smokers than nonsmoking control subjects during placebo treatment, 8.0+/-0.6% versus 12.1+/-1.1%, (P=0.003). Atorvastatin increased endothelium-dependent vasodilation in smokers to 10.5+/-1.3% (P=0.017 versus placebo) but did not change endothelium-dependent vasodilation in control subjects (to 11.0+/-0.8%, P=NS). Endothelium-independent vasodilation did not differ between groups during placebo treatment and was not significantly affected by atorvastatin. Multivariate analysis did not demonstrate any association between baseline lipid levels or the change in lipid levels and endothelium-dependent vasodilation. Cutaneous nitrotyrosine levels and skin microvessel eNOS mRNA, but not ENOS activity, were increased in smokers compared with controls but unaffected by atorvastatin treatment. Atorvastatin restores endothelium-dependent vasodilation in normocholesterolemic cigarette smokers independent of changes in lipids. These results are consistent with a lipid-independent vascular benefit of statins but could not be explained by changes in eNOS message and tissue oxidative stress. These findings implicate a potential role for statin therapy to restore endothelial function and thereby investigate vascular disease in cigarette smokers.

Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus.

Oxidative stress decreases the bioavailability of endothelium-derived nitric oxide in diabetic patients. We investigated whether impaired endothelium-dependent vasodilation (EDV) in diabetes can be improved by long-term administration of oral antioxidants. Forty-nine diabetic subjects [26 Type 1 (T1) and 23 Type 2 (T2)] and 45 matched healthy control subjects were randomized to receive oral vitamin C (1,000 mg) and vitamin E (800 IU) daily or matching placebo for 6 mo. Vascular ultrasonography was used to determine brachial artery EDV and endothelium-independent vasodilation (EIV). EDV was decreased in both T1 (4.9 +/- 0.9%, P = 0.015) and T2 (4.1 +/- 1.0%, P < 0.01) subjects compared with control subjects (7.7 +/- 0.7%). EIV was decreased in T2 (15.0 +/- 1.2%, P < 0.01) but not T1 subjects (18.5 +/- 2.3%, P = 0.3) compared with controls (21.8 +/- 1.8%). Administration of antioxidant vitamins increased EDV in T1 (by 3.4 +/- 1.4%, P = 0.023) but not T2 subjects (by 0.5. +/- 0.4%, P = 0.3). Antioxidant therapy had no significant affect on EIV. Oral antioxidant therapy improves EDV in T1 but not T2 diabetes. These results are consistent with the lack of clinical benefit in studies that have included primarily T2 diabetic patients.

Inhibition of protein kinase Cbeta prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans.

The bioavailability of nitric oxide is decreased in animal models and humans with diabetes mellitus. Hyperglycemia, in particular, attenuates endothelium-dependent vasodilation in healthy subjects. In vitro and in vivo animal studies implicate activation of protein kinase Cbeta as an important mechanism whereby hyperglycemia decreases endothelium-derived nitric oxide. Accordingly, this study tested the hypothesis that inhibition of protein kinase Cbeta would prevent impairment of endothelium-dependent vasodilation in healthy humans exposed to hyperglycemia. This study was a randomized, double-blind, placebo-controlled, crossover trial. Healthy subjects were treated with an orally active, selective, protein kinase Cbeta inhibitor, LY333531, or matching placebo once a day for 7 days before vascular function testing. Forearm blood flow was measured using venous-occlusion, strain-gauge plethysmography. Endothelium-dependent vasodilation was measured via incremental brachial artery administration of methacholine chloride (0.3 to 10 microg/min) during euglycemia and after 6 hours of hyperglycemic clamp. The forearm blood flow dose-response curve to methacholine was significantly attenuated by hyperglycemia after placebo treatment (P=0.009 by ANOVA, euglycemia versus hyperglycemia) but not after treatment with LY333531. Inhibition of protein kinase Cbeta prevents the reduction in endothelium-dependent vasodilation induced by acute hyperglycemia in healthy humans in vivo. These findings suggest that hyperglycemia impairs endothelial function, in part, via protein kinase Cbeta activation.