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Signet-ring cell carcinomas (SRCCs) tend to present at higher stages and thus are generally associated with a worse prognosis. It has been postulated that a deficiency of E-cadherin may be causal in the pathogenesis of SRCC in animal models. In this study, we systemically analyzed the expression of E-cadherin and β-catenin, a key component of the cadherin complex, in 137 consecutive SRCCs of various organ systems to explore the significance of these molecules in the pathogenesis and progression of SRCCs. Seventy-six percent of SRCCs showed loss or reduced E-cadherin expression. Aberrant β-catenin expression, defined as loss of membranous expression and nuclear/cytoplasmic subcellular localization, was observed in 60% of these cases, with the altered β-catenin expression observed most commonly in the breast (93%) and least in the lung (38%) primaries. Further, the aberrant β-catenin was significantly associated with pathologic nodal stage (P=0.002) and clinical stage (P=0.02). Our findings demonstrated that reduced membranous E-cadherin and aberrant β-catenin expression were frequent events in SRCCs of various organs, and that the altered β-catenin expression was significantly associated with advanced disease. The observations further support the importance of these molecules in the pathogenesis of SRCCs, and indicate the fundamental role of the Wnt/β-catenin signaling pathway in the progression of these tumors. Further investigations of the downstream molecules in this cascade may provide potential novel therapeutic targets for this aggressive tumor type.

Despite mounting evidence that large intramural leiomyomas decrease fecundity during in vitro fertilization cycles, few studies have demonstrated a mechanism for this impact. We hypothesize that large intramural leiomyomas (IM) decrease the expression of endometrial implantation factors during the window of implantation. We prospectively recruited sub-fertile patients with IM 3 cm or greater in size planning myomectomy and performed endometrial biopsies the day of planned myomectomy (n = 9). Preoperative screening demonstrated no intercavitary lesions. Control endometrial samples were obtained from young, normally menstruating women free of uterine leiomyomas (n = 8). Endometrial samples were obtained in the mid-secretory phase (average cycle day for control patients and intramural leiomyoma patients were 24.5 and 21.3, respectively). Expression of implantation markers HOXA10, leukemia inhibitory factor (LIF), ER-α, and PR was compared using quantitative immunohistochemistry. Standard descriptive statistics were used to compare H-scores between the cohorts. Patients with intramural leiomyomas were found to have decreased LIF compared to controls (p value

The purpose of this study was to evaluate the safety, efficacy, and immunogenicity of a plasmid vaccine, pNGVL4a-CRT-E7(detox), administered either intradermally, intramuscularly, or directly into the cervical lesion, in patients with HPV16-associated CIN2/3.Eligible patients with HPV16(+) CIN2/3 were enrolled in treatment cohorts evaluating pNGVL4a-CRT-E7(detox), administered by either particle-mediated epidermal delivery (PMED), intramuscular injection (IM), or cervical intralesional injection, at study weeks 0, 4, and 8. Patients were monitored for local injection site and systemic toxicity. A standard therapeutic resection was performed at week 15. The primary endpoints were safety and tolerability. Secondary endpoints included histologic regression and change in cervical HPV viral load. Exploratory endpoints included immune responses in the blood and in the target tissue.Thirty-two patients with HPV16(+) CIN2/3 were enrolled onto the treatment phase of the study, and were vaccinated. Twenty-two of 32 patients (69%) experienced vaccine-specific related adverse events. The most frequent vaccine-related events were constitutional and local injection site in nature, and were grade 1 or less in severity. Histologic regression to CIN 1 or less occurred in 8 of 27 (30%) patients who received all vaccinations and underwent LEEP. In subject-matched comparisons, intraepithelial CD8+ T cell infiltrates increased after vaccination in subjects in the intralesional administration cohort.pNGVL4a-CRT-E7(detox) was well-tolerated, elicited the most robust immune response when administered intralesionally, and demonstrated preliminary evidence of potential clinical efficacy.

To investigate whether tumor cells could be detected in the vagina of women with serous ovarian cancer through TP53 analysis of DNA samples collected by placement of a vaginal tampon.Women undergoing surgery for a pelvic mass were identified in the gynecologic oncology clinic. They placed a vaginal tampon before surgery, which was removed in the operating room. Cells were isolated and DNA was extracted from both the cells trapped within the tampon and the primary tumor. In patients with serous carcinoma, the DNA was interrogated for the presence of TP53 mutations using a method capable of detecting rare mutant alleles in a mixture of mutant and wild-type DNA.Thirty-three patients were enrolled. Eight patients with advanced serous ovarian cancer were included for analysis. Three had a prior tubal ligation. TP53 mutations were identified in all eight tumor samples. Analysis of the DNA from the tampons revealed mutations in three of the five patients with intact tubes (sensitivity 60%) and in none of the three patients with tubal ligation. In all three participants with mutation detected in the tampon specimen, the tumor and the vaginal DNA harbored the exact same TP53 mutation. The fraction of DNA derived from exfoliated tumor cells ranged from 0.01% to 0.07%.In this pilot study, DNA derived from tumor was detected in the vaginas of 60% of patients with ovarian cancer with intact fallopian tubes. With further development, this approach may hold promise for the early detection of this deadly disease.

// Zachary C. Dobbin 1,2 , Ashwini A. Katre 1 , Adam D. Steg 1 , Britt K. Erickson 1 , Monjri M. Shah 1 , Ronald D. Alvarez 1 , Michael G. Conner 3 , David Schneider 4 , Dongquan Chen 5 and Charles N. Landen 6 1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham 2 NIH Medical Scientist Training Program, University of Alabama at Birmingham 3 Department of Pathology, University of Alabama at Birmingham 4 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham 5 Division of Preventative Medicine, Department of Medicine, University of Alabama at Birmingham 6 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Virginia, Charlottesville, VA Correspondence: Charles N. Landen Jr, email: // Keywords : Ovarian Cancer, Patient-derived xenograft, cancer stem cells, chemoresistance, animal models of cancer Received : August 08, 2014 Accepted : August 18, 2014 Published : August 19, 2014 Abstract A cornerstone of preclinical cancer research has been the use of clonal cell lines. However, this resource has underperformed in its ability to effectively identify novel therapeutics and evaluate the heterogeneity in a patient’s tumor. The patient-derived xenograft (PDX) model retains the heterogeneity of patient tumors, allowing a means to not only examine efficacy of a therapy, but also basic tenets of cancer biology in response to treatment. Herein we describe the development and characterization of an ovarian-PDX model in order to study the development of chemoresistance. We demonstrate that PDX tumors are not simply composed of tumor-initiating cells, but recapitulate the original tumor’s heterogeneity, oncogene expression profiles, and clinical response to chemotherapy. Combined carboplatin/paclitaxel treatment of PDX tumors enriches the cancer stem cell populations, but persistent tumors are not entirely composed of these populations. RNA-Seq analysis of six pair of treated PDX tumors compared to untreated tumors demonstrates a consistently contrasting genetic profile after therapy, suggesting similar, but few, pathways are mediating chemoresistance. Pathways and genes identified by this methodology represent novel approaches to targeting the chemoresistant population in ovarian cancer

We report a case of extramedullary hematopoiesis (EMH) in uterine leiomyoma and associated numerous intravascular thrombi. A 29-year-old nulliparous female presented with heavy vaginal bleeding and a hematocrit of 22%. No bone marrow biopsy has been performed. She had a history of uterine leiomyomata and menorrhagia for a year. A transvaginal ultrasound confirmed the presence of a uterine leiomyoma. The patient was treated conservatively with oral contraceptive pills due to desire for fertility. However, she continued to have heavy vaginal bleeding and developed bilateral upper extremity deep vein thrombosis and multiple superficial vein thromboses after two months. An exploratory laparotomy with uterine myomectomy was performed. Gross examination of the specimen revealed a single nodular mass measuring10.0×9.5×7.5 cm with a white-tan swirling cut surface. Microscopic examination revealed benign smooth muscle consistent with leiomyoma and numerous intravascular thrombi both with areas of EMH. Immunohistochemical stains confirmed the presence of all three benign lineages of hematopoietic cells. Occurrence of EMH in uterine leiomyoma and intravascular thrombi is very rare. It may be related to systemic hematopoietic stimulation due to severe chronic anemia and local presence of hematopoietic growth factors and/or cytokines.

Advanced cases of epithelial ovarian, primary peritoneal, and primary tubal malignancies have a relatively poor prognosis and collectively remain the most deadly of all gynecologic malignancies. Although traditionally thought of as one disease process, ongoing research suggests that there is not 1 single site or cell type from which these cancers arise. A majority of the serous tumors appear to originate from dysplastic lesions in the distal fallopian tube. Therefore, what we have traditionally considered “ovarian” cancer may in fact be tubal in origin. In this article, we will review epithelial ovarian cancer classification and genetics, theories regarding cells of origin with a focus on tubal intraepithelial carcinoma, and implications for prevention and screening.

Malignant transformation in a mature cystic teratoma (MCT) is rare, with a reported incidence of approximately 1% to 3%. To our knowledge, no case has been reported previously with the invasion of malignant tumor of MCT into the adjacent small intestine. We report a case of squamous cell carcinoma arising within a MCT and invading into the adjacent small bowel. The patient is a 73-yr-old African American woman who noted the presence of a relatively asymptomatic abdominal mass over the past 40 yr. The mass had become more symptomatic over the past several months, with right-sided abdominal pain and constipation. She underwent an exploratory laparatomy, which demonstrated a cystic abdominal mass measuring 24 cm in diameter and weighing 8 kg. The mass contained necrotic debris, a cloudy fluid, hair, and cartilage. It was adherent to the small intestine in an area associated with focal thickening of the cystic wall of the mass. Histologically, the mass demonstrated a MCT within which arose a well-differentiated squamous cell carcinoma. At the point of attachment to the small intestine, histologic sections demonstrated a transmural invasion of the squamous cell carcinoma into the attached segment of the small intestine through the muscularis propria and the submucosa reaching the mucosal surface. Thirteen regional lymph nodes were isolated near the portion of the small intestine involved with the tumor; however, none of them exhibited metastatic carcinoma.

In this report, we present the case of a 32-year-old woman with Wegener's granulomatosis of the uterine cervix, review the literature, and discuss the differential diagnosis.

Describe the effect of 50 mcg vaginal 17-β-estradiol (E2) cream on vaginal maturation, serum estrogen levels, atrophic symptoms, and biomarkers of oxidative stress and tissue remodeling in postmenopausal women without prolapse.Seventeen women, 65 years or older, applied intravaginal E2 cream nightly for eight weeks, then twice weekly for eight weeks. Vaginal biopsies, serial blood draws, and atrophic symptoms were obtained at baseline, eight, and sixteen weeks. Changes in atrophic symptoms, vaginal maturation indices (VMI), and serum E2 were measured. Immunohistochemical staining characterized levels of transforming growth factor-beta (TGF-β), nuclear factor kappa B (NFKB), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and thrombospondin (TSP).Serum E2 levels (pg/ml) were unchanged from baseline (mean (SD)) 7.7 (3.3) to eight 9.7 (5.7) and sixteen 8.7 (5.8) (p=0.24) weeks. VMI (mean (SD)) improved from baseline 34.2 (18.3) to eight 56.7 (13.1) and sixteen 54.5 (11.3) (p0.001) weeks with no difference between eight and sixteen weeks. Vaginal dryness (p=0.03) and itching (p=0.02) improved. Tissue biomarker levels did not change (TGF-β p=0.35, NFKB p=0.74, eNOS p=0.80, iNOS p=0.24, TSP p=0.80).Vaginal E2 improved atrophic symptoms and VMI without elevating serum E2. Tissue remodeling biomarkers did not change.

To prospectively evaluate in a blinded fashion the accuracy of frozen section in endometrial cancer.Sixty patients with endometrial cancer or complex atypical hyperplasia were consecutively enrolled. Intraoperatively, a frozen section was obtained, processed, and stored for interpretation by blinded pathologists. Final pathologic diagnosis was conducted in the usual fashion with the pathologists blinded to frozen results. Histologic grade and myometrial invasion on frozen section was correlated with final pathology.Median age was 61 years (range, 39-82 years). Fifty-seven percent of patients were white, and mean body mass index was 40 mg/kg2. Depth of invasion on frozen correlated with final pathology in 67% (95% confidence interval [CI] 55-79%). Twenty-eight percent (95% CI 17-39%) of patients were upstaged from frozen to final. Patients with no invasion on frozen were upstaged in 46% (95% CI 28-64%). Histologic grade on frozen correlated with final pathology in 58% (95% CI 46-70%); 38% (95% CI 26-50%) of patients were upgraded by final grade. Patients with frozen grade 1 histology or less were upgraded in 61% (95% CI 45-77%). Clinically relevant upstaging occurred in 11 patients (18%) (95% CI 8-28%).Frozen section for histologic grade and depth of myometrial invasion in endometrial cancer correlates poorly with final pathology. Because a large number of patients are potentially understaged with the use of frozen section with a subsequent risk of over and under treatment, we recommend consideration of comprehensive surgical staging for all patients with endometrial cancer.II-2.

A 23-year-old female underwent a cesarean section for breech presentation at term. Her postpartum course was complicated by multiple admissions for pelvic pain presumed to be endometritis. Her symptoms were temporarily alleviated with intravenous antibiotics during each hospitalization. Imaging to evaluate persistent abdominal pain revealed a large cystic right lower quadrant mass adjacent to the ovary. Findings at diagnostic laparoscopy included a 15-cm × 4-cm appendix with pathology confirming myxoglobulosis. This case describes the only reported case of myxoglobulosis of the appendix presenting as a rare cause of pelvic pain in a postpartum patient. (J GYNECOL SURG 20:127)

Background: Despite its favorable prognosis, endometrial stromal sarcoma (ESS) commonly recurs in the abdomen and pelvis. Rarely, it recurs in the cardiovascular system. A case of isolated cardiac ESS recurrence without concurrent vascular or abdominal disease is presented in this report. Case: A 53-year-old woman with previously diagnosed and treated ESS presented to her physician with tachycardia and fatigue. Transthoracic echocardiogram revealed an intra-atrial pedunculated mass without caval involvement. Results: Surgical resection was performed successfully with alleviation of the patient'sher symptoms. Pathology confirmed isolated intracardiac recurrent ESS. Conclusions: This is the first documented case of intracardiac recurrence of ESS without concurrent abdominal or intracaval disease. This isolated recurrence supports a hematogenous mechanism of spread for ESS rather than intracavitary diffusion. Aggressive surgical management continues to be an option for treatment. (J GYNECOL SURG 28:140)

Genetic changes occurring in different stages of pre-cancer lesions reflect causal events initiating and promoting the progression to cancer. Coexisting pre-cancerous lesions including low- and high-grade squamous intraepithelial lesion (LGSIL and HGSIL), and adjacent “normal” cervical epithelium from six formalin-fixed paraffin-embedded (FFPE) samples were selected. Tissues from these 18 samples were isolated using laser capture microdissection, RNA was extracted and sequenced. RNA-sequencing (RNA-seq) generated 2.4 billion raw reads in 18 samples, of which approximately 50.1% mapped to known and annotated genes in the human genome. There were 40 genes up-regulated and 3 down-regulated (normal to LGSIL) in at least one third of the sample pairs (same direction and FDR p

Objective. The Wnt/β-catenin pathway is known to regulate cellular proliferation and plays a role in chemoresistance. Niclosamide, an FDA approved salicyclamide derivative used for the treatment of tapeworm infections, targets the Wnt/β-catenin pathway. Therefore, the objective of this study was to investigate niclosamide as a potential therapeutic agent for ovarian cancer. Methods. Tumor cells isolated from 34 patients' ascites with primary ovarian cancer were treated with niclosamide (0.1 to 5 μM) ± carboplatin (5 to 150 μM). Cell viability was assessed using the ATP-lite assay. LRP6, Axin 2, Cyclin D1, survivin and cytosolic free β-catenin levels were determined using Western blot analysis. Tumorspheres were treated, and Wnt transcriptional activity was measured by the TOPflash reporter assay. ALDH and CD133 were analyzed by Flow cytometry and IHC. ALDH1A1 and LRP6 were analyzed by IHC in solid tumor and in ascites before and after treatment with niclosamide. Results. Combination treatment produced increased cytotoxicity compared to single agent treatment in 32/34 patient samples. Western blot analysis showed a decrease in Wnt/β-catenin pathway proteins and the expression of target genes. A significant reduction of Wnt/β-catenin signaling was confirmed by TOPflash assay. There was increased staining of ALDH1A1 and LRP6 in ascites compared to solid tumor which decreased after treatment. Conclusion. This study demonstrates that niclosamide is a potent Wnt/β-catenin inhibitor. Targeting the Wnt/β-catenin pathway led to decreased cellular proliferation and increased cell death. These findings warrant further research of this drug and other niclosamide analogs as a treatment option for ovarian cancer.

Nonpuerperal uterine inversion is an extremely rare gynecologic event. The vast majority of nonpuerperal inversions occur in association with a uterine tumor, of which approximately 20% are malignant. The case of a 74-year-old patient with suspected primary cervical sarcoma is presented. At the time of surgery, nonpuerperal uterine inversion was identified. High-grade endometrial stromal sarcoma was confirmed on pathologic examination. The etiologic factors that constitute the differential diagnosis are discussed, as well as strategies for managing this unusual entity.

Background. Clear cell adenocarcinoma (CCA) of the vagina is traditionally treated with radical surgical resection with tailored postoperative radiation when indicated. Due to a bimodal distribution, women of reproductive age are frequently affected and could benefit from radical trachelectomy to preserve fertility. Case. A 22 year old female was diagnosed with clinical stage I vaginal clear cell adenocarcinoma in the left fornix abutting the cervix. The patient desired future fertility; therefore, she underwent radical abdominal trachelectomy and upper vaginectomy. Twenty-eight months after initial surgery, she has no evidence of recurrence with regular menstrual cycles. Conclusion. For patients with CCA of the upper vagina, where removal of the cervix is necessary, a radical trachelectomy with upper vaginectomy should be considered to conserve fertility.

Background. Although mature cystic teratoma is the most common tumor of the ovary, squamous cell carcinoma arising from a mature teratoma is a rare event. Prognosis depends on clinical stage, grade, and recently described mode of tumor infiltration. Case. This case involves a 52-year-old woman with stage II squamous cell carcinoma arising in a mature cystic teratoma of the left ovary. Final pathology demonstrated poorly differentiated squamous cell carcinoma with gamma mode of tumor infiltration. The patient completed adjuvant chemotherapy and subsequently died of progressive disease. Conclusion. Squamous cell carcinoma arising from a benign cystic teratoma is a rare event. Studies have shown stage, grade, and mode of infiltration to be predictors of recurrence and prognosis. This case supports the growing evidence linking the mode of tumor infiltration with overall prognosis of survival.

Background Positron emission tomography (PET) is commonly used to detect occult or recurrent malignancy, including tumors of the female genital tract. Recently, there have been reports of PET scans used in patients with Gestational Trophoblastic Disease (GTD). Case A 22-year-old female presented with vaginal bleeding and elevated β-hCG 7 months after a spontaneous vaginal delivery of a healthy infant. She had a history of molar pregnancy and persistent GTD requiring multi-agent chemotherapy. Metastatic evaluation with computed tomography and magnetic resonance imaging showed no evidence of GTD. A positron emission tomography/computed tomography (PET/CT) scan revealed a focus of metabolic activity in the left pelvis. The patient underwent an exploratory laparotomy that revealed metastatic choriocarcinoma in the left broad ligament. Conclusion PET/CT may be useful in the evaluation of occult choriocarcinoma when conventional imaging fails to identify metastatic disease.

Altered glycosylation is a key hallmark of tumor cells; still, the role of individual glycosyltransferases remains unclear. ST6Gal-I is a tumor-associated sialyltransferase which catalyzes the addition of a sialic acid sugar to substrate glycoproteins. Addition of the negatively-charged sialic acid by ST6Gal-I has been shown to alter receptor conformation, clustering, and surface retention, leading to changes in downstream signaling. In this study we assayed ST6Gal-I by immunohistochemistry and report the great majority of patient ovarian and pancreatic tumors express this enzyme. In contrast, the normal epithelium expresses minimal ST6Gal-I. Enzyme expression in ovarian cancers is enriched during metastasis and correlates with worse progression-free and overall survival. Recent evidence points to ST6Gal-I activity in stem/progenitor cells. In light of this, we investigated whether ST6Gal-I functionally promotes a cancer stem cell (CSC) phenotype, i.e. resistance to chemotherapy, survival as tumorspheroids, and ability to initiate tumors. We previously reported that ST6Gal-I activity confers resistance to cisplatin; we now show its activity additionally confers resistance to gemcitabine in pancreatic tumor cells. ST6Gal-I expressing cells are enriched in patient derived xenografts (PDX) treated with gemcitabine suggesting that these cells preferentially survive chemotherapy in vivo. In addition to chemoresistance, ST6Gal-I promotes the growth of pancreatic and ovarian cell lines in tumorspheroid culture. Moreover, ST6Gal-I expressing primary tumor cells isolated from ovarian cancer ascites or PDX tumors survive in tumorspheroid culture, whereas ST6Gal-I negative cells do not. Conversely, forced expression of ST6Gal-I protects tumor cells exposed to the ascites fluid milieu in vitro, while non-ST6Gal-I expressing cells succumb to this inflammatory environment. In a limiting dilution tumor initiating assay, ST6Gal-I expressing cells have a higher tumor incidence and form larger tumors compared to cells with ST6Gal-I knockdown. We next created a conditional mouse model with forced ST6Gal-I expression in the intestinal tract and used AOM-DSS chemically-induced carcinogenesis model to evaluate tumor formation. Compared with wildtype mice, ST6Gal-I knock-in mice have a greater tumor burden, evidenced by increased tumor number and area. As a novel mechanistic link beteween ST6Gal-I and the CSC phenotype, direct modulation of ST6Gal-I levels in tumor cells regulates the expression of stem-related transcription factors, Sox9 and Slug, implicated in tumor progression. The finding that a distinct glycosyltransferase governs the expression of key transcription factors highlights the tumor glycome as a driving factor in CSC behavior. Citation Format: Matthew J. Schultz, Andrew T. Holdbrooks, Asmi Chakraborty, William E. Grizzle, Charles N. Landen, Donald J. Buchsbaum, Michael G. Conner, Rebecca C. Arend, Karina J. Yoon, Chris A. Klug, Daniel C. Bullard, Robert A. Kesterson, Patsy G. Oliver, Amber K. O’Connor, Bradley K. Yoder, Susan L. Bellis. The tumor associated sialyltransferase ST6Gal-I promotes a cancer stem cell phenotype and upregulates stem-related transcription factors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3327.

Purpose: Endoglin (CD105) is a membranous protein overexpressed in tumor-associated endothelial cells, chemoresistant populations of ovarian cancer cells, and potentially stem cells. Our objective was to evaluate the effects and mechanisms of targeting endoglin in ovarian cancer. Experimental Design: Global and membranous endoglin expression was evaluated in multiple ovarian cancer lines. In vitro, the effects of siRNA-mediated endoglin knockdown with and without chemotherapy were evaluated by MTT assay, cell-cycle analysis, alkaline comet assay, γ-H2AX foci formation, and quantitative PCR. In an orthotopic mouse model, endoglin was targeted with chitosan-encapsulated siRNA with and without carboplatin. Results: Endoglin expression was surprisingly predominantly cytoplasmic, with a small population of surface-positive cells. Endoglin inhibition decreased cell viability, increased apoptosis, induced double-stranded DNA damage, and increased cisplatin sensitivity. Targeting endoglin downregulates expression of numerous DNA repair genes, including BARD1, H2AFX, NBN, NTHL1, and SIRT1. BARD1 was also associated with platinum resistance, and was induced by platinum exposure. In vivo, antiendoglin treatment decreased tumor weight in both ES2 and HeyA8MDR models when compared with control (35%–41% reduction, P < 0.05). Endoglin inhibition with carboplatin was associated with even greater inhibitory effect when compared with control (58%–62% reduction, P < 0.001). Conclusions: Endoglin downregulation promotes apoptosis, induces significant DNA damage through modulation of numerous DNA repair genes, and improves platinum sensitivity both in vivo and in vitro. Antiendoglin therapy would allow dual treatment of both tumor angiogenesis and a subset of aggressive tumor cells expressing endoglin and is being actively pursued as therapy in ovarian cancer. Clin Cancer Res; 19(1); 170–82. ©2012 AACR.

BACKGROUND: Uterine leiomyosarcoma is an aggressive tumor that has a propensity for distant metastasis. Distant sites of spread include the lung, liver, brain, and bone. CASE: A woman in her 5th decade was diagnosed with stage IV leiomyosarcoma of the uterus. Distant metastasis in the chest was confirmed by thoracotomy at the time of her original diagnosis. She subsequently experienced multiple episodes of metastasis including metastatic disease to her thyroid. She survived 71 months after diagnosis of stage IV disease. CONCLUSION: Our case represents the first reported experience with uterine leiomyosarcoma metastatic to the thyroid. Additionally the case is notable because the patient experienced multiple episodes of asymptomatic stable disease after repetitive chemotherapeutic regimens.

Purpose: Within heterogeneous tumors, subpopulations often labeled cancer stem cells (CSC) have been identified that have enhanced tumorigenicity and chemoresistance in ex vivo models. However, whether these populations are more capable of surviving chemotherapy in de novo tumors is unknown. Experimental Design: We examined 45 matched primary/recurrent tumor pairs of high-grade ovarian adenocarcinomas for expression of CSC markers ALDH1A1, CD44, and CD133 using immunohistochemistry. Tumors collected immediately after completion of primary therapy were then laser capture microdissected and subjected to a quantitative PCR array examining stem cell biology pathways (Hedgehog, Notch, TGF-β, and Wnt). Select genes of interest were validated as important targets using siRNA-mediated downregulation. Results: Primary samples were composed of low densities of ALDH1A1, CD44, and CD133. Tumors collected immediately after primary therapy were more densely composed of each marker, whereas samples collected at first recurrence, before initiating secondary therapy, were composed of similar percentages of each marker as their primary tumor. In tumors collected from recurrent platinum-resistant patients, only CD133 was significantly increased. Of stem cell pathway members examined, 14% were significantly overexpressed in recurrent compared with matched primary tumors. Knockdown of genes of interest, including endoglin/CD105 and the hedgehog mediators Gli1 and Gli2, led to decreased ovarian cancer cell viability, with Gli2 showing a novel contribution to cisplatin resistance. Conclusions: These data indicate that ovarian tumors are enriched with CSCs and stem cell pathway mediators, especially at the completion of primary therapy. This suggests that stem cell subpopulations contribute to tumor chemoresistance and ultimately recurrent disease. Clin Cancer Res; 18(3); 869–81. ©2011 AACR.

To evaluate patterns of failure and overall survival for patients with surgical stage I uterine carcinosarcoma managed conservatively without adjuvant therapy. A computerized database identified 27 patients whose conditions have been diagnosed with surgical stage I uterine carcinosarcoma from 1993 to 2002. Charts were abstracted for patient demographics, tumor characteristics, recurrence, and survival. Of 27 patients, 23(85%) did not receive adjuvant therapy after undergoing total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and paraaortic lymphadenectomy. Five patients were stage IA, 14 were stage IB, and 4 were stage IC. Fourteen patients had either poorly differentiated endometrioid carcinoma alone or in combination with papillary serous carcinoma (61%) as their epithelial tumor component. The median nodal count was 9 (range, 3-21). Eleven patients are alive without evidence of disease with a median follow-up of 63 months (range, 12-164 months). Eleven patients had recurrence with a median time to recurrence of 13 months (range, 6-39 months), and all are dead of disease. Univariate analysis demonstrated that poorly differentiated epithelial or papillary serous histologic diagnosis was the only predictor variable associated with recurrence and, consequently, death (P = 0.04). Approximately 50% of patients with surgical stage I carcinosarcoma who are observed without adjuvant therapy will experience a recurrence. Because most patients will recur distantly, systemic chemotherapy should be considered for patients with early stage uterine carcinosarcoma.

Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is the most common hereditary cancer syndrome in the United States and Europe. More than 50% of women diagnosed with Lynch syndrome will present with a gynecologic malignancy as their sentinel cancer; the majority of these cancers will be endometrial cancer.1 HNPCC is caused by a germline mutation in the DNA mismatch repair mechanism that works to ensure the fidelity of the genome during cell division.2 The most common mutations are MLH1, MSH2, MSH6, and PMS2; defects in these genes result in microsatellite instability.3 Per the Modified Bethesda criteria recommendations, patients less than age 50 diagnosed with colorectal cancer should undergo testing to determine whether they have a genetic mutation associated with Lynch syndrome (see the Box). Although approximately 11% of patients under the age of 50 diagnosed with endometrial cancer will have a mutation consistent with Lynch syndrome,4 no recommendations for genetic testing exist specific to endometrial cancer.5 Modified Bethesda Criteria Tumors from individuals should be tested for microsatellite instability in the following situations: Colorectal cancer diagnosed in a patient who is less than 50 years of age. Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors,* regardless of patient age. Colorectal cancer with the microsatellite instability-H–like histology diagnosed in a patient who is less than 60 years of age. Colorectal cancer diagnosed in a patient with one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed before the age of 50. Colorectal cancer diagnosed in a patient with two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age. *HNPCC-related tumors include colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome; and carcinoma of the small bowel. The purpose of this study was to estimate the frequency of mismatch repair deficiencies detected by immunohistochemistry and microsatellite instability testing in women less than age 50 with endometrial cancer. Additionally, we sought to evaluate whether obesity affected the frequency of mismatch repair deficiencies.

This chapter will be devoted to infrequently encountered lesions of the female reproductive tract. Some of these will be lesions that are rarely seen, while others will be lesions that you may anticipate seeing from time to time, although certainly not everyday.

The purpose of this study was to explore whether endometrial microbial colonization and plasma cell endometritis are risk factors for adverse pregnancy outcomes, and whether these outcomes are influenced by interactions between interconceptional antibiotics and the micro-flora.Subgroup analyses of data from a double-blind, randomized, placebo-controlled trial of a course of metronidazole plus azithromycin given every 4 months to women with a prior preterm delivery to prevent recurrent preterm delivery. Endometrial cultures and histology were obtained at randomization and repeated 2 weeks after the first treatment. Fifty-nine on antibiotics versus 65 on placebo had pregnancy outcomes. Prevalence of adverse pregnancy outcomes (pregnancy loss or preterm birth37 weeks) was stratified by treatment group and endometrial characteristics. Subgroups were assessed and screened for potential interaction (P values for significance set a priori at.01), prior to formal statistical testing for interaction (P values.05).The prevalence of adverse pregnancy outcome was 62.7% in the presence of endometrial microbial colonization at baseline (any microbe) and 50% in the absence of colonization (RR = 1.25; 99% CI 0.42-3.7). Prevalence of adverse pregnancy outcomes was 61.9% with plasma cell endometritis, and 70.8% without; RR = 0.87 (0.50-1.5). There was a nonsignificant reduction in adverse pregnancy outcome in the absence of Gardnerella vaginalis or gram-negative rods with RR (95% CI) = 0.60 (0.3-1.2) and 0.66 (0.4-1.2), respectively. In the presence of these microbes, antibiotics appeared to increase adverse outcomes: RR = 1.5 (1.1-2.0) and 1.5 (1.1-2.1), respectively. This reversal of impact represents a crossover interaction.Neither baseline endometrial microbial colonization nor plasma cell endometritis were risk factors for adverse pregnancy outcome. However, colonization with specific microbes interacted with antibiotics to increase adverse outcomes.

OBJECTIVE A pilot study to determine genomic microarray differences in patients with normal cervical tissue and cervical intraepithelial neoplasia (CIN) 3. MATERIALS AND METHODS After institutional review board approval, patients referred to the University of Alabama at Birmingham Colposcopy Clinic for a loop electrosurgical excisional procedure were identified. Tissue biopsies of both normal tissue and CIN 3 from fresh loop electrosurgical excisional procedure specimens were obtained and sent to pathology for histological confirmation. Procurement of these 2 types of tissue from the same patient controls for different types of human papillomavirus infection, smoking and nutritional status, age, immunocompetency, and other microenvironment factors (i.e., the patient serves as their own control). Standard RNA extraction techniques (Qiagen, Inc., Valencia, CA) were used to prepare the tissue specimens for microarray analysis with the Affymetrix GeneChip U133A expression array (Affymetrix, Inc., Santa Clara, CA). Paired samples were eligible for microarray analysis only when both normal tissue and CIN 3 were confirmed by pathology. The data were then subsequently subjected to a log-like transformation and analyzed with a t test. For this study, p

The purpose of this study was to evaluate the impact of an interconception antibiotic regimen on endometrial microbial flora and histologic type.This was a secondary analysis of a double-blind randomized placebo-controlled trial of prophylactic metronidazole plus azithromycin that was given to 241 women (antibiotics, 118 women; placebo, 123 women) with a previous preterm delivery to prevent recurrent preterm delivery. Endometrial cultures and histologic types were obtained at randomization and 2 weeks after treatment. The prevalence of either the new acquisition or the resolution of individual microbes, categories of microbes, and plasma cell endometritis were compared by chi-square or Fishers' exact tests.Overall, antibiotics were associated with lower acquisition and higher resolution of microbes. Of women without Gardnerella at baseline, 14% of the women who received antibiotics vs 34% of the women who received placebo had positive endometrial culture for the organism after treatment (P.05); of those women with G. vaginalis at baseline, 57% of the women who received antibiotics vs 33% of the women who received placebo (P.05) had a negative follow-up culture. Other gram-negative rods, especially aerobes in general, manifested similar patterns. The impact on anaerobes and plasma cell endometritis was not definitive, but there was a trend toward the increased resolution of the former (77% vs 55%) and reduced acquisition of the latter (28% vs 50%).The antibiotic regimen prevented the acquisition and promoted the resolution, but not the eradication, of gram-negative rods such as G. vaginalis and the aerobic subcategory.

Background. Placental site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic disease (GTD) that is generally resistant to conventional chemotherapeutic treatment. Patients with localized disease are usually managed with hysterectomy. Case. A 29-year-old female presented with vaginal bleeding and an elevated serum human chorionic gonadotropin (HCG). After initial observation, the patient experienced continued vaginal bleeding and a persistently elevated HCG. Therefore, she underwent a dilation and curettage and final pathology revealed PSTT. Since the patient desired future fertility, the patient received combination chemotherapy with etoposide, methotrexate, actinomycin-D followed by etoposide and cisplatin (EMA-EP). The patient had a complete response to chemotherapy and subsequently delivered a term infant 2 years after completion of therapy. Conclusion. PSTT is thought to be a chemoresistant disease and the preferred method of treatment is hysterectomy or local uterine resection. However, combination chemotherapy is a reasonable option in a properly counseled patient who strongly desires future fertility.

Background. Basosquamous cell carcinoma (BSC) of the vulva is a rare entity with interesting prognostic and therapeutic implications. Currently, there is no definitive treatment due to its low incidence. Case. A case of recurrent BSC of the vulva treated with unilateral radical vulvectomy and unilateral lymph node dissection is reported. Conclusion. BSC is a rare disorder of the vulva. The metastatic potential of this tumor is not fully understood, but likely is intermediate between squamous cell carcinoma and basal cell carcinoma. Local recurrence is common and close follow-up is warranted.

Objective This study was undertaken to determine whether asymptomatic bacterial vaginosis (BV) is associated with an increased risk of endometrial microbial colonization or plasma cell endometritis in nonpregnant women. Study design In this observational cohort study conducted between August 1995 and August 2001, microbial cultures (n = 769) and histopathology (n = 482) were performed on endometrial specimens obtained from women with a recent preterm or term delivery (83 ± 16 days). Endometritis was defined as the presence of plasma cells. BV was defined using Amsel and Nugent criteria. Results The study population was 71% black, 29% white, 69% single, and 31% had 12 years or more of education. Endometrial cultures were positive for at least 1 microorganism in 83% (n = 637/769) of the women and plasma cell endometritis was present in 39% (n = 190/482). BV was present in 26% (n = 191/722) by Amsel and 38% (n = 289/769) by Nugent criteria. Women with Nugent-BV (RR [relative risk] = 1.12, 95% CI 1.05-1.19) but not Amsel-BV (RR = 1.06, 95% CI 1.00-1.13) were significantly more likely to have a positive endometrial culture. A consistent and significant association was observed between BV (by Amsel or Nugent criteria) and an increased frequency of endometrial colonization with BV-associated microorganisms grouped and defined in various ways (RR ranged from 1.96-4.22). No association between BV and plasma cell endometritis was observed. Conclusion Asymptomatic BV is associated with a modest increased likelihood of endometrial microbial colonization and colonization by BV-associated bacteria but is not associated with plasma cell endometritis in nonpregnant women.

Background. Although uterine anomalies are uncommon, gynecologists must be aware of the anatomical challenges that may be encountered from these anomalies. Cervical cancer in the context of a mullerian lateral fusion defect is rare. Case. A case of a unilateral IB1 squamous cell carcinoma of the cervix in the setting of a complete uterovaginal septum and cervix duplex is described. Conclusion. Uterine anomalies compound diagnostic difficulty of routine pathology. Thorough examination and evaluation are crucial for timely diagnosis and treatment. Genital tract duplication, although rare, should always be considered.

Objective This study was undertaken to determine whether endometrial microbial colonization or plasma cell endometritis is increased after spontaneous versus indicated preterm delivery or a spontaneous term delivery. Study design Postpartum, endometrial specimens were obtained after a spontaneous (mean 83, ± 17.6 days) or indicated (mean 83, ± 16.7 days) preterm delivery before 34 weeks' gestation and after a spontaneous term delivery (mean 82, ± 15.7 days; P =.980). Cultures for aerobic and anaerobic bacteria, Trichomonas vaginalis , and genital mycoplasmas were performed. Histologic endometritis was defined as the presence of plasma cells. Results The study population (n=820) was 71% black, 29% white, 69% unmarried, and 31% had less than 12 years of education. Endometrial cultures were positive for at least 1 microorganism in 82% of the women. No significant difference in positive endometrial cultures were observed among women after a spontaneous versus an indicated preterm delivery (85% vs 79%, P =.102), or a spontaneous preterm versus a spontaneous term delivery (85% vs 81%, P =.123). Plasma cell endometritis was present in 39% of 506 specimens sufficient for histologic examination and was also similar in the three groups ( P =.160). Conclusion Microbial colonization of the endometrium and plasma cell endometritis are similar 3 months after spontaneous or indicated preterm or term births. Therefore, chronic infection and inflammation of the endometrium (documented at 3 months postpartum) do not appear to be risk factors for subsequent delivery in women with a prior spontaneous delivery less than 34 weeks' gestation.

Background . Metastatic cancer to the vulva is a rare diagnosis and is estimated to account for 5–8% of all vulvar cancers. Case . A 57-year-old postmenopausal woman was referred for the evaluation of a new vulvar mass. CT scan of the pelvis demonstrated a 4 × 6 cm lobular mass of the left labia. An outpatient excisional biopsy revealed a poorly differentiated large cell carcinoma with prominent necrosis and focal perineural invasion consistent with a bronchogenic carcinoma. A subsequent PET scan of the chest revealed a large primary lung carcinoma confirmed by CT-guided biopsy that was identical to the vulvar tumor. Conclusion . This case represents the only literature described primary lung carcinoma presenting as a vulvar metastasis.

Twenty-three patients with primary small cell carcinoma of the uterine cervix are presented. Their ages ranged between 23 and 63 years (average, 43 years). Blood spotting or vaginal bleeding was the most common clinical presentation. Histologically, the tumors were densely cellular and showed trabecular nesting or a sheet-like pattern. The neoplastic cells had scant cytoplasm, round nuclei, absence of nucleoli, and finely dispersed chromatin. Nuclear molding, single cell necrosis, and high mitotic activity were found in all tumors. There was a minor component of large cell neuroendocrine carcinoma in three cases, while foci of adenocarcinoma were identified in two cases. Immunohistochemical studies were performed in all 23 tumors which showed immunoreactivity for cytokeratin. Ten small cell carcinomas were immunoreactive for chromogranin, 13 for synaptophysin, and 10 expressed p53 protein. Treatment modalities included hysterectomy alone or combined with chemotherapy and/or radiation therapy. A few patients received chemotherapy and/or radiation alone. Follow-up information was obtained in 22 cases; 15 patients died of tumor between 6 and 43 months, while seven patients have remained alive 12 to 273 months. One patient was lost to follow-up. Small cell carcinoma of the cervix is a highly aggressive neoplasm. However, early diagnosis and combined therapeutic modalities may lead to longer survival in some patients. Although the use of immunohistochemistry may be helpful in the diagnosis, small cell carcinoma still remains a morphologic diagnosis.

Objective. The objective of this study was to determine whether clinicopathologic findings or the immunohistochemical presence of molecular markers are predictive of clinical outcome in patients with small cell carcinoma of the cervix (SCCC). Methods. A retrospective review of cases of carcinoma of the cervix was conducted to identify SCCC. From 1978 to 1999, 16 patients were identified at our institution with the diagnosis of SCCC. Microscopic sections of paraffin-embedded tissue specimens were evaluated for confirmation of diagnosis. Specimens were immunohistochemically stained with antibodies to three neuroendocrine markers: neuron-specific enolase, chromagranin (CGR), and synaptophysin. Specimens were also stained for protein expression of p53, erbB2, proliferating cell nuclear antigen, and c- myc. The relationship between molecular markers and clinical outcome was determined. Results. All 16 cases met the histologic criteria for SCCC. Fourteen of 16 tumors (88%) stained positive for neuroendocrine differentiation. Eleven of 16 patients (69%) died from disease with a median survival of 19 months; there were 3 long-term survivors (greater than 5 years). CGR was positive in 8 (50%) specimens and was found to be highly predictive of death ( P = 0.001). Complete loss of p53 protein was seen in 8 patients, 7 of whom died with a median survival of 20 months. Conclusion. Immunohistochemistry can be helpful in confirming difficult cases of SCCC. Further studies are necessary to define molecular markers that may be predictive of outcome in patients with SCCC.

To assess the prognostic significance of molecular biomarkers, particularly c-erbB-2 and p53, through study of prospective clinical data and archival breast cancer tissues for women accrued to the Alabama Breast Cancer Project.Defining molecular abnormalities in breast cancer is an important strategy for early detection, assessment of prognosis, and treatment selection. Evidence is strong that selective biomarkers, including c-erbB-2 and p53, have prognostic significance in breast cancer. Few studies have analyzed the prognostic significance of coexpression of biomarkers.Study patients were those accrued to the Alabama Breast Cancer Project (1975-1978) who had archival breast cancer tissues available for analysis. Criteria for entrance into the Alabama Breast Cancer Project were T1-3 breast cancer with M0 status. Age, nodal status, and histologic grade were also documented. Patients were randomized to radical versus modified radical mastectomy, and node-positive patients were also randomized to adjuvant chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]) versus melphalan. Archival breast cancer tissues were studied for c-erbB-2, TGF-alpha, p53, cathepsin D, bcl-2, and estrogen and progesterone receptor expression using immunohistochemistry. Survival curves were developed using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test, multivariate analysis using a rank regression model.Three hundred eleven patients were accrued to the Alabama Breast Cancer Project, and paraffin-embedded breast cancer tissues for 90 patients were available for immunohistochemical analysis of molecular biomarkers. Univariate analysis showed nodal status, c-erbB-2 expression, and p53 expression to have prognostic significance. Coexpression of c-erbB-2 and p53 was also found to have prognostic significance by the log-rank test. Multivariate analysis showed T stage, nodal status, c-erbB-2 expression, and p53 expression to have independent prognostic significance.These data suggest that c-erbB-2 and p53 expression in breast cancer have prognostic significance. After median follow-up of 16 years, coexpression of c-erbB-2 and p53 may have more prognostic significance than traditional prognostic factors such as T stage and nodal status. Prospective study of large numbers of patients with breast cancer is encouraged to validate these findings.

Twenty-four years after apparently successful treatment for nodular lymphocyte predominant Hodgkin's disease (nLPHD), a 41-year old male developed "B" symptoms and extensive adenopathy. A right axillary lymph node biopsy showed two distinct regions including (1) histiocyte-rich B-cell lymphoma and (2) diffuse small T-cell lymphoma. A clonal rearrangement of the gene for the T-cell receptor beta chain confirmed the presence of a T-cell neoplasm, and this was further confirmed by selective polymerase chain reaction (PCR) on this morphologic zone. PCR on the morphologic B-cell lymphoma confirmed the presence of an immunoglobulin gene rearrangement. These two regions were separated by a less-defined zone containing a mixture of small CD57 positive T lymphocytes, small B lymphocytes, and rare lymphocytic and histiocytic (L&H) cells, highly suggestive of recurrent LPHD. The development of composite B-cell and T-cell lymphoma in this patient raises the speculation that nLPHD may be a neoplasm of lymphoid cells, which can differentiate in both B- and T-cell directions, with the "L&H" cells constituting their B-cell progeny.

A large number of very early spontaneous preterm births are ascribed to bacterial infection of the upper genital tract or chorioamnionitis, without symptoms in either instance. Many believe that ascending infection by bacteria initially present in the cervix and vagina leads to microbial colonization of the chorioamnion and amniotic fluid. This study was an attempt to determine whether antibiotic treatment during the interpregnancy interval in women having a previous preterm birth before 34 weeks gestational age might lower the risk of spontaneous preterm birth in a subsequent pregnancy. A total of 241 women with a history of spontaneous birth before 34 weeks gestational age were randomized, in a double-masked trial, to receive either 2 1-g doses of azithromycin orally 4 days apart plus 750 mg daily of sustained-release metronidazole for 1 week or identical-appearing placebos. The regimen was repeated at 4-month intervals until a subsequent pregnancy began, as was the case for 124 women, 59 of whom received antibiotics. The antibiotic-treated and control women were similar in most respects, but the actively treated women were significantly more compliant in keeping study appointments and taking their assigned medications. Approximately 80% of women in both groups received a course of treatment within 6 months before the subsequent conception. Positive endometrial cultures at the time of randomization were comparably frequent in the antibiotic and placebo groups: 86% and 91%, respectively. Median numbers of individual microbial species isolated from the endometrium also did not differ significantly. Plasma cell endometritis was found in 31% of the antibiotic group and 47% of placebo recipients. Repeat endometrial cultures taken 2 weeks later showed a lower number of individual bacterial species in 49% of women given antibiotics and 31% of the control group. There was no apparent difference in the resolution of endometritis. The risk of a subsequent preterm birth did not differ significantly between the 2 groups, and the same was the case for miscarriage before 15 weeks gestation. Although not statistically significant, average gestational age at delivery was 2.4 weeks shorter in the antibiotic group, and average birth weight was 418 g lower than in the placebo group.

Introduction: A cornerstone of preclinical ovarian cancer research over the last 30 years has been the use of cell lines both in vitro and in vivo. This resource has underperformed in its ability to identify effective novel therapeutics and evaluate the heterogeneity of an ovarian neoplasm. Developing a patient-derived xenograft (PDX) allows for a comprehensive study of the heterogeneous tumor and potentially the identification of cellular populations responsible for chemoresistance and recurrence, but has not been fully characterized for ovarian cancer. We have developed an ovarian PDX model to demonstrate many important similarities and differences between these and primary patient tumors, and begun to explore its utility in identifying mediators of chemoresistance and personalizing therapy. Methods: Tumors removed from patients undergoing primary tumor reductive surgery were implanted into the subcutaneous flanks of SCID mice. Once a tumor developed, it was expanded into additional mice to propagate a PDX line. Tumors were analyzed for heterogeneity by examination of the tumor initiating cell populations, its stromal content with HLA immunohistochemistry, and proliferation with Ki-67. Cohorts of PDX lines were treated with maximum-tolerated dose of combined carboplatin and paclitaxel or vehicle and response was compared between the PDX and the patient. Chemoresistant PDX lines were generated by treatment with MTD carboplatin and paclitaxel until no evidence of disease (NED), observation until recurrence, and retreatment until fully resistant. RNAseq was conducted comparing treated PDX lines to the untreated PDX lines (n=6 pair) to identify important mediators of chemotherapy resistance. Finally, PDX lines were characterized for defects in homologous recombination (HR) repair with an ex vivo assay, correlating HR status with response to PARP inhibition in vivo. Results: Refinement of xenografting procedures yields an 85% success rate in establishing a PDX. PDX tumors maintain the patient's histology, but the stromal component is replaced by murine cells in the first generation. The xenografts retain primary tumor heterogeneity, at least in expression of putative tumor initiating cells (TIC) (ALDH: 17% vs 19%, CD44: 2.4% vs 5%, CD133 10% vs 3%). However, treatment with chemotherapy significantly increases these populations (ALDH1 increased to 36.1% from 16.2% (p=0.002); CD133 increased to 33.8% from 16.2% (p=0.026), suggesting a role in chemotherapy resistance. The treated PDX tumors showed a decrease in Ki67 staining (from 64% to 34%, p=0.001), suggesting dormancy is induced in the surviving population. The PDX tumors show similar response to chemotherapy as patient tumors, in that PDX tumors from patients with a partial response respond more slowly (if at all) than those from patients achieving a complete response (mean change in tumor volume -5.11% vs -63.73%, p=0.029). RNAseq comparing treated and untreated PDX lines indicate only 54 common genes with a significant change in mRNA (p Conclusions: The ovarian PDX model recapitulates patient tumor heterogeneity and mirrors response to chemotherapy. This model may prove superior in predicting response to therapy in patients, and allows a better model to study complex tumor biology that is impacted by tumor heterogeneity, such as survival of small populations with chemotherapy. Citation Format: Zachary C. Dobbin, Ashwini K. Katre, Monjri M. Shah, Britt K. Erickson, Hauping Chen, Ronald D. Alvarez, Michael G. Conner, Dongquan Chen, Charles N. Landen. An ovarian patient-derived xenograft model to identify the chemoresistant population. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A58.

Beta-catenin is essential for two cellular systems: the membrane-bound, E-cadherin-associated form critical for cell adhesion, and the membrane-uncomplexed beta-catenin required for transducing Wnt signaling. It is now known that beta-catenin gene mutations with subsequent nuclear/cytoplasmic protein overaccumulation play a key role in tumorigenesis of various organs. Signet-ring cell carcinoma (SRCC) has been traditionally applied to a subtype of adenocarcinoma …

We report a case of extramedullary hematopoiesis (EMH) in uterine leiomyoma associated with numerous intravascular thrombi. A 29-year-old female, gravida 0, para 0, presented with heavy vaginal bleeding. Her hematocrit was 22%. She had a documented history of uterine leiomyomata and menorrhagia for a year. Transvaginal ultrasound confirmed the presence of a …

Objectives The objectives of this study are to determine the utility of re-excision after a primary diagnosis of vulvar carcinoma by assessing the frequency of residual carcinoma found upon re-excision and to quantitate the wound breakdown and carcinoma recurrence rates. Methods We reviewed 1122 cases of VIN or vulvar carcinoma. Women who underwent re-excisional procedures, as part of their initial surgical treatment were identified. Associations between the margin status of the original excisional sample and histology of re-excision, as well as association between the depth of invasion upon initial excision and histology of re-excision were analyzed with Chi-square tests. Results We identified 84 evaluable patients, 72 with stage I disease, 4 with stage II, and 7 with stage III disease. Upon the initial excisional procedure, 33 patients (39%) had carcinoma-positive margins, 27 patients had VIN-positive margins (32%) and 24 patients (28%) had negative margins (>1mm). Upon re-excision, 1/24 (4%) patients with negative margins, 2/27 (7%) patients with VIN-positive margins, and 11/33 (33%) patients with carcinoma-positive margins were found to have carcinoma in the re-excision specimens ( p χ 2 =31). Deeper tumor invasion of the initial excisional specimen (1–12mm) was associated with a higher chance of finding carcinoma upon re-excision (range 18–42%, depending on depth of invasion) ( p =0.015, χ 2 =19). Nineteen patients (23%) had vulvar wound breakdown post re-excision. Twelve patients (15%) experienced recurrences. Conclusions The yield of micro- or invasive carcinoma at re-excision is low, with a high wound breakdown rate. Re-excision should be considered for patients with margins positive for carcinoma, especially for women with deep invasion, while women with VIN or close but clear margins may be followed.

Background: Endoglin (ENG, CD105) is a protein markedly overexpressed in tumor-associated endothelial cells, and a target for anti-angiogenic therapy. Recently we have noted it to be overexpressed in chemoresistant ovarian cancer cells as well. Our objective was to evaluate the effects and mechanisms of targeting endoglin specifically in ovarian cancer cells. Methods: Endoglin expression was assessed in multiple ovarian cancer lines by Western blot, immunohistochemistry, and flow cytometry. Anti-endoglin siRNAs were used to downregulate expression in ES2 and HeyA8MDR. In vitro, the effects of endoglin-knockdown individually and with chemotherapy were evaluated by MTT assay, cell-cycle analysis, alkaline comet assay, γ-H2AX foci formation and qPCR array for mediators of DNA damage and repair. In an orthotopic murine model, mice inoculated with ES2 or HeyA8MDR cell lines were administered chitosan-encapsulated anti-ENG siRNA or control siRNA with and without carboplatin. PCNA, γH2AX, and 53BP1 IHC and the TUNEL assay were performed to examine biologic effects of endoglin knockdown. Results: Endoglin is expressed to varying degrees by multiple ovarian cancer cell lines. Expression was on the cell surface, consistent with its recognized role as a cofactor with TGF-beta receptor, in only 5% of cells, with most other cells having cytoplasmic expression. In ES2 and HeyA8MDR cell lines, endoglin inhibition decreased cell viability, increased apoptosis, induced double-stranded DNA damage, and increased cisplatin sensitivity. Endoglin downregulation led to a decrease in expression of several DNA repair genes, including NBN, NTHL1, BARD1, H2AFX and SIRT1, and an increase in expression of DDIT3 and PPP1R15A. BARD1-specific downregulation, in turn, led to a significant decrease in BRCA1 expression, likely through ubiqutinylation. In vivo, anti-endoglin treatment decreased tumor weight in both ES2 and HeyA8MDR models when compared to control (35-41% reduction, p Citation Format: Angela J. Ziebarth, Somaria Nowsheen, Adam D. Steg, Monjri M. Shah, Ashwini A. Katre, Zachary C. Dobbin, Anil K. Sood, Michael G. Conner, Eddy S. Yang, Charles N. Landen. Endoglin (CD105) is a target for ovarian cancer cell-specific therapy through induction of DNA damage. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5475. doi:10.1158/1538-7445.AM2013-5475 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.