A pilot study of pNGVL4a-CRT/E7(detox) for the treatment of patients with HPV16+ cervical intraepithelial neoplasia 2/3 (CIN2/3).

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: pNGVL4a-CRT-E7(detox) was well-tolerated, elicited the most robust immune response when administered intralesionally, and demonstrated preliminary evidence of potential clinical efficacy.

Radical surgical cytoreduction in the treatment of ovarian carcinosarcoma.

OBJECTIVE: Carcinosarcomas are rare and aggressive ovarian malignancies. Treatment recommendations, which include surgical cytoreduction followed by platinum based chemotherapy, have been based on small amounts of retrospective data or extrapolated from experience with high-grade epithelial ovarian adenocarcinoma. Our objective was to determine the effects of radical primary cytoreduction on progression-free survival (PFS) and overall survival (OS). METHODS: Following IRB approval, records of women with ovarian carcinosarcomas diagnosed between 2000 and 2012 at our institution were reviewed. Demographics, tumor characteristics, treatments, PFS, and OS were collected. Patients were divided into three groups based on the amount of residual disease: >1cm of disease, ≤ 1 cm of disease, or no visible disease. Chi-square and student's t-test were used to compare variables among groups. Kaplan-Meier survival curves were generated and compared with the log-rank test. RESULTS: 51 patients with ovarian carcinosarcoma were identified and all underwent primary cytoreductive surgery. Following surgical cytoreduction, 18 patients (35%) had no visible disease, 20 (39%) had ≤ 1 cm of disease, and 13 (25%) had >1cm of residual disease. Median PFS varied significantly among groups: 29 vs. 21 vs. 2 months (p=0.036) as did median OS: 57 vs. 32 vs. 11 months (p=0.015). When patients with stage 3 disease were analyzed separately, median OS still varied significantly among groups: 57 versus 31 versus 3 months (p=0.009). CONCLUSION: Degree of surgical cytoreduction appears to correlate with PFS and OS. Radical surgery resulting in no visible disease is recommended for the upfront surgical treatment of ovarian carcinosarcoma.

Pre-operative imaging with CA125 is a poor predictor for granulosa cell tumors.

OBJECTIVE: To determine the radiographic characteristics of ovarian granulosa cell tumors (GCTs) and to evaluate the use of CA125 levels >35 in combination with imaging as an algorithm for preoperative diagnosis. METHODS: A retrospective analysis of women from two academic medical centers who were diagnosed with ovarian GCT between January 1998 and August 2012 was conducted. Clinical data included tumor appearance on pre-operative imaging and CA125 levels. Ovarian cysts were defined as complex if imaging exhibited multicystic areas, hemorrhagic, solid, or cystic and solid components. A CA125 level >35 was abnormal. RESULTS: One hundred and fifteen women were diagnosed with GCTs, of whom 63 underwent pre-operative imaging. Median age at surgery was 46 years (12-87). Forty women had preoperative ultrasounds, 43 had CT scans and 20 underwent both modalities. GCTs were almost exclusively classified as complex cysts in 62 (98%) cases. The most common morphology was solid and cystic (n=44 (70%)). Forty-four (70%) patients had tumors >10 cm. Forty-two patients had a pre-operative CA125 performed. Eighteen (43%) patients had complex masses and CA125 >35. Twenty-three (55%) had CA125 <35 with a complex mass, and one (2%) had a unilocular cyst with a CA125 >35. CONCLUSIONS: In this study, there was a near equal distribution of patients with complex masses and CA125 levels > or <35. If established strategies to predict malignancy are applied to GCTs, we will frequently fail to make the diagnosis pre-operatively. Additional research is necessary to generate an appropriate algorithm to guide pre-operative referral to a gynecologic oncologist.

Low yield of residual vulvar carcinoma and dysplasia upon re-excision for close or positive margins.

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<0.0001, 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.

The role of the fallopian tube in the origin of ovarian cancer.

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.

Juxtatumoral stromal reactions in uterine endometrioid adenocarcinoma and their prognostic significance.

Uterine endometrioid adenocarcinoma is the most common invasive tumor of the female genital tract in the United States. Tumor invading into myometrium frequently induces juxtatumoral stromal changes resulting in a desmoplastic reaction or host inflammatory response. However, the relationship between stromal reactions and tumor progression in these tumors has not been well established. We thus examined a total of 103 consecutive cases of invasive uterine endometrioid adenocarcinoma in an attempt to determine if an association exists between the stromal reactions and other well-defined histologic and clinical prognostic factors. We found that the presence of a desmoplastic reaction was associated with a higher International Federation of Gynecology and Obstetrics (FIGO) grade (P<0.01) and lymphovascular invasion (LVI) (P<0.05), and advanced FIGO stage (stage IB vs. IC, P<0.01; stage I vs. II/III/IV, P<0.05). The intensity of the inflammatory lymphocytic response (none/mild vs. moderate/severe) was inversely associated with advanced tumor stage (P<0.05), but not associated with tumor grade or LVI. Our findings revealed that a strong lymphocytic stromal response was predominantly found in the uterine endometrioid adenocarcinomas with early clinical stages. In contrast, a juxtatumoral desmoplastic reaction was more frequently identified in moderately to poorly differentiated tumors with LVI and advanced clinical stages. Multivariate analysis showed that a desmoplastic reaction, LVI, and advanced FIGO stage were significantly associated with unfavorable outcome. The presence of a desmoplastic reaction in the stroma should prompt the pathologist to search for other histologically unfavorable prognostic indicators such as cervical involvement and nodal metastasis. This is even more important in those cases where no staging procedure was performed and in cases where the tumor was an incidental finding.

Impact of a weekly multidisciplinary tumor board conference on the management of women with gynecologic malignancies.

BACKGROUND: The objective of this study was to evaluate the impact of a weekly tumor board conference on the management of patients with gynecologic malignancies. METHODS: The medical records of consecutive patients referred to a multidisciplinary gynecologic oncology tumor board were reviewed. Patient demographics were abstracted from medical records and tumor board minutes. An evaluation was made whether the pathological or radiological findings were changed by the tumor board consultants. If a discrepancy existed, it was determined whether the change impacted clinical management. RESULTS: From January 2004 to December 2006, 741 patients presented at the tumor board were evaluable. Seventy-one percent of the patients were presented for pathology review and 29% for radiology review. The most common diagnoses were ovarian cancer (29%), endometrial cancer (26%), and cervical cancer (12%). Of the 526 pathology reviews, 27% had a change in diagnosis; this discrepancy altered clinical management 74% of the time (20% of all reviews). Of the 215 radiology presentations, 89% were reviewed to confirm recurrent or persistent disease; malignant disease was confirmed 74% of the time. Review of imaging studies resulted in a new diagnosis or upstaging 10% of the time. CONCLUSIONS: A multidisciplinary tumor board allows a wide range of gynecologic diagnoses and clinical scenarios to be discussed. Careful review of pathology results in a change in the clinical management of 20% of patients presented at the tumor board. The majority of radiology reviews are presented to confirm persistent or recurrent cancer before recommending further therapy.

Large, Non-Cavity Distorting Intramural Leiomyomas Decrease Leukemia Inhibitory Factor in the Secretory Phase Endometrium.

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 < 0.001). Expressions of HOXA10 and PR were no different between cohorts; however, ER-α showed a trend toward increased expression in the fibroid cohort (p value 0.07). LIF is downregulated in the endometrium of patients with large IM. This study is among the first to show decreased LIF expression in patients with uterine leiomyomas. We hypothesize that this difference from previously published work is due to sampling the endometrium at the height of LIF expression. Further work is needed to show if LIF downregulation is corrected with leiomyoma resection.

Patterns of failure for conservatively managed surgical stage I uterine carcinosarcoma: implications for adjuvant therapy.

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.

p16 Improves interobserver agreement in diagnosis of anal intraepithelial neoplasia.

OBJECTIVES: Evaluation of anal intraepithelial neoplasia (AIN) is subjective. Previous studies have shown p16 and Ki-67 expressions to correlate with AIN grade. Biomarkers like p16 and Ki-67 may improve interobserver agreement. The objectives were (1) to determine the extent of interobserver agreement in evaluating AIN on routine hematoxylin and eosin (H&E) sections and (2) to test whether p16 and/or Ki-67 staining improve interobserver diagnostic agreement. MATERIALS AND METHODS: Seventy-seven anal specimens were retrieved. Sections were stained with monoclonal antibodies against p16 and Ki-67. Blind to the original diagnoses, 4 pathologists assessed H&E alone, p16 alone, Ki-67 alone, and all 3 simultaneously. Diagnoses were normal/reactive, AIN I/HPV, AIN II, and AIN III. Agreement was calculated using kappa and S statistics. RESULTS: Pathologists were board certified and had 2 to 25 years (mean = 13.6 years) of experience. Fair agreement was observed using H&E diagnosis alone (kappa = 0.38, S = 0.56). The p16 diagnostic evaluation demonstrated the highest agreement (kappa = 0.57, S = 0.73). Interobserver agreement for Ki-67 alone and for H&E/p16/Ki-67 combined were comparable to that of H&E alone (kappa = 0.4, S = 0.54 and kappa = 0.44, S = 0.62, respectively). When the pathologists' diagnoses for all diagnostic evaluations were compared with consensus diagnoses, the lowest average magnitude of disagreement was seen with Ki-67 alone, followed by p16 alone, H&E/p16/Ki-67 combined, and H&E alone. CONCLUSIONS: Interobserver agreement for diagnosis of AIN was fair when based solely on H&E preparation. p16 alone improved interobserver agreement and demonstrated superior agreement when compared with H&E, Ki-67, and H&E/p16/Ki-67 combined.

Recurrent genetic alterations and biomarker expression in primary and metastatic squamous cell carcinomas of the vulva.

Using a comprehensive next-generation sequencing pipeline (143 genes), Oncomine Comprehensive v.2, we analyzed genetic alterations on a set of vulvar squamous cell carcinomas (SCCs) with emphasis on the primary and metastatic samples from the same patient, to identify amenable therapeutic targets. Clinicopathologic features were reported and genomic DNA was extracted from 42 paraffin-embedded tumor tissues of 32 cases. PD-L1 expression was evaluated in 20 tumor tissues (10 cases with paired primary and metastatic tumors). Fifteen (88%) of 17 successfully analyzed HPV-unrelated SCCs harbored TP53 mutations. 2 different TP53 mutations had been detected in the same tumor in 4 of 15 cases. Other recurrent genetic alterations in this group of tumors included CDKN2a mutations (41%), HRAS mutations (12%), NOTCH1 mutations (12%) and BIRC3 (11q22.1-22.2) amplification (12%). Six HPV-related tumors harbored PIK3CA, BAP1, PTEN, KDR, CTNNB1, and BRCA2 mutations, of which, one case also contained TP53 mutation. Six cases showed identical mutations in paired primary site and distant metastatic location and four cases displayed different mutational profiles. PD-L1 expression was seen in 6 of 10 primary tumors and all 6 paired cases showed discordant PD-L1 expression in the primary and metastatic sites. Our results further confirmed the genetic alterations that are amenable to targeted therapy, offering the potential for individualized management strategies for the treatment of these aggressive tumors with different etiology. Discordant PD-L1 expression in the primary and metastatic vulvar SCCs highlights the importance of evaluation of PD-L1 expression in different locations to avoid false negative information provided for immunotherapy.

Lynch syndrome in women less than 50 years of age with endometrial cancer.

OBJECTIVE: To estimate the frequency of mismatch repair deficiencies associated with hereditary nonpolyposis colorectal cancer, or Lynch syndrome, in women less than age 50 with endometrial cancer. METHODS: Consecutive patients less than age 50 diagnosed with endometrial adenocarcinoma were identified. Available pathologic specimens were freshly sliced, and protein expression for MLH1, MSH2, MSH6, and PMS2 was evaluated by immunohistochemistry. Slides were scored on a semiquantitative method with complete absence of any of the four proteins suggesting a deficiency. All results were confirmed by microsatellite instability testing. RESULTS: Sixty-one pathology specimens were analyzed. Twenty-one (34%) of the tumors had absence of staining of at least one of the four mismatch repair proteins determined by immunohistochemistry and confirmed by microsatellite instability testing. Obese patients were less likely than nonobese patients to have a mismatch repair deficiency (21% versus 59%, respectively). Non-obese patients had a relative risk for a mismatch repair deficiency of 5.5 (95% confidence interval 1.6-19.1; P=.01). CONCLUSION: Many women diagnosed with endometrial cancer before age 50 will have a mismatch repair deficiency discovered by immunohistochemistry and microsatellite instability testing. A number of young women diagnosed with endometrial cancer will require further genetic testing for mismatch repair mutations. LEVEL OF EVIDENCE: III.

Diffuse endometritis in the setting of umbilical endometriosis: a case report.

BACKGROUND: Umbilical endometriosis is rare and can be a challenging diagnosis in the absence of classic signs and symptoms. CASE: A case of severe, primary, spontaneous umbilical endometriosis with foci of plasma cell endometritis and diffuse stromal lymphovascular presence occurred. CONCLUSION: Despite a lengthy differential, endometriosis must be considered in the evaluation of an umbilical mass. The presence of plasma cell endometritis and stromal lymphovascular elements in the absence of pelvic endometriosis lends evidence to the theory of lymphovascular transport as an etiology of extrapelvic endometriosis.

Next-generation Sequencing Reveals Recurrent Somatic Mutations in Small Cell Neuroendocrine Carcinoma of the Uterine Cervix.

Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare but extremely aggressive tumor. While high-risk human papillomavirus (HPV) is involved at an early stage of oncogenesis in many tumors, additional driving events have been postulated to facilitate the progression of SCNECs. Identification of oncogenic drivers could guide targeted therapy of this neoplasm. Clinicopathologic features of 10 cervical SCNECs are reported. Analyses included immunohistochemical evaluation of p16, p53, synaptophysin, and chromogranin expression; in situ hybridizations and polymerase chain reaction for high-risk HPV and/or HPV 18; and next-generation sequencing based on a 637-gene panel. The patients ranged in age from 28 to 68 years (mean, 45.6 y; median, 40.5 y). All tumors had diffuse p16 and synaptophysin expression. All but 1 tumor was positive for chromogranin (extent of staining ranged from focal to diffuse). HPV 18 was detected in 6 tumors and HPV 35 in 1 tumor. At least 1 driver mutation was detected in 8 tumors. Four cases harbored TP53 somatic mutations, 3 of which correlated with an aberrant p53 staining pattern. Four PIK3CA mutations (p.G106A, p.N345T, p.E545K, and p.E545D) were detected in 3 tumors, 2 of which also harbored TP53 mutations. Oncogenic driver mutations involving KRAS, Erbb2, c-Myc, NOTCH1, BCL6, or NCOA3 were detected in 4 tumors. Mutations in caretaker tumor suppressors PTEN, RB1, BRCA1, BRCA2, and ARID1B were also identified in 4 tumors that commonly coharbored activating oncogenic mutations. Targeted next-generation gene sequencing identified genetic alterations involving the MAPK, PI3K/AKT/mTOR, and TP53/BRCA pathways in SCNECs. The presence of genetic alterations that are amenable to targeted therapy in SCNECs offers the potential for individualized management strategies for treatment of this aggressive tumor.

Reduced E-Cadherin and Aberrant ß-Catenin Expression are Associated With Advanced Disease in Signet-Ring Cell Carcinomas.

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 ß-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 ß-catenin expression, defined as loss of membranous expression and nuclear/cytoplasmic subcellular localization, was observed in 60% of these cases, with the altered ß-catenin expression observed most commonly in the breast (93%) and least in the lung (38%) primaries. Further, the aberrant ß-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 ß-catenin expression were frequent events in SRCCs of various organs, and that the altered ß-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/ß-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.

Inflammatory pseudotumor of pelvic lymph nodes.

BACKGROUND: Inflammatory pseudotumor is a rare benign cause of lymphadenopathy previously reported in several anatomic locations that can simulate malignant neoplasm. CASE: A postmenopausal woman presented with abdominal pain, generalized malaise, leukocytosis, and intermittent fevers up to 102 degrees F. A 5-day course of antibiotics was given with persistence of symptoms. Computed tomography of the abdomen and pelvis demonstrated an ill-defined, retroperitoneal soft-tissue density, and lymphadenopathy. She underwent an exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and unilateral pelvic and paraaortic lymphadenotomy. Histologic examination revealed inflammatory pseudotumor of the lymph nodes, with immunohistochemical studies demonstrating actin-positive myofibroblastic cells. Four months after surgery, the patient remains asymptomatic without evidence of disease. CONCLUSION: Inflammatory pseudotumor of the pelvic lymph nodes is a rare entity and should be included in the differential diagnosis of patients with persistent fever and lymphadenopathy.

Association of asymptomatic bacterial vaginosis with endometrial microbial colonization and plasma cell endometritis in nonpregnant women.

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.

The Tumor-Associated Glycosyltransferase ST6Gal-I Regulates Stem Cell Transcription Factors and Confers a Cancer Stem Cell Phenotype.

The glycosyltransferase ST6Gal-I, which adds α2-6-linked sialic acids to substrate glycoproteins, has been implicated in carcinogenesis; however, the nature of its pathogenic role remains poorly understood. Here we show that ST6Gal-I is upregulated in ovarian and pancreatic carcinomas, enriched in metastatic tumors, and associated with reduced patient survival. Notably, ST6Gal-I upregulation in cancer cells conferred hallmark cancer stem-like cell (CSC) characteristics. Modulating ST6Gal-I expression in pancreatic and ovarian cancer cells directly altered CSC spheroid growth, and clonal variants with high ST6Gal-I activity preferentially survived in CSC culture. Primary ovarian cancer cells from patient ascites or solid tumors sorted for α2-6 sialylation grew as spheroids, while cells lacking α2-6 sialylation remained as single cells and lost viability. ST6Gal-I also promoted resistance to gemcitabine and enabled the formation of stably resistant colonies. Gemcitabine treatment of patient-derived xenograft tumors enriched for ST6Gal-I-expressing cells relative to pair-matched untreated tumors. ST6Gal-I also augmented tumor-initiating potential. In limiting dilution assays, subcutaneous tumor formation was inhibited by ST6Gal-I knockdown, whereas in a chemically induced tumor initiation model, mice with conditional ST6Gal-I overexpression exhibited enhanced tumorigenesis. Finally, we found that ST6Gal-I induced expression of the key tumor-promoting transcription factors, Sox9 and Slug. Collectively, this work highlighted a previously unrecognized role for a specific glycosyltransferase in driving a CSC state. Cancer Res; 76(13); 3978-88. ©2016 AACR.