Intradural-extramedullary inflammatory pseudotumour of the cervical spinal cord of a dog.

An 8-year-old mixed-breed dog was presented with cervical hyperesthesia, tetraparesis, and mild proprioceptive ataxia in all four limbs. 3 Tesla MRI showed a dorsal compressive intradural-extramedullary mass at the level of C1-C2, isointense to the gray matter with a hypointense ventral core on T2 weighted images (WI), isointense on T1WI, with a strong and homogeneous contrast enhancement. A C1-C2 partial dorsal laminectomy was performed, and the lesion was removed en bloc. The histopathological and immunohistochemical analysis defined the diagnosis of inflammatory pseudotumor.

Using Genomic Variation to Distinguish Ovarian High-Grade Serous Carcinoma from Benign Fallopian Tubes.

The preoperative diagnosis of pelvic masses has been elusive to date. Methods for characterization such as CA-125 have had limited specificity. We hypothesize that genomic variation can be used to create prediction models which accurately distinguish high grade serous ovarian cancer (HGSC) from benign tissue. METHODS: In this retrospective, pilot study, we extracted DNA and RNA from HGSC specimens and from benign fallopian tubes. Then, we performed whole exome sequencing and RNA sequencing, and identified single nucleotide variants (SNV), copy number variants (CNV) and structural variants (SV). We used these variants to create prediction models to distinguish cancer from benign tissue. The models were then validated in independent datasets and with a machine learning platform. RESULTS: The prediction model with SNV had an AUC of 1.00 (95% CI 1.00-1.00). The models with CNV and SV had AUC of 0.87 and 0.73, respectively. Validated models also had excellent performances. CONCLUSIONS: Genomic variation of HGSC can be used to create prediction models which accurately discriminate cancer from benign tissue. Further refining of these models (early-stage samples, other tumor types) has the potential to lead to detection of ovarian cancer in blood with cell free DNA, even in early stage.

Enhancing progestin therapy via HDAC inhibitors in endometrial cancer.

Uterine endometrial cancer (EC) incidence and deaths are on the rise. Hormone therapy, a traditional treatment regimen for this disease, uses progesterone and its synthetic analogue, progestin, to induce cell differentiation, apoptosis, and inhibition of invasion. This therapy is highly effective for progesterone receptor (PR) positive tumors in the short term. However, responsiveness decreases over time due to loss of PR expression; acquired resistance leads to treatment failure and poor prognosis. Primary resistance occurs in advanced, PR-negative tumors. Regardless, progestin therapy can be effective if the PR downregulation mechanism is reversed and if functional PR expression is restored. Using histone deacetylase inhibitors (HDACi), we inhibited cell proliferation in three EC cell lines and restored functional PR expression at the mRNA and protein levels. Two HDACi were tested using an endometrial xenograft tumor model: entinostat, an oral drug, and romidepsin, an IV drug. In vitro and in vivo studies support that entinostat decreased EC tumor growth, induced differentiation, and increased expression of the PR-targeted gene, PAEP. These findings supported the approval of a new NIH NCTN clinical trial, NRG-GY011, which concluded that dual treatment of MPA and entinostat, decreased expression of the proliferation marker, Ki67, but did not increase PR expression relative to single treatment with MPA in this short-term study. Therefore, a more potent HDACi, romidepsin, was investigated. Romidepsin treatment inhibited tumor growth and enhanced progestin treatment efficacy. More importantly, PR, PAEP, and KIAA1324 expressions were upregulated. Using a chromatin immunoprecipitation assay, we verified that HDACi can reverse PR downregulation mechanisms in mice models. Other potential drug efficacy markers, such as CD52, DLK1, GALNT9, and GNG2, were identified by transcriptome analysis and verified by q-PCR. Many of the upregulated drug efficacy markers predict favorable patient outcomes, while downregulated genes predict worse survival. Here, our current data suggests that romidepsin is a more potent HDACi that has the potential to achieve more robust upregulation of PR expression and may be a more promising candidate for future clinical trials.

The role of minimally invasive gynecologic surgeons in the era of subspecialties: when to refer and consult.

PURPOSE OF REVIEW: Minimally invasive gynecologic surgery (MIGS) is a subspecialty focus of obstetrics and gynecology with focused expertise on complex benign gynecologic disorders. To date, no formal recommendations have been made in defining a referral system for MIGS. This article reviews the evidence regarding common disorders and procedures and their outcomes, and posits a basis for MIGS referral. RECENT FINDINGS: In instances where intraoperative and perioperative features may pose clinical challenges to the surgeon and ultimately the patient, the literature suggests the following scenarios may have adverse outcomes, and therefore, benefit from the skills of MIGS subspecialists: fibroids - at least five myomas, myoma size at least 9 cm, and suspected myoma weight at least 500 g; endometriosis - presence of endometrioma(s), suspected stage III/IV endometriosis, and requirement for advanced adjunct procedures; hysterectomy - uteri at least 250 g or 12 weeks estimated size, at least three prior laparotomies, obesity, and complex surgical history with suspected adhesive disease. SUMMARY: A referral system for MIGS subspecialists has proven benefits for both the gynecologic surgical community as well as the patients and their outcomes. This article provides evidence for collaboration with MIGS especially as it relates to leiomyomatous uteri, endometriosis, and complex hysterectomies.

Neumotórax catamenial

RESUMEN Introducción: El neumotórax catamenial es aquel neumotórax espontáneo y recurrente que se presenta relacionado con el ciclo menstrual. Más frecuente en mujeres con edad fértil por encima de los 30 años de edad y a predominio del hemitórax derecho. El diagnóstico primario es difícil y el tratamiento que mejores resultados registra es la cirugía por técnicas de mínimo acceso, asociada a tratamiento hormonal. Objetivo: Presentar un caso de neumotórax catamenial, sus características clínicas y el procedimiento videotoracoscópico empleado. Caso clínico: Paciente de 48 años de edad, con antecedentes de dolor torácico y tos al inicio de la menstruación. Además, dos neumotórax espontáneos derechos anteriores. Ingresó de urgencia con el diagnóstico de neumotórax espontáneo derecho. Se realizó biopsia, frenorrafia y pleurodesis por videotoracoscopía. Conclusiones: Los elementos clínicos y radiológicos inducen a pensar en el diagnóstico de neumotórax catamenial, apoyado por la presencia de fenestraciones diafragmáticas y la no reaparición del cuadro de neumotórax después del cierre de los defectos diafragmáticos y el tratamiento satisfactorio con pleurodesis con talco, por cirugía de mínimo acceso.

ABSTRACT Introduction: The catamenial pneumothorax is that spontaneous and recurrent pneumothorax related with the menstrual cycle. More frequent in women with fertile age above the 30 years of age and predominance of the right hemithorax. The primary diagnosis is difficult and the treatment that best results recorded is the surgery by minimal access techniques associated with hormone treatment. Objective: Present a case of catamenial neumothorax, to describe their clinical characteristics and the videothoracoscopic proceeding used. Clinical case: 48 years old female patient, with history of chest pain and coughing at the beginning of menstruation and having suffered two spontaneous rights pneumothorax. We performed biopsy, phrenorraphy and pleurodesis by videothoracoscopy, after 18 months the symptomatology did not reappear. Conclusions: The clinical and radiological elements induce to think of the diagnosis of catamenial pneumothorax, supported by the presence of diaphragmatic fenestrations and the not reappearance of the pneumothorax frame after the closure of the diaphragmatic defects and satisfactory treatment with talc pleurodesis by minimal access surgery.

Identification of Novel Fusion Transcripts in High Grade Serous Ovarian Cancer.

Fusion genes are structural chromosomal rearrangements resulting in the exchange of DNA sequences between genes. This results in the formation of a new combined gene. They have been implicated in carcinogenesis in a number of different cancers, though they have been understudied in high grade serous ovarian cancer. This study used high throughput tools to compare the transcriptome of high grade serous ovarian cancer and normal fallopian tubes in the interest of identifying unique fusion transcripts within each group. Indeed, we found that there were significantly more fusion transcripts in the cancer samples relative to the normal fallopian tubes. Following this, the role of fusion transcripts in chemo-response and overall survival was investigated. This led to the identification of fusion transcripts significantly associated with overall survival. Validation was performed with different analytical platforms and different algorithms to find fusion transcripts.

Identification of Novel lncRNAs in Ovarian Cancer and Their Impact on Overall Survival.

Long non-coding RNA's (lncRNA) are RNA sequences that do not encode proteins and are greater than 200 nucleotides in length. They regulate complex cellular mechanisms and have been associated with prognosis in various types of cancer. We aimed to identify lncRNA sequences that are associated with high grade serous ovarian cancer (HGSC) and assess their impact on overall survival. RNA was extracted from 112 HGSC patients and 12 normal fallopian tube samples from our Biobank tissue repository. RNA was sequenced and the Ultrafast and Comprehensive lncRNA detection and quantification pipeline (UClncR) was used for the identification of lncRNA sequences. Univariate logistic and multivariate lasso regression analyses identified lncRNA that was associated with HGSC. Univariate and multivariate Cox proportional hazard ratios were used to evaluate independent predictors of survival. 1943 of 16,325 investigated lncRNA's were differentially expressed in HGSC as compared to controls (p < 0.001). Nine of these demonstrated association with cancer after multivariate lasso regression. Our multivariate analysis of survival identified four lncRNA's associated with survival in HGSC. Three out of these four were found to be independently significant after accounting for all clinical covariates. Lastly, seven lncRNAs were independently associated with initial response to chemotherapy; four portended a worse response, while three were associated with improved response. More research is needed, but there is potential for these lncRNAs to be used as biomarkers of HGSC or predictors of treatment outcome in the future.

Interval debulking surgery is not worth the wait: a National Cancer Database study comparing primary cytoreductive surgery versus neoadjuvant chemotherapy.

OBJECTIVE: In previous studies, neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary cytoreductive surgery as initial treatment for advanced epithelial ovarian cancer. Our study aimed to compare surgical and survival outcomes between the two treatments in a large national database. METHODS: Data were extracted from the National Cancer Database from January 2004 to December 2015. Patients with FIGO (International Federation of Gynecologists and Obstetricians) stage III-IV epithelial ovarian cancer and known sequence of treatment were included: primary cytoreductive (surgery=26 717 and neoadjuvant chemotherapy=9885). Tubal and primary peritoneal cancer diagnostic codes were not included. Residual disease after treatment was defined based on recorded data: R0 defined as microscopic or no residual disease; R1 defined as macroscopic residual disease. Multivariate Cox proportional HR was used for survival analysis. Multivariate logistic regression analysis was utilized to compare mortality between groups. Outcomes were adjusted for significant covariates. Validation was performed using propensity score matching of significant covariates. RESULTS: A total of 36 602 patients were included in the analysis. Patients who underwent primary cytoreductive surgery had better survival than those treated with neoadjuvant chemotherapy followed by interval surgery, after adjusting for age, co-morbidities, stage, and residual disease (p<0.001). Primary cytoreductive surgery patients with R0 disease had best median survival (62.6 months, 95% CI 60.5-64.5). Neoadjuvant chemotherapy patients with R1 disease had worst median survival (29.5 months, 95% CI 28.4-31.9). There were small survival differences between primary cytoreductive surgery with R1 (38.9 months) and neoadjuvant chemotherapy with R0 (41.8 months) (HR 0.93, 95% CI 0.87 to 1.0), after adjusting for age, co-morbidities, grade, histology, and stage. Neoadjuvant chemotherapy had 3.5 times higher 30-day mortality after surgery than primary cytoreductive surgery (95% CI 2.46 to 5.64). The 90-day mortality was higher for neoadjuvant chemotherapy in multivariate analysis (HR 1.31, 95% CI 1.06 to 1.61) but similar to primary cytoreductive surgery after excluding high-risk patients. CONCLUSIONS: Most patients with advanced epithelial ovarian cancer may benefit from primary cytoreductive surgery. Patients treated with neoadjuvant chemotherapy should be those with co-morbidities unfit for surgery.

Differential DNA methylation in high-grade serous ovarian cancer (HGSOC) is associated with tumor behavior.

The epigenome offers an additional facet of cancer that can help categorize patients into those at risk of disease, recurrence, or treatment failure. We conducted a retrospective, nested, case-control study of advanced and recurrent high-grade serous ovarian cancer (HGSOC) patients in which we assessed epigenome-wide association using Illumina methylationEPIC arrays to characterize DNA methylation status and RNAseq to evaluate gene expression. Comparing HGSOC tumors with normal fallopian tube tissues we observe global hypomethylation but with skewing towards hypermethylation when interrogating gene promoters. In total, 5,852 gene interrogating probes revealed significantly different methylation. Within HGSOC, 57 probes highlighting 17 genes displayed significant differential DNA methylation between primary and recurrent disease. Between optimal vs suboptimal surgical outcomes 99 probes displayed significantly different methylation but only 29 genes showed an inverse correlation between methylation status and gene expression. Overall, differentially methylated genes point to several pathways including RAS as well as hippo signaling in normal vs primary HGSOC; valine, leucine, and isoleucine degradation and endocytosis in primary vs recurrent HGSOC; and pathways containing immune driver genes in optimal vs suboptimal surgical outcomes. Thus, differential DNA methylation identified numerous genes that could serve as potential biomarkers and/or therapeutic targets in HGSOC.

Manejo del paciente portador de sangrado digestivo alto en el servicio de urgencias / Upper digestive bleeding patient management in the emergency department

Introducción: el sangrado digestivo alto constituye uno de los síndromes más frecuentes en servicios de urgencias. La endoscopia oral y los medicamentos antiácidos y protectores de la mucosa gástrica, hacen menos frecuente el empleo de intervenciones quirúrgicas en el manejo del paciente con sangrado digestivo alto. La necesidad del tratamiento quirúrgico no siempre puede obviarse. Objetivo: describir las características clínicas de los pacientes con sangrado digestivo alto atendidos en el Hospital Militar Dr. Joaquín Castillo Duany. Métodos: estudio descriptivo transversal. Universo constituido por 92 pacientes con diagnóstico de sangrado digestivo alto. Variables caracterizadas: edad, sexo, tratamiento médico empleado, técnica quirúrgica utilizada, complicaciones posquirúrgicas y estadía hospitalaria. Resultados: el sangrado digestivo alto fue más frecuente en hombres, con más de 40 años de edad, se les aplicó tratamiento médico, la modalidad más frecuente fue la combinación de antiácidos. Se realizó tratamiento endoscópico al 3,2 por ciento de los pacientes, fueron intervenidos quirúrgicamente el 5,4 por ciento. La mitad de los operados padecía úlcera péptica gástrica. La técnica quirúrgica más empleada fue la gastrostomía y gastrorrafia. La estadía hospitalaria fue menor de 5 días. Conclusiones: se evidenció predominio del sangrado digestivo alto en el sexo masculino y en mayores de 40 años. El tratamiento endoscópico y las intervenciones quirúrgicas representaron un bajo porcentaje. La estadía hospitalaria fue más prolongada en pacientes con complicaciones. Los hallazgos en los que más difieren otras investigaciones radican en el incremento del empleo de la endoscopia oral, en combinación con el uso de antisecretores y en las variantes de técnicas quirúrgicas empleadas(AU)

Introduction: upper Digestive Bleeding is one of the most frequent syndromes in emergency services. Oral endoscopy, antacid and protective gastric mucosal medications make the use of surgical interventions less common in the management of upper digestive bleeding patients. However, the need for surgical treatment cannot always be overlooked. Objective: to describe the clinical characteristics of patients with upper digestive bleeding treated at the Military Hospital Dr. Joaquín Castillo Duany. Methods: cross-sectional descriptive study. A universe of 92 patients with a diagnosis of upper digestive bleeding. Variables characterized: Age, sex, medical treatment, surgical technique used, postoperative complications, and hospital stay. Results: upper digestive bleeding was more frequent in men and in patients over 40 years old. In patients in whom medical treatment was applied, the most frequent modality was the combination of anti-H2 antihistamines and proton pump inhibitors. Endoscopic treatment was performed in 3.2 percent of patients, and 5.4 pèrcent was operated on. Half of the patients underwent gastric peptic ulcer, and the most commonly used surgical technique was gastrostomy. The predominant hospital stay was less than 5 days(AU)

Manejo del paciente portador de sangrado digestivo alto en el servicio de urgencias / Upper digestive bleeding patient management in the emergency department

Introducción: el sangrado digestivo alto constituye uno de los síndromes más frecuentes en servicios de urgencias. La endoscopia oral y los medicamentos antiácidos y protectores de la mucosa gástrica, hacen menos frecuente el empleo de intervenciones quirúrgicas en el manejo del paciente con sangrado digestivo alto. La necesidad del tratamiento quirúrgico no siempre puede obviarse. Objetivo: describir las características clínicas de los pacientes con sangrado digestivo alto atendidos en el Hospital Militar Dr. Joaquín Castillo Duany. Métodos: estudio descriptivo transversal. Universo constituido por 92 pacientes con diagnóstico de sangrado digestivo alto. Variables caracterizadas: edad, sexo, tratamiento médico empleado, técnica quirúrgica utilizada, complicaciones posquirúrgicas y estadía hospitalaria. Resultados: el sangrado digestivo alto fue más frecuente en hombres, con más de 40 años de edad, se les aplicó tratamiento médico, la modalidad más frecuente fue la combinación de antiácidos. Se realizó tratamiento endoscópico al 3,2 por ciento de los pacientes, fueron intervenidos quirúrgicamente el 5,4 por ciento. La mitad de los operados padecía úlcera péptica gástrica. La técnica quirúrgica más empleada fue la gastrostomía y gastrorrafia. La estadía hospitalaria fue menor de 5 días. Conclusiones: se evidenció predominio del sangrado digestivo alto en el sexo masculino y en mayores de 40 años. El tratamiento endoscópico y las intervenciones quirúrgicas representaron un bajo porcentaje. La estadía hospitalaria fue más prolongada en pacientes con complicaciones. Los hallazgos en los que más difieren otras investigaciones radican en el incremento del empleo de la endoscopia oral, en combinación con el uso de antisecretores y en las variantes de técnicas quirúrgicas empleadas(AU)

Introduction: upper Digestive Bleeding is one of the most frequent syndromes in emergency services. Oral endoscopy, antacid and protective gastric mucosal medications make the use of surgical interventions less common in the management of upper digestive bleeding patients. However, the need for surgical treatment cannot always be overlooked. Objective: to describe the clinical characteristics of patients with upper digestive bleeding treated at the Military Hospital Dr. Joaquín Castillo Duany. Methods: cross-sectional descriptive study. A universe of 92 patients with a diagnosis of upper digestive bleeding. Variables characterized: Age, sex, medical treatment, surgical technique used, postoperative complications, and hospital stay. Results: upper digestive bleeding was more frequent in men and in patients over 40 years old. In patients in whom medical treatment was applied, the most frequent modality was the combination of anti-H2 antihistamines and proton pump inhibitors. Endoscopic treatment was performed in 3.2 percent of patients, and 5.4 pèrcent was operated on. Half of the patients underwent gastric peptic ulcer, and the most commonly used surgical technique was gastrostomy. The predominant hospital stay was less than 5 days(AU)

Caracterización clínica de pacientes con urgencias quirúrgicas abdominales operados por cirugía videolaparoscópica / Clinical characterization of patients with abdominal surgical emergencies operated by videolaparoscopic surgery

Introducción: el abdomen agudo quirúrgico justifica el mayor porcentaje de intervenciones de urgencia a nivel mundial. El empleo de la cirugía videolaparoscópica en este tipo de afecciones es cada vez más frecuente. Objetivo: caracterizar a los pacientes operados de urgencia con esta modalidad. Métodos: estudio descriptivo y transversal de una serie constituida por 534 pacientes operados de urgencia con enfermedades abdominales agudas por cirugía videolaparoscópica en el Hospital Dr. Joaquín Castillo Duany de Santiago de Cuba, desde el primero de enero de 2013 hasta el 31 de diciembre de 2015. Las principales variables utilizadas fueron: diagnóstico operatorio, tiempo quirúrgico, tiempo de hospitalización, complicaciones, reintervención, causa de reintervención y estado al egreso. Se emplearon medidas de resumen como número, porcentaje y media aritmética. Resultados: las mujeres y los grupos etarios jóvenes fueron los porcentajes más representativos de la serie estudiada (55, 8 por ciento y 46, 6 por ciento respectivamente). La enfermedad más frecuente fue la apendicitis aguda) con 40,3 por ciento. El tiempo quirúrgico promedio fue de 34 minutos. Se egresó al 61,4 por ciento antes de las 24 horas y 1,8 por ciento de los pacientes presentaron complicaciones posoperatorias. Conclusiones: los porcentajes de complicaciones, corta estancia hospitalaria y baja letalidad, son similares a los referentes teóricos internacionales, indicando que la cirugía videolaparoscópica de urgencia es una alternativa útil en los pacientes con abdomen agudo quirúrgico(AU)

Introduction: Acute surgical abdomen justifies the highest percentage of emergency interventions worldwide. The use of videolaparoscopic surgery in these types of conditions is becoming more frequent. Objective: To characterize the emergency operated patients with this modality. Methods: Descriptive and cross-sectional study of a series consisting of 534 patients operated on with acute abdominal diseases by videolaparoscopic surgery at the Hospital Dr. Joaquín Castillo Duany from Santiago de Cuba, from January 1, 2013 to December 31, 2015. The main variables used were: operative diagnosis, surgical time, hospitalization time, complications, reoperation, cause of reoperation and state at discharge. Results: Women and younger age groups represented the most representative percentages of the series studied (55.8 percent and 46.6 percent respectively). The most frequent disease was acute appendicitis) with 40.3 percent. The average surgical time was 34.0 minutes. It was discharged the 61.4 percent before 24 hours and 1.8 percent of patients presented postoperative complications. Conclusions: The percentage of complications, short hospital stay and low lethality, are similar to the international theoretical references, indicating that emergency videolaparoscopic surgery is a useful alternative in patients with acute surgical abdomen(AU)

High stathmin expression is a marker for poor clinical outcome in endometrial cancer: An NRG oncology group/gynecologic oncology group study.

OBJECTIVE: Gynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin. METHODS: We analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer. RESULTS: We first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin. CONCLUSIONS: Our findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases.

Placenta-Specific Protein 1 Expression in Human Papillomavirus 16/18-Positive Cervical Cancers Is Associated With Tumor Histology.

OBJECTIVE: Expression of the trophoblast-specific gene placenta-specific protein 1 (PLAC1) has been detected in a wide variety of cancers. However, to date, PLAC1 expression has not been shown in cervical cancer. We have carried out a preliminary study that shows for the first time that PLAC1 is expressed in cervical cancers. METHODS: A total of 16 primary cervical tumors were obtained from patients shown to be human papillomavirus (HPV) 16/18 positive. Total cellular RNA, genomic DNA, and total protein were purified from each tumor. These materials were then used to determine PLAC1 expression, TP53 mutation status, and p53 expression. RESULTS: The PLAC1 expression was demonstrated in all 16 primary cervical tumors. The highest levels of expression were found in the more aggressive squamous and adenosquamous histologic types compared with adenocarcinomas. Moreover, the proportion of total PLAC1 message coming from the P1 promoter, also termed the distal or cancer promoter, was significantly greater in the more aggressive squamous and adenosquamous histologic types compared with adenocarcinomas. Finally, in spite of all 16 tumors being HPV-16/18 positive, 3 of 8 squamous cell cancers and 2 of 5 adenocarcinomas expressed wild-type p53 protein. Consistent with the recently shown suppression of the PLAC1P1 promoter by wild-type p53, these p53 positive tumors displayed among the lowest P1-specific PLAC1 expression levels. CONCLUSIONS: The PLAC1 expression has been demonstrated for the first time in cervical cancers. This preliminary study has further revealed a complex relationship between PLAC1 expression, cervical cancer histologic type, p53, and HPV type that requires further investigation.

p53 mutation status is a primary determinant of placenta-specific protein 1 expression in serous ovarian cancers.

Placenta-specific protein 1 (PLAC1) expression is co-opted in numerous human cancers. As a consequence of PLAC1 expression, tumor cells exhibit enhanced proliferation and invasiveness. This characteristic is associated with increased aggressiveness and worse patient outcomes. Recently, the presence of the tumor suppressor p53 was shown in vitro to inhibit PLAC1 transcription by compromising the P1, or distal/cancer, promoter. We sought to determine if this phenomenon occurs in primary patient tumors as well. Furthermore, we wanted to know if p53 mutation influenced PLAC1 expression as compared with wild-type. We chose to study serous ovarian tumors as they are well known to have a high rate of p53 mutation. We report herein that the phenomenon of PLAC1 transcription repression does occur in serous ovarian carcinomas but only when TP53 is wild-type. We find that mutant or absent p53 protein de-represses PLAC1 transcription. We further propose that the inability of mutant p53 to repress PLAC1 transcription is due to the fact that the altered TP53 protein is unable to occupy a putative p53 binding site in the PLAC1 P1 promoter thus allowing transcription to occur. Finally, we show that PLAC1 transcript number is significantly negatively correlated with patient survival in our samples. Thus, we suggest that characterizing tumors for TP53 mutation status, p53 protein status and PLAC1 transcription could be used to predict likely prognosis and inform treatment options in patients diagnosed with serous ovarian cancer.

Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182.

Altered expression of cullin-5 (CUL5), a member of the cullin-RING E3 ubiquitin ligase family, has been implicated in a number of types of cancers including breast, cervical and hepatocellular cancers. In the present study, we found that CUL5 expression was significantly decreased in both endometrioid and serous endometrial adenocarcinomas with the more aggressive serous type displaying a higher reduction (-4.3-fold) than the less aggressive endometrioid type (-2.9-fold). Overexpression of CUL5 mRNA and protein in Ishikawa H endometrial cancer cells resulted in decreased cell proliferation and in a reduction in CUL5-RING E3 ligase downstream clients JAK2 and FAS-L. Finally, we demonstrated for the first time that CUL5 is a direct target of miR-182 that we previously showed to be significantly overexpressed in endometrial adenocarcinomas and we provided evidence that increased miR-182 expression is, at least in part, a result of demethylation of its upstream promoter. These data suggest a cascade in which miR-182 expression is epigenetically increased leading to decreased CUL5 expression and increased cellular proliferation. The final step in the cascade may be operating through a decrease in ubiquitination of pro-growth CUL5 ubiquitin ligase clients. This cascade offers a series of potential interventional steps involving epigenetic modification, miRNA and/or gene targeting and ubiquitination.

Downregulation of FOXO1 mRNA levels predicts treatment failure in patients with endometrial pathology conservatively managed with progestin-containing intrauterine devices.

OBJECTIVE: To examine hormone receptor expression levels and downstream gene activation in pre-treatment and post-treatment biopsies in a cohort of patients with endometrial pathology who were being conservatively managed with a progestin-containing intrauterine device (IUD). A molecular signature of treatment failure is proposed. METHODS: A retrospective analysis of pre- and post-treatment biopsy specimens from 10 women treated with progestin-containing IUD for complex atypical hyperplasia (CAH) or grade 1 endometrioid adenocarcinoma was performed. Expression of estrogen receptor (ER), progesterone receptor (PR) and PR target genes was examined by immunohistochemistry (IHC) and quantitative RT-PCR. RESULTS: The mean treatment duration was 14.3 months. Four CAH patients had stable disease or regressed after treatment, and four progressed to endometrioid adenocarcinoma. Both patients with an initial diagnosis of endometrioid adenocarcinoma regressed to CAH or no disease. In general, hormone receptor levels diminished post-treatment compared to pre-treatment biopsies; however, we noted unexpected higher expression of the B isoform of PR (PRB) as well as ER in those patients who progressed to frank cancer. There was a trend towards a non-nuclear cytoplasmic location of PRB in these patients. Importantly, the differentiating impact of PR signaling, as determined by the expression of the progestin-controlled tumor suppressor FOXO1, was lost in individuals who progressed on therapy. CONCLUSIONS: FOXO1 mRNA levels may serve as a biomarker for response to therapy and an indicator of PR function in patients being conservatively managed with a progestin-containing IUD.

A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: Cediranib is a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This phase II study was conducted to assess activity and tolerability of single-agent cediranib in recurrent/persistent endometrial cancer. PATIENTS AND METHODS: Eligible patients had recurrent or persistent endometrial cancer after receiving one or two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group (GOG) performance status of ≤2 (≤1 if two prior cytotoxic regimens given). Cediranib 30mg orally daily for a 28daycycle was administered until disease progression or prohibitive toxicity. Microvessel density (MVD) was measured in tumor tissue from initial hysterectomy specimens and correlated with clinical outcome. Primary endpoints were tumor response and surviving progression-free for six months without subsequent therapy (6-month event-free survival [EFS]). RESULTS: Of 53 patients enrolled, 48 were evaluable for cediranib efficacy and toxicity. Median age was 65.5 years, 52% of patients had received prior radiation, and 73% of patients received only one prior chemotherapy regimen. A partial response was observed in 12.5%. Fourteen patients (29%) had six-month EFS. Median progression-free survival (PFS) was 3.65 months and median overall survival (OS) 12.5 months. No grade 4 or 5 toxicities were observed. A trend towards improved PFS was found in patients whose tumors expressed high MVD. CONCLUSION: Cediranib as a monotherapy treatment for recurrent or persistent endometrial cancer is well tolerated and met protocol set objectives for sufficient activity to warrant further investigation. MVD may be a useful biomarker for activity.

Genetic Deficiency of Mtdh Gene in Mice Causes Male Infertility via Impaired Spermatogenesis and Alterations in the Expression of Small Non-coding RNAs.

Increased expression of metadherin (MTDH, also known as AEG-1 and 3D3/LYRIC) has been associated with drug resistance, metastasis, and angiogenesis in a variety of cancers. However, the specific mechanisms through which MTDH is involved in these processes remain unclear. To uncover these mechanisms, we generated Mtdh knock-out mice via a targeted disruption of exon 3. Homozygous Mtdh knock-out mice are viable, but males are infertile. The homozygous male mice present with massive loss of spermatozoa as a consequence of meiotic failure. Accumulation of γ-H2AX in spermatocytes of homozygous Mtdh knock-out mice confirms an increase in unrepaired DNA breaks. We also examined expression of the DNA repair protein Rad18, which is regulated by MTDH at the post-transcriptional level. In testes from Mtdh exon 3-deficient mice, Rad18 foci were increased in the lumina of the seminiferous tubules. The Piwi-interacting RNA (piRNA)-interacting protein Mili was expressed at high levels in testes from Mtdh knock-out mice. Accordingly, genome-wide small RNA deep sequencing demonstrated altered expression of piRNAs in the testes of Mtdh knock-out mice as compared with wild type mice. In addition, we observed significantly reduced expression of microRNAs (miRNAs) including miR-16 and miR-19b, which are known to be significantly reduced in the semen of infertile men. In sum, our observations indicate a crucial role for MTDH in male fertility and the DNA repair mechanisms required for normal spermatogenesis.