Compassionate Use of REGEN-COV® in Patients With Coronavirus Disease 2019 (COVID-19) and Immunodeficiency-Associated Antibody Disorders.

BACKGROUND: Patients with immunodeficiency-associated antibody disorders are at a higher risk of prolonged/persistent COVID-19 infection, having no viable treatment options. METHODS: A retrospective analysis of patients with primary and/or secondary immunodeficiency-associated antibody disorders who received casirivimab and imdevimab (REGEN-COV®) under emergency compassionate use. Objective were to describe safety and response to REGEN-COV, focusing on the subset of patients who had COVID-19 duration ≥21 days before treatment. RESULTS: Quantitative (change in oxygenation status and/or viral load) and/or qualitative (physician-reported clinical status) outcomes data are reported from 64 patients. Improvement in ≥1 outcome was observed in 90.6% of the overall patient group. Thirty-seven of these had COVID-19 duration ≥21 days before treatment; median time from diagnosis to REGEN-COV treatment was 60.5 days. Of the 29 patients with COVID-19 duration ≥21 days before treatment and available outcome data, 96.6% showed improvement in ≥1 outcome. In the 14 patients with post-treatment reverse transcription-polymerase chain reaction (RT-PCR) results available, 11 (78.6%) reported a negative RT-PCR following treatment, with 5 (45.5%) and 8 (72.7%) patients reporting a negative RT-PCR within 5 days and 21 days of treatment, respectively. Ten of 85 patients (11.8%) experienced serious adverse events; only one was an infusion-related reaction, possibly related to REGEN-COV. Two deaths were reported; neither were attributed to REGEN-COV. CONCLUSIONS: In this retrospective analysis of immunodeficient patients granted REGEN-COV under emergency compassionate use, REGEN-COV treatment was associated with rapid viral clearance and clinical improvement in patients with longstanding COVID-19. Adverse events were consistent with COVID-19 and its associated complications, and due to patients' concurrent medical conditions.

Family history of breast cancer in men with non-BRCA male breast cancer: implications for cancer risk counseling.

PURPOSE: The role of genetic predisposition in male breast cancer (MBC) patients who test negative for a BRCA mutation is unclear. The aim of this study is to define the association between MBC and family history of breast cancer in patients without mutations in BRCA1 or BRCA2. METHODS: We conducted an unmatched case-control study with men who received commercial testing for germline mutations in cancer susceptibility genes, including 3,647 MBC cases who tested negative for deleterious mutations in BRCA1/BRCA2, and 4,269 men with a personal history of colorectal cancer who tested negative for mutations in DNA mismatch repair genes to serve as controls. Associations between family history of breast cancer and MBC were estimated using unconditional multivariable logistic regression with adjustment for age, race/ethnicity and year of testing. RESULTS: Breast cancer in a first- or second-degree relative was associated with a four-fold increased odds of MBC (OR 4.7; 95% CI 4.1, 5.3). Associations with MBC were strongest for family history of breast cancer in 2 or more first-degree relatives (FDR) (OR 7.8; 95% CI 5.2, 11.6), for probands and FDR diagnosed at age < 45 years (OR 6.9; 95% CI 3.9, 12.4), and for family history of MBC (OR 17.9; 95% CI 7.6, 42.1). Findings were confirmed in a sensitivity analysis of MBC cases who tested negative on a 25-gene pan-cancer panel. CONCLUSIONS: MBC patients without mutations in BRCA1/2 have significantly higher odds of a family history of breast cancer, suggesting the existence of unidentified MBC susceptibility alleles.

Evaluation of the 12-Gene Molecular Score and the 21-Gene Recurrence Score as Predictors of Response to Neo-adjuvant Chemotherapy in Estrogen Receptor-Positive, HER2-Negative Breast Cancer.

BACKGROUND: Neo-adjuvant chemotherapy (NaCT) facilitates complete surgical resection in locally advanced breast cancer. Due to its association with improved outcome, complete pathologic response (pCR) to neo-adjuvant treatment has been accepted as a surrogate for long-term outcome in clinical trials of human epidermal growth factor receptor 2 (HER2)-positive, triple-negative, or luminal B breast cancer patients. In contrast, NaCT is effective in only ~ 7-10% of estrogen receptor (ER)-positive, HER2-negative disease. Response biomarkers would enable such patients to be selected for NaCT. METHODS: Two commercially available breast cancer prognostic signatures [12-gene molecular score (MS) and the 21-gene Recurrence Score (RS)] were compared in their ability to predict pCR to NaCT in ER-positive, HER2-negative breast cancer in six public RNA expression microarray data sets. Scores were approximated according to published algorithms and analyzed by logistic regression. RESULTS: Expression data were available for 764 ER-positive, HER2-negative breast cancer samples, including 59 patients with pCR. The two scores were well correlated. Either score was a significant predictor of pCR (12-gene MS p = 9.4 × 10-5; 21-gene RS p = 0.0041). However, in a model containing both scores, the 12-gene MS remained significant (p = 0.0079), while the 21-gene RS did not (p = 0.79). CONCLUSIONS: In this microarray study, two commercial breast cancer prognostic scores were significant predictors of response to NaCT. In direct comparison, the 12-gene MS outperformed the 21-gene RS as a predictive marker for NaCT. Considering pCR as surrogate for improved survival, these results support the ability of both scores to predict chemotherapy sensitivity.

Adherence to practice guidelines is associated with reduced referral times for patients with ovarian cancer.

BACKGROUND: Patients with ovarian cancer tend to receive the highest quality of care at high-volume cancer centers with gynecological oncologists. However, the care that they receive prior to gynecological oncology consult has not been examined. We investigated the quantity and quality of care given to patients with ovarian cancer before being seen by a gynecological oncologist. OBJECTIVE: We evaluated the variability, quantity, and quality of diagnostic testing and physician-referral patterns prior to consultation with a gynecological oncologist, in women with suspicious pelvic masses seen on imaging. STUDY DESIGN: A chart review was performed on patients treated for ovarian cancer at a single institution from 2001 to 2014. We evaluated their workup in 4 categories, drawn from National Comprehensive Care Network guidelines: provider visits, abdominal/pelvic imaging, chest imaging, and tumor markers. Workup was classified as guideline adherent or guideline nonadherent. RESULTS: We identified 335 cases that met our criteria. In the provider visit category, 83.9% of patients received guideline-adherent workup: 77% in the abdominal/pelvic imaging, 98.2% in the chest imaging, and 95.2% in the tumor marker categories. Each patient's workup was assessed as a compilation of the 4 categories, yielding 65.7% patients as having received an adherent workup and 34.3% of workup as nonadherent to guidelines. The timeframe to see a gynecological oncologist for patients with guideline-adherent workup was significantly shorter than for those whose workup was nonadherant (20 vs 86 days, P < .001). A suspicious pelvic mass was identified by obstetrics-gynecology in only 23.9% of patients; 42.7% of patients did not have tumor marker testing before a gynecological oncologist consult. When an obstetrics-gynecology specialist discovered the suspicious pelvic mass, the remaining workup was more likely to be guideline adherent prior to gynecological oncologist referral than when initial imaging was not ordered by an obstetrics-gynecology specialist (P = .18). Survival was not significantly different (P = .103). CONCLUSION: With a guideline-adherent workup, including tumor marker testing, gynecological oncologist referral times can be shortened, minimizing cost inefficiencies and delays that can compromise the effectiveness of downstream care for patients with ovarian cancer. Guidelines should be disseminated beyond the obstetrics-gynecology field.

STAT3 polymorphisms may predict an unfavorable response to first-line platinum-based therapy for women with advanced serous epithelial ovarian cancer.

Cancer stem cells (CSC) contribute to epithelial ovarian cancer (EOC) progression and therapeutic response. We hypothesized that germline single nucleotide polymorphisms (SNPs) in CSC-related genes may predict an initial therapeutic response for women newly diagnosed with EOC. A nested case-control design was used to study 361 women with advanced-stage serous EOC treated with surgery followed by first-line platinum-based combination therapy at Moffitt Cancer Center or as part of The Cancer Genome Atlas Study. "Cases" included 102 incomplete responders (IRs) and "controls" included 259 complete clinical responders (CRs) to therapy. Using Illumina genotyping arrays and imputation, DNA samples were evaluated for 5,509 SNPs in 24 ovarian CSC-related genes. We also evaluated the overall significance of each CSC gene using the admixture maximum likelihood (AML) test, and correlated genotype with EOC tumor tissue expression. The strongest SNP-level associations with an IR to therapy were identified for correlated (r(2) > 0.80) SNPs within signal transducer and activator of transcription 3 (STAT3) [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.32-3.78; p = 0.0027], after adjustment for age, population stratification, grade and residual disease. At the gene level, STAT3 was significantly associated with an IR to therapy (pAML = 0.006). rs1053004, a STAT3 SNP in a putative miRNA-binding site, was associated with STAT3 expression (p = 0.057). This is the first study to identify germline STAT3 variants as independent predictors of an unfavorable therapeutic response for EOC patients. Findings suggest that STAT3 genotype may identify high-risk women likely to respond more favorably to novel therapeutic combinations that include STAT3 inhibitors.

Micro-RNAs associated with the evolution of ovarian cancer cisplatin resistance.

OBJECTIVES: Ovarian cancer (OVCA) is the leading cause of mortality among women with gynecologic malignancy, in part due to the development of chemoresistance. We sought to identify micro-RNAs (miRNAs) associated with in vitro development of OVCA chemoresistance that may also represent potential targets for therapy. METHODS: In this study, four OVCA cell lines (A2780CP, A2780S, IGROV1, and OVCAR5) were serially treated with cisplatin in parallel with measurements of miRNA expression changes. RESULTS: Nine miRNAs were found to be associated with increasing cisplatin resistance (IC50) (p<0.01); however, only 5 of these miRNAs have publically available information. Pathway analysis identified 15 molecular signaling pathways that were represented by genes predicted to be targets of the 5 miRNAs (false discovery rate<0.05), 11 of which are associated with the epithelial-mesenchymal transition (EMT). Further analysis identified 2 of those pathways as being associated with overall survival in 218 patients with OVCA. CONCLUSIONS: Collectively, this panel of miRNAs associated with in vitro evolution of OVCA cisplatin resistance and the pathways identified to be associated with EMT and overall patient survival provide a framework for further investigations into EMT as a therapeutic target in patients with OVCA.

Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions.

Women with germline mutations in the cancer susceptibility genes, BRCA1 or BRCA2, associated with Hereditary Breast & Ovarian Cancer syndrome, have up to an 85% lifetime risk of breast cancer and up to a 46% lifetime risk of ovarian, tubal, and peritoneal cancers. Similarly, women with mutations in the DNA mismatch repair genes, MLH1, MSH2, MSH6, or PMS2, associated with the Lynch/Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome, have up to a 40-60% lifetime risk of both endometrial and colorectal cancers as well as a 9-12% lifetime risk of ovarian cancer. Mutations in other genes including TP53, PTEN, and STK11 are responsible for hereditary syndromes associated with gynecologic, breast, and other cancers. Evaluation of the likelihood of a patient having one of these gynecologic cancer predisposition syndromes enables physicians to provide individualized assessments of cancer risk, as well as the opportunity to provide tailored screening and prevention strategies such as surveillance, chemoprevention, and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes. Evaluation for the presence of a hereditary cancer syndrome is a process that includes assessment of clinical and tumor characteristics, education and counseling conducted by a provider with expertise in cancer genetics, and may include genetic testing after appropriate consent is obtained. This commentary provides guidance on identification of patients who may benefit from assessment for the presence of a hereditary breast and/or gynecologic cancer syndrome.

Complementary and Alternative Medicine Use in Women With Gynecologic Malignancy Presenting for Care at a Comprehensive Cancer Center.

OBJECTIVE: We evaluated complementary and alternative medicine (CAM) practices among women presenting to a National Cancer Institute-designated Comprehensive Cancer Center with a gynecologic malignancy. METHODS: Women with a gynecologic malignancy who had consented to enrollment in our institutional prospective clinical registry between January 2003 and January 2014 and who had completed a questionnaire assessing sociodemographic characteristics, medical histories, quality of life, and CAM use were considered for analysis. RESULTS: Among the 2508 women identified, responses to questions on CAM use were provided by 534 (21.3%). The majority of CAM question respondents were white (93.5%) and older than 50 years (76%). Overall, 464 women (87% of CAM question respondents) used at least 1 CAM therapy during the previous 12 months. The most commonly used CAM categories were biologically based approaches (83.5%), mind and body interventions (30.6%), and manipulative and body-based therapies (18.8%). The most commonly used individual CAM therapies were vitamins and minerals (78%), herbal supplements (27.9%), spiritual healing and prayer (15.1%), and deep breathing relaxation exercises (13.1%). Complementary and alternative medicine use was greatest in age groups 20 to 30 years and older than 65 years and was more prevalent among those who were widowed (P < 0.005), retired (P = 0.02), and with a higher level of education (P < 0.01). There was no association with cancer type, race, or ethnicity. CONCLUSIONS: Complementary and alternative medicine use is common among women being treated for gynecologic malignancy. Given the potential interactions of some CAM modalities with conventional treatment and the possible benefits in controlling symptoms and improving quality of life, providers should discuss CAM with their patients.

Prediction of Optimal Cytoreductive Surgery of Serous Ovarian Cancer With Gene Expression Data.

OBJECTIVES: Cytoreductive surgery is the cornerstone of ovarian cancer (OVCA) treatment. Detractors of initial maximal surgical effort argue that aggressive tumor biology will dictate survival, not the surgical effort. We investigated the role of biology in achieving optimal cytoreduction in serous OVCA using microarray gene expression analysis. METHODS: For the initial model, we used a gene expression signature from a microarray expression analysis of 124 women with serous OVCA, defining optimal cytoreduction as removal of all disease greater than 1 cm (with 64 women having optimal and 60 suboptimal cytoreduction). We then applied this model to 2 independent data sets: the Australian Ovarian Cancer Study (AOCS; 190 samples) and The Cancer Genome Atlas (TCGA; 468 samples). We performed a second analysis, defining optimal cytoreduction as removal of all disease to microscopic residual, using data from AOCS to create the gene signature and validating results in TCGA data set. RESULTS: Of the 12,718 genes included in the initial analysis, 58 predicted accuracy of cytoreductive surgery 69% of the time (P = 0.005). The performance of this classifier, measured by the area under the receiver operating characteristic curve, was 73%. When applied to TCGA and AOCS, accuracy was 56% (P = 0.16) and 62% (P = 0.01), respectively, with performance at 57% and 65%, respectively. In the second analysis, 220 genes predicted accuracy of cytoreductive surgery in the AOCS set 74% of the time, with performance of 73%. When these results were validated in TCGA set, accuracy was 57% (P = 0.31) and performance was at 62%. CONCLUSION: Gene expression data, used as a proxy of tumor biology, do not predict accurately nor consistently the ability to perform optimal cytoreductive surgery. Other factors, including surgical effort, may also explain part of the model. Additional studies integrating more biological and clinical data may improve the prediction model.

MicroRNA miR-214 regulates ovarian cancer cell stemness by targeting p53/Nanog.

Previous studies have shown aberrant expression of miR-214 in human malignancy. Elevated miR-214 is associated with chemoresistance and metastasis. In this study, we identified miR-214 regulation of ovarian cancer stem cell (OCSC) properties by targeting p53/Nanog axis. Enforcing expression of miR-214 increases, whereas knockdown of miR-214 decreases, OCSC population and self-renewal as well as the Nanog level preferentially in wild-type p53 cell lines. Furthermore, we found that p53 is directly repressed by miR-214 and that miR-214 regulates Nanog through p53. Expression of p53 abrogated miR-214-induced OCSC properties. These data suggest the critical role of miR-214 in OCSC via regulation of the p53-Nanog axis and miR-214 as a therapeutic target for ovarian cancer.

A phase II trial of docetaxel and bevacizumab in recurrent ovarian cancer within 12 months of prior platinum-based chemotherapy.

OBJECTIVES: The efficacy and safety of bevacizumab and docetaxel were evaluated in women who developed recurrent epithelial ovarian, fallopian, or peritoneal cancer within 12 months of platinum-based therapy. METHODS: Patients received docetaxel (40 mg/m(2)) on days 1 and 8 and bevacizumab (15 mg/kg) on day 1 of a 21-daycycle. Primary endpoint was 6-month progression-free survival (PFS). RESULTS: Forty-one patients were evaluable for PFS and 38 for best response; 46% had platinum-free intervals (PFI) of <6 months and 54% between 6 and 12 months. The 6-month PFS was 43.9% (95% confidence interval (CI(95%))=28.6-58.2%). Median PFS (months) was 5.2 (CI(95%)=4.4-7.2) for all patients, 6.2 (CI(95%)=4.1-7.4) for patients with PFI <6 months, and 5.1 (CI(95%)=3.0-7.2) for those with PFI ≥ 6 months. Twenty-two patients showed overall response (CR+PR) (57.9%; CI(95%)=40.8-73.7%), and 32 showed clinical benefit (CR+PR+SD) (84.2%; CI(95%)=68.8-94.0%). For those with complete or partial responses, median duration of response was 4.8 months (0.7-14.5). Median overall survival was 12.4 months (CI(95%)=10.0-21.9). The most common grade 3/4 adverse events (AEs) were neutropenia (14.6% of patients), followed by leukopenia, fatigue, metabolic, and gastrointestinal, with 66% showing any grade 3/4 toxicity. Most common AEs of any grade were gastrointestinal (93%), fatigue (73%), and pain (73%). Four (10%) patients developed hypertension, 1 a gastrointestinal perforation, and another a colovesicular fistula. CONCLUSIONS: Bevacizumab and docetaxel administered in patients with recurrent ovarian cancer is an active regimen without new unanticipated toxicities. This combination should be an option for further study or clinical use in recurrent ovarian cancer.

Perifosine, an AKT inhibitor, modulates ovarian cancer cell line sensitivity to cisplatin-induced growth arrest.

OBJECTIVES: AKT, a key regulator of diverse tumor signaling, is associated with progression of many cancers. Here, we investigated 1) the influence of AKT on survival from ovarian cancer (OVCA), 2) the activity of the AKT inhibitor perifosine ± cisplatin, and 3) the molecular determinants of perifosine-response. Phospho-AKT expression values and Affymetrix U133a expression data were downloaded from The Cancer Genome Atlas. METHODS: Pearson correlation was used to determine associations between overall survival from OVCA and therapy response. Genes and represented signaling pathways associated with perifosine-response were explored in OVCA cells (n=10) and the NCI60 cancer cell panel. Pathway expressions, modeled by PCA, were evaluated for influences on survival using publically available clinico-genomic datasets. RESULTS: Phospho-AKT (serine473) expression correlated with survival from OVCA (P<0.05) and platinum-response (P=0.004). In vitro, perifosine showed anti-proliferative effects against OVCA cells and potentiated cisplatin-induced growth arrest. Perifosine-response was associated with the expression (FDR<0.05) of 7 signaling pathways in OVCA cells and 64 signaling pathways in the NCI60 cell panel. Three pathways were found in common: 1) Cytoskeleton remodeling/cytoskeleton remodeling (cyto), 2) cell adhesion/chemokines and adhesion (chemokines), and 3) cytoskeleton remodeling/TGF-WNT (TGF-WNT). The TGF-WNT was associated with survival from OVCA (P=0.0055). CONCLUSIONS: AKT signaling is an important determinant of OVCA response to chemotherapy and overall patient survival. Our data provide insight into the molecular basis to perifosine activity and identifies pathways associated with perifosine sensitivity and patient clinical outcome.

Factors associated with improved toxicity and tolerability of intraperitoneal chemotherapy in advanced-stage epithelial ovarian cancers.

OBJECTIVE: We sought to evaluate the toxicity and tolerability of the intraperitoneal/intravenous regimen by comparing the modified regimen that is used at the Moffitt Cancer Center vs the published findings of the Gynecologic Oncology Group Study 172. STUDY DESIGN: Using the Moffitt database, we evaluated the outcomes of patients who underwent primary optimal cytoreduction for stage IIC-IV epithelial ovarian, tubal, and peritoneal carcinoma followed by the intent-to-treat with intraperitoneal/intravenous chemotherapy. National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) was used to grade adverse events. RESULTS: We analyzed patient data from 2006-2011 and identified 69 patients who met our inclusion criteria. The most frequent grade 3/4 toxicities were neutropenia (48%), gastrointestinal (9%), metabolic (9%), and infection (5%). Remaining toxicities occurred in <5% of patients. Patients received a greater number of cycles compared with the Gynecologic Oncology Group Study 172 (4.28 vs 3.66, respectively; P = .0088). CONCLUSION: With the use of supportive care and the preemptive management of established side-effects, the associated toxicities and tolerability of intraperitoneal chemotherapy can be improved.

Gene expression data reveal common pathways that characterize the unifocal nature of ovarian cancer.

OBJECTIVE: The objective of the study was to evaluate the biological validity of ovarian cancer (OVCA) screening and early detection efforts and to characterize signaling pathways associated with human cancer metastasis and patient survival. STUDY DESIGN: Using genome-wide expression profiling and deoxyribonucleic acid sequencing, we compared pelvic and matched extrapelvic implants from 30 patients with advanced-stage OVCA for expression of molecular signaling pathways and p53 gene mutations. Differentially expressed pathways were further evaluated in a series of primary or early-stage vs metastatic or recurrent cancer samples from 389 ovarian, prostate, and oral cancer patients. Metastasis pathways were also evaluated for associations with survival in 9 independent clinicogenomic datasets from 1691 ovarian, breast, colon, brain, and lung cancer and leukemia patients. The inhibitory effects of 1 pathway (transforming growth factor [TGF]-WNT) on in vitro OVCA cell migration were studied. RESULTS: Pelvic and extrapelvic OVCA implants demonstrated similar patterns of signaling pathway expression and identical p53 mutations. However, we identified 3 molecular pathways/cellular processes that were differentially expressed between pelvic and extrapelvic OVCA samples and between primary/early-stage and metastatic/advanced or recurrent ovarian, oral, and prostate cancers. Furthermore, their expression was associated with overall survival from ovarian cancer (P = .006), colon cancer (1 pathway at P = .005), and leukemia (P = .05). Artesunate-induced TGF-WNT pathway inhibition impaired OVCA cell migration. CONCLUSION: Advanced-stage OVCA has a unifocal origin in the pelvis. Molecular pathways associated with extrapelvic OVCA spread are also associated with metastasis from other human cancers and with overall patient survival. Such pathways represent appealing therapeutic targets for patients with metastatic disease.

Prevalence of viral DNA in high-grade serous epithelial ovarian cancer and correlation with clinical outcomes.

INTRODUCTION: Currently 11 infectious agents are classified as carcinogenic but the role of infectious agents on outcomes of epithelial ovarian cancer is largely unknown. OBJECTIVE: To explore the association between infectious agents and ovarian cancer, we investigated the prevalence of viral DNA in primary ovarian cancer tumors and its association with clinical outcomes. METHODS: Archived tumors from 98 patients diagnosed with high-grade serous epithelial ovarian cancer were collected between 1/1/1994 and 12/31/2010. After DNA extraction, Luminex technology was utilized to identify polymerase chain reaction-amplified viral DNA for 113 specific viruses. Demographic data and disease characteristics were summarized using descriptive statistics. We used logistic regression and Cox proportional hazards model to assess associations between tumor viral status and disease outcome and between tumor viral presence and overall survival (OS), respectively. RESULTS: Forty-six cases (45.9%) contained at least one virus. Six highly prevalent viruses were associated with clinical outcomes and considered viruses of interest (VOI; Epstein-Barr virus 1, Merkel cell polyomavirus, human herpes virus 6b, and human papillomaviruses 4, 16, and 23). Factors independently associated with OS were presence of VOI (HR 4.11, P = 0.0001) and platinum sensitivity (HR 0.21, P<0.0001). Median OS was significantly decreased when tumors showed VOI versus not having these viruses (22 vs 44 months, P<0.0001). Women <70 year old with VOI in tumors had significantly lower median OS versus age-matched women without VOI (20 vs 57 months, P = 0.0006); however, among women ≥70 years old, there was no difference in OS by tumor virus status. CONCLUSIONS: The presence of a VOI was significantly associated with a lower OS. These findings may have implications for clinical management of ovarian cancer but require additional studies.

Fascin protein is critical for transforming growth factor ß protein-induced invasion and filopodia formation in spindle-shaped tumor cells.

Fascin, an actin-bundling protein overexpressed in all carcinomas, has been associated with poor prognosis, shorter survival, and more metastatic diseases. It is believed that fascin facilitates tumor metastasis by promoting the formation of invasive membrane protrusions. However, the mechanisms by which fascin is overexpressed in tumors are not clear. TGFß is a cytokine secreted by tumor and mesenchymal cells and promotes metastasis in many late stage tumors. The pro-metastasis mechanisms of TGFß remain to be fully elucidated. Here we demonstrated that TGFß induced fascin expression in spindle-shaped tumor cells through the canonical Smad-dependent pathway. Fascin was critical for TGFß-promoted filopodia formation, migration, and invasion in spindle tumor cells. More importantly, fascin expression significantly correlates with TGFß1 and TGFß receptor I levels in a cohort of primary breast tumor samples. Our results indicate that elevated TGFß level in the tumor microenvironment may be responsible for fascin overexpression in some of the metastatic tumors. Our data also suggest that fascin could play a central role in TGFß-promoted tumor metastasis.

The BCL2 antagonist of cell death pathway influences endometrial cancer cell sensitivity to cisplatin.

OBJECTIVE: To identify pathways that influence endometrial cancer (EC) cell sensitivity to cisplatin and to characterize the BCL2 antagonist of cell death (BAD) pathway as a therapeutic target to increase cisplatin sensitivity. METHODS: Eight EC cell lines (Ishikawa, MFE296, RL 95-2, AN3CA, KLE, MFE280, MFE319, HEC-1-A) were subjected to Affymetrix Human U133A GeneChip expression analysis of approximately 22,000 probe sets. In parallel, endometrial cell line sensitivity to cisplatin was quantified by MTS assay, and IC(50) values were calculated. Pearson's correlation test was used to identify genes associated with response to cisplatin. Genes associated with cisplatin responsiveness were subjected to pathway analysis. The BAD pathway was identified and subjected to targeted modulation, and the effect on cisplatin sensitivity was evaluated. RESULTS: Pearson's correlation analysis identified 1443 genes associated with cisplatin resistance (P<0.05), which included representation of the BAD-apoptosis pathway. Small interfering RNA (siRNA) knockdown of BAD pathway protein phosphatase PP2C expression was associated with increased phosphorylated BAD (serine-155) levels and a parallel increase in cisplatin resistance in Ishikawa (P=0.004) and HEC-1-A (P=0.02) cell lines. In contrast, siRNA knockdown of protein kinase A expression increased cisplatin sensitivity in the Ishikawa (P=0.02) cell line. CONCLUSION: The BAD pathway influences EC cell sensitivity to cisplatin, likely via modulation of the phosphorylation status of the BAD protein. The BAD pathway represents an appealing therapeutic target to increase EC cell sensitivity to cisplatin.

Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.

Preoperative enoxaparin is safe to use in major gynecologic surgery for prophylaxis of venous thromboembolism: a retrospective cohort study.

OBJECTIVE: To evaluate the safety of preoperative enoxaparin in patients undergoing major gynecologic oncology surgery. METHODS: We identified a retrospective cohort group of patients undergoing major gynecologic oncology surgery from June 2002 to June 2004. Exclusion criteria included laparoscopic surgery, inferior vena cava filter, history of venous thromboembolism, and current anticoagulation for prior venous thromboembolism. All patients received prophylaxis with sequential pneumatic compression devices and early ambulation. We identified patients who received (preoperative and postoperative) enoxaparin (20-40 mg) and compared them to patients who received no additional prophylaxis other than pneumatic compression alone. Patient outcomes including estimated blood loss, blood transfusions, operative time, and length of hospital stay were collected. Statistical analysis was performed using the χ Wilcoxon rank sum tests. This study was approved by the institutional review board. RESULTS: We identified 122 patients who met our study criteria; there were 63 patients who received preoperative enoxaparin and 59 patients who received no additional prophylaxis. Both groups were similar in age, body mass index, race, comorbidities, cancer diagnosis, and surgical procedure. There was no significant difference between the enoxaparin group and the sequential pneumatic compression devices-only group regarding transfusion rates (29% and 27%; P = 0.86), operating time (150 and 140 minutes; P = 0.16), blood loss greater than 500 cc (35% and 37%; P = 0.79), and length of stay (5 vs 6 days). CONCLUSION: The use of preoperative enoxaparin is not associated with increased blood loss, transfusion requirements, operative time, or hospital stay among patients having major gynecologic surgery.