Inferior vena cava ultrasonography before general anesthesia cannot predict arterial hypotension in patients undergoing vascular surgery.

INTRODUCTION: Intraoperative hypotension (IH) is an independent predictor of mortality. Some experts have suggested that ultrasound measurement of the inferior vena cava (IVC) in spontaneous ventilation can predict IH. OBJECTIVE: To evaluate the capacity of ultrasound measures of IVC in spontaneous ventilation to predict episodes of IH after anaesthesia induction. PATIENTS AND METHODS: We studied 55 high-risk cardiac patients undergoing vascular surgery. The maximum (dIVCmax) and minimum (dIVCmin) diameter of the IVC were measured and the collapsibility index CI = (dIVCmax-dIVCmin)/dIVCmax was calculated prior to anaesthesia induction. Three definitions of IH were used: systolic blood pressure (SBP) less than 100 mmHg, mean arterial pressure (MAP) less than 60 mmHg, and a decrease in MAP greater than or equal to 30% compared to baseline. RESULTS: There were no significant differences in dIVCmax or in CI between patients presenting IH after anaesthesia induction and those who did not. ROC curves for dIVCmax showed an area under the curve of 0.55 (0.39-0.70), 0.69 (0.48-0.90), and 0.57 (0.42-0.73) and ROC curves for the CI were 0.62 (0.47-0.78), 0.60 (0.41-0.78) and 0.62 (0.47-0.78) for the 3 definitions of IH (<100 mmHg, MAP < 60 mmHg, and MAP ≥30% baseline), respectively. CONCLUSIONS: Ultrasound measurements of IVC in spontaneous ventilation are not good predictors of IH after anaesthesia induction in these patients. The optimal cut-off points show low specificity and moderate sensitivity for predicting IH.

Creating work environments where people of all genders in gynecologic oncology can thrive: An SGO evidence-based review.

Equality, equity, and parity in the workplace are necessary to optimize patient care across all aspects of medicine. Gender-based inequities remain an obstacle to quality of care, including within the now majority women subspecialty of gynecologic oncology. The results of the 2020 SGO State of the Society Survey prompted this evidence-based review. Evidence related to relevant aspects of the clinical care model by which women with malignancies are cared for is summarized. Recommendations are made that include ways to create work environments where all members of a gynecologic oncology clinical care team, regardless of gender, can thrive. These recommendations aim to improve equality and equity within the specialty and, in doing so, elevate the care that our patients receive.

Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer.

BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes. PATIENTS AND METHODS: Ninety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46 months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400 mg twice daily or cediranib 30 mg daily and olaparib capsules 200 mg twice daily until disease progression. RESULTS: In this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P = 0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7 months, P = 0.002) and OS (37.8 versus 23.0 months, P = 0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3 months, hazard ratio 0.64; P = 0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension. CONCLUSIONS: Combination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT0111648.

The new classifications of ovarian, fallopian tube, and primary peritoneal cancer and their clinical implications.

The roles of histologic characterization and staging are to provide reproducible metrics for cancer classification with which to direct the most appropriate clinical care and to yield the most stable reliable system to allow both prospective and retrospective data analysis. Both the histologic and staging classifications of malignant ovarian/tubal/peritoneal cancers have recently changed. The World Health Organization sponsored a review and reclassification of the pathology of cancers of the ovaries, fallopian tubes, and peritoneum, and published these updates in 2014. In so doing, they codified the two-tiered grading system that has been in use in serous ovarian cancers for nearly a decade. In parallel, FIGO reviewed and updated the surgical staging system, applied to all histotypes of ovarian, tubal, and peritoneal cancers, also published in 2014. In both cases, the changes made are meant to encompass a better understanding of disease, but both have important merits and drawbacks. Changes in staging complicate analysis of retrospective data against current data. Though in some aspects controversial, the changes overall are meant to represent a better biologic understanding of disease that we hope will lead to an improvement in patient care and directed therapy.

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG): clinical trial design for rare ovarian tumours.

This manuscript reports the consensus statements on designing clinical trials in rare ovarian tumours reached at the fifth Ovarian Cancer Consensus Conference (OCCC) held in Tokyo, November 2015. Three important questions were identified concerning rare ovarian tumours (rare epithelial ovarian cancers (eOC), sex-cord stromal tumours (SCST) and germ cell tumours (GCT)): (i) What are the research and trial issues that are unique to rare ovarian tumours? There is a lack of randomised phase III data defining standards of care which makes it difficult to define control arms, but identifies unmet needs that merit investigation. Internationally agreed upon diagnostic criteria, expert pathological review and translational research are crucial. (ii) What should be investigated in rare eOC, GCT and SCST? Trials dedicated to each rare ovarian tumour should be encouraged. Nonetheless, where the question is relevant, rare eOC can be included in eOC trials but with rigorous stratification. Although there is emerging evidence suggesting that rare eOC have different molecular profiles, trials are needed to define new type-specific standards for each rare eOC (clear cell, low grade serous and mucinous). For GCTs, a priority is reducing toxicities from treatment while maintaining cure rates. Both a robust prognostic scoring system and more effective treatments for de novo poor prognosis and relapsed GCTs are needed. For SCSTs, validated prognostic markers as well as alternatives to the current standard of bleomycin/etoposide/cisplatin (BEP) should be identified. (iii) Are randomised trials feasible? Randomised controlled trials (RCT) should be feasible in any of the rare tumours through international collaboration. Ongoing trials have already demonstrated the feasibility of RCT in rare eOC and SCST. Mucinous OC may be considered for inclusion, stratified, into RCTs of non-gynaecological mucinous tumours, while RCTs in high risk or relapsed GCT may be carried out as a subset of male and/or paediatric germ cell studies.

Anestesia regional periférica para revascularización arterial de miembros inferiores. Revisión bibliográfica y casos clínicos / Peripheral regional anesthesia for arterial revascularization of lower limbs. Bibliographical review and clinical cases

Introducción: La tendencia actual es diferir la cirugía de revascularización de miembros inferiores hasta etapas avanzadas, lo que explica que sean pacientes de mayor complejidad con alta morbimortalidad cardíaca y respiratoria. Los mayores avances para reducirlas, se han desarrollado en la preparación de los pacientes y en las técnicas quirúrgicas. La elección de la técnica anestésica no ha sido considerada un factor determinante. Los bloqueos regionales presentan potenciales ventajas, como mayor estabilidad hemodinámica y respiratoria. Objetivo: Realizar una revisión bibliográfica y presentación de casos clínicos sobre la utilidad de los bloqueos periféricos para anestesia en la cirugía de revascularización de miembros inferiores. Material y métodos: La búsqueda se realizó a través de la base de datos Medline, LILACS y SciELO. Se incluyeron estudios donde los bloqueos periféricos se utilizaron para anestesia. Se describen dos casos clínicos. Resultados: Se seleccionaron 4 artículos originales, 3 de ellos eran estudios descriptivos de la técnica y el cuarto una comparación con anestesia general inhalatoria. 2más correspondieron a casos clínicos. Conclusiones: No existe evidencia suficiente que permita concluir que reducen la mortalidad o la morbilidad cuando se la compara con las demás técnicas anestésicas. Esto puede ser debido al diseño metodológico de los estudios, a la no utilización de la ecografía como guía y la no sistematización de los bloqueos. El análisis de los casos clínicos sugiere que en situaciones específicas como pacientes de alto riesgo cardíaco y respiratorio, bajo tratamiento con anticoagulantes y antiagregantes estos presentan ventajas sobre las otras técnicas.

Background: The current trend is to defer revascularization surgery from lower limbs to advanced stages, which explains why they are more complex patients with high cardiac and respiratory mortality. The choice of anesthetic technique remains controversial. Regional blockades have potential advantages, such as hemodynamic and respiratory stability. Our primary objective was a bibliographic review to assess the peripheral blockages for anesthesia in lower limb revascularization surgery. Our secondary objective was report two clinical cases. Material and methods: The search was performed through the Medline, LILACS and SciELO database. We included studies where peripheral blocks were used for anesthesia. Two clinical cases are described. Results: Four original articles were selected, 3 of which were descriptive studies of the technique and the fourth a comparison with general inhalation anesthesia. 2 more corresponded to clinical cases. Conclusions: There is insufficient evidence to conclude that peripheral nerve block reduce mortality or morbidity when compared with other anesthetic techniques. This may be due to the methodological design of the studies, to the non-use of echocardiography as a guide and the non-systematization of the blocks. The analysis of the clinical cases suggests that this technique is a good option in specific situations as patients with high cardiac and respiratory risk, under treatment with anticoagulants and antiplatelets drugs.

Microcirculatory changes during cardiac surgery with cardiopulmonary bypass. / Alteraciones microcirculatorias en cirugía cardíaca con circulación extracorpórea.

OBJECTIVE: To evaluate microcirculation in intermediate and high mortality risk patients undergoing cardiac surgery (CS) with cardiopulmonary bypass (CPB). PATIENTS AND METHODS: The study included 22 patients with a Euroscore >3. Using the Videomicroscopy Side Stream Dark Field system, and evaluation was made of, capillary density, proportion of perfused capillaries, density of perfused capillaries, microcirculatory flow index (MFI), and heterogeneity flow index. Three to five video sequences were recorded: after induction of anaesthesia (T1), at the beginning of the CPB (T2), before finalising CPB (T3), at the end of the surgery, and before the patient was transferred to Intensive Care Unit (T4). Mean arterial pressure decreased, while the blood lactate increased significantly, when comparing the initial and final values (P<.05). MFI increased significantly in T3 and T4 (P<.05) with regards to the initial values. When the patients with and without postoperative complications were compared, significant differences were found in, Euroscore, left ventricular ejection fraction, and MFI in T3. CONCLUSIONS: in patients with intermediate/high preoperative risk, CS and CBP can involve an increase in MFI and blood lactate at the end of the study. These alterations suggest the possibility of a functional microcirculatory shunt at tissue perfusion level, secondary to the surgical injury and the CPB. Further investigation is needed to have a better understanding of the mechanisms involved.

[Anaestheia for valve replacement in the second trimester of pregnancy]. / Anestesia para sustitución valvular en el segundo trimestre del embarazo.

Cardiac surgery in the pregnant woman gives rise to several anesthetic challenges, as the mother, but mainly the fetus, have a risk of high morbidity and mortality. In this context, the cardiopulmonary bypass is the most complex period, owing to the risks of fetal hypoxia it entails. Due to the absence, for ethical reasons, of prospective trials that provide generally accepted guidelines in intraoperative management, it means that physicians have to work based on case reports in the literature. These procedures also require team coordination to be successful. The case is presented of a 19 weeks pregnant woman, who required a mitral valve replacement, which was achieved with success, and enabled her to complete her pregnancy without complications. Details are provided on the published references on which our management was based.

PARP Inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies.

Poly(ADP-ribose)polymerase inhibitors (PARPis) have shown promising activity in patients with BRCA1/2 mutation-associated (BRCA1/2(MUT+)) ovarian and breast cancers. Accumulating evidence suggests that PARPi may have a wider application in the treatment of sporadic high-grade serous ovarian cancer, and cancers defective in DNA repair pathways, such as prostate, endometrial, and pancreatic cancers. Several PARPis are currently in phase 1/2 clinical investigation, with registration trials now being designed. Olaparib, one of the most studied PARPis, has demonstrated activity in BRCA1/2(MUT+) and BRCA-like sporadic ovarian and breast cancers, and looks promising in prostate and pancreatic cancers. Understanding more about the molecular abnormalities involved in BRCA-like tumors, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers, is critical to rapidly advancing the field of PARPi therapy and improve clinical outcomes.

Clinical implications of using molecular diagnostics for ovarian cancers.

In the era of morphologic diagnostics, any epithelial tumor on or involving the ovaries was presumed to come from and be strictly of ovarian origin, apart from the rare but clearly metastatic tumors. Thus, many women who might have had small fallopian tube primary cancers that rapidly extended on to or into the ovary were deemed to have ovarian cancer. Now, as we begin to better understand that there are different types of cancers of nonuterine Muellerian origin, we expand upon the morphologic to add the molecular characteristics. Morphomolecular characteristics are being applied to drive clinical advances including development and optimization of predictive and prognostic biomarkers, redefinition of historical controls, and consideration of novel clinical trial designs. Ovarian cancer, not a common cancer to start with, is now subdivided into types, making ever smaller clinical cohorts. The first studies evaluating tubo-ovarian Muellerian cancers of morphomolecular types have begun. Deleterious mutations in BRCA1 or 2 have been validated as the first new predictive and prognostic biomarker of the high-grade serous ovarian cancer type and polyADPribose polymerase inhibitors, the first targeted agents for this morphomolecular entity. Similar progress is developing in other tubo-ovarian cancer types. This new knowledge is driving the building of a structure-function-type relationship that is generating novel clinically applicable hypotheses for testing.

Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions.

BACKGROUND: We tested the hypothesis that BRCA1/2 mutation carriers with ovarian cancer are at higher risk of carboplatin hypersensitivity reactions (HSRs). METHODS: Medical records of women enrolled in two carboplatin+olaparib clinical trials (NCT01237067/NCT01445418) were reviewed. A maximum of eight cycles containing carboplatin were administered. RESULTS: All women (N=87) had good performance status and end-organ function. Incidences of carboplatin HSR before enrolment and on study were 17% and 21%, respectively. Most patients who developed carboplatin HSR had a deleterious BRCA1/2 mutation (93%) vs 50% in patients without HSR (P<0.0001). Multivariable analysis accounting for potential confounding variables including age, history of allergies, and cumulative prior carboplatin cycles confirmed deleterious BRCA1/2 mutation as an independent risk factor for carboplatin HSR (odds ratio 13.1 (95% confidence interval 2.6-65.4), P=0.0017). Mutation carriers had onset of carboplatin HSR at lower cumulative exposure (P=0.003). No significant difference in outcome was observed on our study between patients with and without a history of HSR. CONCLUSION: Deleterious BRCA1/2 mutation increased susceptibility and shortened time to carboplatin HSR, independently of other reported factors. These data suggest that at-risk women should be counselled regarding likelihood, symptoms, and potential earlier onset of carboplatin HSRs.

Contribution of the coronary sinus blood to the pulmonary artery oxygen saturation gradient in cardiac surgery patients.

BACKGROUND: The coronary sinus oxygen saturation (SO2) can affect the oxygen saturation of the superior vena cava (superior cava SO2) and the pulmonary artery (pulmonary artery SO2), causing a gradient between the latter two (ΔSO2), as has been observed in different physiological and pathological conditions. The objective of the study was to evaluate the different determinants of ΔSO2 in cardiac surgery patients. METHODS: An observational, prospective study was carried out on 18 patients undergoing elective cardiac surgery. Blood samples were obtained from the superior vena cava, the pulmonary artery, the inferior vena cava, and the coronary sinus before extracorporeal circulation. RESULTS: The following measurements were made: superior cava SO2, pulmonary artery SO2, coronary sinus SO2, and inferior cava SO2. The mean values (± SD) were as follows: superior cava SO2=76.4±12.6%; inferior cava SO2=72.7±15.8%; coronary sinus SO2=46.6±17.0%; and pulmonary artery SO2=71.9±12.9%. The ΔSO2 was 4.5±5.5%. The average oxygen saturation (SO2avg=[Superior cava SO2 + inferior cava SO2]/2) was 74.6±13.7%. The superior cava SO2 was significantly higher than the pulmonary artery SO2, and the ΔSO2 was significantly different from zero (P≤0.05). No significant differences were found between the superior cava SO2 and the inferior cava SO2, and both were significantly different from the coronary sinus SO2. The difference between SO2avg and the pulmonary artery SO2 was 2.74±4.4%. CONCLUSION: The observed ΔSO2 could only be explained by dilution of the superior cava SO2 with blood with a lower SO2. The coronary sinus blood contributed to generate this gradient.

Proteomics as a guiding tool for more effective personalized therapy.

Ovarian cancer remains the deadliest gynecological malignancy in the Western world and is most often diagnosed at a rarely curable late stage. Examination of protein end points has been employed as an investigative mechanism to guide targeted therapy and to stratify ovarian cancer. Proteomics allows characterization of the proteins and the associated protein and peptide modifications. This has given us insight into the perturbations of signaling pathways within tumor cells and has improved the discovery of new drug targets and possible prognostic indicators of outcome and disease response to therapy. Development of validated assays that survey the genetic and/or proteomic make-up of an individual tumor will add greatly to the histological classification of the tumor and may lead to different treatment approaches tailored to the unique expression pattern of each individual patient. It is anticipated that application of proteomics may bring to reality the clinical adoption of molecular stratification, e.g. not, 'is the gene overexpressed?', but 'is the pathway upregulated?' This will be successful if validated peptide biomarkers are applied for patient selection prospectively and with inclusion of preplanned biological correlates. These events will guide future directions of proteomics as a selector and as a validator and will guide how we integrate proteomics information daily into patient care and into selecting therapy of advanced and recurrent ovarian cancer and other cancers.

Nanocrystalline diamond microelectrode arrays fabricated on sapphire technology for high-time resolution of quantal catecholamine secretion from chromaffin cells.

The quantal release of oxidizable molecules can be successfully monitored by means of polarized carbon fiber microelectrodes (CFEs) positioned in close proximity to the cell membrane. To partially overcome certain CFE limitations, mainly related to their low spatial resolution and lack of optical transparency, we developed a planar boron-doped nanocrystalline diamond (NCD) prototype, grown on a transparent sapphire wafer. Responsiveness to applied catecholamines as well as the electrochemical and optical properties of the NCD-based device were first characterized by cyclic voltammetry and optical transmittance measurements. By stimulating chromaffin cells positioned on the device with external KCl, well-resolved quantal exocytotic events could be detected either from one NCD microelectrode, or simultaneously from an array of four microelectrodes, indicating that the chip is able to monitor secretory events (amperometric spikes) from a number of isolated chromaffin cells. Spikes detected by the planar NCD device had comparable amplitudes, kinetics and vesicle diameter distributions as those measured by conventional CFEs from the same chromaffin cell.

Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity.

BACKGROUND: We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing. METHODS: Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1-5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg(-1). DL5 alternated between bevacizumab 10 mg kg(-1)-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg(-1) (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1-5 were analysed. RESULTS: Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand-foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation > or =4 months (53%; median 6 (4-26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4-37 months. CONCLUSION: Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.

Ovarian cancer in the proteomics era.

Ovarian cancer presents a diagnostic challenge because of its subtle clinical presentation and elusive cell of origin. Two new technologies of proteomics have advanced the dissection of the underlying molecular signaling events and the proteomic characterization of ovarian cancer: mass spectrometry and protein array analysis. Mass spectrometry can provide a snapshot of a proteome in time and space, with sensitivity and resolution that may allow identification of the elusive "needle in the haystack" heralding ovarian cancer. Proteomic profiling of tumor tissue samples can survey molecular targets during treatment and quantify changes using reverse phase protein arrays generated from tumor samples captured by microdissection, lysed and spotted in serial dilutions for high-throughput analysis. This approach can be applied to identify the optimal biological dose of a targeted agent and to validate target to outcome link. The evolution of proteomic technologies has the capacity to advance rapidly our understanding of ovarian cancer at a molecular level and thus elucidate new directions for the treatment of this disease.

Unlocking diamond's potential as an electronic material.

In this paper, we review the suitability of diamond as a semiconductor material for high-performance electronic applications. The current status of the manufacture of synthetic diamond is reviewed and assessed. In particular, we consider the quality of intrinsic material now available and the challenges in making doped structures suitable for practical devices. Two practical applications are considered in detail. First, the development of high-voltage switches capable of switching voltages in excess of 10 kV. Second, the development of diamond MESFETs for high-frequency and high-power applications. Here device data are reported showing a current density of more than 30 mA mm(-1) along with small-signal RF measurements demonstrating gigahertz operation. We conclude by considering the remaining challenges which will need to be overcome if commercially attractive diamond electronic devices are to be manufactured.

Progress in ovarian cancer research: proceedings of the 5th Biennial Ovarian Cancer Research Symposium.

Ovarian cancer remains the most lethal gynecological malignancy. The 5th Biennial Symposium overviewed the progress of ovarian cancer research over the last few years. Molecularly based technologies have allowed the identification of multiple biomarkers to aid in ovarian cancer diagnosis and treatment. Furthermore, data analysis systems evaluating the behavior of these markers have been designed. Therapeutic use of ovarian cancer protein markers has been fueled by the development of animal models that more closely simulate the pathogenesis of ovarian cancer, and multiple new therapies are being developed that may have impact against the disease. Finally, the design of clinical trials both for ovarian cancer treatment and prevention are key in advancing the science of ovarian cancer into the clinic. The need for strategies that would optimize patient participation in clinical trials is paramount.

Ovarian cancer in the proteomics era: diagnosis, prognosis, and therapeutics targets.

Ovarian cancer is clinically quiet as it plants seeds of metastases in the peritoneal cavity, even during early stages when there is highest potential for cure. The only available biomarker is CA125, which has an unacceptably low sensitivity and specificity for diagnostic use. Highly sensitive and specific tools to further optimize early diagnosis and treatment are needed. We propose that proteomic technologies have an important role to play in the development of these tools. Mass spectrometry platforms, such as surface-enhanced laser desorption/ionization time-of-flight, may be used to mine patient's serum for proteomic signatures that are shed by tumor and stroma. Such signatures could serve as a diagnostic tool during early-stage disease and as a remission-monitoring tool in later-stage disease. Reverse-phase protein microarrays are a new microproteomic tool to profile signaling pathways in ovarian cancer, thus identifying therapeutic targets while simultaneously suggesting prognostic indicators. Proteomic technologies have the capacity to build upon our genomic and clinical understanding of ovarian cancer by moving the focal point to the tumor and its microenvironment. This unique proteomic vantage point allows the creation of tools that will aid clinicians in making rational decisions in the diagnosis and treatment of women with ovarian cancer.

Malignant effusions are sources of fibronectin and other promigratory and proinvasive components.

Metastatic dissemination is the primary cause of death in ovarian cancer (OvCa) patients, and dissemination to pleural and peritoneal effusions is a common clinical event. Effusion samples were collected from 15 OvCa patients. Twenty-six samples were collected prospectively, two were archival, and eight were taken from patients with other malignancies. Twenty-nine samples were from malignant ascites, and seven specimens were pleural fluids. In addition, six ascites and two pleural fluids from noncancer patients were studied as effusion controls. Effusion supernatants were tested for migration-stimulation activity, using A2058 human melanoma cells as the index responder cell. Malignant samples induced a 400-1200% increase in migration. Sixty percent of the migration was inhibited by incubation of the malignant fluid with antifibronectin (FN) antibody, in contrast to 75% inhibition of control fluid-stimulated migration (P = 0.017). Gelatin zymography and Western blot analyses showed that latent and activated MMP-2 and MMP-9 collagenases, and tissue inhibitor of metalloproteinase-2 (TIMP-2) were present in all malignant fluids. Serial samples were taken from several patients, and a trend for correlation between MMPs and clinical behavior of the tumors was shown. Free TIMP-2 correlated with CA-125 levels in two patients for whom serial samples were available. The demonstration of promigratory and proinvasive activity in malignant effusions is consistent with their association with other metastatic disease in OvCa patients and their function as a haven for metastatic cells.