Deep, noninvasive imaging and surgical guidance of submillimeter tumors using targeted M13-stabilized single-walled carbon nanotubes.

Highly sensitive detection of small, deep tumors for early diagnosis and surgical interventions remains a challenge for conventional imaging modalities. Second-window near-infrared light (NIR2, 950-1,400 nm) is promising for in vivo fluorescence imaging due to deep tissue penetration and low tissue autofluorescence. With their intrinsic fluorescence in the NIR2 regime and lack of photobleaching, single-walled carbon nanotubes (SWNTs) are potentially attractive contrast agents to detect tumors. Here, targeted M13 virus-stabilized SWNTs are used to visualize deep, disseminated tumors in vivo. This targeted nanoprobe, which uses M13 to stably display both tumor-targeting peptides and an SWNT imaging probe, demonstrates excellent tumor-to-background uptake and exhibits higher signal-to-noise performance compared with visible and near-infrared (NIR1) dyes for delineating tumor nodules. Detection and excision of tumors by a gynecological surgeon improved with SWNT image guidance and led to the identification of submillimeter tumors. Collectively, these findings demonstrate the promise of targeted SWNT nanoprobes for noninvasive disease monitoring and guided surgery.

Robustness of chemometrics-based feature selection methods in early cancer detection and biomarker discovery.

In omics studies aimed at the early detection and diagnosis of cancer, bioinformatics tools play a significant role when analyzing high dimensional, complex datasets, as well as when identifying a small set of biomarkers. However, in many cases, there are ambiguities in the robustness and the consistency of the discovered biomarker sets, since the feature selection methods often lead to irreproducible results. To address this, both the stability and the classification power of several chemometrics-based feature selection algorithms were evaluated using the Monte Carlo sampling technique, aiming at finding the most suitable feature selection methods for early cancer detection and biomarker discovery. To this end, two data sets were analyzed, which comprised of MALDI-TOF-MS and LC/TOF-MS spectra measured on serum samples in order to diagnose ovarian cancer. Using these datasets, the stability and the classification power of multiple feature subsets found by different feature selection methods were quantified by varying either the number of selected features, or the number of samples in the training set, with special emphasis placed on the property of stability. The results show that high consistency does not necessarily guarantee high predictive power. In addition, differences in the stability, as well as agreement in feature lists between several feature selection methods, depend on several factors, such as the number of available samples, feature sizes, quality of the information in the dataset, etc. Among the tested methods, only the variable importance in projection (VIP)-based method shows complementary properties, providing both highly consistent and accurate subsets of features. In addition, successive projection analysis (SPA) was excellent with regards to maintaining high stability over a wide range of experimental conditions. The stability of several feature selection methods is highly variable, stressing the importance of making the proper choice among feature selection methods. Therefore, rather than evaluating the selected features using only classification accuracy, stability measurements should be examined as well to improve the reliability of biomarker discovery.

Long-term outcomes of photodynamic therapy for a positive resection margin after conization for cervical intraepithelial neoplasia grade 3.

BACKGROUND: Positive resection margins after conization or loop electrosurgical excision procedure (conization/LEEP) are associated with increased risks of recurrence or residual cervical intraepithelial neoplasia (CIN). Herein, we investigated the long-term outcomes of photodynamic therapy (PDT) for incomplete excision of CIN3. METHODS: We retrospectively reviewed the medical charts of 73 patients treated with PDT between 2000 and 2011. Patients who underwent conization/LEEP before PDT within 6 months were included. The primary outcomes were the complete response (CR) rate after 1 year and human papillomavirus (HPV) eradication rate at 6 months after PDT. RESULTS: A total of 34 patients with positive resection margins were finally enrolled. The median patient age was 33 years. Carcinoma in situ was diagnosed in 25 patients and CIN3 in 7 patients. The CR rate was 97.1% after 1 year. Except for one case of a persistent disease, there was no recurrence or newly developed disease during the median follow-up of 84 months (range, 12-224 months). The HPV eradication rate of PDT following conization/LEEP after 6 months was 96.9% (31/32). Photosensitivity was identified in five patients and cervical stenosis in one patient. CONCLUSIONS: In conclusion, PDT could be an effective therapeutic option for patients with a positive resection margin after conization/LEEP for CIN3. It could reduce the residual or recurrence rate of CIN lesions with tolerable adverse events.

Ovarian cancer: markers of response.

OBJECTIVES: Despite improved knowledge regarding the etiology of ovarian cancer, as well as application of aggressive surgery and chemotherapy, there has been only a modest change in the mortality statistics over the last 30 years. Given these results and the evolution of targeted therapies, there is an increasing need for prognostic and predictive factors to stratify patients for individualized care. Many laboratories have also investigated the specific individual biomarkers correlating them with clinicopathologic characteristics. Unfortunately, the vast majorities of these biomarkers have not proved clinically valuable. In this article, we review published genomic signatures including data generated in our laboratory for their relevance. METHODS: Multiple published expression profiling articles were selected for review and discussion. Genomic studies were separated from those with dichotomized survival data and unsupervised analysis to identify discreet subsets of tumors and studies that generated activated pathways. RESULTS: The identification of prognostic and predictive individual biomarkers has been common. Few of these have been validated. Genomic profiles have been obtained that distinguish short- from long-term survivors. The relevance of these studies to the large number of patients within the extremes remains unclear. Unsupervised clustering studies of ovarian cancers have identified potential subsets of tumors that reflect different clinical behavior. These studies will require large numbers of independent samples for validation. Another approach has been to identify genes that correlate with patient survival as a continuous variable. These genes are then placed into biologic context using pathway analysis. These pathways provide potential therapeutic targets, and those patients whose tumors express these targets may be most effectively treated by using inhibitors specific for the pathway. CONCLUSIONS: There is a major need for prognostic and predictive biomarkers for ovarian cancer. With the development of new genomic technologies, there is an opportunity to identify gene expression signatures that can be used to stratify patients according to their ultimate survival and response to chemotherapy. Large independent sets and robust statistical techniques will be required to fully exploit this approach.

Methods for Systematic Identification of Membrane Proteins for Specific Capture of Cancer-Derived Extracellular Vesicles.

Analysis of cancer-derived extracellular vesicles (EVs) in biofluids potentially provides a source of disease biomarkers. At present there is no procedure to systematically identify which antigens should be targeted to differentiate cancer-derived from normal host cell-derived EVs. Here, we propose a computational framework that integrates information about membrane proteins in tumors and normal tissues from databases: UniProt, The Cancer Genome Atlas, the Genotype-Tissue Expression Project, and the Human Protein Atlas. We developed two methods to assess capture of EVs from specific cell types. (1) We used palmitoylated fluorescent protein (palmtdTomato) to label tumor-derived EVs. Beads displaying antibodies of interest were incubated with conditioned medium from palmtdTomato-expressing cells. Bound EVs were quantified using flow cytometry. (2) We also showed that membrane-bound Gaussia luciferase allows the detection of cancer-derived EVs in blood of tumor-bearing animals. Our analytical and validation platform should be applicable to identify antigens on EVs from any tumor type.

Patient selection guidelines in MR-guided focused ultrasound surgery of uterine fibroids: a pictorial guide to relevant findings in screening pelvic MRI.

Uterine leiomyomas (fibroids), the most common benign tumor in women of childbearing age, can cause symptoms including dysmenorrhea, menorrhagia, urinary symptoms, pain and infertility. Hysterectomy is a common approach to treating uterine fibroids, and less invasive surgical approaches such as myomectomy and uterine artery embolization also have been shown to alleviate symptoms. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is the only totally non-invasive surgical approved method for treating uterine fibroids. In clinical trials, MRgFUS resulted in significant relief of uterine fibroid symptoms. The safe and effective use of MRgFUS is affected by fibroid type and location, position relative to adjacent anatomical structures and the presence of co-existent pelvic disease. Additionally, successful outcomes with MRgFUS have been correlated with the volume of fibroids ablated during the procedure. Thus, selection of patients in whom sufficient fibroid volumes can be treated safely using the MRgFUS system is critical for successful outcomes. The MR images in this pictorial essay provide examples of uterine fibroids for which MRgFUS should be considered and is designed to facilitate the selection of patients for whom MRgFUS is most likely to provide sustained symptom relief.

Management of high-risk hydatidiform mole and persistent gestational trophoblastic neoplasia: the Korean experience.

OBJECTIVE: To test the efficacy of a new scoring system to differentiate high-risk hydatidiform mole (H-mole) and initiate early selective postmolar chemotherapy. STUDY DESIGN: According to Kim's scoring system, 262 patients were identified as high-risk H-mole patients. Fifty (19.1%) received early chemotherapy, and the rest constituted the control group. Salvage therapy with etoposide, methotrexate, actinomycin D/etoposide, cisplatin (EMA/EP) and taxol, cisplatin/taxol, etoposide (TP/TE) was applied in 21 cases of ultra-high-risk GTT. RESULTS: None of the 50 cases in the early chemotherapy group progressed to persistent GTT. However, 58.9% in the control group developed GTT with 8.0% drug resistance. Of those receiving salvage therapy in the 21 ultra-high-risk GTT cases resistant to EMA/CO, 10 of 14 (71%) receiving EMA/EP and 4 of 7 (57.1%) receiving TP/TE achieved remission. CONCLUSION: Early postmolar chemotherapy for high-risk H-mole is effective in preventing progression to persistent GTT and treatment failure. Ultra-high-risk GTT should be approached with multimodal treatment, including EMA/EP and TP/TE regimens.

Sustained, low-dose intraperitoneal cisplatin improves treatment outcome in ovarian cancer mouse models.

Intraperitoneal (IP) chemotherapy for ovarian cancer treatment prolongs overall survival by 16 months compared to intravenous chemotherapy but is not widely practiced due to catheter-related complications and complexity of administration. An implantable, nonresorbable IP microdevice was used to release chemotherapeutic agent at a constant rate of approximately 1.3 µg/h in vitro and 1.0 µg/h in vivo. Studies conducted in two orthotopic murine models bearing human xenografts (SKOV3 and UCI101) demonstrate that continuous dosing reduces tumor burden to the same extent as weekly IP bolus drug injections. Treatment-induced toxicity was quantified via body weight loss and complete blood count. The microdevice resulted in significantly less toxicity than IP bolus injections, despite administration of higher cumulative doses (total area under the concentration-time curve of 3049 ng day/mL with the microdevice vs. 2118 ng-day/mL with IP bolus injections). This preclinical study supports the concept that reduced toxicity with similar efficacy outcomes can be achieved by continuous dosing in ovarian cancer patients currently treated with IP therapy.

Studying changes in the incidence, diagnosis and management of GTD: the South Korean model.

OBJECTIVE: To evaluate the changing epidemiologic picture and clinical characteristics of gestational trophoblastic disease (GTD) in South Korea over the past 5 decades. STUDY DESIGN: Patient data were collected from 37 hospitals nationwide, the Korean Research Institute of Trophoblastic Disease registry and CHA University Comprehensive Gynecologic Cancer Center from the years of 1970s through the year 2002. Demographic data, pretreatment evaluation, treatment modality, chemotherapeutic regimen and their results according to the clinical International Federation of Gynecology and Obstetrics classification and World Health Organization prognostic score were analyzed. Management of high-risk gestational trophoblastic tumor (GTT) was reviewed in depth. RESULTS: The nationwide incidence of hydatidiform mole and GTT dropped from 40.0 per 1,000 deliveries and 5.0 per 1,000 deliveries, respectively, in the 1970s to 2.0 per 1,000 deliveries and 0.5 per 1,000 deliveries, respectively, in the 1990s. The rate of decline was slower in 2000-2002. Significant changes were also noted in age distribution, interval between the preceding pregnancy and disease, gravidity and parity, and distribution of low- and high-risk groups of GTT. CONCLUSION: The dramatic improvement in GTD over the past 5 decades in South Korea can be attributed to the following factors: refinement in terminology and classification, advances in pretreatment evaluation, development of effective chemotherapeutic agents, application of multimodal treatment and novel chemoagents for high-risk GTT.

Successful use of magnetic resonance-guided focused ultrasound surgery to relieve symptoms in a patient with symptomatic focal adenomyosis.

OBJECTIVE: To report a successful treatment of symptomatic adenomyosis using magnetic resonance-guided focused ultrasound surgery (MRgFUS). DESIGN: Case study. SETTING: General hospital. PATIENT(S): A 47-year-old premenopausal woman with focal symptomatic adenomyosis. INTERVENTION(S): MRgFUS. MAIN OUTCOME MEASURE(S): Score on the Uterine Fibroids Symptoms Quality of Life (UFS-QOL) questionnaire and the degree of menstrual pain. RESULT(S): Uterine Fibroids Symptoms reduced from 53 to 28 and the degree of menstrual pain reduced from 10 to 5. CONCLUSION(S): For adenomyosis patients who wish to preserve their uterus, MRgFUS may be a promising alternative to hysterectomy. Additional studies of the safety and efficacy of MRgFUS in this indication should be conducted.