Use of a multi-drug regimen gemcitabine, 5-fluorouracil, irinotecan, cisplatin, bevacizumab, docetaxel, and cyclophosphamide (GFIP/BDC) for heavily pretreated relapsed epithelial ovarian, fallopian tube and primary peritoneal cancer.

BACKGROUND: Epithelial ovarian cancer has the highest fatality rate of all gynecologic malignancies. Although the majority of patients achieve complete clinical response after initial cytoreductive surgery and platinum-based chemotherapy, most recur and almost all will eventually acquire platinum-resistance for which treatment options become limited. The objective of the study was to describe response and tolerability of metronomic chemotherapy regimen GFIP/BDC, a modification of the G-FLIP regimen, in patients with persistent or recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer. METHODS: A retrospective descriptive analysis of 20 patients from a single academic institution who received combination GFIP/BDC therapy from January 1, 2011 to August 31, 2016 for persistent or recurrent EOC/FT/PP. Treatment consisted of a 2-day combination of gemcitabine 300 mg, 5-fluorouracil 500 mg/m2, irinotecan 20-30 mg/m2, cisplatin 20 mg/m2, bevacizumab 4 mg/kg, docetaxel 20 mg/m2, and cyclophosphamide 200 mg/m2 administered every 14 days. Toxicities were retrospectively graded using CTCAE v4.0. RESULTS: Twenty patients were identified with a median age 57.5 years (range 32-71). A total of 85% of patients were non-Hispanic white, 90% had cancer of high-grade serous histology, and all had a GOG performance status of 0-1. Patients had received a median of 3 prior regimens and 95% were platinum-resistant. Median number of cycles of GFIP/BDC administered was 9 (range 3-48) and patients remained on treatment for a median of 5.1 months (range 1.5-24). Eleven patients (55%) experienced a partial clinical response with a median duration of 6 months (range 1.5-20). Six patients (30%) survived progression free for at least 6 months. Ten patients (50%) experienced at least one grade 3/4 adverse event. Grade 3 adverse events were hematologic (n = 5), constitutional (n = 3), gastrointestinal (n = 3), neurologic (n = 2), and vascular (n = 1). There was only one grade 4 adverse event which was severe neutropenia. Patients discontinued treatment due to disease progression 65% (n = 13), toxicity 20% (n = 4), patient preference 10% (n = 2), and 5% (n = 1) is currently on treatment. CONCLUSIONS: Selected patients with epithelial ovarian, fallopian tube or primary peritoneal cancer who have failed multiple lines of conventional cytotoxic treatment may benefit from GFIP/BDC. Toxicity might be a limiting factor for administration.

Primary breast cancer of the vulva with concurrent breast and endometrial cancers: A case report and literature review.

•Breast cancer originating from the vulva is extremely rare.•There are no guidelines for the treatment of such cancers.•More research is needed to uncover a possible genetic predisposition.

Hysterectomy at the time of risk-reducing surgery in BRCA carriers.

In this study, women at risk for BRCA were surveyed to understand their choice of prophylactic surgery and associated risk of uterine cancers. The study was conducted as an anonymous online web-based survey that assessed personal and family histories and choice of prophylactic surgery. Respondents were targeted through social media groups that bring awareness to hereditary breast and ovarian cancer. The study cohort included an international group of 601 respondents. The majority were female (99.3%), in their 40s (34.2%), and had completed college or graduate school (68.8%). 87% of respondents carry BRCA gene mutation. Of 339 respondents who underwent risk-reducing salpingo-oophorectomy (RRSO), 55.8% had a hysterectomy at time of RRSO. Most common reasons for hysterectomy at time of RRSO included: 39% provider recommendation, 27.6% personal desire, 9.7% benign indications, 1.6% cancer in uterus, 1.1% precancerous uterine lesion, and 21.1% other (N = 185). In this cohort, nine were diagnosed with uterine cancer. Three were diagnosed after risk-reducing surgery. Both patients with uterine serous carcinoma were BRCA1 carriers. Two thirds of BRCA carriers surveyed had undergone RRSO. Of these, more than half had hysterectomy at time of RRSO. One third chose to have hysterectomy based on surgeon recommendation. <1% (2 out of 258) of BRCA1 gene mutation carriers reported being diagnosed with uterine serous carcinomas. While this incidence is low, it may be an underestimate based on the limitations of this study. Additional studies are needed to select which patients will benefit from concurrent hysterectomy and RRSO.

Feasibility and diagnostic performance of hybrid PET/MRI compared with PET/CT for gynecological malignancies: a prospective pilot study.

PURPOSE: The purpose of the study was to assess the feasibility and diagnostic performance of FDG-PET/MR imaging compared to PET/CT for staging of patients with a gynecological malignancy. METHODS: 25 patients with a gynecological malignancy were prospectively enrolled into this pilot study. Patients underwent sequential full-body PET/CT and PET/MR of the abdomen and pelvis after administration of a single dose of F-18 FDG. PET/MRI and PET/CT images were independently reviewed by two expert radiologists. Readers were blinded to the results of the other imaging procedures. Clinical and pathologic information was abstracted from medical charts. RESULTS: 18 patients were included in the final analysis with a median age of 62 years (range 31-88). 61% of patients (11/18) had cervical cancer, while the remaining patients had endometrial cancer. PET/MRI as compared to PET/CT detected all primary tumors, 7/7 patients with regional lymph nodes, and 1/1 patient with an abdominal metastasis. Two patients had additional lymph nodes outside of the abdominopelvic cavity detected on PET/CT that were not seen on PET/MRI, whereas 6 patients had parametrial invasion and one patient had invasion of the bladder seen on PET/MRI not detected on PET/CT. Five cervical cancer patients had discordant clinical vs. radiographic staging based on PET/MRI detection of soft tissue involvement. Management changed for two patients who had clinical stage IB1 and radiographic stage IIB cervical cancer. CONCLUSIONS: PET/MRI is feasible and has at least comparable diagnostic ability to PET/CT for identification of primary cervical and endometrial tumors and regional metastases. PET/MRI may be superior to PET/CT for initial radiographic assessment of cervical cancers.

Applying Precision Medicine to Ovarian Cancer: Proof-of-Principle for a "Molecular Second Look".

OBJECTIVES: The objectives of this study were to assess if targeted investigation for tumor-specific mutations by ultradeep DNA sequencing of peritoneal washes of ovarian cancer patients after primary surgical debulking and chemotherapy, and clinically diagnosed as disease free, provides a more sensitive and specific method to assess actual treatment response and tailor future therapy and to compare this "molecular second look" with conventional cytology and histopathology-based findings. METHODS/MATERIALS: We identified 10 patients with advanced-stage, high-grade serous ovarian cancer who had undergone second-look laparoscopy and for whom DNA could be isolated from biobanked paired blood, primary and recurrent tumor, and second-look peritoneal washes. A targeted 56 gene cancer-relevant panel was used for next-generation sequencing (average coverage, >6500×). Mutations were validated using either digital droplet polymerase chain reaction (ddPCR) or Sanger sequencing. RESULTS: A total of 25 tumor-specific mutations were identified (median, 2/patient; range, 1-8). TP53 mutations were identified in at least 1 sample from all patients. All 5 pathology-based second-look positive patients were confirmed positive by molecular second look. Genetic analysis revealed that 3 of the 5 pathology-based negative second looks were actually positive. In the 2 patients, the second-look mutations were present in either the original primary or recurrent tumors. In the third, 2 high-frequency, novel frameshift mutations in MSH6 and HNF1A were identified. CONCLUSIONS: The molecular second look detects tumor-specific evidence of residual disease and provides genetic insight into tumor evolution and future recurrences beyond standard pathology. In the precision medicine era, detecting and genetically characterizing residual disease after standard treatment will be invaluable for improving patient outcomes.

Multi-site N-Glycan mapping study 2: UHPLC.

In the first part of this publication, the results from an international study evaluating the precision (i.e., repeatability and reproducibility) of N-glycosylation analysis using capillary electrophoresis of APTS-labeled N-glycans were presented. The corresponding results from ultra-high performance liquid chromatography (UHPLC) with fluorescence detection are presented here from 12 participating sites. All participants used the same lot of samples, reagents, and columns to perform the assays. Elution time, peak area and peak area percent values were determined for all peaks ≥0.1% peak area, and statistical analysis was performed following ISO 5725-2 guideline principles. The results demonstrated adequate reproducibility, within any given site as well across all sites, indicating that standard UHPLC-based N-glycan analysis platforms are appropriate for general use.

Laparoscopic surgery for gynecologic cancer in low- and middle-income countries (LMICs): An area of need.

Over 90% of people living in low- and middle-income countries (LMICs) do not have access to surgical care. In the absence of appropriate surgical care, there is high morbidity and mortality from surgically curable diseases, such as cervical cancer. Laparoscopic surgery for gynecologic cancer in LMICs is extremely limited. The benefits of laparoscopy over open surgery are even more pronounced in LMICs than in resource-rich countries. Barriers to implementation of laparoscopic surgery in LMICs should be identified and addressed in order to improve global cancer care and the lives of women worldwide.

Cervical cancer screening and treatment in Uganda.

Cervical cancer is the leading cause of cancer death among women in Uganda. Given the high prevalence of genital human papillomavirus infection, the current unavailability of radiotherapy, and the absence of a national cervical cancer prevention and control program, these deaths will likely increase. Efforts to organize an effective cervical cancer screening and treatment program will require adequate financial resources, the development of infrastructure, training needed manpower, and surveillance mechanisms of the targeted women. Screening with VIA (visual inspection with acetic acid) and HPV DNA testing on self-collected samples with processing at a specific site could, for the first time, make national, large-scale population-based screening feasible in Uganda. Combining screening efforts with timely treatment of all screen positives for HPV infection can prevent progression to invasive cervical cancer. To date, this is the most effective intervention in closing the current prevention gap. Training of health professionals, ongoing construction of new radiotherapy bunkers, and opening of regional centers are all geared towards improving cervical cancer care in Uganda. The Uganda Cancer Institute Bill establishes the Institute as a semi-autonomous agency mandated to undertake and coordinate the prevention and treatment of cancer. Its implementation will be a milestone in cervical cancer prevention and control. However, execution will require political will and an increase in domestic and international investment.

Spontaneous Rupture of a Leiomyoma Causing Life-Threatening Intra-Abdominal Hemorrhage.

Background. Uterine fibroids are common benign tumors in women. Clinical manifestations are well known. Acute complications necessitating emergent surgical intervention are rare. Case. We report a case of a 53-year-old woman with a history of uterine fibroids presenting with acute-onset severe abdominal pain. Imaging indicated massive free fluid and a large partially solid uterine mass. Vitals were consistent with hypovolemic shock. Examination revealed a surgical abdomen. She underwent an emergent laparotomy and total hysterectomy. Surgery revealed 4.5 L of hemoperitoneum and a 15 cm degenerated uterine fibroid with active bleeding. Pathology was consistent with intraoperative findings. She required transfusion of numerous blood products perioperatively. Her postoperative course was uncomplicated. Conclusion. It is rare for a uterine fibroid to spontaneously rupture. However, prompt recognition of this severe complication is critical for expeditious, life-saving surgical management.

Retreatment with aromatase inhibitor therapy in the management of granulosa cell tumor.

•Over 90% of granulosa cell tumors have a FOXL2 mutation that contributes to aromatase upregulation.•Chemotherapy has demonstrated limited efficacy in the treatment of granulosa cell tumors.•A patient with recurrent granulosa cell tumor responded briefly to anastrazole treatment.•Retreatment with another aromatase inhibitor letrozole led to a durable response of 24 months.

Multi-Site N-glycan mapping study 1: Capillary electrophoresis - laser induced fluorescence.

An international team that included 20 independent laboratories from biopharmaceutical companies, universities, analytical contract laboratories and national authorities in the United States, Europe and Asia was formed to evaluate the reproducibility of sample preparation and analysis of N-glycans using capillary electrophoresis of 8-aminopyrene-1,3,6-trisulfonic acid (APTS)-labeled glycans with laser induced fluorescence (CE-LIF) detection (16 sites) and ultra high-performance liquid chromatography (UHPLC, 12 sites; results to be reported in a subsequent publication). All participants used the same lot of chemicals, samples, reagents, and columns/capillaries to run their assays. Migration time, peak area and peak area percent values were determined for all peaks with >0.1% peak area. Our results demonstrated low variability and high reproducibility, both, within any given site as well across all sites, which indicates that a standard N-glycan analysis platform appropriate for general use (clone selection, process development, lot release, etc.) within the industry can be established.

Metrics of the gynecologic oncology literature focused on cited utilization and costs.

OBJECTIVE: The newest findings on literature utilization relevant to gynecologic oncology were published by Thomson Reuters during June 2013 as determinants of journal standing. Our objective was to assess the different metrics reported for relative impact and cost for journals relevant to gynecologic oncology. METHODS: 55 journals were evaluated for Impact Factor (IF), 5 Year IF, Immediacy Index, Cited Half Life, Eigenfactor (EF) Score, Article Influence (AI) scores and subscription costs obtained from publisher information. RESULTS: CA-A Cancer Journal for Clinicians had the highest IF (101.78) & AI (24.502). The top EF cancer-specific journals were the Journal of Clinical Oncology, Cancer Research, Clinical Cancer Research and Oncogene. Rankings for Gynecologic Oncology (409 articles, 18,243 citations) were IF = 3.929, 43/55, EF = 0.038, 28/55, and AI = 1.099, 44/55, all higher than the previous year. The IF improved from the 5 year IF in 31 journals, including Gynecologic Oncology, 29/31. Subscription costs for Gynecologic Oncology compared favorably to other journals. CONCLUSIONS: The high utilization of review information in CA-A Cancer Journal for Clinicians and Nature Review Cancer illustrated by the IF coupled with a relatively low number of articles and short cited half life indicates that they serve as a leading source of quoted cancer statistics (CA-A Cancer Journal for Clinicians). Rankings for Gynecologic Oncology and the International Journal of Gynecologic Cancer have improved. Regardless of specialty size, the Impact Factor for Gynecologic Oncology is respectably strong. The decreased IF in 44% of the journals may reflect the international economy's effect on cancer research.

New media simulation stories in nursing education: a quasi-experimental study exploring learning outcomes.

New media simulation stories are short multimedia presentations that combine simulation, digital technology, and story branching to depict a variety of healthcare-related scenarios. The purpose of this study was to explore whether learning outcomes were enhanced if students viewed the results of both correct and incorrect nursing actions demonstrated through new media simulation stories. A convenience sample of 109 undergraduate nursing students in a family-centered maternity course participated in the study. Study findings suggests that students who viewed both correct and incorrect depictions of maternity nursing actions scored better on tests than did those students who viewed only correct nursing actions.

Storytelling in the digital world: achieving higher-level learning objectives.

Nursing students are not passive media consumers but instead live in a technology ecosystem where digital is the language they speak. To prepare the next generation of nurses, educators must incorporate multiple technologies to improve higher-order learning. The author discusses the evolution and use of storytelling as part of the digital world and how digital stories can be aligned with Bloom's Taxonomy so that students achieve higher-level learning objectives.

Development and validation of a chronic copper biotic ligand model for Ceriodaphnia dubia.

A biotic ligand model (BLM) to predict chronic Cu toxicity to Ceriodaphnia dubia was developed and tested. The effect of cationic competition, pH and natural organic matter complexation of Cu was examined to develop the model. There was no effect of cationic competition using increasing Ca and Na concentrations in our exposures. However, we did see a significant regression of decreasing toxicity (measured as the IC25; concentration at which there was a 25% inhibition of reproduction) as Mg concentration increased. However, taking into account the actual variability of the IC25 and since the relative increase in IC25 due to additional Mg was small (1.5-fold) Mg competition was not included in the model. Changes in pH had a significant effect on Cu IC25, which is consistent with proton competition as often suggested for acute BLMs. Finally, natural organic matter (NOM) was added to exposures resulting in significant decreases in toxicity. Therefore, our predictive model for chronic Cu toxicity to C. dubia includes the effect of pH and NOM complexation. The model was validated with Cu IC25 data generated in six natural surface waters collected from across Canada. Using WHAM VI, we calculated Cu speciation in each natural water and using our model, we generated "predicted" IC25 data. We successfully predicted all Cu IC25 within a factor of 3 for the six waters used for validation.

Craving and control: methamphetamine users' narratives.

In this article the authors explore the experience of craving of methamphetamine users and seek to illuminate how differences in craving contribute to use patterns. Using in-depth interviewing, data were collected from 82 active methamphetamine users in the metropolitan Atlanta area. The constant comparison method common in grounded theory guided the data analysis. Narrative responses corresponded with three types of craving described in the literature: cue-, drug- and withdrawal-induced. However, the narratives also problematize this typological view as well as the characterization of craving as invariably leading to drug use. Types of craving cues were sometimes inseparable, and users indicated that the different types of craving could occur in the same situation. Further, many users described being able to overcome craving through personalized methods of control. This study complements the largely quantitative work on craving and highlights the importance of improving drug abuse treatment and harm reduction programs.

Influence of natural organic matter source on acute copper, lead, and cadmium toxicity to rainbow trout (Oncorhynchus mykiss).

Natural organic matter (NOM) was concentrated from various sites across Canada using a portable reverse-osmosis unit to obtain a range of NOM types, from mainly allochthonous (terrestrially derived) to mainly autochthonous (aquatically derived) NOM. The addition of NOM to Cu exposures in ion-poor water always decreased Cu toxicity to rainbow trout (Oncorhynchus mykiss, approximately 1 g) over a 96-h period, and the degree of protection varied with respect to NOM source. A good correlation was found between the specific absorbance coefficient (SAC) and time to reach 50% mortality (LT50; p < 0.001), indicating that more optically dark, allochthonous-like NOM decreases Cu toxicity better than does optically light, more autochthonous-like NOM. A similar, good relationship between NOM source and Pb toxicity was seen (p < 0.001), once confounding effects of Ca binding to NOM were accounted for. No significant relationship between Cd toxicity and NOM optical quality was seen (p = 0.082), and in toxicity tests with Cd the presence of some of the NOM sources increased Cd toxicity compared to Cd-only controls. Specific absorbance coefficients were used as a proxy measurement of NOM aromaticity in our study, and fluorescence indices were run on some NOM samples to obtain percent aromaticity for each sample. A good correlation was found between SAC and percent aromaticity, indicating that the simple SAC measurement is a reasonable indication of NOM aromaticity and of metal binding by NOM.

A lead-gill binding model to predict acute lead toxicity to rainbow trout (Oncorhynchus mykiss).

Rainbow trout (Oncorhynchus mykiss, approximately 2 g) were exposed to 0.6-1.0 microM Pb (125-200 microgl(-1)) for 3 h in ion-poor water. Complexing ligands (citrate, ethylenediamine, organic matter (OM)) or competing cations (Ca, Mg, Na) were added to the water. After exposure, trout gills were removed and analyzed for accumulated Pb. From these exposures, a conditional equilibrium binding constant (K) for Pb-gill binding was calculated (log K(Pb-gillPb)=6.0), plus conditional binding constants for cationic competition at the Pb binding sites and for Pb binding to OM in the water. These log K values were entered into the MINEQL+ aquatic chemistry equilibrium program, to calculate binding of Pb by trout gills. Two versions of the Pb-gill binding model were generated, one of which took into account OM quality as indicated by a simple measure of OM aromaticity, the specific absorption coefficient. The two model versions were tested against acute Pb toxicity (as the time to reach 50% fish mortality; LT50) during 1-week exposures of trout to 3.9 microM Pb in water collected from across southern Ontario. Both versions of the model generated highly significant correlations between the LT50 values and gill Pb concentrations calculated from measured exposure water chemistry, with the OM quality version correlating slightly better. Water pH also correlated well with the LT50 values, because the Pb exposures were in the pH range (7-8) where there is a nearly linear relationship between water pH and inorganic complexation of Pb. Advantages of the Pb-gill binding model include its completeness and the flexibility inherent in its conceptual framework, for example the inclusion of competition by Ca and H(+) for Pb binding sites on gills, and inclusion of complexation of Pb in the water column by natural OM and by carbonate.