Hypoxia-Inducible Expression of Annexin A6 Enhances the Resistance of Triple-Negative Breast Cancer Cells to EGFR and AR Antagonists.

Physiological changes such as hypoxia in the tumor microenvironment (TME) endow cancer cells with malignant properties, leading to tumor recurrence and rapid progression. Here, we assessed the effect of hypoxia (1% Oxygen) on the tumor suppressor Annexin A6 (AnxA6) and the response of triple-negative breast cancer (TNBC) cells to epidermal growth factor receptor (EGFR) and androgen receptor (AR) targeted therapies. We demonstrate that brief exposure of TNBC cells to hypoxia (within 24 h) is associated with down regulation of AnxA6 while > 24 h exposure cell type dependently stimulated the expression of AnxA6. Hypoxia depicted by the expression and stability of HIF-1/2α led to up regulation of the HIF target genes SLC2A1, PGK1 as well as AR and the AR target genes FABP-4 and PPAR-γ, but the cellular levels of AnxA6 protein decreased under prolonged hypoxia. Down regulation of AnxA6 in TNBC cells inhibited, while AnxA6 over expression enhanced the expression and cellular levels of HIF-1/2α, SLC2A1 and PGK1. RNAi mediated inhibition of hypoxia induced AnxA6 expression also strongly inhibited glucose uptake and ROS production in AnxA6 expressing TNBC cells. Using a luciferase reporter assay, we confirm that short-term exposure of cells to hypoxia inhibits while prolonged exposure of cells to hypoxia enhances AnxA6 promoter activity in HEK293T cells. Compared to cells cultured under normoxia, TNBC cells were more resistant to lapatinib under hypoxic conditions, and the downregulation of AnxA6 sensitized the cells to EGFR as well as AR antagonists. These data suggest that AnxA6 is a hypoxia inducible gene and that targeting AnxA6 upregulation may be beneficial in overcoming TNBC resistance to EGFR and/or AR targeted therapies.

Identification of MAGEC2/CT10 as a High Calcium-Inducible Gene in Triple-Negative Breast Cancer.

The expression of the melanoma/cancer-testis antigen MAGEC2/CT10 is restricted to germline cells, but like most cancer-testis antigens, it is frequently upregulated in advanced breast tumors and other malignant tumors. However, the physiological cues that trigger the expression of this gene during malignancy remain unknown. Given that malignant breast cancer is often associated with skeletal metastasis and co-morbidities such as cancer-induced hypercalcemia, we evaluated the effect of high Ca2+ on the calcium-sensing receptor (CaSR) and potential mechanisms underlying the survival of triple-negative breast cancer (TNBC) cells at high Ca2+. We show that chronic exposure of TNBC cells to high Ca2+ decreased the sensitivity of CaSR to Ca2+ but stimulated tumor cell growth and migration. Furthermore, high extracellular Ca2+ also stimulated the expression of early response genes such as FOS/FOSB and a unique set of genes associated with malignant tumors, including MAGEC2. We further show that the MAGEC2 proximal promoter is Ca2+ inducible and that FOS/FOSB binds to this promoter in a Ca2+- dependent manner. Finally, downregulation of MAGEC2 strongly inhibited the growth of TNBC cells in vitro. These data suggest for the first time that MAGEC2 is a high Ca2+ inducible gene and that aberrant expression of MAGEC2 in malignant TNBC tissues is at least in part mediated by an increase in circulating Ca2+via the AP-1 transcription factor.

Reduced Expression of Annexin A6 Induces Metabolic Reprogramming That Favors Rapid Fatty Acid Oxidation in Triple-Negative Breast Cancer Cells.

The ability of cancer cells to alter their metabolism is one of the major mechanisms underlying rapid tumor progression and/or therapeutic resistance in solid tumors, including the hard-to-treat triple-negative breast cancer (TNBC) subtype. Here, we assessed the contribution of the tumor suppressor, Annexin A6 (AnxA6), in the metabolic adaptation of basal-like (AnxA6-low) versus mesenchymal-like (AnxA6-high), as well as in lapatinib-resistant TNBC cells. Using model basal-like and mesenchymal-like TNBC cell lines, we show that TNBC cells also exhibit metabolic heterogeneity. The downregulation of AnxA6 in TNBC cells generally attenuated mitochondrial respiration, glycolytic flux, and cellular ATP production capacity resulting in a quiescent metabolic phenotype. We also show that AnxA6 depletion in mesenchymal-like TNBC cells was associated with a rapid uptake and mitochondrial fatty acid oxidation and diminished lipid droplet accumulation and altered the lipogenic metabolic phenotype of these cells to a lypolytic metabolic phenotype. The overexpression or chronic lapatinib-induced upregulation of AnxA6 in AnxA6-low TNBC cells reversed the quiescent/lypolytic phenotype to a more lipogenic/glycolytic phenotype with gluconeogenic precursors as additional metabolites. Collectively, these data suggest that the expression status of AnxA6 in TNBC cells underlies distinct metabolic adaptations of basal-like and mesenchymal-like TNBC subsets in response to cellular stress and/or therapeutic intervention and suggest AnxA6 as a biomarker for metabolic subtyping of TNBC subsets.

Key event-informed risk models for benzene-induced acute myeloid leukaemia.

Occupational exposure to benzene at levels of 10 ppm or more has been associated with increased risk of acute myeloid leukaemia (AML). The mode of action (MOA) for AML development leading to mortality is anticipated to include multiple earlier key events, which can be observed in hematotoxicity and genetic toxicity in peripheral blood of exposed workers. Prevention of these early events would lead to prevention of the apical, adverse outcomes, the morbidity and mortality caused by the myelodysplastic syndromes (MDS) and AML. Incorporation of key event information should modify the risk model, but few modification approaches have been suggested. To that end, two approaches to risk model modification are described that use sub-linear and segmented linear increases in risk below key events, while maintaining a linear increase in AML mortality risk beginning at 2 ppm, the lowest observed adverse effect concentration (LOAEC) identified for hemato- and geno- toxicity in high quality studies of human occupational exposure. Below 2 ppm two different modification approaches to quantitative risk models were applied: a continuously decreasing slope model and a segmented modification in slope. These two approaches provide greater flexibility to incorporate MOA information in risk model development and selection.

The rapid endocytic uptake of fetuin-A by adherent tumor cells is mediated by Toll-like receptor 4 (TLR4).

Fetuin-A is a serum glycoprotein synthesized and secreted into blood by the liver and whose main physiological function is the inhibition of ectopic calcification. However, a number of studies have demonstrated that it is a multifunctional protein. For example, endocytic uptake of fetuin-A by tumor cells resulting in rapid cellular adhesion and spreading has been reported. The precise uptake mechanism, however, has been elusive. The present studies were done to determine whether Toll-like receptor-4 (TLR4), which has been previously shown to be a receptor for fetuin-A and is commonly expressed in immune cells, could take part in the rapid uptake (< 3 min) of fetuin-A by tumor cells. Rapid uptake of fetuin-A was inhibited by the specific TLR4 inhibitor CLI-095 and also attenuated in TLR4 knockdown prostate tumor cells. Inhibition of TLR4 by CLI-095 also attenuated the rapid adhesion of tumor cells as well as invasion through a bed of Matrigel. The data suggest mechanisms by which TLR4 modulates the adhesion and growth of tumor cells.

Modes of action considerations in threshold expectations for health effects of benzene.

Understanding the Mode of Action (MOA) for a chemical can help guide decisions in development of Occupational Exposure Limits (OELs). Where sufficient information exists, it can provide the OEL developer the basis for selecting either a health-based or risk-based approach. To support the development of an OEL for benzene, scientific information relevant to MOA assessment for risk-based and health-based OEL approaches was reviewed. Direct-acting mutagenicity was considered as a basis for a risk-based OEL, versus MOAs consistent with a health-based approach: indirect mutagenicity via topoisomerase II inhibition, indirect mutagenicity via reactive oxygen species generation, or an immune-based bone marrow dysfunction. Based on the evidence against direct DNA reactivity, threshold expectations for remaining MOAs, and evidence for dose rate affecting acute myeloid leukemia and myelodysplastic syndrome risk, the weight of evidence favors a health-based OEL approach. In the case of benzene, development of an OEL based on observations of earlier key events (i.e., hematologic changes and genetic toxicity) is anticipated to provide protection from later adverse outcomes such as leukemia.

Diverse Roles of Annexin A6 in Triple-Negative Breast Cancer Diagnosis, Prognosis and EGFR-Targeted Therapies.

The calcium (Ca2+)-dependent membrane-binding Annexin A6 (AnxA6), is a multifunctional, predominantly intracellular scaffolding protein, now known to play relevant roles in different cancer types through diverse, often cell-type-specific mechanisms. AnxA6 is differentially expressed in various stages/subtypes of several cancers, and its expression in certain tumor cells is also induced by a variety of pharmacological drugs. Together with the secretion of AnxA6 as a component of extracellular vesicles, this suggests that AnxA6 mediates distinct tumor progression patterns via extracellular and/or intracellular activities. Although it lacks enzymatic activity, some of the AnxA6-mediated functions involving membrane, nucleotide and cholesterol binding as well as the scaffolding of specific proteins or multifactorial protein complexes, suggest its potential utility in the diagnosis, prognosis and therapeutic strategies for various cancers. In breast cancer, the low AnxA6 expression levels in the more aggressive basal-like triple-negative breast cancer (TNBC) subtype correlate with its tumor suppressor activity and the poor overall survival of basal-like TNBC patients. In this review, we highlight the potential tumor suppressor function of AnxA6 in TNBC progression and metastasis, the relevance of AnxA6 in the diagnosis and prognosis of several cancers and discuss the concept of therapy-induced expression of AnxA6 as a novel mechanism for acquired resistance of TNBC to tyrosine kinase inhibitors.

Derivation of an occupational exposure limit for benzene using epidemiological study quality assessment tools.

This paper derives an occupational exposure limit for benzene using quality assessed data. Seventy-seven genotoxicity and 36 haematotoxicity studies in workers were scored for study quality with an adapted tool based on that of Vlaanderen et al., 2008 (Environ Health. Perspect. 116 1700-5). These endpoints were selected as they are the most sensitive and relevant to the proposed mode of action (MOA) and protecting against these will protect against benzene carcinogenicity. Lowest and No- Adverse Effect Concentrations (LOAECs and NOAECs) were derived from the highest quality studies (i.e. those ranked in the top tertile or top half) and further assessed as being "more certain" or "less certain". Several sensitivity analyses were conducted to assess whether alternative "high quality" constructs affected conclusions. The lowest haematotoxicity LOAECs showed effects near 2 ppm (8 h TWA), and no effects at 0.59 ppm. For genotoxicity, studies also showed effects near 2 ppm and showed no effects at about 0.69 ppm. Several sensitivity analyses supported these observations. These data define a benzene LOAEC of 2 ppm (8 h TWA) and a NOAEC of 0.5 ppm (8 h TWA). Allowing for possible subclinical effects in bone marrow not apparent in studies of peripheral blood endpoints, an OEL of 0.25 ppm (8 h TWA) is proposed.

Reciprocal expression of Annexin A6 and RasGRF2 discriminates rapidly growing from invasive triple negative breast cancer subsets.

Actively growing tumors are often histologically associated with Ki67 positivity, while the detection of invasiveness relies on non-quantitative pathologic evaluation of mostly advanced tumors. We recently reported that reduced expression of the Ca2+-dependent membrane-binding annexin A6 (AnxA6) is associated with increased expression of the Ca2+ activated RasGRF2 (GRF2), and that the expression status of these proteins inversely influence the growth and motility of triple negative breast cancer (TNBC) cells. Here, we establish that the reciprocal expression of AnxA6 and GRF2 is at least in part, dependent on inhibition of non-selective Ca2+ channels in AnxA6-low but not AnxA6-high TNBC cells. Immunohistochemical staining of breast cancer tissues revealed that compared to non-TNBC tumors, TNBC tumors express lower levels of AnxA6 and higher Ki67 expression. GRF2 expression levels strongly correlated with high Ki67 in pretreatment biopsies from patients with residual disease and with residual tumor size following chemotherapy. Elevated AnxA6 expression more reliably identified patients who responded to chemotherapy, while low AnxA6 levels were significantly associated with shorter distant relapse-free survival. Finally, the reciprocal expression of AnxA6 and GRF2 can delineate GRF2-low/AnxA6-high invasive from GRF2-high/AnxA6-low rapidly growing TNBCs. These data suggest that AnxA6 may be a reliable biomarker for distant relapse-free survival and response of TNBC patients to chemotherapy, and that the reciprocal expression of AnxA6 and GRF2 can reliably delineate TNBCs into rapidly growing and invasive subsets which may be more relevant for subset-specific therapeutic interventions.

Implication of calcium activated RasGRF2 in Annexin A6-mediated breast tumor cell growth and motility.

The role of AnxA6 in breast cancer and in particular, the mechanisms underlying its contribution to tumor cell growth and/or motility remain poorly understood. In this study, we established the tumor suppressor function of AnxA6 in triple negative breast cancer (TNBC) cells by showing that loss of AnxA6 is associated with early onset and rapid growth of xenograft TNBC tumors in mice. We also identified the Ca2+ activated RasGRF2 as an effector of AnxA6 mediated TNBC cell growth and motility. Activation of Ca2+ mobilizing oncogenic receptors such as epidermal growth factor receptor (EGFR) in TNBC cells or pharmacological stimulation of Ca2+ influx led to activation, subsequent degradation and altered effector functions of RasGRF2. Inhibition of Ca2+ influx or overexpression of AnxA6 blocked the activation/degradation of RasGRF2. We also show that AnxA6 acts as a scaffold for RasGRF2 and Ras proteins and that its interaction with RasGRF2 is modulated by GTP and/or activation of Ras proteins. Meanwhile, down-regulation of RasGRF2 and treatment of cells with the EGFR-targeted tyrosine kinase inhibitor (TKI) lapatinib strongly attenuated the growth of otherwise EGFR-TKI resistant AnxA6 high TNBC cells. These data not only suggest that AnxA6 modulated Ca2+ influx and effector functions of RasGRF2 underlie at least in part, the AnxA6 mediated TNBC cell growth and/or motility, but also provide a rationale to target Ras-driven TNBC with EGFR targeted therapies in combination with inhibition of RasGRF2.

Phase 2 Study of Weekly Paclitaxel Plus Estramustine in Metastatic Hormone-Refractory Prostate Carcinoma: ECOG-ACRIN Cancer Research Group (E1898) Trial.

INTRODUCTION: This multicenter phase 2 study assessed the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: We enrolled 77 patients who had received no prior chemotherapy for CRPC between 1998 and 2000; a total of 74 subjects were eligible for the study. Each 8-week cycle included paclitaxel 90 mg/m2 provided intravenously weekly for 6 weeks, followed by 2 weeks off therapy and oral estramustine 280 mg twice daily for 3 days beginning 24 hours before the first dose of paclitaxel. The primary end point was rate of objective or prostate-specific antigen (PSA) response at 16 weeks. A 50% response rate was considered of further interest. RESULTS: Eligible patients received a median of 3 cycles (range, 1-10 cycles). The response rate among patients with measurable disease was 34% (95% confidence interval [CI], 19-52). The PSA response rate was 58% (95% CI, 47-70). Clinical benefit rate was 45% (95% CI, 33-57). The median progression-free survival was 5.9 months (95% CI, 4.4-6.7). The median overall survival was 17.6 months (95% CI, 14.6-20.8). The most common clinical grade 3/4 toxicities were fatigue (14%) and sensory neuropathy (7%). Grade 3/4 hematologic toxicities included lymphopenia (21%) and anemia (9%). There was one toxicity-related death. Quality-of-life scores improved by week 8, but the change was not statistically significant. CONCLUSION: The combination has activity defined by PSA declines in CRPC but did not meet the protocol-specified end point for efficacy as defined by objective response rate. Since this study was conducted, more effective, better-tolerated regimens have been developed.

Quantitative Infrared Absorption Spectra and Vibrational Assignments of Crotonaldehyde and Methyl Vinyl Ketone Using Gas-Phase Mid-Infrared, Far-Infrared, and Liquid Raman Spectra: s-cis vs s-trans Composition Confirmed via Temperature Studies and ab Initio Methods.

Methyl vinyl ketone (MVK) and crotonaldehyde are chemical isomers; both are also important species in tropospheric chemistry. We report quantitative vapor-phase infrared spectra of crotonaldehyde and MVK vapors over the 540-6500 cm-1 range. Vibrational assignments of all fundamental modes are made for both molecules on the basis of far- and mid-infrared vapor-phase spectra, liquid Raman spectra, along with density functional theory and ab initio MP2 and high energy-accuracy compound theoretical models (W1BD). Theoretical results indicate that at room temperature the crotonaldehyde equilibrium mixture is approximately 97% s-trans and only 3% s-cis conformer. Nearly all observed bands are thus associated with the s-trans conformer, but a few appear to be uniquely associated with the s-cis conformer, notably ν16c at 730.90 cm-1, which displays a substantial intensity increase with temperature (70% upon going from 5 to 50 o C). The intensity of the corresponding mode of the s-trans conformer decreases with temperature. Under the same conditions, the MVK equilibrium mixture is approximately 69% s-trans conformer and 31% s-cis. W1BD calculations indicate that for MVK this is one of those (rare) cases where there are comparable populations of both conformers, approximately doubling the number of observed bands and exacerbating the vibrational assignments. We uniquely assign the bands associated with both the MVK s-cis conformer as well as those of the s-trans, thus completing the vibrational analyses of both conformers from the same set of experimental spectra. Integrated band intensities are reported for both molecules along with global warming potential values. Using the quantitative IR data, potential bands for atmospheric monitoring are also discussed.

Assignment of the Fundamental Modes of Hydroxyacetone Using Gas-Phase Infrared, Far-Infrared, Raman, and ab Initio Methods: Band Strengths for Atmospheric Measurements.

Hydroxyacetone (acetol) is a simple organic molecule of interest in both the astrophysical and atmospheric communities. It has recently been observed in biomass burning events and is a known degradation product of isoprene oxidation. However, its vibrational assignment has never been fully completed, and few quantitative data are available for its detection via infrared spectroscopy. Our recent acquisition of both the pressure-broadened gas-phase data and the far-IR spectra now allow for unambiguous assignment of several (new) bands. In particular, the observed C-type bands of several fundamentals (particularly in the far-infrared) and a few combination bands demonstrate that the monomer is in a planar (Cs) conformation, at least a majority of the time. As suggested by other researchers, the monomer is a cis-cis conformer stabilized by an intramolecular O-H···O═C hydrogen bond forming a five-membered planar ring structure. Band assignments in the Cs point group are justified (at least for a good fraction of the molecules in the ensemble) by the presence of the C-type bands. The results and band assignments are well confirmed by both ab initio MP2-ccpvtz calculations and GAMESS (B3LYP) theoretical calculations. In addition, using vetted methods for quantitative measurements, we report the first IR absorption band strengths of acetol (also in electronic format) that can be used for atmospheric monitoring and other applications.

Quantitative IR spectrum and vibrational assignments for glycolaldehyde vapor: glycolaldehyde measurements in biomass burning plumes.

Glycolaldehyde (GA, 2-hydroxyethanal, C2H4O2) is a semivolatile molecule of atmospheric importance, recently proposed as a precursor in the formation of aqueous-phase secondary organic aerosol (SOA). There are few methods to measure GA vapor, but infrared spectroscopy has been used successfully. Using vetted protocols we have completed the first assignment of all fundamental vibrational modes and also derived quantitative IR absorption band strengths using both neat and pressure-broadened GA vapor. Even though GA is problematic due to its propensity to both dimerize and condense, our intensities agree well with the few previously published values. Using the ν10 band Q-branch at 860.51 cm(-1), we have also determined GA mixing ratios in biomass burning plumes generated by field and laboratory burns of fuels from the southeastern and southwestern United States, including the first IR field measurements of GA in smoke. The GA emission factors were anti-correlated with modified combustion efficiency confirming release of GA from smoldering combustion. The GA emission factors (grams of GA emitted per kilogram of biomass burned on a dry mass basis) had a low dependence on fuel type consistent with the production mechanism being pyrolysis of cellulose. GA was emitted at 0.23 ± 0.13% of CO from field fires, and we calculate that it accounts for ∼18% of the aqueous-phase SOA precursors that we were able to measure.

Quantitative infrared intensity studies of vapor-phase glyoxal, methylglyoxal, and 2,3-butanedione (diacetyl) with vibrational assignments.

Glyoxal, methylglyoxal, and 2,3-butanedione (diacetyl) are all known biomass burning effluents and suspected aerosol precursors. Pressure-broadened quantitative infrared spectra of glyoxal, methylglyoxal, and diacetyl vapors covering the 520-6500 cm(-1) range are reported at 0.112 cm(-1) resolution, each with a composite spectrum derived from a minimum of 10 different sample pressures for the compound, representing some of the first quantitative intensity data for these analytes. Many vibrational assignments for methylglyoxal are reported for the first time, as are some near-IR and far-IR bands of glyoxal and diacetyl. To complete the vibrational assignments, the far-infrared spectra (25-600 cm(-1)) of all three vapors are also reported, those of methylglyoxal for the first time. Density functional theory and ab initio MP2 theory are used to help assign vibrational modes. Potential bands for atmospheric monitoring are discussed.

The infrared spectra of Bacillus bacteria part I: vegetative Bacillus versus sporulated cells and the contributions of phospholipids to vegetative infrared spectra.

This paper highlights the distinctions between the infrared (IR) absorption spectra of vegetative versus sporulated Bacillus bacteria. It is observed that there are unique signatures clearly associated with either the sporulated or vegetative state and that vegetative cells (or cell debris) can contribute to the spore spectra. A distinct feature at approximately 1739 cm(-1) appears to be unique to vegetative cell spectra and can also be used as an indicator of vegetative cells or cell debris in the spore spectra. The data indicate that the band arises from a lipid-soluble species such as an ester or phospholipid carbonyl bond and are consistent with it being either phosphatidyl glycerol (PG) or phosphatidylethanolamine (PE), two major classes of phospholipids found in vegetative cells of Bacillus species. A companion work discusses bands associated with the sporulated state.

The infrared spectra of Bacillus bacteria part II: sporulated Bacillus--the effect of vegetative cells and contributions of calcium dipicolinate trihydrate, CaDP.3H2O.

Our previous paper showed that certain infrared (IR) peaks, e.g., the peak at 1739 cm(-1), are due to varying (trace) amounts of vegetative cells amongst the Bacillus spores and that these and other vegetative bands are associated with lipid-soluble compounds, likely an ester or phospholipid. This work investigates the infrared spectra of eight different sporulated Bacillus bacteria. For the endospores it is observed that peaks at 1441, 1277, and 1015 cm(-1) along with a distinct quartet of peaks at 766, 725, 701, and 659 cm(-1) are clearly associated with calcium dipicolinate trihydrate, CaDP.3H2O. It is emphasized that the spore peaks, especially the quartet, arise from the calcium dipicolinate trihydrate and not from dipicolinic acid or other dipicolinate hydrate salts. The CaDP.3H2O infrared peaks and the effects of hydration are studied using quantum chemistry in the PQS software package. The quartet is associated with many modes including contributions from the Ca2+ counterion and hydration waters including Ca-O-H bends, H2O-Ca-O torsions, and O-C-O bends. The 1441 and 1015 cm(-1) modes are planar pyridine modes with the 1441 cm(-1) mode primarily a ring C-N stretch and the 1015 cm(-1) mode primarily a ring C-C stretch.

Chronic physical effects and health care utilization in long-term ovarian germ cell tumor survivors: a Gynecologic Oncology Group study.

PURPOSE: This study compares late effects of treatment on physical well-being and utilization of health care resources between ovarian germ cell tumor (OGCT) survivors and age/race/education-matched controls. PATIENTS AND METHODS: Eligible patients had OGCT treated with surgery and chemotherapy and were disease-free for at least 2 years at time of enrollment. The matched control group was selected from acquaintances recommended by survivors. Symptoms and function were measured using previously validated scales. Health care utilization was assessed by questions regarding health insurance coverage and health services utilization. RESULTS: One hundred thirty-two survivors and 137 controls completed the study. Survivors were significantly more likely to report a diagnosis of hypertension (17% v 8%, P = .02), and marginally hypercholesterolemia (9.8% v 4.4%, P = .09), and hearing loss (5.3% v 1.5%, P = .09) compared with controls. There were no significant differences in the rates of self-reported arthritis, heart, pulmonary or kidney disease, diabetes, non-OGCT malignancies, anxiety, hearing loss, or eating disorders between groups. Among chronic functional problems, numbness, tinnitus, nausea elicited by reminders of chemotherapy (v general nausea triggers for controls), and Raynaud's symptoms were reported more frequently by survivors. Patients who received vincristine, dactinomycin, and cyclophosphamide in addition to cisplatin therapy had increased functional complaints, particularly numbness and nausea. Health care utilization was similar, but 15.9% of survivors reported being denied health insurance versus 4.4% of controls (P < .001). CONCLUSION: Although a few sequelae of treatment persist, in general, OGCT survivors enjoy a healthy life comparable to that of controls.

Case-control comparison of quality of life in long-term ovarian germ cell tumor survivors: a gynecologic oncology group study.

Ovarian germ cell cancer is a rare tumor. Approximately 1000 to 2000 women in the United States will be diagnosed with ovarian germ cell cancer in 2007. When it occurs, it is usually diagnosed before age 20 and is highly responsive to therapy. Most patients live a full life span. The 5-year relative survival rate is 95%. This article describes differences in quality of life issues between ovarian germ cell cancer survivors and young women who have not experienced cancer and were matched to survivors on age, education, and race (by the acquaintance control method). Survivors and controls completed mail and phone surveys. A multivariable logistic regression model was adjusted for age, education, household income, marital status, and perception of fertility. Compared to controls, germ cell cancer survivors expressed more reproductive concerns and reported worse sexual functioning, but they also experienced greater appreciation of life and more affective (i.e., emotional) social support. Future research is suggested to test interventions to enhance quality of life for ovarian germ cell cancer survivors in the areas of sexual functioning and reproductive concerns, but only for survivors who are in distress or in need of the support. Potential screening questions are offered for clinicians, but further research is needed to assess their validity as screening tools.

Reproductive and sexual function after platinum-based chemotherapy in long-term ovarian germ cell tumor survivors: a Gynecologic Oncology Group Study.

PURPOSE: To compare malignant ovarian germ cell tumor survivors with a matched control group of females on menstrual and reproductive outcomes, sexual functioning, and dyadic adjustment. PATIENTS AND METHODS: Eligible patients met the following criteria: (1) history of malignant ovarian germ cell tumor; (2) treatment with surgery plus platinum-based chemotherapy; (3) age at least 18 years and continuously disease-free with minimum follow-up of 2 years; (4) capability of completing questionnaire and telephone interview; and (5) completion of written informed consent. The control group was drawn from acquaintances recommended by survivors and matched for age, race, and education. Scales with established reliability and validity were used to measure quality-of-life concepts of sexual functioning and social networks. RESULTS: One hundred thirty-two survivors and 137 controls completed the study. Of 132 survivors, 71 (53.8%) had fertility-sparing surgery. Of fertile survivors, 62 (87.3%) reported still having menstrual periods. Twenty-four survivors reported 37 offspring after cancer treatment. Compared with controls, survivors had significantly greater reproductive concerns (P < .0001), less sexual pleasure (P = .003), and lower scores on the total Sexual Activity Scale Score (P = .001). However, survivors had better dyadic consensus (P = .004), dyadic satisfaction (P = .005), and dyadic cohesion (P = .014). CONCLUSION: Women who had fertility-sparing surgery were very likely to retain menstrual function and fertility after chemotherapy. Although there is some increase in gynecologic symptoms and diminution in sexual pleasure, survivors tended to have stronger, more positive relationships with significant others.