Motivated by previous indications that beta-adrenergic signaling can regulate tumor cell gene expression in model systems, we sought to determine whether similar dynamics occur in primary human ovarian cancer. DNA microarray analyses of 10 ovarian carcinomas identified 266 human transcripts that were differentially expressed in tumors from patients with elevated biobehavioral risk factors (high depressive symptoms and low social support) relative to grade-and stage-matched tumors from low-risk patients. Promoter-based bioinformatic analyses confirmed increased activity of several beta-adrenergically-linked transcription control pathways, including CREB/ATF, NF-κB/ Rel, STAT, and Ets family transcription factors. Consistent with increased beta-adrenergic signaling, high biobehavioral risk patients also showed increased intra-tumor concentrations of norepinephrine (but no difference in plasma norepinephrine). These data show that genome-wide transcriptional profiles are significantly altered in patients with high behavioral risk profiles, and they identify betaadrenergic signal transduction as a likely mediator of those differences.

A B S T R A C T PurposeInflammatory processes have been implicated in the pathogenesis of both depression and cancer. Links between depressive symptoms, interleukin-6 (IL-6), and cortisol dysregulation have been demonstrated in cancer patients, but vegetative versus affective components of depression have been minimally examined. The objective of the current study was to examine associations between IL-6, diurnal cortisol rhythms, and facets of depression in epithelial ovarian cancer patients. Patients and MethodsPatients awaiting surgery for a pelvic mass suspected for ovarian cancer completed questionnaires, collected salivary samples for 3 days presurgery, and gave a presurgical blood sample. Ascites was obtained during surgery. IL-6 was measured by enzyme-linked immunosorbent assay and cortisol by a chemiluminescence immunoassay. The final sample included 112 invasive ovarian cancer patients (86 advanced stage, 26 early stage) and 25 patients with tumors of low malignant potential (LMP). ResultsAdvanced-stage ovarian cancer patients demonstrated elevations in vegetative and affective depressive symptoms, plasma IL-6, and the cortisol area under the curve (AUC) compared with patients with LMP tumors (all P Ͻ .05). Among invasive ovarian cancer patients, greater vegetative depression was related to elevated IL-6 in plasma (P ϭ .008) and ascites (P ϭ .024), but affective depression was unrelated to IL-6. Elevations in total depression (P ϭ .026) and vegetative depression (P ϭ .005) were also related to higher evening cortisol levels. Plasma IL-6 was related to greater afternoon and evening cortisol and cortisol AUC (all P values Ͻ .005). ConclusionThese results demonstrate significant relationships between IL-6, cortisol, and vegetative depression, and may have implications for treatment of depression in ovarian cancer patients.

Hydration with saline or saline + furosemide appears to be associated with less cisplatin nephrotoxicity than saline + mannitol.

A B S T R A C T PurposePrevious research has demonstrated relationships of social support with disease-related biomarkers in patients with ovarian cancer. However, the clinical relevance of these findings to patient outcomes has not been established. This prospective study examined how social support relates to long-term survival among consecutive patients with ovarian cancer. We focused on two types of social support: social attachment, a type of emotional social support reflecting connections with others, and instrumental social support reflecting the availability of tangible assistance. Patients and MethodsPatients were prospectively recruited during a presurgical clinic visit and completed surveys before surgery. One hundred sixty-eight patients with histologically confirmed epithelial ovarian cancer were observed from the date of surgery until death or December 2010. Clinical information was obtained from medical records. ResultsIn a Cox regression model, adjusting for disease stage, grade, histology, residual disease, and age, greater social attachment was associated with a lower likelihood of death (hazard ratio [HR], 0.87; 95% CI, 0.77 to 0.98; P ϭ .018). The median survival time for patients with low social attachment categorized on a median split of 15 was 3.35 years (95% CI, 2.56 to 4.15 years). In contrast, by study completion, 59% of patients with high social attachment were still alive after 4.70 years. No significant association was found between instrumental social support and survival, even after adjustment for covariates. ConclusionSocial attachment is associated with a survival advantage for patients with ovarian cancer. Clinical implications include the importance of screening for deficits in the social environment and consideration of support activities during adjuvant treatment.

Purpose: Stromal cells in the tumor microenvironment, such as macrophages, play an active role in tumor growth and angiogenesis. However, little is known about relationships of biobehavioral factors with angiogenic cytokines and matrix metalloproteinases (MMP) produced by stromal cells. This study examined distress, MMPs, and angiogenic cytokines in ovarian cancer patients and in vitro. Experimental Design: Patients suspected of ovarian cancer completed preoperative questionnaires. At surgery, 56 were confirmed to have epithelial ovarian cancer. Tumor samples were analyzed for macrophage (CD68 + ) and tumor cell levels of MMP-2, MMP-9, and vascular endothelial growth factor. In vitro stimulation of isolated macrophage cells by the stress hormones norepinephrine and cortisol was done to assess effects on MMP-9. Results: Depressed patients showed significant elevations of MMP-9 in CD68 + cells, adjusting for stage (P < 0.0001). Patients with higher levels of current stress (P = 0.01), life stress over the last 6 months (P = 0.004), and general negative affect (P = 0.007) also showed significantly greater MMP-9 in CD68 + cells. In contrast, higher social support was associated with lower levels of MMP-9 (P = 0.023) and vascular endothelial growth factor (P = 0.036) in tumor cells. In vitro analyses showed that macrophage MMP-9 production could be directly enhanced (up to a 2-fold increase) by the stress hormones norepinephrine and cortisol. Conclusions: Ovarian cancer patients with elevated depressive symptoms, chronic stress, and low social support showed elevations in MMP-9 in tumor-associated macrophages. Direct in vitro enhancement of stromal MMP-9 production by stress hormones was also shown. These findings may have implications for patient outcomes in ovarian cancer.Recent reports have shown that neuroendocrine stress hormones are able to stimulate the production of proangiogenic factors and matrix metalloproteinases (MMP) from ovarian cancer cells, thereby enhancing the invasive and metastatic potential of these cells (1 -3). Similar neuroendocrine-induced enhancement of MMPs and vascular endothelial growth factor (VEGF) has been observed from cell lines from other cancers (4, 5). Behavioral distress has been linked to higher levels of angiogenic cytokines such as VEGF and interleukin-6 in ovarian cancer patients (6, 7). Stromal cells in the tumor microenvironment such as macrophages are known to play an active role in the promotion of tumor growth and angiogenesis (8). However, little is known about relationships of behavioral distress with angiogenic cytokines and MMPs produced by stromal cells, which is the focus of the current study.Tumor-associated macrophages (TAM) are a major component of most, if not all, tumor microenvironments (9) and are recruited to tumors by several growth factors and chemotactic factors. In the presence of a proinflammatory tumor microenvironment, macrophages are induced to switch from their

In this study, PVI FU does not show improved outcome over weekly cisplatin. Future research should explore combinations of FU with cisplatin, new radiosensitizers, and active drugs combined with RT to reduce the high rate of pelvic and distant treatment failure still seen in advanced cervix cancer.

Purpose-To determine whether maintaining Hgb levels ≥ 12.0 g/dL with recombinant human erythropoietin (R-HUEPO) compared to "standard" treatment (transfusion for Hgb ≤ 10.0 g/dL) improves progression-free survival (PFS), overall survival (OS) and local control (LC) in women receiving concurrent weekly cisplatin and radiation (CT/RT) for carcinoma of the cervix. In addition, to determine whether platinum-DNA adducts were associated with clinical characteristics or outcome.Methods-Patients with stage IIB-IVA cervical cancer and Hgb < 14.0 g/dL were randomly assigned to CT/RT ± R-HUEPO (40,000 units SC weekly). R-HUEPO was stopped if Hgb > 14.0 g/ dL. Endpoints were PFS, OS and LC. Platinum-DNA adducts were quantified using immunocytochemistry assay in buccal cells.Results-Between 08/01 and 09/03, 109 of 114 patients accrued were eligible. Fifty-two received CT/RT and 57 CT/RT plus R-HUEPO.The study closed prematurely, with less than 25% of the planned accrual, due to potential concerns for thromboembolic event (TE) with R-HUEPO. Median follow-up was 37 months (range 9.8-50.4 months). PFS and OS at three years were 66% and 74% for CT/RT and 58% and 60% for CT/RT + R-HUEPO, respectively. TE occurred in 4/52 receiving CT/RT and 11/57 with CT/RT + R-HUEPO, not all considered treatment related. No deaths occurred from TE. High platinum-adducts were associated with inferior PFS and LC.

N‐Chlorination reactions of alkyl‐, cycloalkyl‐, heterocyclic, and aromatic amines by HOCl have been investigated in the gas and aqueous phase. Density functional (B3LYP), double hybrid (B2PLYPD), and composite theoretical model (G3B3) have been used to assess steric, electronic, and solvent effects on the reactivity of different families of amines toward HOCl. When solvent effects are included by using CPCM/UAHF model, all computational methods predict the same order of reactivity within each group of amines. In agreement with experimental data, heterocyclic amines have the highest reactivity, with energy barriers calculated between 160 and 225 kJ mol−1 (B2PLYPD/AUG‐cc‐pVTZ//B3LYP/6‐31G(d) level). The substituted anilines are the least reactive species, with energy barriers calculated as high as 300 kJ mol−1. Two different reaction mechanisms of N‐chlorination have been considered in the gas phase: the one which includes the transition state TSa with cyclic arrangement of four atoms (N, Cl, O, and H) involved in an intramolecular rearrangement, and the second in which the hydrogen‐bridged structure TSb is characterized with the linear NClO moiety. The former is energetically more feasible (ca. 120 kJ mol−1) for alkyl‐, cycloalkyl‐, and heterocyclic amines, whereas the latter is operative in the case of aromatic amines. If two water molecules are explicitly included in the calculations, the rate‐determining transition state TSw has been located for N‐chlorination of all amines under study. It is characterized by eight‐membered ring geometry in which water molecules assist the simultaneous transfer of the three hydrogen atoms coupled with the NCl bond formation. To reproduce the experimentally observed trends in reactivity of amines, the inclusion of bulk and specific solvent effects is mandatory. Steric effects have been found to govern the reactivity of alkylamines, that is, more bulkier amines react slower with HOCl. It has been found that electronic structure parameters (HOMO–LUMO gap, natural bond orbital occupancy, and NPA charge on N atom) can be successfully used as descriptors for the reactivity of heterocyclic and aromatic amines. These results indicate the predictive power of our computational approach, which can be applied to calculate nucleophilic reactivities of more complex structures of environmentally or biologically relevant amines. © 2012 Wiley Periodicals, Inc.