Emese Zsiros

Trends in educational differences in adolescent daily smoking across Europe, 2002–10

BACKGROUND Across Europe, tobacco use is more prevalent among secondary school students attending vocational tracks compared with students attending academic tracks. The purpose of the present study is to describe trends in social inequality in daily smoking among adolescents between 2002 and 2010 by addressing both absolute social inequality (prevalence difference between vocational and academic tracks) and relative social inequality (prevalence ratio) in seven European countries. METHODS Analyses were based on data from 15-year-olds who participated in the Health Behaviour in School-aged Children study in 2002, 2006 and 2010 in Belgium, Croatia, France, Germany, Hungary, Italy and The Netherlands (total N = 32 867). RESULTS Overall, daily smoking decreased between 2002 and 2010 in Belgium, France, Germany and The Netherlands, increased in Croatia and remained stable in Hungary and Italy. Considerable differences in daily smoking according to educational track existed in all countries. Absolute educational inequalities increased dramatically in Croatia and Italy, while relative inequalities showed a tendency to increase in all countries (significant in Belgium and The Netherlands). CONCLUSIONS Conclusions on social inequality in adolescent smoking may appear differently when described by absolute and relative measures. Especially the large increase in absolute educational inequalities in daily smoking in Croatia and Italy are worrisome and warrant attention from the public health domain. The findings underline the need for appropriate smoking policies and interventions in vocational schools across Europe.

The combination of intravenous bevacizumab and metronomic oral cyclophosphamide is an effective regimen for platinum-resistant recurrent ovarian cancer

Objective To determine the efficacy, progression-free survival (PFS) and overall survival (OS) for the combination of intravenous bevacizumab and oral cyclophosphamide in heavily pretreated patients with recurrent ovarian carcinoma. Methods A retrospective review was performed for all patients with recurrent ovarian carcinoma treated with intravenous bevacizumab 10 mg/kg every 14 days and oral cyclophosphamide 50 mg daily between January 2006 and December 2010. Response to treatment was determined by Response Evaluation Criteria in Solid Tumors criteria and/or CA-125 levels. Results Sixty-six eligible patients were identified. Median age was 53 years. Fifty-five patients (83%) had undergone optimal cytoreduction. All patients were primarily or secondarily platinum resistant at the time of administration of bevacizumab and cyclophosphamide. The median number of prior chemotherapy treatments was 6.5 (range, 3 to 16). Eight patients (12.1%) had side effects which required discontinuation of bevacizumab and cyclophosphamide. There was one bowel perforation (1.5%). Overall response rate was 42.4%, including, complete response in 7 patients (10.6%), and partial response in 21 patients (31.8%), while 15 patients (22.7%) had stable disease and 23 patients (34.8%) had disease progression. Median PFS for responders was 5 months (range, 2 to 14 months). Median OS from initiation of bevacizumab and cyclophosphamide was 20 months (range, 2 to 56 months) for responders and 9 months (range, 2 to 51 months) for non-responders (p=0.004). Conclusion Bevacizumab and cyclophosphamide is an effective, well-tolerated chemotherapy regimen in heavily pretreated patients with recurrent ovarian carcinoma. This combination significantly improved PFS and OS in responders. Response rates were similar and favorable to the rates reported for similar patients receiving other commonly used second-line chemotherapeutic agents.

Immunotherapy for ovarian cancer: recent advances and perspectives.

Purpose of review Epithelial ovarian cancer is the most frequent cause of gynecologic cancer-related mortality in women, and prognosis for patients with recurrent or metastatic disease is extremely poor. Therefore, there is an enormous unmet need for the development of novel therapies in this indication. Although surgery and chemotherapy can improve survival rates, it is necessary to integrate alternative strategies, such as immunotherapy to improve the outcomes for patients with advanced ovarian cancer. Recent findings We will discuss the rationale of immunotherapy and some of the mechanisms of immunogenicity in ovarian cancer. We will highlight current results with cancer vaccines, adoptive T-cell therapy and immunomodulatory agents and will summarize the immune effects of selected chemotherapeutic agents, radiotherapy and recent results with combinatorial approaches in this disease setting. We will also discuss recent and potential future therapeutic interventions that might circumvent tumor-mediated immunosuppression. Summary Dramatic increase in the number of immunotherapy clinical trials was seen in the past decade with promising results in enhancing antitumor immune response and cancer vaccine efficacy. The future challenge for immunotherapy against ovarian cancer is to use a combinatorial approach to test rational, potentially synergistic immunotherapy combinations that can induce efficient antitumor immunity and prolong patients’ survival.

Adoptive T-Cell Therapy Is a Promising Salvage Approach for Advanced or Recurrent Metastatic Cervical Cancer

Cervical cancer is one of the leading causes of cancer-related death in women worldwide. Although the disease is frequently curable in early stages with surgery alone or surgery and adjuvant chemoradiotherapy, there are no effective therapies for advanced or recurrent metastatic cervical cancers. Recently, antiangiogenic therapy using bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, has demonstrated clinical efficacy in combination with paclitaxel and cisplatin, leading to its regulatory approval for advanced and recurrent cervical cancer. Although this represents some progress in the treatment of patients with cervical cancer, the addition of bevacizumab is unlikely to translate into durable cure for the majority of these patients. Thus, there is an enormous clinical need to develop novel effective strategies, such as immunotherapy, for this patient population. Persistent infection with specific high-risk human papillomavirus (HR-HPV; eg, HPV-16, HPV-18, HPV-31, HPV-33, and HPV45) has been identified as an essential factor in the pathogenesis of the majority of cervical cancers, with detectable HR-HPV in up to 99.7% of carcinoma specimens. Similar to nononcogenic viruses, such as influenza and cytomegalovirus, HPV is highly immunogenic and elicits immune responses in humans. Although prophylactic HPV vaccines targeting L1 and L2 virion structural proteins have demonstrated efficacy in preventing HPV-related cancers, therapeutic vaccines targeting E6 and E7 oncoproteins have not produced significant clinical responses. The barrier to establishing an effective therapeutic HPV vaccine against cervical cancer has been a lack of clinical response to any of the existing regimens. This is probably because of the relatively low magnitude of vaccine-induced immune responses, and tumormediated immune suppression. In the article that accompanies this editorial, Stevanovic et al present a promising adoptive T-cell therapy (ACT) approach by which patients with recurrent, chemotherapyresistant metastatic cervical cancer were treated with a single infusion of ex vivo–expanded tumor-infiltrating T cells. In contrast with tumor vaccination strategies, ACT allows for more rigorous control over the magnitude of the targeted response by appropriate in vitro manipulation and selection of the T cells used for therapy. Tumor-reactive effector cells of a desired specificity and phenotype can be identified in vitro, exposed to cytokines and immunomodulators that influence differentiation during priming, expanded to large numbers, and produce frequencies of antigen-specific T cells in the peripheral blood that are more than 10-fold greater than those possible by current vaccine regimens alone. Initial results that demonstrated the potential of T-cell immunotherapy to eradicate solid tumors came from the National Cancer Institute in studies of adoptive transfer of in vitro–selected tumor-infiltrating lymphocytes (TILs). In a pioneering clinical trial in 13 patients with melanoma, adoptive transfer of ex vivo–amplified autologous tumor-infiltrating T cells induced objective clinical responses in six patients and mixed responses in four additional patients. However, results in solid tumors and epithelial malignancies are still limited, mainly because of the technical challenges in obtaining enough tumor specimens and isolating and expanding tumor-reactive T cells. In the protocol used by Stevanovic et al, the T cells were obtained from tumor specimens that required a surgical excision of 1 cm tumor in each patient, expanded with interleukin-2 (IL-2), and used for ACT. T-cell products were tested for reactivity against HPV-16 or HPV-18 E6 and E7 oncoproteins. T-cell infusion was preceded by lymphodepleting chemotherapy and was followed by the administration of multiple doses of aldesleukin. In the study, nine patients were treated using this protocol, and three patients showed objective tumor response. Of these, two patients (both young, age 36 years, who were experiencing progression during receipt of palliative treatment) had a durable complete clinical response that lasted more than a year. Although the numbers are small, these results are impressive and suggest that this highly personalized therapeutic modality warrants further investigation. Importantly, the treatment was safe and well tolerated, but, as expected, the major toxicity resulted from the preconditioning lymphodepleting chemotherapy before the infusion. It is currently well recognized that the preconditioning step is critical for achieving a high level of T-cell engraftment because it creates space for the adoptively transferred T cells to populate in the absence of host-cell competition. Although the number of patients was too small to draw a general conclusion, the results clearly showed a correlation between HPV reactivity of the infused T-cell products and objective clinical responses. First, only when the infusion product had reactivity against the HPV E6 and E7 peptides did the patient show objective clinical response. Second, in patients with objective responses, HPV-specific T JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 14 MAY 1

The Ovarian Cancer Chemokine Landscape Is Conducive to Homing of Vaccine-Primed and CD3/CD28–Costimulated T Cells Prepared for Adoptive Therapy

Purpose: Chemokines are implicated in T-cell trafficking. We mapped the chemokine landscape in advanced stage ovarian cancer and characterized the expression of cognate receptors in autologous dendritic cell (DC)–vaccine primed T cells in the context of cell-based immunotherapy. Experimental Design: The expression of all known human chemokines in patients with primary ovarian cancer was analyzed on two independent microarray datasets and validated on tissue microarray. Peripheral blood T cells from five HLA-A2 patients with recurrent ovarian cancer, who previously received autologous tumor DC vaccine, underwent CD3/CD28 costimulation and expansion ex vivo. Tumor-specific T cells were identified by HER2/neu pentamer staining and were evaluated for the expression and functionality of chemokine receptors important for homing to ovarian cancer. Results: The chemokine landscape of ovarian cancer is heterogeneous with high expression of known lymphocyte-recruiting chemokines (CCL2, CCL4, and CCL5) in tumors with intraepithelial T cells, whereas CXCL10, CXCL12, and CXCL16 are expressed quasi-universally, including in tumors lacking tumor-infiltrating T cells. DC-vaccine primed T cells were found to express the cognate receptors for the above chemokines. Ex vivo CD3/CD28 costimulation and expansion of vaccine-primed Tcells upregulated CXCR3 and CXCR4, and enhanced their migration toward universally expressed chemokines in ovarian cancer. Conclusions: DC-primed tumor-specific T cells are armed with the appropriate receptors to migrate toward universal ovarian cancer chemokines, and these receptors are further upregulated by ex vivo CD3/CD28 costimulation, which render T cells more fit for migrating toward these chemokines. Clin Cancer Res; 21(12); 2840–50. ©2015 AACR.

History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium

PurposeSurvival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype.MethodsUsing pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes.ResultsHistory of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01–1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88–1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87–1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35–0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03–1.40, HR = 1.28; 95% CI = 1.05–1.55, and HR = 1.63; 95% CI = 1.20–2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53–0.94.ConclusionsHistories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.

Tumor-associated macrophages: Co-conspirators and orchestrators of immune suppression in endometrial adenocarcinoma

During the past decade remarkable progress has been made in understanding the interactions between the immune system and cancer. This has led to the rapid growth of cancer immunotherapy as a therapeutic modality for several tumor types, with demonstration of meaningful and durable clinical benefits. Unfortunately, tumors erect several cellular and molecular tolerogenic barriers that conspire to dampen anti-tumor immune responses, limit the efficacy of immunotherapy leading to escape from immune attack. Among these, tumor associated macrophages (TAMs) have attracted considerable recent attention because of their association with tumor progression, angiogenesis and immune suppression. An understanding of the relative contribution of immune suppressive mechanisms for individual cancer types will be crucial for developing the most effective immunotherapy combination for that disease. In this regard, unlike ovarian and other solid tumors, the immunological landscape of the endometrial cancer microenvironment is relatively understudied. In this issue of the journal, Kübler et al. present their results of a detailed study focusing on the prognostic significance of TAMs, and another subset of T cells that counteract anti-tumor adaptive immune responses, FoxP3 regulatory T cells (Tregs) in endometrial cancer. Cancer initiation, progression and invasion occur in a complex and dynamic microenvironment, where tumor-infiltrating immune cells have a dual role with the potential to exhibit both proand antitumor activities. TAMs are the major inflammatory components of the stroma in many tumors [1]. They originate from circulating monocytes and further undergo M1 (classical) or M2 (alternative) activation in response to microenvironmental signals [2,3]. Recruitment of macrophages to the tumor microenvironment is governed by various chemokines and growth factors produced by cancer cells, such as CC chemokine ligand 2 (CCL-2), macrophage colony-stimulating factor (MCSF) and vascular endothelial growth factor (VEGF) [4]. The question is: how domacrophages, that are normally a fundamental part of innate defense mechanisms, become enemies of the adaptive anti-tumor immune response upon arrival in the tumor microenvironment? The explanation for this paradoxical role of macrophages lies in their functional plasticity. Bacterial stimuli, IFN-γ, and granulocyte–macrophage colony stimulating factor support a M1-polarized phenotype, which is characterized by production of high levels of proinflammatory cytokines, promotion of Th1 T cell response and strong tumoricidal activity. In contrast, MCSF, IL-4, and IL-13 favors the generation of immunosuppressive M2 macrophages that are involved in tissue remodeling and tumor progression [2]. Fully polarized M1 and M2 macrophages are the extremes of a continuum of functional states and there are several other distinct populations that share features of both types [1,2,5]. Ultimately the tumor microenvironment shapes the TAM phenotype

Paternal lineage early onset hereditary ovarian cancers: A Familial Ovarian Cancer Registry study

Given prior evidence that an affected woman conveys a higher risk of ovarian cancer to her sister than to her mother, we hypothesized that there exists an X-linked variant evidenced by transmission to a woman from her paternal grandmother via her father. We ascertained 3,499 grandmother/granddaughter pairs from the Familial Ovarian Cancer Registry at the Roswell Park Cancer Institute observing 892 informative pairs with 157 affected granddaughters. We performed germline X-chromosome exome sequencing on 186 women with ovarian cancer from the registry. The rate of cancers was 28.4% in paternal grandmother/granddaughter pairs and 13.9% in maternal pairs consistent with an X-linked dominant model (Chi-square test X2 = 0.02, p = 0.89) and inconsistent with an autosomal dominant model (X2 = 20.4, p<0.001). Paternal grandmother cases had an earlier age-of-onset versus maternal cases (hazard ratio HR = 1.59, 95%CI: 1.12–2.25) independent of BRCA1/2 status. Reinforcing the X-linked hypothesis, we observed an association between prostate cancer in men and ovarian cancer in his mother and daughters (odds ratio, OR = 2.34, p = 0.034). Unaffected mothers with affected daughters produced significantly more daughters than sons (ratio = 1.96, p<0.005). We performed exome sequencing in reported BRCA negative cases from the registry. Considering age-of-onset, one missense variant (rs176026 in MAGEC3) reached chromosome-wide significance (Hazard ratio HR = 2.85, 95%CI: 1.75–4.65) advancing the age of onset by 6.7 years. In addition to the well-known contribution of BRCA, we demonstrate that a genetic locus on the X-chromosome contributes to ovarian cancer risk. An X-linked pattern of inheritance has implications for genetic risk stratification. Women with an affected paternal grandmother and sisters of affected women are at increased risk for ovarian cancer. Further work is required to validate this variant and to characterize carrier families.

Prognostic value of miliary versus non-miliary sub-staging in advanced ovarian cancer

OBJECTIVE The presence of miliary disease during initial ovarian cancer debulking may reflect a distinct mode of peritoneal spread independent from size-based tumor staging and may explain variation in response to treatment and survival outcomes. To infer the prevalence, presentation and clinical implications of miliary disease we reviewed existing surgical records. METHODS Reports were available for 1008 primary debulking surgeries for ovarian, primary peritoneal or fallopian tube cancer between 2001 and 2015 (685 reports from 2005 to 2015). Clinical outcome data was available for 938 patients. We analyzed a high-stage sub-cohort for survival (N=436). RESULTS Most records were evaluable for miliary disease (761/938); for these, the miliary phenotype was highly prevalent (249/761, 32.7%) and often accompanied by ascites (185/249, 74%). While optimal debulking rates were unaffected by miliary disease, total resection (R0) rates were poorer. Liver, stomach, spleen or bladder appeared to be sporadically involved while the omentum, mesentery, bowel, peritoneum and diaphragm were affected simultaneously (Spearman rho>0.5). Overall, miliary disease was associated with worse progression free survival, overall survival, and time from relapse to death independent of stage. Survival effects were particularly strong for Stage IV disease where median overall survival varied by over 30months (log-rank p=0.002). CONCLUSIONS Miliary disease is an identifiable surgical phenotype reflecting a distinct clinical trajectory that adds prognostic information to standard disease burden-based staging. These findings should permit further retrospective investigation in a wider cohort and prompt the consideration of prospective structured operative reporting standards and treatment strategies.

History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report

Background:Findings from in vitro studies suggest that increased exposure to thyroid hormones can influence progression of ovarian tumours. However, epidemiologic evidence on this topic is limited.Methods:We pooled data from 11 studies from the Ovarian Cancer Association Consortium. Using multivariate Cox proportional hazards models, we estimated associations between hyper- and hypothyroidism and medications prescribed for these conditions with 5-year all-cause survival among women diagnosed with invasive ovarian cancer.Results:Overall, there was a nonsignificant association with history of hyperthyroidism (n=160 cases) and mortality (HR=1.22; 95% CI=0.97–1.53). Furthermore, diagnosis of hyperthyroidism within the 5 years before ovarian cancer diagnosis was associated with an increased risk of death (HR=1.94; 95% CI=1.19–3.18). A more modest association was observed with history of hypothyroidism (n=624 cases) and mortality (HR=1.16; 95% CI=1.03–1.31). Neither duration of hypothyroidism nor use of thyroid medications was associated with survival.Conclusions:In this large study of women with ovarian cancer, we found that recent history of hyperthyroidism and overall history of hypothyroidism were associated with worse 5-year survival.