Coping strategies and quality of life: a longitudinal study of high-grade glioma patient-caregiver dyads.

BACKGROUND: Among a sample of patient-informal caregiver dyads in the specific context of new diagnoses of high-grade glioma in the time-frame between diagnosis and the third month following diagnosis, we examine whether the coping strategies implemented by the patients and their caregivers influenced their own quality of life (QoL) and the QoL of their relatives. METHODS: Thirty-eight dyads with patients having recent diagnoses of high-grade glioma were involved in this longitudinal study. The self-reported data include QoL (Patient-Generated Index, EORTC QLQ-C30, and CareGiver Oncology Quality of Life), and coping strategies (BriefCope). Data were collected at T1 corresponding to the time-frame between diagnosis and postsurgical treatment initiation and T2 corresponding to the 3-month post-inclusion follow-up. RESULTS: Coping strategies based on social support and avoidance were the least used at baseline and the 3-month follow-up, both for patients and caregivers. At the 3-month follow-up, the use of social support at baseline was significantly related to lower scores of QoL for the patients and with higher QoL for the caregivers. For the patient, the use of problem-solving or positive thinking at baseline was not related to his/her QoL, while it was related to more satisfactory QoL scores for the caregiver. The use of avoidance at baseline was linked to a higher 3-month QoL for the patients and a lower 3-month QoL for the caregivers. Using the specific dyadic analyses (actor-partner interdependence model), the 3-month patient's QoL was lower (ß = - 0.322; p = 0.03) when the patient mobilized the social support strategy at baseline, but was higher(ß = 0.631; p < 10- 3) when his/her informal caregiver used this strategy. After adjustment for sex, age, and baseline PGI score, the link between high use of the social support strategy at baseline by the caregiver and the patient's 3-month QoL, remained present (positive partner effect; ß =0.675; p < 10- 3). CONCLUSION: The QoL for patients and their informal caregivers since the time of diagnosis is directly related to the use of coping strategies based on social support at time of diagnosis.

Female genital mutilation/cutting in Italy: an enhanced estimation for first generation migrant women based on 2016 survey data.

BACKGROUND: Migration flows of women from Female Genital Mutilation/Cutting practicing countries have generated a need for data on women potentially affected by Female Genital Mutilation/Cutting. This paper presents enhanced estimates for foreign-born women and asylum seekers in Italy in 2016, with the aim of supporting resource planning and policy making, and advancing the methodological debate on estimation methods. METHODS: The estimates build on the most recent methodological development in Female Genital Mutilation/Cutting direct and indirect estimation for Female Genital Mutilation/Cutting non-practicing countries. Direct estimation of prevalence was performed for 9 communities using the results of the survey FGM-Prev, held in Italy in 2016. Prevalence for communities not involved in the FGM-Prev survey was estimated using to the 'extrapolation-of-FGM/C countries prevalence data method' with corrections according to the selection hypothesis. RESULTS: It is estimated that 60 to 80 thousand foreign-born women aged 15 and over with Female Genital Mutilation/Cutting are present in Italy in 2016. We also estimated the presence of around 11 to 13 thousand cut women aged 15 and over among asylum seekers to Italy in 2014-2016. Due to the long established presence of female migrants from some practicing communities Female Genital Mutilation/Cutting is emerging as an issue also among women aged 60 and over from selected communities. Female Genital Mutilation/Cutting is an additional source of concern for slightly more than 60% of women seeking asylum. CONCLUSIONS: Reliable estimates on Female Genital Mutilation/Cutting at country level are important for evidence-based policy making and service planning. This study suggests that indirect estimations cannot fully replace direct estimations, even if corrections for migrant socioeconomic selection can be implemented to reduce the bias.

Relationship between magnetic resonance imaging characteristics and plasmatic levels of MMP2 and MMP9 in patients with recurrent high-grade gliomas treated by Bevacizumab and Irinotecan.

Matrix metalloproteases MMP2 and MMP9 are involved in cancer angiogenesis and invasion. We recently demonstrated that plasma MMP2 and MMP9 levels could both predict response to bevacizumab in patients with recurrent high-grade glioma (HGG). We examined the potential relationship between MMP2/MMP9 plasma levels and glioma imaging characteristics. In this retrospective, monocentric study, MRI before bevacizumab administration for HGG patients was independently analyzed for contrast enhancement (CE) and FLAIR sequences. Contemporary MMP2 and MMP9 plasma levels were assessed using ELISA kits. We analyzed 28 patients with a median Karnofsky Performance Status of 70 (range 50-80). A diffuse pattern was observed in 14 patients (50%). We did not observe any correlation between baseline imaging features and plasma levels of MMP2 or MMP9. We found no association between baseline MMP levels and diffuse MRI patterns. In univariate analyses, diffuse pattern, multi-focal disease, tumor diameter, surface area, and volume had no impact on outcome, while the number of lobes involved in CE and crossing of the midline by CE were associated with a worse progression-free survival (p = 0.072 and p = 0.012, respectively) and overall survival (p = 0.012 and p < 0.001, respectively). In patients with recurrent high-grade glioma treated with a bevacizumab-based regimen, our exploratory analysis of multiple MRI tumor characteristics at baseline failed to detect a relationship between imaging feature and plasma levels of MMP2 and MMP9. Our results suggests that number of lobes involved in CE and crossing of the midline by CE are associated with outcome although the potential prognostic versus predictive role of these markers warrant further investigation.

Estimating the number of foreign women with female genital mutilation/cutting in Italy.

BACKGROUND: Female genital mutilation/cutting (FGM/C), is an emerging topic in Europe as a consequence of the increasing proportion of women migrating from Africa. The prevalence of FGM/C is however unknown in Europe, as there are no country-representative surveys on this topic. The aim of this study is to provide an estimate for Italy for the year 2010. METHODS: This study relies on the results of the First Survey on Women at Risk of FGM/C held in Italy in 2010. This cross-sectional survey involved 1000 migrants from the main FGM/C practicing countries aged 15-49 living in the Italian region of Lombardy. The estimate presented is based on a method combining direct estimates for the communities involved in the survey and indirect estimates for other communities. Indirect estimations were obtained using a refinement of the most general extrapolation-of-country-prevalence-data method. RESULTS: It is estimated that some 57 000 foreign girls and women aged 15-49 with FGM/C were living in Italy in 2010. The Nigerian community is the most affected, with around 20 000 women with FGM/C (35.5% of the total number women affected in Italy), followed by the Egyptian community (around 18 600 women with FGM/C; 32.5%). Another 15% of the women affected are from the Horn of Africa, notably from Ethiopia (3200 women; 5.5%), Eritrea (2800 women; 4.9%) and Somalia (2300 women; 4%). CONCLUSIONS: This study offers an additional methodological advancement by proposing a combination of direct and indirect estimation of FGM/C. The results are crucial information to plan interventions and targeted policies.

Angiopoietin-2 May Be Involved in the Resistance to Bevacizumab in Recurrent Glioblastoma.

Despite encouraging response rate of bevacizumab (BVZ) in recurrent glioblastoma, many patients do not respond to this schedule and most of the responders develop an early relapse. Plasma concentrations of VEGF, PlGF, Ang2, and sTie2 were assessed by ELISA before and during BVZ treatment in seventy patients. Baseline levels of VEGF-A, and PlGF were higher in patients than in healthy volunteers, whereas no difference was found for Ang2, and sTie2. No biomarker at baseline was associated with response, PFS or OS. At recurrence, the authors observed an increase of Ang2 suggesting that Ang2/sTie2 could be involved in the resistance to BVZ.

VEGFA SNP rs2010963 is associated with vascular toxicity in recurrent glioblastomas and longer response to bevacizumab.

Although anti-VEGF therapy is widely used in high-grade gliomas, no predictor of response or toxicity has been reported yet. We investigated here the association of the functional single nucleotide polymorphism (SNP) rs2010963, located in the 5' untranslated terminal region of the VEGFA gene, with survival, response to bevacizumab (BVZ) and vascular toxicity. The rs2010963 was genotyped by Taqman assay in blood DNA from 954 glioma patients with available survival data, including 225 glioblastoma (GBM) patients treated with BVZ. VEGFA plasma levels were assessed by ELISA in 87 patients before treatment. Thrombo-hemorragic adverse events were recorded during BVZ treatment or not, and in an independent population of 92 GBM patients treated with temozolomide. The CC genotype was associated with the occurrence of thrombo-hemorragic events (CC 25 versus CG 13.5 and GG 5.2 %; P = 0.0044) during BVZ. A similar but weaker and non significant trend was observed in patients not receiving BVZ. A CC genotype was associated with higher levels of plasma VEGFA at baseline (107.6 versus 57.50 pg/mL in heterozygotes (CG) and 52.75 pg/mL in GG patients, P = 0.035 and P = 0.028 respectively). The CC genotype tended to be associated to longer PFS when treated with BVZ (P = 0.05), but not when treated with the temozolomide treatment. Our data suggest that the rs2010963 genotype is associated with longer PFS, higher risk of vascular events in recurrent GBM especially treated with BVZ, and higher plasma VEGFA concentration. It may help to identify patients at risk of vascular adverse events during BVZ treatment.

Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study.

BACKGROUND: Temozolomide (TMZ) administered daily with radiation therapy (RT) for 6 weeks, followed by adjuvant TMZ for 6 cycles, is the standard therapy for newly diagnosed glioblastoma (GBM) patients. Although TMZ is considered to be a safe drug, it has been demonstrated to cause severe myelotoxicity; in particular, some case reports and small series studies have reported severe myelotoxicity developing during TMZ and concomitant RT. We performed a prospective study to analyze the incidence of early severe myelotoxicity and its possible clinical and genetic factors. PATIENTS AND METHODS: From November 2010 to July 2012, newly diagnosed GBM patients were enrolled. They were eligible for the study if they met the following criteria: pathologically proven GBM, age 18 years and older, an Eastern Cooperative Oncology Group performance status of 0 to 2, adequate renal and hepatic function, and adequate blood cell counts before starting TMZ plus RT. Grading of hematologic toxicity developing during radiation and TMZ was based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Clinical factors from all patients were recorded. The methylation status and polymorphic variants of O-methylguanine-DNAmethyl-transferase gene in peripheral blood mononuclear cells, and polymorphic genetic variants of genes involved in the pharmacokinetics and pharmacodynamics of TMZ, were analyzed. For genetic analyses, patients with toxicity were matched (1:2) for age, performance status, anticonvulsants, and proton pump inhibitors with patients without myelotoxicity. RESULTS: We enrolled 87 consecutive GBM patients: 32 women and 55 men; the average age was 60 years. During TMZ and RT, 4 patients (5%) showed grade 3-4 myelotoxicity, and its median duration was 255 days. Predictor factors of severe myelotoxicity were female sex, pretreatment platelet count of ≤3,00,000/mm, methylated O-methylguanine-DNA methyltransferase promoter in the hematopoietic cell system, and specific polymorphic variants of the cytochrome P450 oxidoreductase and methionine adenosyltransferase 1A genes. CONCLUSIONS: Although we studied a small population, we suggest that both clinical and genetic factors might simultaneously be associated with severe myelosuppression developed during TMZ plus RT. However, our results deserve validation in larger prospective studies and, if the factors associated with severe myelotoxicity are validated, dose adjustments of TMZ for those patients may reduce the risk of severe myelotoxicity during the concomitant treatment.

Successful treatment of multiple intracranial meningiomas with the antiprogesterone receptor agent mifepristone (RU486).

BACKGROUND: Meningiomas are the most frequent primary brain tumor in adults. Evidence suggests that female sex hormones play a role in the meningioma tumorigenesis. In particular, progesterone, has a receptor (PR) that is highly expressed in the majority of grade I meningiomas. Multiple meningiomas (diffuse meningiomatosis) are less frequent, but have a higher female predominance and a higher PR expression. They are, therefore, attractive candidates for anti-PR therapy. METHODS: We treated three consecutive women with multiple meningiomas with mifepristone (RU 486). It is a synthetic steroid with high affinity for both progesterone and glucocorticoid receptors. RESULTS: The treatment was well tolerated, and we observed an important and long-lasting clinical (3/3) and radiological response (2/3) or stabilisation. All the three patients are now stable after five to nine years of treatment. CONCLUSIONS: These encouraging results strongly support a prospective clinical trial in this preselected population.

Systemic treatments for brain metastases from breast cancer, non-small cell lung cancer, melanoma and renal cell carcinoma: an overview of the literature.

The frequency of metastatic brain tumors has increased over recent years; the primary tumors most involved are breast cancer, lung cancer, melanoma and renal cell carcinoma. While radiation therapy and surgery remain the mainstay treatment in selected patients, new molecular drugs have been developed for brain metastases. Studies so far report interesting results. This review focuses on systemic cytotoxic drugs and, in particular, on new targeted therapies and their clinically relevant activities in brain metastases from solid tumors in adults.

The combination of carmustine wafers and fotemustine in recurrent glioblastoma patients: a monoinstitutional experience.

BACKGROUND: To date, there is no standard treatment for recurrent glioblastoma. We analyzed the feasibility of second surgery plus carmustine wafers followed by intravenous fotemustine. METHODS: Retrospectively, we analyzed patients with recurrent glioblastoma treated with this multimodal strategy. RESULTS: Twenty-four patients were analyzed. The median age was 53.6; all patients had KPS between 90 and 100; 19 patients (79%) performed a gross total resection > 98% and 5 (21%) a gross total resection > 90%. The median progression-free survival from second surgery was 6 months (95% CI 3.9-8.05) and the median OS was 14 months (95% CI 11.1-16.8 months). Toxicity was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia. CONCLUSION: This multimodal strategy may be feasible in patients with recurrent glioblastoma, in particular, for patients in good clinical conditions.

An overview of fotemustine in high-grade gliomas: from single agent to association with bevacizumab.

Fotemustine is a third-generation nitrosourea showing efficacy in various types of tumors such as melanoma and glioma. We reviewed the most important studies on fotemustine treatment in glioma patients analyzing its pharmacological profile and its activity and safety. Fotemustine was used as single agent or in association with new targeted drugs such as bevacizumab; fotemustine was used both as first-line chemotherapy before temozolomide era and in refractory-temozolomide patients during temozolomide era. Finally, analyzing and comparing the activity and safety of fotemustine alone or in combination with bevacizumab versus other nitrosoureas such as lomustine, we may suggest that the combination treatment with bevacizumab and fotemustine may be active and tolerable in patients with high grade gliomas.

An ANOCEF genomic and transcriptomic microarray study of the response to irinotecan and bevacizumab in recurrent glioblastomas.

BACKGROUND: We performed a retrospective study to assess whether the initial molecular characteristics of glioblastomas (GBMs) were associated with the response to the bevacizumab/irinotecan chemotherapy regimen given at recurrence. RESULTS: Comparison of the genomic and gene expression profiles of the responders (n = 12) and nonresponders (n = 13) demonstrated only slight differences and could not identify any robust biomarkers associated with the response. In contrast, a significant association was observed between GBMs molecular subtypes and response rates. GBMs assigned to molecular subtype IGS-18 and to classical subtype had a lower response rate than those assigned to other subtypes. In an independent series of 33 patients, neither EGFR amplification nor CDKN2A deletion (which are frequent in IGS-18 and classical GBMs) was significantly associated with the response rate, suggesting that these two alterations are unlikely to explain the lower response rate of these GBMs molecular subtypes. CONCLUSION: Despite its limited sample size, the present study suggests that comparing the initial molecular profiles of responders and nonresponders might not be an effective strategy to identify biomarkers of the response to bevacizumab given at recurrence. Yet it suggests that the response rate might differ among GBMs molecular subtypes.

Treatment of malignant gliomas in elderly patients: a concise overview of the literature.

Gliomas are the most frequent primary brain tumors and the incidence data has increased in the elderly population. Unfortunately, prospective studies on this population are few and so the right treatment is unknown. In the elderly patients no standard treatment has been established and therefore the optimal treatment should be individualized. We performed a review analyzing the prognostic and predictive factors, the clinical studies, and the correct management of this population.

Bevacizumab-Based Therapy for Patients with Brain Metastases from Non-Small-Cell Lung Cancer: Preliminary Results.

BACKGROUND: Bevacizumab is a recombinant humanized monoclonal antibody that obstructs the vascular endothelial growth factor (VEGF) pathway. Despite its extensive employment in the treatment of primary tumors of the brain, experience of brain metastatic disease, a frequent complication in patients with lung cancer, is very limited. On the basis of the strong antiedemigenous effect and no risk of intracranial bleeding, we administered a bevacizumab-based chemotherapy to patients with non-small-cell lung cancer (NSCLC) and symptomatic metastatic brain lesions who were not suitable candidates for a specific local therapy. METHODS: The patients received bevacizumab 7.5 mg/kg and cisplatin 75 mg/m(2) on day 1, and gemcitabine 1,250 mg/m(2) on days 1 and 8, every 21 days. RESULTS: We studied 13 patients with clinical and radiological progressive brain metastases; the majority had a treatment-naïve disease. Bevacizumab-based chemotherapy was found to be well tolerated and effective: progression-free survival (PFS) was 9.1 months (range: 0.9-39.2+) and overall survival (OS) was 9.6 months (range 3-41.5+). CONCLUSIONS: Bevacizumab-based therapy proved to be feasible and safe. The PFS and the OS data are very encouraging as well as the symptomatic benefit due to bevacizumab's high capacity to provide a long-lasting decrease of perilesional edema.

Bevacizumab as front-line treatment of brain metastases from solid tumors: a case series.

BACKGROUND: Despite the large use of bevabizumab in the treatment of primary tumors of the brain, there is only limited experience with brain metastases (BM) and no experience in the treatment of previously untreated secondary brain lesions. PATIENTS AND METHODS: We treated patients with BM, not suitable for local treatment, with a bevacizumab-based therapy associated with chemotherapy or interferon-α, as indicated for the primary cancer type. RESULTS: We studied 18 patients with BM mostly from lung and renal adenocarcinoma, and the majority of patients had a treatment-naïve brain disease. Bevacizumab was found to be effective: the response rate was 60% partial responses with 40% disease stabilizations. The progression-free survival was 14 months and the overall survival was 15 months. Moreover, bevacizumab has a high capability of providing a long-lasting clinical benefit and reducing edema. CONCLUSION: Bevacizumab for treatment of BM is feasible and the efficacy data are very encouraging.

Hypertension as a biomarker in patients with recurrent glioblastoma treated with antiangiogenic drugs: a single-center experience and a critical review of the literature.

Treatment with angiogenesis inhibitors is becoming a cornerstone of modern anticancer therapy. Hypertension (HTN) is a common adverse event during antiangiogenic treatment and might represent a cancer biomarker in patients with recurrent glioblastoma treated with angiogenesis inhibitors. In a retrospective study, we analyzed 53 patients with recurrent glioblastoma treated with antiangiogenic drugs. Thirty patients were treated with sorafenib and 23 patients were treated with bevacizumab. All patients underwent brain gadolinium-enhanced MRI assessments according to the Radiologic Assessment in Neuro-Oncology criteria every 2 months or when clinically indicated. Blood pressure was measured before and during the treatment. We investigated whether treatment-related HTN may be associated with outcome in patients treated with antiangiogenic drugs. After 2 months of treatment, 24 patients (45%) achieved disease control: stable disease (17 patients) or a partial response (seven patients). The median overall survival from the start of antiangiogenic treatment was 7.3 months [95% confidence interval (CI) 6.02-8.5]; the median progression-free survival (PFS) was 2.7 months (95% CI 1.5-3.5); and the 6-month PFS was 32%. Twenty patients (38%) developed grades 2-3 HTN within 2 months of treatment. A significant association was found between HTN and disease control rate, and HTN and 6-month PFS; no significant association was found between HTN and the median PFS. According to univariate and multivariate analyses, HTN was related to a longer survival from antiangiogenic drug administration: 9.8 versus 4.8 months (P=0.001; hazard ratio=3.5, 95% CI 1.6-7.6). Our data indicate that HTN may be an effective biomarker in patients with recurrent glioblastoma treated with antiangiogenic drugs; in particular, it may be associated with a favorable effect on disease control, 6-month PFS, and the median overall survival.

Treating patients with metastatic renal carcinoma: an escape from Phase III.

The wide availability of drugs for the treatment of advanced renal cell carcinoma has recently provided many alternatives for patients historically treated with immunotherapy alone. The six drugs currently available for the treatment of metastatic renal cell carcinoma became available to physicians after the approval processes performed by regulatory agencies, based mainly on the results of Phase III studies. Owing to the stringent entry criteria of the studies, patients are not representative of the entire population. Results of Phase III studies are extrapolated to all renal cell carcinoma populations without taking into account patients with different comorbidities. The purpose of this review is to analyze and weigh the safety data available for the drugs approved for metastatic renal cell carcinoma and to suggest the best therapy in terms of both efficacy and safety based on the multiplicity of features of each patient in relation to the main characteristics of each agent.

Cilengitide in bevacizumab-refractory high-grade glioma: two case reports and critical review of the literature.

High-grade gliomas (HGG) are aggressive and highly vascularized brain tumours. Despite multimodality therapy including surgery, radiation therapy and in many cases temozolomide chemotherapy, the prognosis is dismal. Salvage therapies following progression after radiation therapy and chemotherapy have historically yielded disappointing results. Bevacizumab is an interesting antiangiogenic drug used as a second-line treatment but although most patients benefit, essentially all patients ultimately progress. Moreover, some clinical studies have documented low activity of a second attempt at vascular endothelial growth factor pathway inhibition after failure of a first. The use of another drug with a different angiogenic pathway inhibition may probably result in a higher activity. Here, we describe, to our knowledge for the first time, the activity and safety of cilengitide, an agent with a different antiangiogenic and anti-invasive activity, administered in two bevacizumab-refractory patients with HGG. In addition, we present a rapid review of the activity of cilengitide in HGG.