Pandemic whole-virion, Vero-cell-derived, adjuvant-free influenza A H1N1 vaccine in patients with solid tumors and hematologic malignancies receiving concurrent anticancer treatment: Immunogenicity, tolerability, and acceptability during the pandemic situation.

Patients with malignancies are considered to be at increased risk of acquiring influenza. Because of higher complication and case fatality rates, preventive measures such as vaccination are of great interest. The objective of this study was to assess the acceptability, tolerability and immunogenicity of an adjuvant-free whole-virion pandemic influenza A (H1N1) vaccine in cancer patients with ongoing anticancer treatment during a 'pandemic situation'. Adult patients with hematologic malignancies or solid tumors and concurrent cytotoxic, targeted, and/or hormone therapy were recruited during the influenza A (H1N1) pandemic in 2009/2010 and were offered free vaccine. Antibody titers were measured using virus-specific hemagglutination inhibition assay and ELISA. Among 285 patients with solid tumors who were offered vaccination during their therapy, 260 (91.2%) declined and 25 (8.8%) accepted. Seventeen patients with hematologic malignancies were also vaccinated during therapy; 23 healthy individuals served as a control group. When measured using hemagglutination-inhibition assays, rates of seroprotection, seroconversion, and geometric mean titer ratios after the second vaccination were 96%, 70%, and 4.1 respectively among the healthy individuals, 90%, 52%, and 4.3 among patients with solid tumors, and 67%, 13%, and 1.5 among patients with hematologic malignancies during therapy (P<0.05). When measured using ELISA, seropositivity differed significantly among the three groups after the second vaccination: healthy individuals 74%, patients with solid tumors 57%, those with hematologic malignancies 13% (P<0.001). The vaccine was well tolerated. Our results demonstrate a low uptake of the well tolerated adjuvant-free influenza A (H1N1) vaccine by cancer patients receiving anticancer treatment during the pandemic of 2009/2010. Among the vaccinated patients, the immune response was weaker than that in healthy individuals. The immune response in patients with hematological malignancies was low. Two doses of vaccine are needed in these immunosuppressed patients.

Evaluation of diagnostic and treatment approaches towards acute dyspnea in a palliative care setting among medical students at the University of Vienna.

BACKGROUND: Dyspnea is common in advanced cancer patients with opioids as first line treatment. OBJECTIVES: To evaluate the level of knowledge about diagnosis and treatment of dyspnea in palliative care patients among 4th year students. METHODS: A case report was distributed to the students describing acute dyspnea in a lung cancer patient. Students were asked to rank their diagnosis and treatment options by importance. RESULTS: 633 medical students in their 4th year attended a seminar about palliative care. Of these, 423 (77%) completed the case report. The most frequent diagnostic option was measuring patient's oxygen saturation (n = 388), followed by auscultation (n = 339). As treatment options, students chose the delivery of oxygen (n = 393) as most important. The application of opioids was suggested by a total of 138 students. CONCLUSION: Although students did not have practical skills in treating advanced cancer patients with acute dyspnea, 32.6% would suggest an opioid as treatment option.

Longitudinal brain imaging of five malignant glioma patients treated with bevacizumab using susceptibility-weighted magnetic resonance imaging at 7 T.

Malignant glioma is a rare tumor type characterized by prominent vascular proliferation. Antiangiogenic therapy with the monoclonal antibody bevacizumab is considered as a promising therapeutic strategy, although the effect on tumor vascularization is unclear. High-field susceptibility-weighted imaging (SWI) visualizes the microvasculature and may contribute to the investigation of antiangiogenic therapy responses in gliomas. We prospectively studied five adult malignant glioma patients treated with bevacizumab-containing regimens. In each patient, we performed three 7-T SWI and T1-weighted imaging investigations (baseline and 2 and 4 weeks after the start of bevacizumab treatment). In addition, we imaged a postmortem brain of a patient with glioblastoma using 7-T SWI and performed detailed histopathological analysis. We observed almost total resolution of brain edema in three of five patients after initiation of bevacizumab therapy. In one case with rapid increase of the lesion size despite bevacizumab therapy, SWI showed progressive increase of irregular hypointense structures, most likely corresponding to increasing amounts of pathological microvasculature. In one case with progressive neurological decline, 7-T images showed multiple intratumoral microhemorrhages after the first bevacizumab application. Correlation of postmortem neuroimaging with histopathology confirmed that SWI-positive structures correspond to tumor vasculature. The experience from our case series indicates that longitudinal 7-T SWI seems to be an appropriate method for investigation of changes in brain tumor vascularization over time under antiangiogenic therapy.

Pilot study on sex hormone levels and fertility in women with malignant gliomas.

The standard treatment of patients with high-grade gliomas based on conformal radiation therapy (RT) with or without chemotherapy (CT) may induce endocrine deficiencies of pituitary and subsequently also of peripheral hormones. In 24 premenopausal women with high-grade gliomas treated with RT and CT, hormonal changes and their impact on quality of life were investigated. Serum concentrations of gonadal, pituitary and of thyroid hormones were measured at various time points after initial anti-neoplastic therapy. Additionally, endovaginal ultrasound was performed and patients' quality of life (QLQ) and female role functioning were assessed. Of 24 patients, 23 (96%) reported a change in their menstrual pattern. Twenty-one patients reported at least transient amenorrhoea with a mean duration of 26.1 months (3-96 months). Increased prolactin serum levels were found in 10 women, 8 of them with amenorrhoea. Thirteen women showed menopausal or perimenopausal hormone pattern, 3 a pattern compatible with hypogonadism. Changes in thyroid hormone levels were seen in 8 patients. Furthermore, patients complained about fatigue and menopausal symptoms, like flushes, weakness and gain of weight. They felt a decrease of libido combined with the loss of attractiveness as a female, and an increased need for tender care and security. The hormonal deficiencies in female patients with malignant gliomas require thorough evaluation and individualized diagnosis and sometimes intervention.

Treating rheumatic patients with a malignancy.

Management of patients with inflammatory rheumatic disease and a history of (or even a current) malignant disease poses some particular challenges. As direct evidence of the risk of (recurrent or de novo) malignancy in patients with a history of malignant disease is scarce, such a risk may be estimated indirectly from the principal carcinogenicity of the respective drug to be used or (also indirectly) from cancer reactivation data from the transplant literature. In general, cancer risk is increased in patients receiving combination immunosuppressive treatment, but the risk in patients receiving individual drugs (with the exception of alkylating agents) remains entirely unclear. Indirect evidence supports the intuitive concept that the risk of cancer decreases over time after a successful cancer treatment. The only two studies in rheumatic patients with a cancer history were small and have not been able to show an increase in cancer reactivation. The risk of reactivation also depends on the site and location of the prior malignancy. In conclusion, the decision to treat a patient with a history of cancer immunosuppressively should be shared by the rheumatologist and the oncologist. Once the decision is established, such patients need intensive and close monitoring.

Clinical outcome with bevacizumab in patients with recurrent high-grade glioma treated outside clinical trials.

BACKGROUND: Patients with recurrent high-grade glioma (HGG) have a poor prognosis and there is no defined standard of care. High levels of vascular endothelial growth factor (VEGF) expressed in HGG make the anti-VEGF monoclonal antibody bevacizumab (BEV) of particular interest. PATIENTS AND METHODS: In an ongoing registry data were collected from patients who have received BEV for the treatment of recurrent HGG. The primary objective was the identification of any clinical benefit as assessed by change in Karnofsky Performance Score (KPS), decreased steroid use and duration of treatment. RESULTS: Two hundred and twenty-five patients with HGG were included (176 glioblastoma; 49 anaplastic glioma; median age 52 years). KPS improved in 10% of patients and remained stable in 68%. Steroids were stopped in 37.6% of patients. Median duration of treatment was 5.5 months; 19.1% of patients were treated for more than 12 months. Median overall survival from beginning of BEV treatment was 8.5 months. At the time of analysis, 169 patients (75.1%) had died and 56 patients (24.9%) were alive. Only 21 patients (9.3%) discontinued treatment due to toxicity. CONCLUSIONS: Our data reveal valuable palliation with preservation of KPS and an option for steroid withdrawal in patients treated with BEV, supporting the role of this therapy in late-stage disease.

Immature and absolute platelet count changes and thrombocytopenia in malignant glioma.

BACKGROUND: Temozolomide (TMZ) is commonly used for the therapy of malignant glioma and induces thrombocytopenia in a fraction of patients. Currently, no biomarkers predicting TMZ-induced thrombocytopenia are available. In this study, we investigated whether changes in platelet count (PLT) or the immature platelet fraction (IPF) may serve as predictor of TMZ-induced thrombocytopenia in malignant glioma patients. METHODS: We prospectively included 52 malignant glioma patients receiving TMZ-containing therapy regimens in this study. Platelet counts and IPF were determined at each clinical follow-up visit (weekly during concomitant radiochemotherapy or at least monthly during TMZ monotherapy) using the Sysmex XE-2100 system. We explored the diagnostic utility of PLT change/day and IPF change/day from the last to the current follow-up visit for the prediction of clinically relevant thrombocytopenia (PLT < 100·000 µl(-1) ) at the next follow-up visit. RESULTS: Relevant thrombocytopenia was observed in 10 of 234 occasions. The areas under the receiver operating characteristic curves for PLT absolute change/day, PLT relative change/day and IPF relative change/day were 0·675, 0·703 and 0·663, respectively. The Youden indices (maximum sum of sensitivity and specificity minus one) were 0·31, 0·39, and 0·29, respectively. The corresponding positive predictive values were 16%, 57%, and 6·7%, and the negative predictive values were 97%, 97%, and 98%, respectively. CONCLUSIONS: The rather moderate diagnostic potential of our data indicate that the time course of PLT counts and IPF measured at routine clinical follow-up are not useful for the prediction of thrombocytopenia in glioma patients treated with TMZ.

Neurocognitive training in patients with high-grade glioma: a pilot study.

Although their neurocognitive performance is one of the major concerns of patients with high-grade gliomas (HGG) and although neurocognitive deficits have been described to be associated with negative outcome, neurocognitive rehabilitation is usually not integrated into the routine care of patients with malignant gliomas. In this pilot trial, a weekly group training session for attention, verbal, and memory skills was offered to patients with HGG with pre and post-training evaluation. Eleven patients, six with glioblastoma multiforme and five with WHO grade III gliomas, median age 50 years, with a Karnofsky performance score of 80-100 participated in ten group training sessions of 90 min. For evaluation at baseline and after the training by a neuropsychologist not involved in care or training of the patients, Trail Making Tests A and B (TMTA and TMTB), Hopkins Verbal Learning Test (HVLT), and the Controlled Oral Word Association Test (COWA) were used. Comparison of mean group differences between baseline and at post-training evaluation after 12 weeks revealed improvement across all neurocognitive variables. The patients showed a great diversity in their performances, with worsening, improvement, and stabilization. However, a significant group difference was detected only for the HVLT (score 19.6 +/- 8.9 at baseline, 23.6 +/- 8.8 after 12 weeks, P = 0.04). This pilot study shows that neurocognitive training in patients with HGG is feasible as group training with weekly sessions and might be able to induce improvements in attention and memory skills.

Frequent MGMT (0(6)-methylguanine-DNA methyltransferase) hypermethylation in long-term survivors of glioblastoma: a single institution experience.

BACKGROUND: The aim of this retrospective study was to analyse the MGMT (0(6)-methylguanine-DNA methyltransferase) promoter methylation status in long-term surviving (≥ 3 years) patients with glioblastoma multiforme (GBM). METHODS: The methylation status of the MGMT promoter was determined by bisulfite modification of the DNA and subsequent methylation-specific polymerase-chain-reaction (MSP). DNA was extracted from routinely formalin-fixed and paraffin-embedded tumour tissue samples. RESULTS: MSP yielded interpretable results in only 14 of 33 (42%) long-term surviving patients with GBM. A methylated band was seen in 3 of 14, methylated as well as unmethylated bands in 8 of 14 and an only unmethylated band in 3 of 14 patients, thus, yielding MGMT promoter methylation in 11 of 14 patients. The two groups of patients with methylated and unmethylated MGMT promoter status were too small to draw any firm statistical conclusions. CONCLUSIONS: Long-term surviving patients with GBM have very frequently intratumoural MGMT promoter methylation. This phenomenon discriminates long-term survivors from a non-selected group of patients with GBM. The standardization of the MSP for the determination of the MGMT promoter methylation status seems to be necessary in order to make this methodology a more reliable one.

A prospective, open label, randomized phase II trial of weekly docetaxel versus weekly vinorelbine as first line chemotherapy in patients with androgen independent prostate cancer.

PURPOSE: In previous phase I to III studies docetaxel and vinorelbine have shown promising activity in androgen independent prostate cancer. In the present trial we assessed the efficacy and tolerability of single agent low dose docetaxel vs vinorelbine in patients with advanced androgen independent prostate cancer. MATERIALS AND METHODS: A total of 40 chemotherapy naive patients with histologically proven androgen independent prostate cancer, adequate androgen ablation, and clinical and/or biochemical progression were randomly assigned to receive either 25 mg/m(2) docetaxel (arm A) or 25 mg/m(2) vinorelbine (arm B) weekly. Treatment was continued until clinical and/or biochemical progression. In cases of progression patients switched to the alternative treatment arm. The primary end point was time to disease progression. Secondary end points included prostate specific antigen response rates in sequential treatment, analgesic response and toxicity. RESULTS: The current analysis showed a doubled risk of progression in treatment arm B. The median time to first disease progression was 14.5 months for arm A vs 4.4 months for arm B. The proportion of patients with a greater than 50% prostate specific antigen decrease on first line therapy was significantly higher in arm A (62.5%) compared to arm B (11.1%) (p = 0.0033). After progression to docetaxel second line vinorelbine yielded a greater than 50% prostate specific antigen response rate of 28.6% vs 62.5% for second line docetaxel. Clinically significant toxicity occurred more often in arm B with neutropenia grade 4 seen in 22% and grade 3 in 28% of patients (p = 0.0005) during the first treatment phase. CONCLUSIONS: While weekly application of both cytotoxic agents was well tolerated, this study demonstrates the superiority of docetaxel vs vinorelbine as monotherapy in the treatment of androgen independent prostate cancer.

Promoter hypermethylation of GSTP1, AR, and 14-3-3sigma in serum of prostate cancer patients and its clinical relevance.

OBJECTIVE: Hypermethylation of tumor suppressor genes (TSG) is thought to play an important role in tumorigenesis of prostate cancer. The main focus of research was the detection of TSG hypermethylation in cancer tissue. Our aim was to evaluate the feasibility of detection of hypermethylated genes in serum of prostate cancer patients and its correlation with clinicopathological parameters. METHODS: One hundred twenty-five serum samples from 62 patients with hormone refractory prostate cancer (HRPC), 14 patients with early disease, and 49 healthy controls were examined. After DNA extraction and sodium-bisulfite treatment, conventional methylation-specific PCR (MSP) was performed for glutathione S-transferase P1 (GSTP1), androgen receptor (AR), and 14-3-3sigma. RESULTS: In serum of HRCP patients, frequency of GSTP1, AR, and 14-3-3sigma hypermethylation was 32.2, 40.3, and 86.6%, respectively. In serum of patients with early disease frequency of GSTP1, AR, and 14-3-3sigma, hypermethylation was 21.4, 35.7, and 85.7%. In healthy controls, frequency of GSTP1, AR, and 14-3-3sigma hypermethylation was 0, 26.5, and 55.1%, respectively. There was a significant increase of frequency of TSG hypermethylation for GSTP1 and 14-3-3sigma in HRPC patients, in comparison with healthy controls. GSTP1 hypermethylation in HRPC patients was significantly correlated with differentiation of cancer and metastatic disease. CONCLUSIONS: Hypermethylation of TSG can be detected in serum of prostate cancer patients. Some hypermethylated TSG can be detected in serum of healthy controls. GSTP1 was not detectable in controls and correlated significantly with Gleason score and stage of disease. Therefore, this gene may be a promising new tool in prostate cancer diagnosis.

Perturbation of the tumor necrosis factor--related apoptosis-inducing ligand cascade in ovarian cancer: overexpression of FLIPL and deregulation of the functional receptors DR4 and DR5.

PURPOSE: Epithelial ovarian cancer is the most common cause of mortality from gynecologic malignancies. Due to advanced stage at diagnosis, most patients need systemic treatment in addition to surgery. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family with a promising toxicity profile and synergistic activity with chemotherapeutic agents. EXPERIMENTAL DESIGN: We used an arrayed panel of epithelial ovarian cancer tissue to assess the protein expression of TRAIL and the clinically most relevant members of its pathway death receptors 4 and 5 (DR4 and DR5) and the long form of FLICE inhibitory protein (FLIPL). RESULTS: We could show that a majority (66.2%) of the tumor tissues displayed either reduced DR4/DR5 expression (20.6%), increased FLIPL expression (39.7%), or both (5.9%) as determined by immunohistochemistry. Furthermore, higher TRAIL expression in the surrounding connective tissue but not in the tumor cells is significantly (P<0.05) linked with favorable overall survival in advanced-stage patients. CONCLUSIONS: Mechanisms to escape the immune surveillance mediated by TRAIL are developed by ovarian cancer cells in a high percentage. TRAIL expression in the ovarian cancer microenvironment has an effect on overall survival. These findings enhance our understanding of ovarian cancer pathology and might be helpful in guiding TRAIL-based therapy in future.

Common death receptor 4 (DR4) polymorphisms do not predispose to ovarian cancer.

OBJECTIVE: Polymorphisms of death receptor 4 (DR4) might impair the apoptotic signal transduction and lead to dysregulation of the homeostasis between cell survival and cell death, promoting tumor development and progression. METHODS: We performed an analysis of known DR4 polymorphisms, namely G442A, C626G, and A1322G, in germ line DNA of 97 ovarian cancer patients and controls as well as in established ovarian cancer cell lines. RESULTS: Patient and matched control populations were not differing significantly in case of G442A (P = 0.736) and C626G alterations (P = 0.699). For the A1322G transversion, we generated population data for the first time and could find a rate of 19% heterozygotes and 3% homozygotes. Again, we could not detect any significant difference between patients and controls (P = 0.326). CONCLUSION: To summarize, alterations of the DR4 gene do not lead to clinically relevant ovarian cancer predisposition and are therefore most unlikely to contribute to familial ovarian cancer.

The efficacy of trastuzumab in Her-2/neu-overexpressing metastatic breast cancer is independent of p53 status.

PURPOSE: Her-2/neu and p53-mediated signalling have been shown to interact at various cellular levels. However, the clinical relevance of p53 alterations in patients receiving trastuzumab for Her-2/neu-overexpressing metastatic breast cancer (MBC) remains unknown. The present study was performed to corroborate previous in vitro findings from our laboratory showing that trastuzumab induces growth arrest and apoptosis in a p53-independent manner. METHOD: Retrospective immunohistochemical (IHC) analysis for p53 protein expression was carried out on tumour specimens from 104 patients receiving trastuzumab-based treatment for Her-2/neu-overexpressing MBC at a single institution. p53 status was correlated with response (R) and clinical benefit (CB), median progression-free survival (PFS) time and overall survival (OAS) time in univariate and multivariate analyses. RESULTS: Characteristics were similar between p53-negative and p53-positive tumours (all P>0.05). In univariate analyses, R (39% vs 26%, P=0.208), CB (70% vs 57%, P=0.218), PFS (6.2 months vs 4.2 months, P=0.186) and OAS (23.8 months vs 23.2 months, P=0.650) were similar for p53-positive tumours and p53-negative tumours, respectively. In multivariate analyses, p53 status was not a significant predictor of R, CB, PFS or OAS (all P>0.05). CONCLUSIONS: p53 status, as determined by IHC, is not a predictor of the clinical efficacy of trastuzumab-based treatment in patients with Her-2/neu-overexpressing MBC.