Heart Rate Variability in Surgical Patients Experiencing Live Bedside Music; An Explorative Study.

It's known that surgery elicits a stress response involving the autonomic nervous system (ANS) which is important in general recovery but can also have detrimental effects in older patients. Music seems to positively effect postoperative recovery, although the mechanism requires further unravelling. Our objective was to explore the response of the ANS to live bedside music in older surgical patients, by using heart rate variability (HRV) as a proxy. This explorative prospective non-randomized controlled cohort study included 101 older non-cardiac surgical patients, with a median age of 70 (range 60-88 years). HRV was measured in a cohort receiving live bedside music provided by professional musicians and in a control group that did not receive music. HRV was measured pre-intervention, during the intervention, 30 min after the intervention, and again after three hours. Mixed linear modelling was used to assess the effect of the intervention compared to the control group over time. A significant change in both the low and high frequency bands (p = 0.041) and (p = 0.041) respectively, was found over time in the music group compared to the control group indicating relaxation and increased parasympathetic activity in the music group. Other measures revealed a trend but no significant effect was shown. These results provide a first glance and contribute to a better understanding of the effect of music on the recovery of older surgical patients.

Individualized Dosing Patterns in the Treatment of Older Patients with Gastrointestinal Stromal Tumors: Results of a Registry-Based Observational National Cohort Study Including 871 Patients.

BACKGROUND: While the effectiveness of tyrosine kinase inhibitors (TKIs) seems similar in older patients with gastrointestinal stromal tumors (GIST) compared with younger patients, toxicities in older patients treated with TKIs more often lead to discontinuation of treatment. OBJECTIVE: To better understand the age-related pharmacology and pharmacodynamic differences in patients with GIST treated with TKIs, the primary aim of this study was to evaluate TKI dosing patterns in older patients with GIST, while the secondary aims were to evaluate differences in imatinib trough plasma concentrations between age groups and to compare the overall survival (OS) in patients with and without dose reductions in all treatment lines in a palliative setting. METHODS: Patients (18 years of age or older) with histologically proven GIST diagnosed between January 2009 and June 2021 and treated with one or more lines of TKIs were selected from the Dutch GIST Registry (DGR) database. Age groups were divided into younger patients (age <70 years) and older patients (age ≥70 years). All imatinib trough plasma concentrations of blood withdrawals taken from initiation of imatinib until a maximum of 1 year of treatment with imatinib were collected. Reasons for first adjustment of treatment were classified as adverse event, dose modification, progressive disease and other reasons. The next treatment steps after first adjustment of treatment were defined as dose escalation, dose reduction, dose interruption, or end of treatment. The association of dose reduction and OS was analyzed using the landmark approach. RESULTS: Overall, 871 patients were included in this study, including 577 younger patients and 294 older patients. Older patients more often had an adverse event as the reason for first adjustment of treatment with both imatinib (45.6%; p < 0.001) and sunitinib (58.6%; p = 0.224) compared with younger patients (19.5% and 42.7%, respectively). Adjustment of imatinib and sunitinib after starting on a standard dose because of an adverse event most often resulted in dose reduction in both age groups. Median trough plasma concentrations of all samples taken within the first year after initiation of imatinib were higher in older patients (1228 ng/mL, interquartile range [IQR] 959-1687) compared with younger patients (1035 ng/mL [IQR 773-1377]; p < 0.001). No significant differences were seen between OS in patients with or without dose reduction in all treatment lines (imatinib: p = 0.270; sunitinib: p = 0.547; and regorafenib: p = 0.784). CONCLUSION: Older patients showed higher imatinib trough plasma concentrations compared with younger patients and also had earlier and more often adverse events as the reason for first adjustment of treatment with imatinib followed by dose reduction. However, in a landmark analysis, patients with imatinib dose reductions had no poorer outcomes compared with patients not requiring a dose reduction.

Live bedside music for hospitalized older adults: A qualitative descriptive interview study.

INTRODUCTION: Hospitalization may have a major impact on older patients as it is often a period of psychosocial vulnerability. Music is one of the most described art forms used in healthcare. Applied in clinical settings, it can affect a patients' emotional and psychosocial well-being. Incorporating a wider perspective of health promotion that aims to advance not only physical health, but a patients' overall well-being, is part of a person-centred approach to care. We developed an innovative participatory music practice in which professional musicians and music therapists visited patients at their bedside for 10-15 min in a Dutch and Austrian hospital. This qualitative study explores the added value of live bedside music practice for older hospitalized patients in Austria and the Netherlands. METHODS: Semi-structured interviews were conducted between October 2020 and February 2022 with 23 hospitalized patients aged ≥60 years. Due to the COVID-19 pandemic, the music sessions in Austria were facilitated by establishing a live connection between musicians and patients using a tablet. Data were transcribed verbatim and performed qualitative content analysis following the steps of thematic analysis. The COnsolidated criteria for REporting Qualitative research (COREQ) checklist was applied to report data collection, analysis and results. RESULTS: Four themes emerged from the data analysis. Participants described the perceived influences of live bedside music in terms of (1) emotional release, (2) positive distraction, (3) alterations in contact and (4) shared humanity. Overall, participants positively valued the live bedside music practice and expressed a desire for its continuation. CONCLUSION: This study explores the experiences and the added value of live bedside music for older hospitalized patients. By facilitating distraction and emotional release and enhancing nurse-patient interactions, live bedside music can significantly improve hospital experiences for older patients. Results reveal that live bedside music provides a positive patient experience and can be part of integrative and holistic care for hospitalized older patients. Live bedside music can attend to the emotional needs of older patients which are often under addressed in clinical settings but are crucial for enhancing their well-being.

Disadvantaged Subgroups Within the Global Head and Neck Cancer Population: How Can We Optimize Care?

Within the global head and neck cancer population, there are subgroups of patients with poorer cancer outcomes independent from tumor characteristics. In this article, we review three such groups. The first group comprises patients with nasopharyngeal cancer in low- and middle-income countries where access to high-volume, well-resourced radiotherapy centers is limited. We discuss a recent study that is aiming to improve outcomes through the instigation of a comprehensive radiotherapy quality assurance program. The second group comprises patients with low socioeconomic status in a high-income country who experience substantial financial toxicity, defined as financial hardship for patients due to health care costs. We review causes and consequences of financial toxicity and discuss how it can be mitigated. The third group comprises older patients who may poorly tolerate and not benefit from intensive standard-of-care treatment. We discuss the role of geriatric assessment, particularly in relation to the use of chemotherapy. Through better recognition and understanding of disadvantaged groups within the global head and neck cancer population, we will be better placed to instigate the necessary changes to improve outcomes and quality of life for patients with head and neck cancer.

'What matters to you?' Health outcome prioritisation in treatment decision-making for older patients.

BACKGROUND: for shared decision-making, it is important to discuss of the patients' priorities in order to align treatment decisions with these priorities. OBJECTIVE: to assess the most important health outcome for older patients on the verge of making a treatment decision, using the Outcome Prioritization Tool (OPT). Secondary objectives were the feasibility of the OPT and patient variables associated with prioritising different health outcomes. DESIGN: retrospective cohort study. SETTING AND SUBJECTS: at the University Medical Hospital Groningen, the Netherlands, 350 patients were included who visited the geriatric outpatient clinic during the work-up regarding a complex treatment decision (such as cancer treatment or heart valve replacement). METHODS: during geriatric assessment, patients prioritised between four health outcomes, using the OPT. RESULTS: median age was 78.5 years, 172 (49.1%) were referred regarding a treatment decision for a malignant disease. Cognitive impairment was present in 23.6%. Most patients (55.2%) prioritised maintaining independence as their most important goal, followed by extending life in 21.1%. Only cognitive impairment was significantly associated with prioritising extending life as the most important health outcome. For 107 patients (30.6%), the OPT was not feasible; these patients more often had malnutrition and assisted living. CONCLUSIONS: the main health outcome of older patients on the verge of making a treatment decision was maintaining independence, followed by extending life. Patients with cognitive impairment more often prioritised extending life. The OPT was feasible as a decision aid for most patients. For optimal shared decision-making, it is crucial to take patient preferences into account.

Was it worth it? Benefits of transcatheter aortic valve implantation from a patient's perspective.

OBJECTIVES: Transcatheter aortic valve implantation (TAVI) is an important treatment option for patients with severe aortic stenosis. To improve patient selection, shared decision-making is recommended to elicit patients' treatment expectations and goals. We assessed patients' expectations and goals before TAVI treatment and whether these were met after treatment. Additionally, we evaluated how meeting these goals aligned with quality of life and functional recovery. DESIGN: A mixed method study. SETTING: An academic medical center. PARTICIPANTS: Seventy-four patients undergoing TAVI between 2015 and 2017. MEASUREMENTS: Patients' expectations and goals were assessed qualitatively before treatment. Six to twelve months post procedure, quality of life was measured with the EuroQuol-5D and any change in the number of dependencies in (instrumental) activities of daily living was assessed. RESULTS: Mean age of patients was 81.5 years, and 37.8% were male. Regaining the ability to engage in a specific hobby or activity was the most important treatment goal (33 patients, 54.1%), followed by reducing symptoms (19 patients 31.1%). 66.2% of patients stated that their treatment goal was met. Quality of life was higher in this group, as compared with patients who had not met their treatment goal. Twenty-three patients (31.1%) showed functional improvement. CONCLUSION: TAVI patients were quite capable of eliciting treatment goals and a majority stated, after treatment, that these had been met patients' experience of treatment benefits regarding these goals had poor alignment with functional outcomes. This raises questions regarding relevant outcome measurements in this population, and could aid in improving shared decision-making and patient selection for TAVI.

How well do healthcare professionals know of the priorities of their older patients regarding treatment outcomes?

OBJECTIVES: For shared decision making, it is crucial to identify patients' priorities regarding health outcomes. Our aim was to study whether healthcare professionals know these priorities. METHODS: In this cross-sectional study we included older patients who had to make a treatment decision, their general practitioners (GPs) and their medical specialists. Agreement between the patients' main health outcome as prioritised by using the Outcome Prioritization Tool (OPT) and the perception of the same outcome by their healthcare professionals. RESULTS: Eighty-seven patients were included. Median age was 76 years, 87.4% of patients presented with malignant disease. The majority prioritised maintaining independence (51.7%), followed by extending life (27.6%). The agreement between patients and healthcare professionals was low (GPs 41.7%, kappa 0.067, p = 0.39), medical specialists 40.3%, kappa 0.074, p = 0.33). Positively related to agreement was patient's age > 75, and a longer relation with their patients (for GPs), and the patient having no partner (for medical specialist). Having a malignant disease, dependent living and functional deficits were negatively related to agreement. CONCLUSIONS: Healthcare professionals have poor perceptions of their patients' priorities. PRACTICE IMPLICATIONS: To realise patient-centered care, it is crucial to discuss priorities explicitly with all patients.

The effect of treatment modifications by an onco-geriatric MDT on one-year mortality, days spent at home and postoperative complications.

OBJECTIVES: Decision-making in older patients with cancer can be complex, as benefits of treatment should be weighed against possible side-effects and life-expectancy. A novel care pathway was set up incorporating geriatric assessment into treatment decision-making for older cancer patients. Treatment decisions could be modified following discussion in an onco-geriatric multidisciplinary team (MDT). We assessed the effect of treatment modifications on outcomes. MATERIALS AND METHODS: This retrospective study was performed in the surgical department of a University Hospital. Patients of 70 years and older with a solid malignancy were included. All patients underwent a nurse-led geriatric assessment (GA) and were discussed in an onco-geriatric MDT. This could result in a modified or an unchanged treatment advice compared to the regular tumor board. Primary outcome was one-year mortality. Secondary outcomes were post-operative complications and days spent in hospital in the first year after inclusion. RESULTS: For the 184 patients in the analyses, the median age was 77.5 years and 41.8% were female. For 46 patients (25%), the treatment advice was modified by the onco-geriatric MDT. There was no significant difference in one-year mortality between the unchanged and modified group (29.7% versus 26.1%, p = 0.7). There were, however, significantly fewer days spent in hospital (median 5 vs 8.5 days p = 0.02) and fewer grade II or higher postoperative complications (13.3% versus 35.5% p = 0.005) in the modified group. CONCLUSION: Incorporating geriatric assessment in decision-making did not lead to excess one-year mortality, but did result in fewer complications and days spent in hospital.

Using the Outcome Prioritization Tool (OPT) to assess the preferences of older patients in clinical decision-making: A review.

Shared decision making can guide patients facing difficult treatment decisions, with a trade-off between risks and benefits, taking patient goals and preferences into account. The Outcome Prioritization Tool (OPT) was developed to facilitate the discussion of goals and preferences with older patients in an encompassing, non-disease-specific way. The OPT is used in both primary and secondary healthcare for several treatment decisions, but data regarding the tool are limited. A concise review yielded two developmental articles, four articles describing three studies using the OPT, and one study protocol. All studies were performed among older patients. In those studies, the majority of patients ranked maintaining independence as most important. The tool has been shown to be feasible for both patients and healthcare providers.

Determinants of health-related quality of life in elderly ovarian cancer patients: The role of frailty and dependence.

OBJECTIVE: To investigate the impact of frailty and dependence on health-related quality of life (HRQOL) in elderly women diagnosed with epithelial ovarian cancer (EOC). METHODS: Data was gathered from a prospectively collected data biobank, OncoLifeS (Oncological Life Study) at the University Medical Center of Groningen. Women with a diagnosis of EOC, ≥65 years of age, with baseline assessment available from January 2016 to May 2018 were included. HRQOL was determined using the EORTC QLQ-C30 yielding scores on Global Health Status, five functional scales, three symptom scales, and six single items. The summary score was also calculated. Frailty was measured using the Groningen Frailty Indicator (GFI), and dependence using the Instrumental Activities of Daily Living (IADL). To evaluate the impact of frailty and dependence on HRQOL, linear regression was performed. Analyses were adjusted for age and tumor stage. RESULTS: 84 patients were included. Median age was 71 years (IQR: 68-75), 78% had advanced stage and 81% serous histology. Overall, the median global health status was 67 (IQR: 50-83). HRQOL scales with lowest scores were: role functioning (median: 66.7; IQR: 33-100), fatigue (median: 33.3; IQR: 22-56) and insomnia (median: 33.3; IQR: 0-67). Being frail was associated with worse functioning on all HRQOL scales and higher symptom scores (p = .001). Conversely, being independent was associated with better functioning on all HRQOL scales and lower symptom scores. These associations remained significant after adjusting for age and tumor stage. CONCLUSION: In women ≥65 years, diagnosed with EOC, frailty and dependence are associated to reduced HRQOL. These associations remain significant adjusting for age and stage.

How to incorporate geriatric assessment in clinical decision-making for older patients with cancer. An implementation study.

INTRODUCTION: With the accumulating evidence on the added value on prediction of outcomes of geriatric assessment (GA) in older patients with cancer, the question shifts from whether performing a GA is useful, to how to implement this into standard practice in a feasible and effective way. The effect of implementing GA, and assessment of patient preferences on treatment recommendations by an onco-geriatric multidisciplinary team (MDT), was compared to the recommendation previously made by the tumor board (care as usual). METHODS: Patients aged 70 years and older with a solid malignancy who were referred to a tertiary care center for diagnosis and treatment recommendations, as provided by a tumor board, were included. The intervention consisted of: a nurse-led GA and assessment of patient preferences prior to the start of oncological treatment, discussing this in an onco-geriatric MDT, and weighing all this information in a structured, stepwise manner. Treatment recommendations formulated by this onco-geriatric MDT were compared to the treatment recommendations by the tumor board. RESULTS: Of 236 eligible patients, 197 were included. For 27%, treatment recommendations from the onco-geriatric MDT differed from the recommendations formulated by the tumor board. These modifications were mostly towards less intensive curative or palliative treatment. Thirteen percent of patients were subsequently referred to a geriatrician in order to reach a treatment recommendation. DISCUSSION: Implementing an onco-geriatric care trajectory, using GA and assessment of patient preferences, resulted in an adjustment of treatment recommendations for a quarter of patients. Thirteen percent needed subsequent referral to a geriatrician.

Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1.

Many epigenetically inactivated genes involved in ovarian cancer (OC) development and progression remain to be identified. In this study we undertook an integrated approach that consisted of identification of genome-wide expression patterns of primary OC samples and normal ovarian surface epithelium along with a pharmacologic unmasking strategy using 3 OC and 3 immortalized normal ovarian epithelial cell lines. Our filtering scheme identified 43 OC specific methylated genes and among the 5 top candidates (GULP1, CLIP4, BAMBI, NT5E, TGFß2), we performed extended studies of GULP1. In a training set, we identified GULP1 methylation in 21/61 (34%) of cases with 100% specificity. In an independent cohort, the observed methylation was 40% (146/365) in OC, 12.5% (2/16) in borderline tumors, 11% (2/18) in cystadenoma and 0% (0/13) in normal ovarian epithelium samples. GULP1 methylation was associated with clinicopathological parameters such as stage III/IV (p = 0.001), poorly differentiated grade (p = 0.033), residual disease (p < 0.0003), worse overall (p = 0.02) and disease specific survival (p = 0.01). Depletion of GULP1 in OC cells led to increased pro-survival signaling, inducing survival and colony formation, whereas reconstitution of GULP1 negated these effects, suggesting that GULP1 is required for maintaining cellular growth control.

Feasibility of hospital-initiated non-facilitator assisted advance care planning documentation for patients with palliative care needs.

BACKGROUND: Advance Care Planning (ACP) and its documentation, accessible to healthcare professionals regardless of where patients are staying, can improve palliative care. ACP is usually performed by trained facilitators. However, ACP conversations would be more tailored to a patient's specific situation if held by a patient's clinical healthcare team. This study assesses the feasibility of ACP by a patient's clinical healthcare team, and analyses the documented information including current and future problems within the palliative care domains. METHODS: This multicentre study was conducted at the three Groningen Palliative Care Network hospitals in the Netherlands. Patients discharged from hospital with a terminal care indication received an ACP document from clinical staff (non-palliative care trained staff at hospitals I and II; specialist palliative care nurses at hospital III) after they had held ACP conversations. An anonymised copy of this ACP document was analysed. Documentation rates of patient and contact details were investigated, and documentation of current and future problems were analysed both quantitatively and qualitatively. RESULTS: One hundred sixty ACP documents were received between April 2013 and December 2014, with numbers increasing for each consecutive 3-month time period. Advance directives were frequently documented (82%). Documentation rates of current problems in the social (24%), psychological (27%) and spiritual (16%) domains were low compared to physical problems (85%) at hospital I and II, but consistently high (> 85%) at hospital III. Of 545 documented anticipated problems, 92% were physical or care related in nature, 2% social, 5% psychological, and < 1% spiritual. Half of the anticipated non-physical problems originated from hospital III. CONCLUSIONS: Hospital-initiated ACP documentation by a patient's clinical healthcare team is feasible: the number of documents received per time period increased throughout the study period, and overall, documentation rates were high. Nonetheless, symptom documentation predominantly regards physical symptoms. With the involvement of specialist palliative care nurses, psychological and spiritual problems are addressed more frequently. Whether palliative care education for non-palliative care experts will improve identification and documentation of non-physical problems remains to be investigated.

Association of promoter methylation of VGF and PGP9.5 with ovarian cancer progression.

PURPOSE: To elucidate the role of biological and clinical impact of aberrant promoter hypermethylation (PH) in ovarian cancer (OC). EXPERIMENTAL DESIGN: PH of PGP9.5, HIC1, AIM1, APC, PAK3, MGMT, KIF1A, CCNA1, ESR1, SSBP2, GSTP1, FKBP4 and VGF were assessed by quantitative methylation specific PCR (QMSP) in a training set. We selected two genes (VGF and PGP9.5) for further QMSP analysis in a larger independent validation (IV) set with available clinical data. Biologic relevance of VGF gene was also evaluated. RESULTS: PH frequency for PGP9.5 and VGF were 85% (316/372) and 43% (158/366) respectively in the IV set of samples while no PH was observed in controls. In 372 OC cases with available follow up, PGP9.5 and VGF PH were correlated with better patient survival [Hazard Ratios (HR) for overall survival (OS) were 0.59 (95% Confidence Intervals (CI)  = 0.42-0.84, p = 0.004), and 0.73 (95%CI = 0.55-0.97, p = 0.028) respectively, and for disease specific survival (DSS) were 0.57 (95%CI 0.39-0.82, p = 0.003) and 0.72 (95%CI 0.54-0.96, p = 0.027). In multivariate analysis, VGF PH remained an independent prognostic factor for OS (HR 0.61, 95%CI 0.43-0.86, p<0.005) and DSS (HR 0.58, 95%CI 0.41-0.83, p<0.003). Furthermore, PGP9.5 PH was significantly correlated with lower grade, early stage tumors, and with absence of residual disease. Forced expression of VGF in OC cell lines inhibited cell growth. CONCLUSIONS: Our results indicate that VGF and PGP9.5 PH are potential biomarkers for ovarian carcinoma. Confirmatory cohorts with longitudinal follow-up are required in future studies to define the clinical impact of VGF and PGP9.5 PH before clinical application.

Prognostic cell biological markers in cervical cancer patients primarily treated with (chemo)radiation: a systematic review.

The aim of this study was to systematically review the prognostic and predictive significance of cell biological markers in cervical cancer patients primarily treated with (chemo)radiation. A PubMed, Embase, and Cochrane literature search was performed. Studies describing a relation between a cell biological marker and survival in ≥50 cervical cancer patients primarily treated with (chemo)radiation were selected. Study quality was assessed, and studies with a quality score of 4 or lower were excluded. Cell biological markers were clustered on biological function, and the prognostic and predictive significance of these markers was described. In total, 42 studies concerning 82 cell biological markers were included in this systematic review. In addition to cyclooxygenase-2 (COX-2) and serum squamous cell carcinoma antigen (SCC-ag) levels, markers associated with poor prognosis were involved in epidermal growth factor receptor (EGFR) signaling (EGFR and C-erbB-2) and in angiogenesis and hypoxia (carbonic anhydrase 9 and hypoxia-inducible factor-1α). Epidermal growth factor receptor and C-erbB-2 were also associated with poor response to (chemo)radiation. In conclusion, EGFR signaling is associated with poor prognosis and response to therapy in cervical cancer patients primarily treated with (chemo)radiation, whereas markers involved in angiogenesis and hypoxia, COX-2, and serum SCC-ag levels are associated with a poor prognosis. Therefore, targeting these pathways in combination with chemoradiation may improve survival in advanced-stage cervical cancer patients.

Loss of SerpinA5 protein expression is associated with advanced-stage serous ovarian tumors.

Epithelial ovarian cancer, the most lethal neoplasm of the female genital tract, is usually diagnosed at an advanced stage as obvious symptoms are absent at early stages. This disease is believed to originate from malignant transformation of the ovarian surface epithelium or fallopian tube. Histologically, several subtypes are being recognized, with serous histology accounting for the majority of cases. Serous tumors include serous borderline tumors and serous carcinomas. A better understanding of the tumor biology and molecular mechanisms involved in these tumors is needed, as both patient management and prognosis differ substantially. Previous microarray analysis identified SerpinA5, a uPA inhibitor, as key regulator for indolent borderline behavior. As carcinomas are characterized by loss of SerpinA5 mRNA expression, we hypothesized that SerpinA5 protein expression is reduced or lost in carcinomas when compared with borderline tumors. We performed SerpinA5 immunohistochemical staining on 32 serous borderline tumors, 187 primary serous carcinomas and 62 serous omental metastases. Reduced or absent SerpinA5 protein staining was observed in carcinomas when compared with borderline tumors (P<0.001). SerpinA5 protein expression was significantly lowered in the omental metastases (P<0.001) when compared with the matching primary carcinoma. Interestingly, SerpinA5 protein expression was reduced in advanced-stage borderline tumors, often characterized by micropapillary growth and/or microinvasion, when compared with early-stage borderline tumors (P=0.015). In conclusion, SerpinA5 expression is significantly reduced in advanced-stage serous borderline tumors and serous carcinomas when compared with the early-stage counterparts, and reduction of expression is linked to more aggressive features of borderline tumors.

Potential target antigens for a universal vaccine in epithelial ovarian cancer.

The prognosis of epithelial ovarian cancer (EOC), the primary cause of death from gynaecological malignancies, has only modestly improved over the last decades. Immunotherapeutic treatment using a cocktail of antigens has been proposed as a "universal" vaccine strategy. We determined the expression of tumor antigens in the context of MHC class I expression in 270 primary tumor samples using tissue microarray. Expression of tumor antigens p53, SP17, survivin, WT1, and NY-ESO-1 was observed in 120 (48.0%), 173 (68.9%), 208 (90.0%), 129 (56.3%), and 27 (11.0%) of 270 tumor specimens, respectively. In 93.2% of EOC, at least one of the investigated tumor antigens was (over)expressed. Expression of MHC class I was observed in 78.1% of EOC. In 3 out 4 primary tumors, (over)expression of a tumor antigen combined with MHC class I was observed. These results indicate that a multiepitope vaccine, comprising these antigens, could serve as a universal therapeutic vaccine for the vast majority of ovarian cancer patients.

The extrinsic apoptosis pathway and its prognostic impact in ovarian cancer.

OBJECTIVE: Death ligand FasL, its agonistic receptor Fas, tumor necrosis factor related apoptosis inducing ligand (TRAIL) and its agonistic death receptors DR4 and DR5 are implied in carcinogenesis, tumor immune surveillance and response to chemotherapy. TRAIL receptor agonists are evaluated as anti-cancer agents. This study aimed to relate expression of death ligands/receptors and downstream initiator caspase 8 and its anti-apoptotic homologue FLICE like inhibitory protein (c-FLIP) in ovarian cancers to chemotherapy response and survival. METHODS: Fas, FasL, TRAIL, DR4, DR5, caspase 8 and c-FLIP were determined immunohistochemically on a tissue microarray containing 382 ovarian cancers. Protein expression profiles were correlated with clinicopathologic variables, chemotherapy response and survival. RESULTS: Most tumors expressed DR4, DR5, caspase 8 and c-FLIP. High c-FLIP expression was associated with expression of caspase 8 and both TRAIL receptors. TRAIL and Fas were associated with low tumor grade and better progression-free survival (HR 0.63, p=.018 and HR 0.54, p=.012), respectively, and Fas with disease-specific survival (HR 0.49, p=0.009) in univariate analysis. CONCLUSIONS: Fas and TRAIL loss is associated with dedifferentiation and worse prognosis. Expression of DR4, DR5, caspase 8 and c-FLIP by most ovarian cancers does not correlate with survival. High c-FLIP expression should be taken into account for death receptor targeted therapies.

Survival of ovarian cancer patients overexpressing the tumour antigen p53 is diminished in case of MHC class I down-regulation.

OBJECTIVES: The adaptive immune system seems to play an essential role in the natural course of ovarian cancer. Aim of this study was to establish whether disease-specific survival for patients expressing the tumour antigen p53 is influenced by MHC class I expression or the presence of p53 autoantibodies (p53-Aab). METHODS: P53 and MHC class I expression were analysed in ovarian cancer tissue of 329 patients by immunohistochemistry using tissue microarrays. For 233 patients, pre-treatment serum samples were available to study the presence of p53 autoantibodies by ELISA. Data were linked to clinicopathological parameters and disease-specific survival. RESULTS: P53 overexpression, MHC class I down-regulation in neoplastic cells and serum p53 autoantibodies were observed in 49.4, 38.9 and 15.9% of patients, respectively. MHC class I down-regulation in p53-overexpressing tumours correlated with a 10-month reduced disease-specific survival in univariate analysis (log-rank 4.10; p=0.043). p53-Aab were strongly correlated with p53 overexpression (p<0.001), but did not influence disease-specific survival. CONCLUSIONS: As the prognosis of patients with p53-overexpressing ovarian cancer is affected by the MHC class I status of tumour cells and ovarian cancer patients can generate immune responses to the p53 tumour antigen, the further development of immunotherapy should evaluate strategies to improve MHC class I expression by tumour cells to facilitate antigen presentation in an attempt to increase clinical responses.