A pilot study on the effect of advance care planning implementation on healthcare utilisation and satisfaction in patients with advanced heart failure.

BACKGROUND: Patients with advanced heart failure may benefit from palliative care, including advance care planning (ACP). ACP, which can include referral back to the general practitioner (GP), may prevent unbeneficial hospital admissions and interventional/surgical procedures that are not in accordance with the patient's personal goals of care. AIM: To implement ACP in patients with advanced heart failure and explore the effect of ACP on healthcare utilisation as well as the satisfaction of patients and cardiologists. METHODS: In this pilot study, we enrolled 30 patients with New York Heart Association class III/IV heart failure who had had at least one unplanned hospital admission in the previous year because of heart failure. A structured ACP conversation was held and documented by the treating physician. Primary outcome was the number of visits to the emergency department and/or admissions within 3 months after the ACP conversation. Secondary endpoints were the satisfaction of patients and cardiologists as established by using a five-point Likert scale. RESULTS: Median age of the patients was 81 years (range 33-94). Twenty-seven ACP documents could be analysed (90%). Twenty-one patients (78%) did not want to be readmitted to the hospital and subsequently none of them were readmitted during follow-up. Twenty-two patients (81%) discontinued all hospital care. All patients who died during follow-up (n = 12, 40%) died at home. Most patients and cardiologists indicated that they would recommend the intervention to others (80% and 92% respectively). CONCLUSION: ACP, and subsequent out-of-hospital care by the GP, was shown to be applicable in the present study of patients with advanced heart failure and evident palliative care needs. Patients and cardiologists were satisfied with this intervention.

Outcomes of surgical treatment of non-metastatic gastric cancer in patients aged 70 and older: A systematic review and meta-analysis.

The optimal surgical treatment strategy for gastric cancer in older patients needs to be carefully evaluated due to increased vulnerability of older patients. We performed a database search for randomized controlled trials (RCTs) and cohort studies that included patients ≥70 years with potentially resectable stage I-III gastric cancer. Postoperative and survival outcomes were compared between groups undergoing 1) gastrectomy vs conservative treatment (best supportive care or non-operative treatment), 2) minimally invasive (MIG) vs open gastrectomy (OG), or 3) extended vs limited lymphadenectomy. When possible, results were pooled using risk ratios (RR). Thirty-one studies were included. Six retrospective studies compared overall survival (OS) between gastrectomy (N = 2332) and conservative treatment (N = 246). Longer OS was reported in the gastrectomy group in all studies, but study quality was low and meta-analysis was not feasible. Eighteen cohort studies compared MIG (N = 3626) and OG (N = 5193). MIG was associated with fewer complications (pooled RR 0.68, 95% confidence interval 0.54-0.84). OS was not different between the groups. Two RCTs and five cohort studies compared outcomes between extended (N = 709) and limited lymphadenectomy (N = 1323). Complication rates were comparable between the groups. Two cohort studies found longer OS or cancer-specific survival after extended lymphadenectomy. No quality of life (QoL) or functional outcomes were reported. In older patients with gastric cancer, there is low-quality evidence for better OS after gastrectomy vs conservative treatment. Compared to OG, MIG was associated with less postoperative morbidity. The evidence to support extended lymphadenectomy is limited. QoL and functional outcomes should be addressed in future studies.

Palbociclib dose reductions and the effect on clinical outcomes in patients with advanced breast cancer.

BACKGROUND: This study aimed to provide insights into the real-world use of palbociclib, dose reductions, and drug effectiveness in (older) patients with advanced breast cancer (BC). PATIENTS AND METHODS: Patients with advanced BC treated with palbociclib from 2017 to 2020 were included. The Kaplan-Meier method was used to calculate time to next treatment (TTNT) and overall survival (OS) for patients with or without dose reductions. These clinical outcomes were also compared in subgroup analyses for older patients (≥70 years) and younger patients (<70 years) and for patients discontinuing palbociclib early (<4 administrations). RESULTS: A total of 598 patients with advanced BC were included, with a median age of 64 years. Palbociclib dose reductions occurred in 33% of all patients. Early discontinuation of palbociclib without dose reductions occurred in 23% of the patients. Patients who required a palbociclib dose reduction were older (median age 67 years vs. 63 years). Patients with dose reductions had a significantly higher TTNT of 16.9 vs. 11.4 months (p < 0.001) and median OS of 29.7 vs. 21.9 months (p = 0.003) compared to patients without dose reductions. The TTNT in older patients was significantly longer (16.9 vs. 11.6 months, p = 0.013) than younger patients, but OS was similar (20.7 vs. 26.7 months, p = 0.051). CONCLUSION: Palbociclib dose reductions occurred in real-world practice similarly to the PALOMA-3 trial. Patients with dose reductions had no poorer outcomes compared to patients not requiring a dose reduction. Older patients treated with palbociclib had more frequent dose reductions, but this did not appear to affect OS.

Multidisciplinary decision-making in older patients with cancer, does it differ from younger patients?

BACKGROUND: In order to tailor treatment to the individual patient, it is important to take the patients context and preferences into account, especially for older patients. We assessed the quality of information used in the decision-making process in different oncological MDTs and compared this for older (≥70 years) and younger patients. PATIENTS AND METHODS: Cross-sectional observations of oncological MDTs were performed, using an observation tool in a University Hospital. Primary outcome measures were quality of input of information into the discussion for older and younger patients. Secondary outcomes were the contribution of different team members, discussion time for each case and whether or not a treatment decision was formulated. RESULTS: Five-hundred and three cases were observed. The median patient age was 63 year, 32% were ≥70. In both age groups quality of patient-centered information (psychosocial information and patient's view) was poor. There was no difference in quality of information between older and younger patients, only for comorbidities the quality of information for older patients was better. There was no significant difference in the contributions by team members, discussion time (median 3.54 min) or number of decision reached (87.5%). CONCLUSION: For both age groups, we observed a lack of patient-centered information. The only difference between the age groups was for information on comorbidities. There were also no differences in contributions by different team members, case discussion time or number of decisions. Decision-making in the observed oncological MDTs was mostly based on medical technical information.

Risk attitudes and personality traits predict perceptions of benefits and risks for medicinal products: a field study of European medical assessors.

BACKGROUND: Risk attitudes and personality traits are known predictors of decision making among laypersons, but very little is known of their influence among experts participating in organizational decision making. METHODS: Seventy-five European medical assessors were assessed in a field study using the Domain Specific Risk Taking scale and the Big Five Inventory scale. Assessors rated the risks and benefits for a mock "clinical dossier" specific to their area of expertise, and ordinal regression models were used to assess the odds of risk attitude or personality traits in predicting either the benefit or the risk ratings. RESULTS: An increase in the "conscientiousness" score predicted an increase in the perception of the drug's benefit, and male assessors gave higher scores for the drug's benefit ratings than did female assessors. Extraverted assessors saw fewer risks, and assessors with a perceived neutral-averse or averse risk profile saw greater risks. CONCLUSIONS: Medical assessors perceive the benefits and risks of medicines via a complex interplay of the medical situation, their personality traits and even their gender. Further research in this area is needed to determine how these potential biases are managed within the regulatory setting.

When direct health-care professional communications have an impact on inappropriate and unsafe use of medicines.

Serious safety issues relating to drugs are communicated to health-care professionals via Direct Health-Care Professional Communications (DHPCs). We explored which characteristics determined the impact of DHPCs issued in the Netherlands for ambulatory-care drugs (2001-2008). With multiple linear regression, we examined the impact on the relative change in new drug use post-DHPC of the following: time to DHPC, trend in use, degree of innovation, specialist drug, first/repeated DHPC, DHPC template, and type of safety issue. DHPCs have less impact on use of specialist drugs than nonspecialist drugs (P < 0.05). The DHPCs' impact increased after availability of a template emphasizing the main problem (P < 0.05), and for safety issues with a risk of death and/or disability (both P < 0.05) (adjusted R² = 0.392). Risk communication can be effective, specifically in case of well-structured information, and very serious safety issues. Effectiveness may improve by tailoring DHPCs and adding other communication channels, for example for drugs that are increasingly being used.

Impact of safety-related regulatory action on drug use in ambulatory care in the Netherlands.

The effect of Direct Healthcare Professional Communications (DHPCs) informing health-care providers of serious drug safety issues has been questioned. The aim of this study was to evaluate the impact of DHPCs on drug use.Nationwide dispensing data for the period 2000­2008 for new users of 46 drugs with one or more DHPCs were assessed. Impact on short-term volume of use was evaluated with regression models, and the presence of long-term changes in use was evaluated with interrupted time series analyses incorporating preexisting trends. The short-term prescription level was lower post-DHPC in 28 (48.3%) of 58 cases. Twenty (34.5%) DHPCs resulted in long-term changes in use. A long-term mean reduction in use was observed in 26.7% of cases (95% confidence interval, −15.2 to −38.2%).Long-term changes in use were not significantly related to preexisting trends in use. Although short- and long-term decreases in use were observed after only half and a third of DHPCs, respectively, the decrease was substantial.

Modest effect of p53, EGFR and HER-2/neu on prognosis in epithelial ovarian cancer: a meta-analysis.

BACKGROUND: P53, EGFR and HER-2/neu are the most frequently studied molecular biological parameters in epithelial ovarian cancer, but their prognostic impact is still unequivocal. We performed a meta-analysis to more precisely estimate their prognostic significance. METHODS: Published studies that investigated the association between p53, EGFR and HER-2/neu status and survival were identified. Meta-analysis was performed using a DerSimonian-Laird model. Publication bias was investigated using funnel plots and sources of heterogeneity were identified using meta-regression analysis. RESULTS: A total of 62 studies were included for p53, 15 for EGFR and 20 for HER-2/neu. P53, EGFR and HER-2/neu status had a modest effect on overall survival (pooled HR 1.47, 95% CI 1.33-1.61 for p53; HR 1.65, 95% CI 1.25-2.19 for EGFR and HR 1.67, 95% CI 1.34-2.08 for HER-2/neu). Meta-regression analysis for p53 showed that FIGO stage distribution influenced study outcome. For EGFR and HER-2/neu, considerable publication bias was present. CONCLUSIONS: Although p53, EGFR and HER-2/neu status modestly influences survival, these markers are, by themselves, unlikely to be useful as prognostic markers in clinical practice. Our study highlights the need for well-defined, prospective clinical trials and more complete reporting of results of prognostic factor studies.

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer.

Ovarian cancer is the most frequent cause of death from gynaecological cancer in the Western world. Current prognostic factors do not allow reliable prediction of response to chemotherapy and survival for individual ovarian cancer patients. Epidermal growth factor receptor (EGFR) and HER-2/neu are frequently expressed in ovarian cancer but their prognostic value remains unclear. In this study, we investigated the expression and prognostic value of EGFR, EGFR variant III (EGFRvIII), HER-2/neu and important downstream signalling components in a large series of epithelial ovarian cancer patients. Immunohistochemical staining of EGFR, pEGFR, EGFRvIII, Her-2/neu, PTEN (phosphatase and tensin homologue deleted on chromosome 10), total and phosphorylated AKT (pAKT) and phosphorylated ERK (pERK) was performed in 232 primary tumours using the tissue microarray platform and related to clinicopathological characteristics and survival. In addition, EGFRvIII expression was determined in 45 tumours by RT-PCR. Our results show that negative PTEN immunostaining was associated with stage I/II disease (P=0.006), non-serous tumour type (P=0.042) and in multivariate analysis with a longer progression-free survival (P=0.015). Negative PTEN staining also predicted improved progression-free survival in patients with grade III or undifferentiated serous carcinomas (P=0.011). Positive pAKT staining was associated with advanced-stage disease (P=0.006). Other proteins were expressed only at low levels, and were not associated with any clinicopathological parameter or survival. None of the tumours were positive for EGFRvIII. In conclusion, our results indicate that tumours showing negative PTEN staining could represent a subgroup of ovarian carcinomas with a relatively favourable prognosis.

MEIS and PBX homeobox proteins in ovarian cancer.

Three amino-acid loop extension (TALE) homeobox proteins MEIS and PBX are cofactors for HOX-class homeobox proteins, which control growth and differentiation during embryogenesis and homeostasis. We showed that MEIS and PBX expression are related to cisplatin resistance in ovarian cancer cell lines. Therefore, MEIS1, MEIS2 and PBX expression were investigated immunohistochemically in a tissue microarray (N=232) of ovarian cancers and ovarian surface epithelium (N=15). Results were related to clinicopathologic characteristics and survival. All cancers expressed MEIS1, MEIS2 and PBX in nucleus and cytoplasm. MEIS1 and 2 only stained nuclear in surface epithelium. Nuclear MEIS2 was negatively related to stage, grade and overall survival in univariate analyses. Additionally, MEIS and PBX RNA expression in ovarian surface epithelium and other normal tissues and ovarian cancer versus other tumour types using public array data sets were studied. In ovarian cancer, MEIS1 is highly expressed compared to other cancer types. In conclusion, MEIS and PBX are extensively expressed in ovarian carcinomas and may play a role in ovarian carcinogenesis.

Factors influencing p53 expression in ovarian cancer as a biomarker of clinical outcome in multicentre studies.

The prognostic impact of p53 immunostaining in a large series of tumours from epithelial ovarian cancer patients in a two-centre study was analysed. The study population (n=476) comprised of a retrospective series of 188 patients (Dutch cohort) and a prospective series of 288 patients (Scottish cohort) enrolled in clinical trials. P53 expression was determined by immunohistochemistry on tissue microarrays. Association with progression-free survival (PFS) and overall survival (OS) was analysed by univariate and multivariate Cox regression analysis. Aberrant p53 overexpression was significantly associated with PFS in the Dutch and Scottish cohorts (P=0.001 and 0.038, respectively), but not with OS in univariate analysis. In multivariate analysis, when the two groups were combined and account taken of clinical factors and country of origin of the cohort, p53 expression was not an independent prognostic predictor of PFS or OS. In this well-powered study with minimal methodological variability, p53 immunostaining is not an independent prognostic marker of clinical outcome in epithelial ovarian cancer. The data demonstrate the importance of methodological standardisation, particularly defining patient characteristics and survival end-point data, if biomarker data from multicentre studies are to be combined.

Physicians' views on joint treatment guidelines for primary and secondary care.

OBJECTIVE: Joint drug formularies and treatment guidelines have been developed to reduce problems arising at the interface between primary and secondary care. The aim is to compare the willingness of hospital specialists and general practitioners to use joint treatment guidelines, and to determine the most relevant barriers and facilitators. STUDY DESIGN: A structured survey, consisting of questions about the use of guidelines and formularies in general, and possible barriers and facilitators for using a specific joint guideline. These specific guidelines concerned the treatment of hypertension, heart failure, or diabetes mellitus. SETTING AND STUDY PARTICIPANTS: One hundred and ninety-seven general practitioners and 34 general internists and cardiologists from the north of the Netherlands. RESULTS: Most hospital specialists relied for their prescribing on international guidelines and agreements within their own department, while general practitioners relied more on national and regional guidelines. General practitioners were more supportive than specialists of the initiative to develop joint treatment guidelines, although both groups had concerns regarding the development process. An important barrier for specialists was that they did not perceive a need for these guidelines. As enabling factors, physicians stated that these joint guidelines can lead to harmonization between specialists and general practitioners, and that they can be useful as an educational tool. CONCLUSION: Specialists are less ready to adopt joint treatment guidelines than general practitioners, indicating the need for a different approach to implement such guidelines in the two sectors.

Accelerated decline and prognostic impact of renal function after myocardial infarction and the benefits of ACE inhibition: the CATS randomized trial.

AIMS: Information regarding the cardiorenal axis in patients after a myocardial infarction (MI) is limited. We examined the change in renal function after a first MI, the protective effect of angiotensin converting enzyme (ACE) inhibition and the prognostic value of baseline renal function. METHODS AND RESULTS: The study population consisted of 298 patients with a first anterior wall MI who were randomized to the ACE inhibitor captopril or placebo after completion of streptokinase infusion. Renal function, by means of glomerular filtration rate (GFR), was calculated using the Cockroft-Gault equation (GFR(c)). In the placebo group, renal function (GFR(c)) declined by 5.5 min(-1)within 1 year, vs only 0.5 ml min(-1)in the ACE inhibitor group (P<0.05). This beneficial effect of captopril was most pronounced in patients with the most compromised renal function at baseline. The incidence of chronic heart failure (CHF) within 1 year increased significantly with decreasing GFR(c)(divided into tertiles: 24.0, 28.9, and 41.2%; P<0.01). The risk-ratio for GFR(c)<81 ml min(-1)vs >103 mL min(-1)was 1.86 (95% CI 1.11-3.13; P=0.019). CONCLUSIONS: Renal function markedly deteriorates after a first MI, but is significantly preserved by ACE inhibition. Furthermore, an impaired baseline renal function adds to the prognostic risk of developing CHF in patients after a first anterior MI.

[Diagnostic image (105). A woman with painful nodules. Infection with O. volvulus]. / Diagnose in beeld (105). Een vrouw met pijnlijke noduli. Infectie met O. volvulus.

A 17-year-old woman from the Democratic Republic of Congo presented with painful nodules on the legs and malaise. An infection with Onchocerca volvulus was diagnosed.

Microalbuminuria is related to marked end organ damage in previously untreated, elderly hypertensive patients.

We wondered whether, in an elderly hypertensive population in a primary prevention setting, free from diabetes mellitus and clinical atherosclerosis, differences between end organ damage and microalbuminuria (MA) could be found using a lower level of urinary albumin excretion than that of classically defined MA. From a population survey of 173 previously untreated hypertensive patients (4x blood pressure systolic > or = 160 and < or = 220 mmHg, and/or diastolic > or = 95 and < or = 115 mmHg), mean age 67 +/- 4 years, were screened for MA (defined as albumin excretion between 20 and 300 mg/24 h). End organ damage was determined by B-mode ultrasound scanning of carotid and femoral arteries and echocardiography. Out of 173 hypertensives, 14 showed MA (8%). These hypertensives had a significantly higher intima media thickness (IMT; 1.01 +/- 0.21 vs 0.88 +/- 0.6 mm, p < 0.05) and increased left ventricular mass index (118 +/- 31 vs 103 +/- 22 g/m2, p < 0.05) than hypertensives without MA. Linear regression analysis showed that MA, age, male gender and diastolic blood pressure were independently related to IMT, while systolic blood pressure, male gender and body mass index were independently related to left ventricular mass. Even using lower levels of urinary albumin excretion rate, patients with MA had significantly higher IMT and increased left ventricular mass. Moreover, MA was independently related to IMT in these elderly hypertensives. These results suggest that the threshold value for MA should be reconsidered in hypertension.

Clinical relevance of the gap between pre-marketing trials and medical practice: the case of the cardiovascular drugs.

OBJECTIVES/BACKGROUND: The external validity of trial results of new cardiovascular drugs is limited, because the short-term studies are performed with relatively small, highly selected populations. Using qualitative methods, we examined the clinical relevance of under-representation of subgroups of patients, and the underlying arguments. METHODS: Interviews with 47 physicians and pharmacists involved in the pre- or post-marketing evaluation of cardiovascular drugs, addressing the issue in general and for two new drugs, losartan and atorvastatin, in particular. RESULTS: The respondents were generally familiar with the under-representation of elderly patients, female patients, and patients with comorbidity in pre-marketing trials, but less familiar with details of representation in the cases of losartan and atorvastatin. In particular under-representation of patients with comorbidity was considered relevant. Arguments to confirm or refute the relevance referred to trial methodology, applicability of trial results or aspects of patient treatment. Conditional arguments referred to the aim of the trial, population size, therapeutic drug class or the timing of trials prior to or after drug registration. CONCLUSIONS: To optimise the connection between pre-marketing clinical research and practice, trials should focus more on patient groups relevant to medical practice. If such research is not feasible prior to registration, it should be conducted afterwards. Drug information should allow practitioners to determine variations in the relative effects between subpopulations.

Comparative trials in registration files of cardiovascular drugs: comparator drugs and dosing schemes.

Registration files of 13 cardiovascular drugs were analysed with respect to the number of double-blind phase-III clinical trials, the use of placebo and active comparator drugs and their dosing schemes. Half of the 146 double-blind trials used active comparator drugs. The majority of files included first-choice reference drugs, but we also found trials in three files with lower dosing schemes of comparator drugs and four files which included only placebo or active controlled double-blind trials. To allow a better interpretation of the information provided in European Public Assessment Reports, which are published for every product approved for marketing in the European Union, uniform reporting is recommended on basic details of trial design, such as comparator drugs used and dosing schemes.