[The future of psychiatry and the psychiatrist of the future]. / De toekomst van de psychiatrie en de psychiater van de toekomst.

BACKGROUND: The training curriculum of the psychiatrist needs to be reviewed. To determine the model of the future psychiatrist, the question of how the future psychiatry will look needs to be answered first.
AIM: Assessment of relevant developments in psychiatry and the organisation of psychiatric care with the aim to propose a profile of the future psychiatrist.
METHOD: The recent history of psychiatry as a starting point for a vision of the future.
RESULTS: 1. Psychiatry must use an integrative anthropological theory, in order to be able to understand psychopathology in its essence. 2. Content-driven moral leadership is necessary to prevent psychiatry being tempted by hypes. 3. The tacit social contract between the medical profession and society is under pressure; both parties distrust each other and psychiatrists must regain trust and renew the contract. 4. Psychiatric care must remain affordable, which means a review of the current organisation of care; psychiatry will become network psychiatry. 5. Psychiatrists will work in a network of care providers and the patient will be in control. The psychiatrist will have a flexible role, ranging from managerial to supportive and advisory. Keeping psychotherapeutic skills up-to-date is an essential requirement. 6. Future training should focus on the sustainable employability of the psychiatrist as a human being, on knowledge of history of psychiatry and its socio-economic context, and policy and engagement; and on the skill of conceptual thinking (philosophy).
CONCLUSION: The profession of psychiatry needs a new job profile. The process of development and elaboration should contain the following core elements: broad education, conceptual skills, sensitivity for activism, social involvement, and expertise in treatment of patients with complex problems in diverse settings.

Optimized outcome prediction in breast cancer by combining the 70-gene signature with clinical risk prediction algorithms.

Clinical guidelines for breast cancer treatment differ in their selection of patients at a high risk of recurrence who are eligible to receive adjuvant systemic treatment (AST). The 70-gene signature is a molecular tool to better guide AST decisions. The aim of this study was to evaluate whether adding the 70-gene signature to clinical risk prediction algorithms can optimize outcome prediction and consequently treatment decisions in early stage, node-negative breast cancer patients. A 70-gene signature was available for 427 patients participating in the RASTER study (cT1-3N0M0). Median follow-up was 61.6 months. Based on 5-year distant-recurrence free interval (DRFI) probabilities survival areas under the curve (AUC) were calculated and compared for risk estimations based on the six clinical risk prediction algorithms: Adjuvant! Online (AOL), Nottingham Prognostic Index (NPI), St. Gallen (2003), the Dutch National guidelines (CBO 2004 and NABON 2012), and PREDICT plus. Also, survival AUC were calculated after adding the 70-gene signature to these clinical risk estimations. Systemically untreated patients with a high clinical risk estimation but a low risk 70-gene signature had an excellent 5-year DRFI varying between 97.1 and 100 %, depending on the clinical risk prediction algorithms used in the comparison. The best risk estimation was obtained in this cohort by adding the 70-gene signature to CBO 2012 (AUC: 0.644) and PREDICT (AUC: 0.662). Clinical risk estimations by all clinical algorithms improved by adding the 70-gene signature. Patients with a low risk 70-gene signature have an excellent survival, independent of their clinical risk estimation. Adding the 70-gene signature to clinical risk prediction algorithms improves risk estimations and therefore might improve the identification of early stage node-negative breast cancer patients for whom AST has limited value. In this cohort, the PREDICT plus tool in combination with the 70-gene signature provided the best risk prediction.

Prospective cost-effectiveness analysis of genomic profiling in breast cancer.

BACKGROUND: The cost-effectiveness of the 70-gene signature (70-GS) (MammaPrint®) has earlier been estimated using retrospective validation data. Based on the prospective 5-year survival data of the microarRAy-prognoSTics-in-breast-cancER (RASTER) study, the aim here was to evaluate the cost-effectiveness reflecting the actual use in clinical practice, including reality-based compliance rates. METHODS: Costs and outcomes (quality-adjusted-life-years (QALYs)) were calculated in node-negative (N-) patients included in the RASTER study (n=427). Sensitivity and specificity of the 70-gene and Adjuvant! Online (AO) were based on 5-year distant-disease-free survival (DDFS). Subgroup analyses were performed for two groups for whom benefit of the 70-gene had earlier been reported: (1) ductal, oestrogen receptor-positive (ER+), tumour diameter 10-30 mm, grade II, age 40-70; (2) ductal, oestrogen receptor-positive, tumour diameter 5-30 mm, grade II/III and age 40-70. RESULTS: Based on 5-year survival data, the cost-effectiveness of the 70-gene signature versus AO was prospectively confirmed. The total health care costs per patient were €26,786 for the 70-gene and €29,187 for AO. The quality adjusted life years yielded 12.49 and 11.88, respectively. The subgroups retrieved slightly higher life gains and higher costs, but all resulted finally in a favourable position for the 70-gene signature. CONCLUSIONS: The use of the 70-gene signature, as judged appropriate by doctors and patients and supported by a low risk 70-gene signature as an oncological safe choice, was also found to be cost-effective.

A prospective evaluation of a breast cancer prognosis signature in the observational RASTER study.

The 70-gene signature (MammaPrint™) has been developed on retrospective series of breast cancer patients to predict the risk of breast cancer distant metastases. The microarRAy-prognoSTics-in-breast-cancER (RASTER) study was the first study designed to prospectively evaluate the performance of the 70-gene signature, which result was available for 427 patients (cT1-3N0M0). Adjuvant systemic treatment decisions were based on the Dutch CBO 2004 guidelines, the 70-gene signature and doctors' and patients' preferences. Five-year distant-recurrence-free-interval (DRFI) probabilities were compared between subgroups based on the 70-gene signature and Adjuvant! Online (AOL) (10-year survival probability <90% was defined as high-risk). Median follow-up was 61.6 months. Fifteen percent (33/219) of the 70-gene signature low-risk patients received adjuvant chemotherapy (ACT) versus 81% (169/208) of the 70-gene signature high-risk patients. The 5-year DRFI probabilities for 70-gene signature low-risk (n = 219) and high-risk (n = 208) patients were 97.0% and 91.7%. The 5-year DRFI probabilities for AOL low-risk (n = 132) and high-risk (n = 295) patients were 96.7% and 93.4%. For 70-gene signature low-risk-AOL high-risk patients (n = 124), of whom 76% (n = 94) had not received ACT, 5-year DRFI was 98.4%. In the AOL high-risk group, 32% (94/295) less patients would be eligible to receive ACT if the 70-gene signature was used. In this prospective community-based observational study, the 5-year DRFI probabilities confirmed the additional prognostic value of the 70-gene signature to clinicopathological risk estimations such as AOL. Omission of adjuvant chemotherapy as judged appropriate by doctors and patients and instigated by a low-risk 70-gene signature result, appeared not to compromise outcome.

Additional value and potential use of the 70-gene prognosis signature in node-negative breast cancer in daily clinical practice.

BACKGROUND: The 70-gene prognosis signature has strong prognostic value in node-negative breast cancer, independent of established prognostic factors. It is unclear whether all node-negative patients should receive a signature result. We therefore evaluated its additional prognostic information to a combination of established prognostic guidelines. METHODS: We evaluated 701 patients from three previously described series in whom a signature result was available. Clinical risk was on the basis of Adjuvant! Online (AO), St Gallen guidelines (St G) and Nottingham Prognostic Index (NPI). Overall survival (OS) analyses were carried out in patients treated at the Netherlands Cancer Institute (Amsterdam) who did not receive adjuvant systemic treatment (AST). RESULTS: Only 6% (10 of 156) of estrogen receptor (ER)-negative tumours had a good prognosis signature. The signature was not useful for ER-positive tumours and concordant high AO, high St G and/or high NPI clinical risks (N = 139). The 10-year OS estimate for good signature tumours with these characteristics was <80% and AST would therefore be appropriate irrespective of the signature result. In contrast, for patients with a concordant low AO, low St G and/or low NPI risk and in discordant clinical risk patients, the signature identified low-risk patients in whom AST could be safely withheld (10-year OS > 90%). CONCLUSION: The 70-gene prognosis signature provides additional prognostic information especially in ER-positive lymph node-negative breast cancer patients with a predominant low or discordant clinical risk on the basis of AO, St G and/or NPI.

The impact of inter-observer variation in pathological assessment of node-negative breast cancer on clinical risk assessment and patient selection for adjuvant systemic treatment.

BACKGROUND: It is well known that there is considerable inter-observer variability in assessment of the pathological parameters that are used to select node-negative breast cancer patients for adjuvant systemic treatment. There are only limited data available as to in how many patients this leads to differences in treatment decisions. METHODS: Clinical and pathological data of 694 patients <61 years with primary unilateral T1-4N0M0 breast cancer were analysed. Grade, estrogen receptor (ER) status and human epidermal growth factor receptor 2 (HER2) status were first assessed locally; subsequent central re-evaluation of these parameters was carried out. Clinicopathological low or high risk was assessed using national Dutch guidelines and the Adjuvant! Online (www.adjuvantonline.com). RESULTS: The local pathological examination was discordant with central review for grade, ER and HER2 in 28% (kappa 0.56; grade 2 tumours 35% discordant), 5% (kappa 0.85) and 4% (kappa 0.81) of patients, respectively. If clinical risk were assessed based on Dutch guidelines or Adjuvant! Online, respectively, 15% (one of seven patients; kappa 0.70) or 8% (kappa 0.83) of patients would have been assigned to a different clinical risk group. CONCLUSION: Inter-observer variation in pathological examination of breast carcinomas results in significant differences in grade, ER status, HER2 status, clinicopathological risk and subsequently in adjuvant systemic treatment advice.

Validation of 70-gene prognosis signature in node-negative breast cancer.

PURPOSE: The 70-gene prognosis signature (van't Veer et al., Nature 415(6871):530-536, 2002) may improve the selection of lymph node-negative breast cancer patients for adjuvant systemic therapy. Optimal validation of prognostic classifiers is of great importance and we therefore wished to evaluate the prognostic value of the 70-gene prognosis signature in a series of relatively recently diagnosed lymph node negative breast cancer patients. METHODS: We evaluated the 70-gene prognosis signature in an independent representative series of patients with invasive breast cancer (N = 123; <55 years; pT1-2N0; diagnosed between 1996 and 1999; median follow-up 5.8 years) by classifying these patients as having a good or poor prognosis signature. In addition, we updated the follow-up of the node-negative patients of the previously published validation-series (Van de Vijver et al., N Engl J Med 347(25):1999-2009, 2002; N = 151; median follow-up 10.2 years). The prognostic value of the 70-gene prognosis signature was compared with that of four commonly used clinicopathological risk indexes. The endpoints were distant metastasis (as first event) free percentage (DMFP) and overall survival (OS). RESULTS: The 5-year OS was 82 +/- 5% in poor (48%) and 97 +/- 2% in good prognosis signature (52%) patients (HR 3.4; 95% CI 1.2-9.6; P = 0.021). The 5-years DMFP was 78 +/- 6% in poor and 98 +/- 2% in good prognosis signature patients (HR 5.7; 95% CI 1.6-20; P = 0.007). In the updated series (N = 151; 60% poor vs. 40% good), the 10-year OS was 51 +/- 5% and 94 +/- 3% (HR 10.7; 95% CI 3.9-30; P < 0.01), respectively. The DMFP was 50 +/- 6% in poor and 86 +/- 5% in good prognosis signature patients (HR 5.5; 95% CI 2.5-12; P < 0.01). In multivariate analysis, the prognosis signature was a strong independent prognostic factor in both series, outperforming the clinicopathological risk indexes. CONCLUSION: The 70-gene prognosis signature is also an independent prognostic factor in node-negative breast cancer patients for women diagnosed in recent years.

Laparoscopic rectovaginopexy for rectal prolapse.

BACKGROUND: Open rectovaginopexy is an effective procedure for the treatment of both rectal prolapse and anterior rectocele. This study investigates our results of laparoscopic rectovaginopexy (LRVP). METHODS: A consecutive series of 14 patients (median age, 73 years; range 24-92) with rectal prolapse was planned for LRVP. Pre-, per- and postoperative parameters were recorded. Followup was performed at the outpatients' clinic. RESULTS: The median length of hospital stay was 6 days (range, 3-14). There was one fatal cerebrovascular accident 14 days postoperatively; this patient was excluded from further analysis. Median follow-up was 7 months (range, 0.75-38). During follow-up, 11 of 13 patients (85%) experienced resolution or major improvement of their symptoms. Anal incontinence was diminished in 9 of 13 cases (69%). Constipation improved in 2 of 3 patients (66%). These three patients experienced a combination of both anal incontinence and costipation, preoperatively. Recurrence occurred in 2 patients (15%). Two others had a minor residual mucosal prolapse. No patients reported symptoms suggestive of operation-induced constipation or dyspareunia. CONCLUSIONS: LRVP is feasible, and seems to be an effective procedure for rectal prolapse. No operation-induced constipation was observed in this series. Taking into account the age and co-morbidities of these patients, morbidity and mortality may be considered acceptable.