The metastatic spread of breast cancer accelerates during sleep.

The metastatic spread of cancer is achieved by the haematogenous dissemination of circulating tumour cells (CTCs). Generally, however, the temporal dynamics that dictate the generation of metastasis-competent CTCs are largely uncharacterized, and it is often assumed that CTCs are constantly shed from growing tumours or are shed as a consequence of mechanical insults1. Here we observe a striking and unexpected pattern of CTC generation dynamics in both patients with breast cancer and mouse models, highlighting that most spontaneous CTC intravasation events occur during sleep. Further, we demonstrate that rest-phase CTCs are highly prone to metastasize, whereas CTCs generated during the active phase are devoid of metastatic ability. Mechanistically, single-cell RNA sequencing analysis of CTCs reveals a marked upregulation of mitotic genes exclusively during the rest phase in both patients and mouse models, enabling metastasis proficiency. Systemically, we find that key circadian rhythm hormones such as melatonin, testosterone and glucocorticoids dictate CTC generation dynamics, and as a consequence, that insulin directly promotes tumour cell proliferation in vivo, yet in a time-dependent manner. Thus, the spontaneous generation of CTCs with a high proclivity to metastasize does not occur continuously, but it is concentrated within the rest phase of the affected individual, providing a new rationale for time-controlled interrogation and treatment of metastasis-prone cancers.

[Medical Necessity: A Notoriously Fuzzy and Therefore Dispensable Concept?] / Medizinische Notwendigkeit: Ein entbehrlicher, da notorisch unscharfer Begriff?

The concept of a 'medical necessity' (medN) of interventions is used as a dichotomous attribute with steering and orientating function in various contexts without, however, being precisely defined. We see this lack as a virtue if medN is understood as the dynamic result of transparent, trustworthy, and coherent deliberative procedures on both facts and norms. We suggest using the medN concept relative to health care systems, but independent of economic aspects.

Making use of non-invasive prenatal testing (NIPT): rethinking issues of routinization and pressure.

First mapping the main ethical issues surrounding prenatal testing, we then analyze which concerns are specific to non-invasive methods. Presupposing the privatization premise for reproductive autonomy in fundamentally liberal societies, we go on to specify common concerns about non-invasive prenatal testing (NIPT) covered by the term 'routinization', and conceptually unravel the frequently expressed worry of increasing 'pressure' to test and/or terminate affected pregnancies. We argue that mindful decision-making should be a key educational goal (not only) of NIPT counseling which could be achieved through stepwise disclosure. In addition, we identify indirect social pressure as the most plausible threat to reproductive freedom. While continuous efforts need to be made to prevent such pressure - not least by ensuring balanced availability of options -, restricting testing options, and thus freedom of choice, cannot be the answer to this concern. Lastly, we suggest abandoning the vague term 'routinization' and instead focusing on specified concerns to enable a fruitful debate.

[Placebos and placeboids in clinical practice: conceptual and ethical considerations]. / Placebos und Placeboide in der therapeutischen Praxis ­ begriffliche und ethische Überlegungen.

Reflecting on results of recent placebo research, this article analyzes relevant key concepts and ethical positions. "Placeboids" and possibly open-label placebo treatments should replace any deceptive use of sham medication. Their use should give rise to a critical consideration of the modern patient-physician relationship.

[Medical Methods: What Makes them Necessary? Part I: Medical Methods, medical Necessity and its Main Criteria]. / Medizinische Behandlungsmethoden: Was macht sie medizinisch notwendig? Teil I: Medizinische Methoden, medizinische Notwendigkeit und ihre Hauptkriterien.

OBJECTIVES: "Medical necessity" (MedN) is a fuzzy term. Our project aims at concretising the concept between medical ethics, social law, and social medicine to support health care regulation, primarily within Germany's statutory health insurance system. In a previous publication we identified MedN as a tripartite predicate: A specific clinical condition requires a specific medical intervention to reach a specific medical goal. Our two-part text searches for and discusses criteria to classify medical methods as generally medically necessary (medn), provided a non-trivial clinical condition and a relevant, legitimate, and reachable goal actually exist. In this paper we present the first part of our results. METHODS: Based on an extensive ethical, sociolegal and sociomedical body of literature, and starting with an non-controversial case vignette (thrombolysis in acute stroke), we generally followed a critical reconstructive approach. First we defined the term "medical method". In several interdisciplinary rounds, we then collected and discussed criteria from three sources: methods to develop clinical practice guidelines as compendia of indication rules, the National Model of Prioritisation in Swedish Health Care, and the HTA Core Model of the European Network for Health Technology Assessment as an instrument of political counselling. RESULTS: We identified general clinical efficacy and benefit as the 2 main "medical" criteria of MedN. As a third - epistemic - criterion, the corresponding bodies of evidence are always to be considered. Since clinical and prioritising guidelines grade their recommendations, the question arises whether MedN should be conceptualised as a dichotomous or finer graded predicate. In accord with German social law we advocate for the binary form. Further discussions focused on multifactorial MedN-configurations, the range of the term, and the variability of evidence requirements. CONCLUSIONS: No matter how the content of MedN is conceptualised, it seems impossible to include its criteria in an algorithm. So deliberative effort is indispensable at any stage of developing a programme to classify medical methods as medically necessary.

[Medical Methods: What Makes them Medically Necessary? Part II: Further Criteria, Overuse, Moving Thresholds, and Grey Zones]. / Medizinische Behandlungsmethoden: Was macht sie medizinisch notwendig? Teil II: Weitere Kriterien, Übermaßverbot, wandernde Grenzen und Grauzonen.

OBJECTIVES: "Medical necessity" (MedN) is a fuzzy term. Our project aims at concretising the concept between medical ethics, social law, and social medicine to support health care regulation, primarily within Germany's statutory health insurance system. In Part I, we identified efficacy, (net)benefit, and the corresponding bodies of evidence as obligatory criteria of MedN. This is the second part suggesting and discussing further criteria. METHODS: See Part I RESULTS: (Part II): As further MedN-criteria we critically assessed a method's effectiveness and acceptance in routine care, its potential beneficiaries, theoretical fundament, cost, and being without alternative as well as patients' self-responsibility, cooperation, and preferences. Since MedN has both lower and upper bounds, we had to consider certain cases of mis- and overuse, due for instance to "indication creep" or "disease mongering". CONCLUSIONS: The additional criteria neither establish MedN (when met singly or together) nor exclude it (when not met). If MedN is rejected in view of the 3 obligatory criteria then further information does not overturn the verdict. If a method is already assessed as being medn then further criteria do not make it "more or less necessary". Though we advocated for a binary MedN-concept (Part I) we are nonetheless convinced that not all medical methods deemed medn are equally medically relevant. Respective differences within the range of MedN could be assessed by techniques to prioritise medical conditions, methods, and aims.

[Wife against advance directive: a case-inspired legal and ethical clarification]. / Ehefrau contra Patientenverfügung: eine kasuistisch inspirierte rechtliche und ethische Klärung.

Advance directives and durable powers of attorney are two increasingly used tools for patients' precedent autonomy; however, their combined use, as recommended by major institutions in Germany, might in reality result in various discrepancies between the wording and interpretation of the directive and the surrogate's understanding of the patient's relevant will. In one of the possible conflict constellations, the surrogate wants to overrule a relevant and unambiguous advance directive by reference to a privileged access to the patient's "real" treatment preferences or the presumed will of the patient. Such cases, which must be strictly distinguished from cases with real or alleged leeway for interpretation in the advance directive, can lead to normative uncertainty as well as to substantial psychological distress for all persons involved. Based on an exemplary real clinical case from 2015 (which did not go to court) legal, ethical and pragmatic aspects of the described constellation are discussed. Ethically, caution should be exercised against a relapse into a masked treatment paternalism, which currently seems to be partly caused by judicial exegesis.

Adjuvant treatment recommendations for patients with ER-positive/HER2-negative early breast cancer by Swiss tumor boards using the 21-gene recurrence score (SAKK 26/10).

BACKGROUND: To evaluate the effect of Recurrence Score® results (RS; Oncotype DX® multigene assay ODX) on treatment recommendations by Swiss multidisciplinary tumor boards (TB). METHODS: SAKK 26/10 is a multicenter, prospective cohort study of early breast cancer patients: Eligibility: R0-resection, ≥10% ER+ malignant cells, HER2-, pN0/pN1a. Patients were stratified into low-risk (LR) and non-low-risk (NLR) groups based on involved nodes (0 vs 1-3) and five additional predefined risk factors. Recommendations were classified as hormonal therapy (HT) or chemotherapy plus HT (CT + HT). Investigators were blinded to the statistical analysis plan. A 5%/10% rate of recommendation change in LR/NLR groups, respectively, was assumed independently of RS (null hypotheses). RESULTS: Two hundred twenty two evaluable patients from 18 centers had TB recommendations before and after consideration of the RS result. A recommendation change occurred in 45 patients (23/154 (15%, 95% CI 10-22%) in the LR group and 22/68 (32%, 95% CI 22-45%) in the NLR group). In both groups the null hypothesis could be rejected (both p < 0.001). Specifically, in the LR group, only 5/113 (4%, 95% CI 1-10%) with HT had a recommendation change to CT + HT after consideration of the RS, while 18/41 (44%, 95% CI 28-60%) of patients initially recommended CT + HT were subsequently recommended only HT. In the NLR group, 3/19 (16%, 95% CI 3-40%) patients were changed from HT to CT + HT, while 19/48 (40%, 95% CI 26-55%) were changed from CT + HT to HT. CONCLUSION: There was a significant impact of using the RS in the LR and the NLR group but only 4% of LR patients initially considered for HT had a recommendation change (RC); therefore these patients could forgo ODX testing. A RC was more likely for NLR patients considered for HT. Patients considered for HT + CT have the highest likelihood of a RC based on RS.

Determination of Death: A Discussion on Responsible Scholarship, Clinical Practices, and Public Engagement.

The concept and determination of death by neurological or cardio-circulatory criteria play a crucial role for medical practice, society, and the law. Academic debates on death determination have regained momentum, and recent cases involving the neurological determination of death ("brain death") in the United States have sparked sustained public debate. The determination of death by neurological criterion (irreversible cessation of the whole brain or of the brain stem) is medically practiced in at least 80 countries. However, academic debates persist about the conceptual and scientific validity of death determined by neurological criterion. The cardio-circulatory criterion, which permits organ donation following cardio-circulatory arrest, has also recently been challenged. Given the presence of academic debates, several questions ensue about the responsible conduct of clinicians and scholars involved in clinical practices and academic research. This article identifies tension points for responsible practices in the domains of scholarship, clinical practice, and public discourse and formulates suggestions to stimulate further dialogue on responsible practices and to identify questions in need of further research.

The argument from potentiality in the embryo protection debate: finally "depotentialized"?

Debates on the moral status of human embryos have been highly and continuously controversial. For many, these controversies have turned into a fruitless scholastical endeavor. However, recent developments and insights in cellular biology have cast further doubt on one of the core points of dissent: the argument from potentiality. In this article we want to show in a nonscholastical way why this argument cannot possibly survive. Getting once more into the intricacies of status debates is a must in our eyes. Not merely intellectual coherence but the standing and self-understanding of current stem cell research might profit from finally taking leave of the argument from potentiality.

The Value of Tumour Markers in the Detection of Relapse-Lessons Learned from the Swiss Austrian German Testicular Cancer Cohort Study.

The tumour markers alpha-fetoprotein (AFP), beta human chorionic gonadotropin (ßHCG), and lactate dehydrogenase (LDH) have established roles in the management and follow-up of testicular cancer. While a tumour marker rise can serve as an indicator of relapse, the frequency of false-positive marker events has not been studied systematically in larger cohorts. We assessed the validity of serum tumour markers for the detection of relapse in the Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS). This registry was set up to answer questions on the diagnostic performance and impact of imaging and laboratory tests in the management of testicular cancer, and has included 948 patients between January 2014 and July 2021.A total of 793 patients with a median follow-up of 29.0 mo were included. In total, 71 patients (8.9%) had a proven relapse, which was marker positive in 31 patients (43.6%). Of all patients, 124 (15.6%) had an event of a false-positive marker elevation. The positive predictive value (PPV) of the markers was limited, highest for ßHCG (33.8%) and lowest for LDH (9.4%). PPV tended to increase with higher levels of elevation. These findings underline the limited accuracy of the conventional tumour markers to indicate or rule out a relapse. Especially, LDH as part of routine follow-up should be questioned. Patient summary: With the diagnosis of testicular cancer, the three tumour markers alpha-fetoprotein, beta human chorionic gonadotropin, and lactate dehydrogenase are routinely measured during follow-up to monitor for relapse. We demonstrate that these markers are often falsely elevated, and, by contrast, many patients do not have marker elevations despite a relapse. The results of this study can lead to improved use of these tumour markers during follow-up of testis cancer patients.

Metastatic Potential of Small Testicular Germ Cell Tumors: Implications for Surveillance of Small Testicular Masses.

Incidental detection of urogenital tumors has increased in recent decades owing to the greater use of ultrasonography and cross-sectional imaging. For patients with low-risk prostate cancer or small renal masses, active surveillance represents a valid treatment option. Similarly, for men with small testicular masses <10 mm, active surveillance has been discussed as an alternative to surgery, although little is known regarding the behavior of small testicular germ cell tumors (GCTs). In the Swiss Austrian German Testicular Cancer Cohort Study we identified 849 patients (546 seminoma, 303 nonseminoma) treated with radical inguinal orchiectomy for GCT with a median tumor diameter of 35 mm. A tumor diameter <10 mm was observed in 25 patients (13 seminoma, 12 nonseminoma). Of these, five patients (20%) presented with primary metastatic disease, all of whom had elevated tumor markers and nonseminomatous GCTs. Two patients (8%) with initially localized disease (1 seminoma, 1 nonseminoma) and without elevated tumor markers experienced relapse at 4 mo (nonseminoma) and 14 mo (seminoma) after orchiectomy, despite the fact that the latter had received adjuvant chemotherapy. These findings highlight the metastatic potential of small testicular GCTs and raise the question of whether active surveillance for small testicular masses is safe. Patient summary: This study on testicular cancer assesses the metastatic potential of small testicular germ cell tumors. Men with small testicular masses should be counseled about the malignant potential of small testicular germ cell tumors.

Holding donated human bodies in conservation: A novel interactive safe-keeping system meeting high ethical and safety standards.

"Mortui vivos docent". Learning from donated bodies is widely considered a corner stone in pre-clinical education, advanced clinical training, and scientific progress in medicine. Making such use of dead human bodies must, of course, accord with high ethical standards and legal constraints. Piety and respect towards donors require using their remains (i) for valuable purposes, (ii) with what we call 'practical decency', (iii) in an efficient way, and (iv) with the utmost safety for all parties involved. With regard to these goals, practical aspects of preservation, safekeeping procedures (for up to several years), and complete documentation become of great importance, but have so far only been realized unsatisfactorily. Here, we describe the new Safe-Keeping System-Münster (SKS-Münster) that has been developed and implemented in the Anatomy Department of the University of Münster. Integrated components of the system include a paternoster transport system, a removal station with ventilation and an air barrier, RFID transponder technology, and an easy to use software package allowing the system together to provide all required functions in an unprecedented way.

Challenges of educating for medical professionalism: who should step up to the line?

CONTEXT: The teaching of professionalism has recently become an important issue in medical education. Medical professionalism remains controversial, but several recently published institutional documents on professionalism seem to express an implicit, yet broad consensus on three points: that professionalism mainly consists of adherence to a specific set of professional attributes constitutive of medical role morality and readily identifiable as virtues of medical professionalism (VMP); that medical education needs to focus on the endowment of these attributes, and that medical ethicists should play a central role in assuming this educational responsibility. METHODS: This paper examines the assumption that the task of supporting the development of the VMP should primarily fall to medical ethicists. Considerations in favour of this position are weighted against a set of countervailing considerations. The latter include the charge that the VMP are too vague as educational guidelines, that they may not be teachable, and that the responsibility for their development must be shared across the medical faculty. CONCLUSIONS: Medical ethics educators are right to embrace the professionalism agenda on four conditions: that the limitations of addressing the formation of professional attributes in university-based teaching are recognised; that there is clinical as well as university-based evaluation of professional attributes; that the development of the VMP as a process of professional socialisation is seen as an interdisciplinary educational project, and that the examination and explanation of the cognitive grounds of the VMP are the focus of medical educators' activities.

Psychiatrists' views on different types of advance statements in mental health care in Germany.

BACKGROUND: Advance directives enable patients to ensure that treatment decisions will be based on their autonomous will, even if they are incompetent at the time at which the treatment decision is taken. Although psychiatric advance directives are legally binding in Germany and their benefits are widely acknowledged, they are still infrequently used in German psychiatric practice. AIMS: The aim of this study is to assess psychiatrists' attitudes toward the use of advance statements in mental health care. METHODS: A postal survey of psychiatrists in Germany was carried out to examine their views on advance statements in psychiatry. The survey addressed psychiatrists' experiences of and attitudes toward different types of advance statements, including psychiatric advance statements written by patients without any specific assistance, and joint crisis plans ( 'Behandlungsvereinbarungen'), where involvement of the clinical team is required. A total of 396 responded. RESULTS: Results suggest that generally speaking, respondents held favorable views on joint crisis plans for mental health care. In all, 80.7% of participants agreed that more frequent use of joint crisis plans in clinical practice would be desirable. However, clinicians' attitudes differ largely depending on the type of advance statement. Implications for the use of advance statements in psychiatry are discussed. CONCLUSION: The findings suggest that increasing the support structures available to train physicians and inform patients could lead to increased adoption of advance statements.

Baseline characteristics and patterns of care in testicular cancer patients: first data from the Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS).

BACKGROUND: The majority of germ cell tumour (GCT) patients can be cured by orchiectomy followed by active surveillance or subsequent systemic and/or local treatments. There are various guidelines for a structured follow-up including radiographic and clinical examinations. OBJECTIVE: The Swiss Austrian German Testicular Cancer Cohort Study (SAG TCCS) prospectively evaluates follow-up, indicator of relapse and late toxicities. This is a descriptive analysis; we present baseline characteristics and treatment strategies for the first 299 patients with primary GCT or relapsed GCT after completion of treatment. RESULTS: Of the patients included in this study, 192 (64.2%) had seminoma and 107 (35.8%) non-seminoma. Mean age was 41 years (standard deviation [SD] 11.7) for seminoma and 31 (SD 9.3) years for non-seminoma patients. Median tumour size was 3.5 cm (interquartile range 2.5¬â€’5.0 and 2.3‒4.5 in seminoma and non-seminoma, respectively) in both histological groups. Among seminoma patients, 81 (42.2%) had primary tumours >4cm; 154 (80.2%) seminoma patients had stage I, 26 (13.5%) stage II and 12 (6.3%) stage III disease. Fifty-seven (53.3%) non-seminoma tumours were stage I, 29 (27.1%) stage II and 21 (19.6%) stage III. Marker-positive disease was present in 58 (30.2%) seminoma patients and 78 (72.9%) non-seminoma patients. Of 154 stage I seminoma patients, 89 (57.8%) chose active surveillance and 65 (42.2%) adjuvant chemotherapy. Twenty-six (45.6%) stage I non-seminoma patients had high-risk disease; 23 of these were treated with adjuvant chemotherapy and 3 chose active surveillance. Among the 30 (52.6%) low risk stage I patients, all opted for active surveillance. Twelve (46.2%) stage II seminoma patients had radiotherapy, 14 (53.8%) were treated with three to four cycles of chemotherapy. All stage III seminoma patients, and all stage II and III non-seminoma patients were treated with three to four cycles of chemotherapy. Treatment decisions were made at the respective centre. Eleven patients did not receive therapy that conformed with guidelines. CONCLUSION: It is important to enrol GCT patients in prospective studies in general, but also in follow-up studies to assess baseline characteristics, oncological outcome, and long-term toxicity and to validate the performance of follow-up schedules. This is the first time that the distribution of disease, detailed baseline characteristics and the respective treatment of men with GCT is collected in a prospective manner in German speaking countries (Switzerland, Austria and Germany) and therefore patterns of care have been evaluated. SAG TCCS results will inform on future modifications of surveillance schedules and follow-up procedures. TRIAL REGISTRATION NUMBER: NCT02229916 (Clinicaltrials.gov).

[Choosing Wisely - Klug Entscheiden: conceptual and ethical considerations]. / Choosing Wisely ­ Klug Entscheiden: begriffliche und ethische Überlegungen.

Choosing Wisely and Klug Entscheiden (KE) are recent physician-triggered campaigns that aim at identifying and reducing blatant over-treatment as well as - a specialty of KE - occurring under-treatment. This paper provides some conceptual and normative analyses of these campaigns' goals and justifications.