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Genetic heterogeneity in tumors can show a remarkable selectivity when two or more independent genetic events occur in the same gene. This phenomenon, called composite mutation, points toward a selective pressure, which frequently causes therapy resistance to mutation‐specific drugs. Since composite mutations have been described to occur in sub‐clonal populations, they are not always captured through biopsy sampling. Here, we provide a proof of concept to predict composite mutations to anticipate which patients might be at risk for sub‐clonally driven therapy resistance. We found that composite mutations occur in 5% of cancer patients, mostly affecting the PIK3CA, EGFR, BRAF, and KRAS genes, which are common precision medicine targets. Furthermore, we found a strong and significant relationship between the frequencies of composite mutations with commonly co‐occurring mutations in a non‐composite context. We also found that co‐mutations are significantly enriched on the same chromosome. These observations were independently confirmed using cell line data. Finally, we show the feasibility of predicting compositive mutations based on their co‐mutations (AUC 0.62, 0.81, 0.82, and 0.91 for EGFR, PIK3CA, KRAS, and BRAF, respectively). This prediction model could help to stratify patients who are at risk of developing therapy resistance‐causing mutations.

Practice variability may represent an opportunity to improve care by identifying the differences in outcomes associated with differences in practice. To characterize differences in depression treatment outcomes among individual providers in outpatient psychiatry practices and primary care practices, we examined a longitudinal cohort derived from outpatient electronic health records from two academic medical centers and six community hospitals in Eastern Massachusetts. This cohort included antidepressant-treated individuals with an ICD-9/10 diagnosis of major depressive disorder, and deidentified health care providers treating at least 10 such patients per year between 2008 and 2022. We examined the association between individual provider prescribing characteristics and proportions of treated patients who do not follow up after initial antidepressant prescription or who achieve a stable ongoing prescription. In binomial regression models, among 104 psychiatrists, greater heterogeneity in antidepressant prescribing and lesser proportion of serotonin reuptake inhibitors (SSRIs)1 prescribed were associated with greater rates of achieving stability (for heterogeneity, adjusted odds ratio AOR, 1.55 [95 % CI, 1.22 – 2.06]; for proportion of SSRIs, AOR, 0.01 [95 % CI, 0.00–0.59]). Among 369 primary care physicians, greater volume of depression encounters per year, but not prescribing heterogeneity, was associated with greater rates of achieving stability (for encounters, AOR, 2.15 [95 % CI, 1.61 – 2.89]; for heterogeneity, AOR, 0.99 [95 % CI, 0.85 – 1.15]). Primary care and psychiatry predictors are not the same and therefore suggest potentially distinct strategies to improve clinical outcomes in each setting. Trial Registration: N/A

Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer1-6. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett's oesophagus. These data included 206 biopsies in Barrett's oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case-control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett's-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.

BackgroundThere is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older.MethodsNUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm.ResultsA total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events.ConclusionsDue to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations.

Abstract Background Glioblastoma (GBM) brain tumors lacking IDH1 mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumors almost always fatally recur. Results Using RNA sequencing data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumors, we identify two responder subtypes based on longitudinal changes in gene expression. In two thirds of patients, a specific subset of genes is upregulated from primary to recurrence (Up responders), and in one third, the same genes are downregulated (Down responders), specifically in neoplastic cells. Characterization of the responder subtypes indicates subtype-specific adaptive treatment resistance mechanisms that are associated with distinct changes in the tumor microenvironment. In Up responders, recurrent tumors are enriched in quiescent proneural GBM stem cells and differentiated neoplastic cells, with increased interaction with the surrounding normal brain and neurotransmitter signaling, whereas Down responders commonly undergo mesenchymal transition. ChIP-sequencing data from longitudinal GBM tumors suggests that the observed transcriptional reprogramming could be driven by Polycomb-based chromatin remodeling rather than DNA methylation. Conclusions We show that the responder subtype is cancer-cell intrinsic, recapitulated in in vitro GBM cell models, and influenced by the presence of the tumor microenvironment. Stratifying GBM tumors by responder subtype may lead to more effective treatment.

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

BackgroundIntratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence.MethodsWe used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a 3-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites.ResultsMolecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account.ConclusionOur results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists.

Introduction. Patients with complex forms of posttraumatic stress disorder (PTSD) may benefit from schema therapy. While a small number of studies point to the effectiveness of individual schema therapy in refugees with PTSD, no evidence on group schema therapy (GST) in refugees exists. To illustrate and advocate for the use of GST in refugee patients with treatment-resistant PTSD and comorbid personality pathology, a case report is presented. Presentation. The case concerned the treatment of an East African female refugee who survived sexual and physical violence and loss as a child, as the hostage of a rebel army, and as a victim of human trafficking. She was diagnosed with PTSD, major depressive disorder, and borderline personality disorder. Trauma-focused therapy was hampered by insufficient treatment attendance due to current stress factors and early destructive coping strategies. One year of GST enabled the patient to overcome treatment-undermining patterns and benefit from subsequent trauma-focused therapy. Conclusion. This case suggests that GST may have the potential to improve treatment adherence and the effectiveness of trauma-focused treatment in complex refugee patients. Clinical impressions need to be confirmed in a study that examines the feasibility, acceptability, and preliminary efficacy of GST in refugees with treatment-resistant PTSD and personality pathology.

Abstract Background Inappropriate use of antidepressants (AD), defined as either continuation in the absence of a proper indication or continuation despite the lack of therapeutic efficacy, applies to approximately half of all long term AD users. Methods/design We have designed a cluster randomized controlled clinical trial to assess the (cost-) effectiveness of an antidepressant cessation advice in the absence of a proper indication for maintenance treatment with antidepressants in primary care. We will select all patients using antidepressants for over 9 months from 45 general practices. Patients will be diagnosed using the Composite International Diagnostic Interview (CIDI) version 3.0, extended with questions about the psychiatric history and previous treatment strategies. General practices will be randomized to either the intervention or the control group. In case of overtreatment, defined as the absence of a proper indication according to current guidelines, a cessation advice is given to the general practitioner. In the control groups no specific information is given. The primary outcome measure will be the proportion of patients that successfully discontinue their antidepressants at one-year follow-up. Secondary outcomes are dimensional measures of psychopathology and costs. Discussion This study protocol provides a detailed overview of the design of the trial. Study results will be of importance for refining current guidelines. If the intervention is effective it can be used in managed care programs. Trial registration NTR2032

Abstract Background Doctor-patient communication has been influenced over time by factors such as the rise of evidence-based medicine and a growing emphasis on patient-centred care. Despite disputes in the literature on the tension between evidence-based medicine and patient-centered medicine, patients’ views on what constitutes high quality of doctor-patient communication are seldom an explicit topic for research. The aim of this study is to examine whether analogue patients (lay people judging videotaped consultations) perceive shifts in the quality of doctor-patient communication over a twenty-year period. Methods Analogue patients (N = 108) assessed 189 videotaped general practice consultations from two periods (1982–1984 and 2000–2001). They provided ratings on three dimensions (scale 1–10) and gave written feedback. With a mixed-methods research design, we examined these assessments quantitatively (in relation to observed communication coded with RIAS) and qualitatively. Results 1) The quantitative analyses showed that biomedical communication and rapport building were positively associated with the quality assessments of videotaped consultations from the first period, but not from the second. Psychosocial communication and personal remarks were related to positive quality assessments of both periods; 2) the qualitative analyses showed that in both periods, participants provided the same balance between positive and negative comments. Listening, giving support, and showing respect were considered equally important in both periods. We identified shifts in the participants’ observations on how GPs explained things to the patient, the division of roles and responsibilities, and the emphasis on problem-focused communication (first period) versus solution-focused communication (last period). Conclusion Analogue patients recognize shifts in the quality of doctor-patient communication from two different periods, including a shift from problem-focused communication to solution-focused communication, and they value an egalitarian doctor-patient relationship. The two research methods were complementary; based on the quantitative analyses we found shifts in communication, which we confirmed and specified in our qualitative analyses.

Abstract Background There is little evidence as to whether or not guideline concordant care in general practice results in better clinical outcomes for people with anxiety and depression. This study aims to determine possible associations between guideline concordant care and clinical outcomes in general practice patients with depression and anxiety, and identify patient and treatment characteristics associated with clinical improvement. Methods This study forms part of the Netherlands Study of Depression and Anxiety (NESDA). Adult patients, recruited in general practice (67 GPs), were interviewed to assess DSM-IV diagnoses during baseline assessment of NESDA, and also completed questionnaires measuring symptom severity, received care, socio-demographic variables and social support both at baseline and 12 months later. The definition of guideline adherence was based on an algorithm on care received. Information on guideline adherence was obtained from GP medical records. Results 721 patients with a current (6-month recency) anxiety or depressive disorder participated. While patients who received guideline concordant care (N = 281) suffered from more severe symptoms than patients who received non-guideline concordant care (N = 440), both groups showed equal improvement in their depressive or anxiety symptoms after 12 months. Patients who (still) had moderate or severe symptoms at follow-up, were more often unemployed, had smaller personal networks and more severe depressive symptoms at baseline than patients with mild symptoms at follow-up. The particular type of treatment followed made no difference to clinical outcomes. Conclusion The added value of guideline concordant care could not be demonstrated in this study. Symptom severity, employment status, social support and comorbidity of anxiety and depression all play a role in poor clinical outcomes.

Abstract Background Depression is a common illness, often treated in primary care. Guidelines provide recommendations for referral to mental health care. Several studies investigated determinants of referral, none investigated guideline criteria as possible determinants. We wanted to evaluate general practitioner's referral of depressed patients to mental health care and to what extent this is in agreement with (Dutch) guideline recommendations. Methods We used data of primary care respondents from the Netherlands Study of Depression and Anxiety with major depressive disorder in the past year (n = 478). We excluded respondents with missing data (n = 134). Referral data was collected from electronic patient files between 1 year before and after baseline and self report at baseline and 1-year follow-up. Logistic regression was used to describe association between guideline referral criteria (e.g. perceived need for psychotherapy, suicide risk, severe/chronic depression, antidepressant therapy failure) and referral. Results A high 58% of depressed patients were referred. Younger patients, those with suicidal tendency, chronic depression or perceived need for psychotherapy were referred more often. Patients who had used ≥2 antidepressants or with chronic depression were more often referred to secondary care. Referred respondents met on average more guideline criteria for referral. However, only 8-11% of variance was explained. Conclusion The majority of depressed patients were referred to mental health care. General practitioners take guideline criteria into account in decision making for referral of depressed patients to mental health care. However, other factors play a part, considering the small percentage of variance explained. Further research is necessary to investigate this.

Abstract Background Patients suffering from psychotic disorders have an increased risk of comorbid somatic diseases such as cardiovascular disorders and diabetes mellitus. Doctor-related factors, such as unfamiliarity with these patients, as well as patient-related factors, such as cognitive disturbance and negative symptoms, contribute to suboptimal health care for these patients. General practitioners (GPs) could play a key role in diagnosing and treating this somatic comorbidity as in the Netherlands, almost all residents are registered at a general practice. This study aims to find out whether there are any differences between the levels of health care provided by GPs to patients with psychotic disorders, compared to other types of patients. Methods A cohort of patients with an ICPC code of psychosis and two matched control groups, one consisting of patients with other mental problems and the other one of patients without any mental problems, were followed over a period of 5 years. Results Patients with psychotic disorders (N = 734) contacted the GP practice more often than patients in the control groups. These patients, both adults (p = 0.051) and the elderly (p < 0.005), received more home visits from their GPs. In the adult group (16 to 65 years old inclusive), the number of consultations was significantly higher among both psychosis patients and the group of patients with other mental problems (p < 0.0005). The number of telephone consultations was significantly higher in both age categories, adult group (p < 0.0005), and > 65 years old (p = 0.007). With regard to chronic illnesses, elderly psychosis patients had fewer contacts related to cardiovascular diseases or chronic lung diseases. Conclusion Patients with psychotic disorders contact the GP practice more frequently than other types of patients. Adult psychosis patients with diabetes mellitus, cardiovascular diseases or chronic lung diseases receive the same amount of health care for these diseases as other primary care patients. The finding that older patients with psychotic disorders are diagnosed with cardiovascular diseases and obstructive lung diseases less frequently than other types of elderly patients requires further study.

Abstract Background In view of the increasing number of senior citizens in our society who are likely to consult their GP with age-related health problems, it is important to identify and understand the preferences of this group in relation to the non-medical attributes of GP care. The aim of this study is to improve our understanding about preferences of this group of patients in relation to non-medical attributes of primary health care. This may help to develop strategies to improve the quality of care that senior citizens receive from their GP. Methods Semi-structured interviews (N = 13) with senior citizens (65-91 years) in a judgement sample were recorded and transcribed verbatim. The analysis was conducted according to qualitative research methodology and the frame work method. Results Continuity of care providers, i.e. GP and practice nurses, GPs' expertise, trust, free choice of GP and a kind open attitude were highly valued. Accessibility by phone did not meet the expectations of the interviewees. The interviewees had difficulties with the GP out-of-office hours services. Spontaneous home visits were appreciated by some, but rejected by others. They preferred to receive verbal information rather than collecting information from leaflets. Distance to the practice and continuity of caregiver seemed to conflict for respondents. Conclusions Preferences change in the process of ageing and growing health problems. GPs and their co-workers should be also aware of the changing needs of the elderly regarding non-medical attributes of GP care. Meeting their needs regarding non-medical attributes of primary health care is important to improve the quality of care.

Abstract Background The increasing prevalence of chronic diseases and the growing understanding that lifestyle behaviour plays an essential role in improving overall health suggest a need for increased attention to lifestyle choices in the consulting room. This study aims to examine whether or not healthy and unhealthy lifestyle choices of patients are currently being discussed more often in primary care consultations than in former decades. Furthermore, we are interested in GPs' approach to lifestyle behaviour during consultations. Lastly, we examine whether lifestyle behaviour is discussed more with certain patients during consultations, depending on gender, age and educational background. Method We analysed video-recordings of medical consultations, collected between 1975 and 2008 in Dutch GP practices. Data were analysed using logistic regression. Results This study shows that discussion of smoking behaviour and physical activity has increased somewhat over time. A change in discussion of nutrition and alcohol is, however, less clear. Overall, alcohol use is the least discussed and physical activity the most discussed during consultations. GPs mainly refer to lifestyle when it is relevant to the patient's complaints (symptom approach). GPs' approach to lifestyle behaviour did not change over time. In general, lifestyle behaviour is discussed more with older, male patients (except for nutrition). GPs talk about lifestyle behaviour with patients from different educational backgrounds equally (except for physical activity). Conclusion In recent years there is greater awareness of a healthy lifestyle, which is reflected to a limited extent in this study. Still, lifestyle behaviour is discussed in only a minority of consultations. GPs do not refer to lifestyle behaviour as a routine procedure, i.e. do not include it in primary prevention. This highlights the importance of the introduction of prevention consultations, where GPs can discuss lifestyle issues with patients who do not (yet) have risk symptoms.

Abstract Background Little is known about the course and outcome of untreated anxiety and depression in patients with and without a self-perceived need for care. The aim of the present study was to examine the one-year course of untreated anxiety and depression, and to determine predictors of a poor outcome. Method Baseline and one-year follow-up data were used of 594 primary care patients with current anxiety or depressive disorders at baseline (established by the Composite Interview Diagnostic Instrument (CIDI)), from the Netherlands Study of Depression and Anxiety (NESDA). Receipt of and need for care were assessed by the Perceived Need for Care Questionnaire (PNCQ). Results In depression, treated and untreated patients with a perceived treatment need showed more rapid symptom decline but greater symptom severity at follow-up than untreated patients without a self-perceived mental problem or treatment need. A lower education level, lower income, unemployment, loneliness, less social support, perceived need for care, number of somatic disorders, a comorbid anxiety and depressive disorder and symptom severity at baseline predicted a poorer outcome in both anxiety and depression. When all variables were considered at the same time, only baseline symptom severity appeared to predict a poorer outcome in anxiety. In depression, a poorer outcome was also predicted by more loneliness and a comorbid anxiety and depressive disorder. Conclusion In clinical practice, special attention should be paid to exploring the need for care among possible risk groups (e.g. low social economic status, low social support), and support them in making an informed decision on whether or not to seek treatment.

Abstract Background General practitioners' (GPs') feelings of burnout or dissatisfaction may affect their patient care negatively, but it is unknown if these negative feelings also affect their mental health care. GPs' available time, together with specific communication tools, are important conditions for providing mental health care. We investigated if GPs who feel burnt out or dissatisfied with the time available for their patients, are less inclined to encourage their patients to disclose their distress, and have shorter consultations, in order to gain time and energy. This may result in less psychological evaluations of patients' complaints. Methods We used 1890 videotaped consultations from a nationally representative sample of 126 Dutch GPs to analyse GPs' communication and the duration of their consultations. Burnout was subdivided into emotional exhaustion, depersonalisation and reduced accomplishment. Multilevel regression analyses were used to investigate which subgroups of GPs differed significantly. Results GPs with feelings of exhaustion or dissatisfaction with the available time have longer consultations compared to GPs without these feelings. Exhausted GPs, and GPs with feelings of depersonalisation, talk more about psychological or social topics in their consultations. GPs with feelings of reduced accomplishment are an exception: they communicate less affectively, are less patient-centred and have less eye contact with their patients compared to GPs without reduced accomplishment. We found no relationship between GPs' feelings of burnout or dissatisfaction with the available time and their psychological evaluations of patients' problems. Conclusion GPs' feelings of burnout or dissatisfaction with the time available for their patients do not obstruct their diagnosis and awareness of patients' psychological problems. On the contrary, GPs with high levels of exhaustion or depersonalisation, and GPs who are dissatisfied with the available time, sometimes provide more opportunities to discuss mental health problems. This increases the chance that appropriate care will be found for patients with mental health problems. On the other hand, these GPs are themselves more likely to retire, or risk burnout, because of their dissatisfaction. Therefore these GPs may benefit from training or personal coaching to decrease the chance that the process of burnout will get out of hand.

Abstract Background Depressive and anxiety disorders often go unrecognized in distressed primary care patients, despite the overtly psychosocial nature of their demand for help. This is especially problematic in more severe disorders needing specific treatment (e.g. antidepressant pharmacotherapy or specialized cognitive behavioural therapy). The use of a screening tool to detect (more severe) depressive and anxiety disorders may be useful not to overlook such disorders. We examined the accuracy with which the Four-Dimensional Symptom Questionnaire (4DSQ) and the Hospital Anxiety and Depression Scale (HADS) are able to detect (more severe) depressive and anxiety disorders in distressed patients, and which cut-off points should be used. Methods Seventy general practitioners (GPs) included 295 patients on sick leave due to psychological problems. They excluded patients with recognized depressive or anxiety disorders. Patients completed the 4DSQ and HADS. Standardized diagnoses of DSM-IV defined depressive and anxiety disorders were established with the Composite International Diagnostic Interview (CIDI). Receiver Operating Characteristic (ROC) analyses were performed to obtain sensitivity and specificity values for a range of scores, and area under the curve (AUC) values as a measure of diagnostic accuracy. Results With respect to the detection of any depressive or anxiety disorder (180 patients, 61%), the 4DSQ and HADS scales yielded comparable results with AUC values between 0.745 and 0.815. Also with respect to the detection of moderate or severe depressive disorder, the 4DSQ and HADS depression scales performed comparably (AUC 0.780 and 0.739, p 0.165). With respect to the detection of panic disorder, agoraphobia and social phobia, the 4DSQ anxiety scale performed significantly better than the HADS anxiety scale (AUC 0.852 versus 0.757, p 0.001). The recommended cut-off points of both HADS scales appeared to be too low while those of the 4DSQ anxiety scale appeared to be too high. Conclusion In general practice patients on sick leave because of psychological problems, the 4DSQ and the HADS are equally able to detect depressive and anxiety disorders. However, for the detection of cases severe enough to warrant specific treatment, the 4DSQ may have some advantages over the HADS, specifically for the detection of panic disorder, agoraphobia and social phobia.

Abstract Background Medically unexplained physical symptoms (MUPS) are common in general practice (GP), and are even more problematic as they become persistent. The present study examines the relationship between persistent MUPS in general practice on the one hand and quality of life, social conditions, and coping on the other hand. Additionally, it is examined how patients with persistent MUPS evaluate the quality of GP-care. Methods Data were used from a representative survey of morbidity in Dutch general practice, in which data from the electronic medical records were extracted. A random sample of patients participated in an extensive health interview and completed self-reported measures on social isolation, coping and the quality of GP-care. Patients with persistent MUPS (N = 192) were compared with general practice patients not meeting the criteria for persistent MUPS (N = 7.314), and with a group of patients that visited the GP in comparable rates for medical diagnoses (N = 2.265). Multiple logistic regression analyses were used to control for relevant socio-demographic variables and chronic diseases. Results After adjustment for demographics and chronic diseases, patients with persistent MUPS reported more psychological distress, more functional impairment, more social isolation, and they evaluated the quality of GP-care less positive than the other two patient groups. Although the majority of MUPS patients were positive about the quality of GP-care, they more often felt that they were not taken seriously or not involved in treatment decisions, and more often reported that the GP did not take sufficient time. The three groups did not differ with respect to the statement that the GP unnecessarily explains physical problems as psychological ones. Conclusion Strengthening MUPS patients' social network and encouraging social activities may be a meaningful intervention in which the GP may play a stimulating role. To further improve MUPS patients' satisfaction with GP-care, GPs may pay extra attention to taking sufficient time when treating MUPS patients, taking the problems seriously, and involving them in treatment decisions.

Abstract Background The extra workload induced by patients with mental health problems may sometimes cause GPs to be reluctant to become involved in mental health care. It is known that dealing with patients' mental health problems is more time consuming in specific situations such as in consultations. But it is unclear if GPs who are more often involved in patients' mental health problems, have a higher workload than other GPs. Therefore we investigated the following: Is the attention GPs pay to their patients' mental health problems related to their subjective and objective workload? Methods Secondary analyses were made using data from the Second Dutch National Survey of General Practice, a cross sectional study conducted in the Netherlands in 2000–2002. A nationally representative selection of 195 GPs from 104 general practices participated in this National Survey. Data from: 1) a GP questionnaire; 2) a detailed log of the GP's time use during a week and; 3) an electronic medical registration system, including all patients' contacts during a year, were used. Multiple regression analyses were conducted with the GP's workload as an outcome measure, and the GP's attention for mental health problems as a predictor. GP, patient, and practice characteristics were included in analyses as potential confounders. Results Results show that GPs with a broader perception of their role towards mental health care do not have more working hours or patient contacts than GPs with a more limited perception of their role. Neither are they more exhausted or dissatisfied with the available time. Also the number of patient contacts in which a psychological or social diagnosis is made is not related to the GP's objective or subjective workload. Conclusion The GP's attention for a patient's mental health problems is not related to their workload. The GP's extra workload when dealing in a consultation with patients' mental health problems, as is demonstrated in earlier research, is not automatically translated into a higher overall workload. This study does not confirm GPs' complaints that mental health care is one of the components of their job that consumes a lot of their time and energy. Several explanations for these results are discussed.

Abstract Backgroud The objective is to compare the performance of the MHI-5 and GHQ-12, both measures of general mental health. Therefore, we studied the relationship of the GHQ-12 and MHI-5 with sociodemographic characteristics, self-reported visits to general practice and mental health care, and with diagnoses made by the general practitioner. Methods Data were used from the Second Dutch National Survey of General Practice, which was carried out in 104 practices. This study combines data from a representative sample of the Dutch population with data from general practice. Results The agreement between the GHQ-12 and MHI-5 is only moderate. Both instruments are however similarly associated with demographic characteristics (except age), self-reported health care use, and psychological and social diagnoses in general practice. Conclusions The performance of the MHI-5 and GHQ-12 in terms of predicting mental health problems and related help seeking behaviour is similar. An advantage of the MHI-5 is that it has been widely used, not only in surveys of mental health, but also in surveys of general health and quality of life, and it is shorter. A disadvantage of the MHI-5 is that there is no cut-off point. We recommend a study to establish a valid, internationally comparable cut-off point.

Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution1-3; however, its frequency and clinical impact are unclear. Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that ecDNA amplification frequently occurs in most cancer types but not in blood or normal tissue. Oncogenes were highly enriched on amplified ecDNA, and the most common recurrent oncogene amplifications arose on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number-matched linear DNA, coupled with enhanced chromatin accessibility, and more frequently resulted in transcript fusions. Patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification is common in cancer, is different from chromosomal amplification and drives poor outcome for patients across many cancer types.

Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.

Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.

Sporadic gliomas in companion dogs provide a window on the interaction between tumorigenic mechanisms and host environment. We compared the molecular profiles of canine gliomas with those of human pediatric and adult gliomas to characterize evolutionarily conserved mammalian mutational processes in gliomagenesis. Employing whole-genome, exome, transcriptome, and methylation sequencing of 83 canine gliomas, we found alterations shared between canine and human gliomas such as the receptor tyrosine kinases, TP53 and cell-cycle pathways, and IDH1 R132. Canine gliomas showed high similarity with human pediatric gliomas per robust aneuploidy, mutational rates, relative timing of mutations, and DNA-methylation patterns. Our cross-species comparative genomic analysis provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations.

BackgroundOligodendroglioma is a rare primary central nervous system (CNS) tumor with highly variable outcome and for which therapy is usually not curative. At present, little is known regarding the pathways involved with progression of oligodendrogliomas or optimal biomarkers for stratifying risk. Developing new therapies for this rare cancer is especially challenging. To overcome these challenges, the neuro-oncology community must be particularly innovative, seeking multi-institutional and international collaborations, and establishing partnerships with patients and advocacy groups thereby ensuring that each patient enrolled in a study is as informative as possible.MethodsThe mission of the National Cancer Institute's NCI-CONNECT program is to address the challenges and unmet needs in rare CNS cancer research and treatment by connecting patients, health care providers, researchers, and advocacy organizations to work in partnership. On November 19, 2018, the program convened a workshop on oligodendroglioma, one of the 12 rare CNS cancers included in its initial portfolio. The purpose of this workshop was to discuss scientific progress and regulatory challenges in oligodendroglioma research and develop a call to action to advance research and treatment for this cancer.ResultsThe recommendations of the workshop include a multifaceted and interrelated approach covering: biology and preclinical models, data sharing and advanced molecular diagnosis and imaging; clinical trial design; and patient outreach and engagement.ConclusionsThe NCI-CONNECT program is well positioned to address challenges in oligodendroglioma care and research in collaboration with other stakeholders and is developing a list of action items for future initiatives.

Abstract Targeted cancer therapies have revolutionized treatment but their efficacies are limited by the development of resistance driven by clonal evolution within tumors. We developed “CAPTURE”, a single-cell barcoding approach to comprehensively trace clonal dynamics and capture live lineage-coupled resistant cells for in-depth multi-omics analysis and functional exploration. We demonstrate that heterogeneous clones, either preexisting or emerging from drug-tolerant persister cells, dominated resistance to vemurafenib in BRAFV600E melanoma. Further integrative studies uncovered diverse resistance mechanisms. This includes a previously unrecognized and clinically relevant mechanism, chromosome 18q21 gain, which leads to vulnerability of the cells to BCL2 inhibitor. We also identified targetable common dependencies of captured resistant clones, such as oxidative phosphorylation and E2F pathways. Our study provides new therapeutic insights into overcoming therapy resistance in BRAFV600E melanoma and presents a platform for exploring clonal evolution dynamics and vulnerabilities that can be applied to study treatment resistance in other cancers.

Introduction Glioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and postoperative radiotherapy with concurrent and adjuvant temozolomide-based chemotherapy, tumours inevitably recur. Imaging with O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) has the potential to impact adjuvant radiotherapy (RT) planning, distinguish between treatment-induced pseudoprogression versus tumour progression as well as prognostication.Methods and analysis The FET-PET in Glioblastoma (FIG) study is a prospective, multicentre, non-randomised, phase II study across 10 Australian sites and will enrol up to 210 adults aged ≥18 years with newly diagnosed glioblastoma. FET-PET will be performed at up to three time points: (1) following initial surgery and prior to commencement of chemoradiation (FET-PET1); (2) 4 weeks following concurrent chemoradiation (FET-PET2); and (3) within 14 days of suspected clinical and/or radiological progression on MRI (performed at the time of clinical suspicion of tumour recurrence) (FET-PET3). The co-primary outcomes are: (1) to investigate how FET-PET versus standard MRI impacts RT volume delineation and (2) to determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression. The secondary outcomes are: (1) to investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio, metabolic tumour volume) and progression-free survival and overall survival; (2) to assess the change in blood and tissue biomarkers determined by serum assay when comparing FET-PET data acquired prior to chemoradiation with other prognostic markers, looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with MRI and FET-PET imaging; and (3) to estimate the health economic impact of incorporating FET-PET into glioblastoma management and in the assessment of post-treatment pseudoprogression or recurrence/true progression. Exploratory outcomes include the correlation of multimodal imaging, blood and tumour biomarker analyses with patterns of failure and survival.Ethics and dissemination The study protocol V.2.0 dated 20 November 2020 has been approved by a lead Human Research Ethics Committee (Austin Health, Victoria). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results of the FIG study (TROG 18.06) will be disseminated via relevant scientific and consumer forums and peer-reviewed publications.Trial registration number ANZCTR ACTRN12619001735145

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

Oncogenes are commonly amplified on particles of extrachromosomal DNA (ecDNA) in cancer1,2, but our understanding of the structure of ecDNA and its effect on gene regulation is limited. Here, by integrating ultrastructural imaging, long-range optical mapping and computational analysis of whole-genome sequencing, we demonstrate the structure of circular ecDNA. Pan-cancer analyses reveal that oncogenes encoded on ecDNA are among the most highly expressed genes in the transcriptome of the tumours, linking increased copy number with high transcription levels. Quantitative assessment of the chromatin state reveals that although ecDNA is packaged into chromatin with intact domain structure, it lacks higher-order compaction that is typical of chromosomes and displays significantly enhanced chromatin accessibility. Furthermore, ecDNA is shown to have a significantly greater number of ultra-long-range interactions with active chromatin, which provides insight into how the structure of circular ecDNA affects oncogene function, and connects ecDNA biology with modern cancer genomics and epigenetics.

Recent reports have demonstrated that oncogene amplification on extrachromosomal DNA (ecDNA) is a frequent event in cancer, providing new momentum to explore a phenomenon first discovered several decades ago. The direct consequence of ecDNA gains in these cases is an increase in DNA copy number of the oncogenes residing on the extrachromosomal element. A secondary effect, perhaps even more important, is that the unequal segregation of ecDNA from a parental tumour cell to offspring cells rapidly increases tumour heterogeneity, thus providing the tumour with an additional array of responses to microenvironment-induced and therapy-induced stress factors and perhaps providing an evolutionary advantage. This Perspectives article discusses the current knowledge and potential implications of oncogene amplification on ecDNA in cancer.

Genetic heterogeneity in tumors can show a remarkable selectivity when two or more independent genetic events occur in the same gene. This phenomenon, called composite mutation, points toward a selective pressure, which frequently causes therapy resistance to mutation‐specific drugs. Since composite mutations have been described to occur in sub‐clonal populations, they are not always captured through biopsy sampling. Here, we provide a proof of concept to predict composite mutations to anticipate which patients might be at risk for sub‐clonally driven therapy resistance. We found that composite mutations occur in 5% of cancer patients, mostly affecting the PIK3CA, EGFR, BRAF, and KRAS genes, which are common precision medicine targets. Furthermore, we found a strong and significant relationship between the frequencies of composite mutations with commonly co‐occurring mutations in a non‐composite context. We also found that co‐mutations are significantly enriched on the same chromosome. These observations were independently confirmed using cell line data. Finally, we show the feasibility of predicting compositive mutations based on their co‐mutations (AUC 0.62, 0.81, 0.82, and 0.91 for EGFR, PIK3CA, KRAS, and BRAF, respectively). This prediction model could help to stratify patients who are at risk of developing therapy resistance‐causing mutations. [ABSTRACT FROM AUTHOR]

Key Points: Question: To what extent do differences in clinician setting explain variability in major depression treatments and outcomes? Findings: In this cohort study derived from electronic health record data, antidepressant prescribing patterns and outcomes varied significantly between prescriber groups. Clinician clusters were significantly associated with clinical outcomes. Meaning: Studies of antidepressant prescribing in real-world settings, and efforts at risk stratification or personalization of care, should include information on treatment setting and other clinician-level factors alongside individual patient characteristics. Importance: While abundant work has examined patient-level differences in antidepressant treatment outcomes, little is known about the extent of clinician-level differences. Understanding these differences may be important in the development of risk models, precision treatment strategies, and more efficient systems of care. Objective: To characterize differences between outpatient clinicians in treatment selection and outcomes for their patients diagnosed with major depressive disorder across academic medical centers, community hospitals, and affiliated clinics. Design, Setting, and Participants: This was a longitudinal cohort study using data derived from electronic health records at 2 large academic medical centers and 6 community hospitals, and their affiliated outpatient networks, in eastern Massachusetts. Participants were deidentified clinicians who billed at least 10 International Classification of Diseases, Ninth Revision (ICD-9) or Tenth Revision (ICD-10) diagnoses of major depressive disorder per year between 2008 and 2022. Data analysis occurred between September 2023 and January 2024. Main Outcomes and Measures: Heterogeneity of prescribing, defined as the number of distinct antidepressants accounting for 75% of prescriptions by a given clinician; proportion of patients who did not return for follow-up after an index prescription; and proportion of patients receiving stable, ongoing antidepressant treatment. Results: Among 11 934 clinicians treating major depressive disorder, unsupervised learning identified 10 distinct clusters on the basis of ICD codes, corresponding to outpatient psychiatry as well as oncology, obstetrics, and primary care. Between these clusters, substantial variability was identified in the proportion of selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and tricyclic antidepressants prescribed, as well as in the number of distinct antidepressants prescribed. Variability was also detected between clinician clusters in loss to follow-up and achievement of stable treatment, with the former ranging from 27% to 69% and the latter from 22% to 42%. Clinician clusters were significantly associated with treatment outcomes. Conclusions and Relevance: Groups of clinicians treating individuals diagnosed with major depressive disorder exhibit marked differences in prescribing patterns as well as longitudinal patient outcomes defined by electronic health records. Incorporating these group identifiers yielded similar prediction to more complex models incorporating individual codes, suggesting the importance of considering treatment context in efforts at risk stratification. This cohort study investigates differences between outpatient clinicians in treatment selection and outcomes for their patients diagnosed with major depressive disorder across academic medical centers, community hospitals, and affiliated clinics. [ABSTRACT FROM AUTHOR]

Through regeneration, the endometrium accumulates somatic mutations that can lead to diseases like endometriosis and cancer. Here, the authors use genomics to analyse normal endometrial glands from different patient cohorts, detect rhizome structures with common clonal ancestors and infer clonal expansion dynamics.

Purpose: Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. Experimental design: We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. Results: These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented

We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively.

Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal Analysis Consortium (GLASS) aims to systemically catalog the longitudinal changes in gliomas. The GLASS initiative will provide essential insights into the evolution of glioma toward a lethal phenotype, with the potential to reveal targetable vulnerabilities and, ultimately, improved outcomes for a patient population in need.