Real-World Outcomes of Ribociclib and Aromatase Inhibitor Use in First Line Hormone Receptor Positive, HER2-Negative Metastatic Breast Cancer.

BACKGROUND: International guidelines recommend combining a CDK4/6 inhibitor and endocrine therapy (ET) as first line treatment for hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). Results from MONALEESA-2 demonstrate superior progression free survival (PFS) and overall survival (OS) with ribociclib (CDK4/6 inhibitor) and ET compared to ET alone. Real world outcomes have yet to be reported. MATERIALS AND METHODS: KARMA is a non-interventional registry of Australian patients receiving first-line treatment with ribociclib and aromatase inhibitor (AI), obtained via a Medicine Access Program (MAP) for HR+, HER2- MBC. Outcomes were compared with the ribociclib/letrozole cohort in MONALEESA-2. RESULTS: Data from 160 patients at 17 sites was analysed. Median follow-up is 36.5 months. Compared to MONALEESA-2, patients were numerically younger (54.3 vs. 62 years), with higher rates of bone-only metastases (31% vs. 21%). A total of 63 of 160 (39%) patients remain on treatment. A total of 56% of patients had at least 1 dose reduction, with neutropenia (68%) and abnormal liver enzymes (17%) the most common reasons. A total of 17 of 160 (11%) discontinued treatment due to toxicity, with no treatment related deaths. Median PFS was not reached (95% CI 29.9- NR), with PFS at 12 months and 18 months being 76% and 67% respectively versus 25.3 months, 73% and 63% in MONALEESA-2. CONCLUSION: The ribociclib and AI combination was well tolerated in this real-world setting. The KARMA registry cohort achieved a superior PFS (>36.5 months) to MONALEESA-2, potentially due to more favourable baseline disease characteristics. Less frequent assessment scheduling in this non trial setting may also contribute.

Oncology service initiatives and research in regional Australia.

OBJECTIVE: This paper reflects on the recent growth of cancer research being conducted through some of Australia's rural centres. It encompasses work being done across the fields of clinical, translational and health services research. DESIGN: This is a collaborative piece with contributions from rural health researchers, clinical and cancer services staff from several different regions. CONCLUSION: The past decade has seen an expansion in cancer research in rural and regional Australia driven in part by the recognition that cancer patients in remote areas experience poorer outcomes than their metropolitan counterparts. This work has led to the development of more effective cancer networks and new models of care designed to meet the particular needs of the rural cancer patient. It is hoped that the growth of cancer research in regional centres will, in time, reduce the disparity between rural and urban communities and improve outcomes for cancer patients across both populations.

Caregiver causal attributions in youth psychosis.

AIM: Caregiver causal attributions influence patient and caregiver reactions to psychosis. The current study describes common caregiver causal attributions about psychosis onset in youth, including a subset of first-episode psychosis patients, and the patient and caregiver characteristics that influence these attributions. It also examines if caregiver views are affected by contact with youth mental health services. METHODS: Fifty-one caregivers of 50 youth patients with a diagnosed Diagnostic and statistical manual of mental disorders, fourth edition (DSM-IV) psychotic disorder were interviewed about their causal attributions. Patient and caregiver demographic and clinical predictors were also collected. RESULTS: Caregivers most highly endorsed substance use, genetics, negative peer influences and school stress as individual causes. These findings were consistent across the total sample. Principal components analysis derived three causal categories. Caregivers most frequently endorsed a biological and substance use lifestyle causal category, followed by psychological vulnerability and stress-reactivity causal categories. There was evidence that caregiver and patient factors, as well as contact with youth mental health services, influenced the causal attributions caregivers made about the onset of psychosis. CONCLUSION: Caregivers of youth with psychosis are making causal attributions that are consistent with current aetiological theories of psychosis in youth. The study showed that caregivers are particularly cognizant of genetic and substance use factors in the development and maintenance of psychosis. However, youth mental health services may need to particularly focus on increasing caregiver understanding of the dynamics of stress factors as symptoms, and not causes, of psychosis early in the illness course.

Mentoring in the management of hematological malignancies.

AIM: The Mentoring in Management of Haematological Malignancies (MMHM) project aimed to improve treatment outcomes, coordinate care and provide best practice for patients with hematological cancers, by developing a program of mentoring and multidisciplinary care between a regional and a metropolitan centre. METHODS: A regular multidisciplinary meeting conducted by teleconference was established between a tertiary metropolitan site and a regional practice to discuss cases of patients with hematological malignancies. Information from multidisciplinary team meetings was recorded to capture adherence to process and clinician outcomes. An educational program was developed. A gap analysis was performed to identify differences in routine practice between the two centers. Clinician satisfaction with mentoring and educational interventions was assessed by structured survey. RESULTS: The MMHM project developed a formal mentoring system to improve the management of patients by building on established links and developing an innovative model of web-based multidisciplinary care. The project established a novel multidisciplinary meeting between a metropolitan and regional site. Common treatment policies were adopted between the two sites. Development of an educational framework and mentoring for health-care professionals in regional areas was achieved by tutorials and workshops. Most participating clinicians indicated their high level of satisfaction with the mentoring project. CONCLUSION: The MMHM project was a successful pilot of a mentoring program in hematological cancers between metropolitan and regional centers that resulted in improved referral links, facilitated better care coordination, updated treatment policies and guidelines and increased clinician satisfaction and knowledge.

Functional and biochemical alterations of the medial frontal cortex in obsessive-compulsive disorder.

CONTEXT: The medial frontal cortex (MFC), including the dorsal anterior cingulate and the supplementary motor area, is critical for adaptive and inhibitory control of behavior. Abnormally high MFC activity has been a consistent finding in functional neuroimaging studies of obsessive-compulsive disorder (OCD). However, the precise regions and the neural alterations associated with this abnormality remain unclear. OBJECTIVE: To examine the functional and biochemical properties of the MFC in patients with OCD. DESIGN: Cross-sectional study combining volume-localized proton magnetic resonance spectroscopy and functional magnetic resonance imaging with a task encompassing inhibitory control processes (the Multi-Source Interference Task) designed to activate the MFC. SETTING: Healthy control participants and OCD patients recruited from the general community. PARTICIPANTS: Nineteen OCD patients (10 males and 9 females) and 19 age-, sex-, education-, and intelligence-matched control participants recruited from the general community. MAIN OUTCOME MEASURES: Psychometric measures of symptom severity, Multi-Source Interference Task behavioral performance, blood oxygen level-dependent activation, and proton magnetic resonance spectroscopy brain metabolite concentrations. RESULTS: Multi-Source Interference Task behavioral performance did not differ between OCD patients and control subjects. Reaction time interference and response errors were correlated with blood oxygen level-dependent activation in the dorsal anterior cingulate region in both groups. Compared with controls, OCD patients had greater relative activation of the supplementary motor area and deactivation of the rostral anterior cingulate during high- vs low-conflict (incongruent > congruent) trials. Patients with OCD also showed reduced levels of neuronal N-acetylaspartate in the dorsal anterior cingulate region, which was negatively correlated with their blood oxygen level-dependent activation of the region. CONCLUSIONS: Hyperactivation of the MFC during high- vs low-conflict conditions in patients with OCD may be a compensatory response to a neuronal abnormality in the region. This relationship may partly explain the nature of inhibitory control deficits that are frequently seen in this group and may serve as a focus of future treatment studies.

Evidence for neuronal dysfunction in the anterior cingulate of patients with schizophrenia: a proton magnetic resonance spectroscopy study at 3 T.

The anterior cingulate region is thought to be dysfunctional in schizophrenia, but whether this is the result of reduced neuronal integrity or changes in neurotransmitter systems remains an issue of debate. Fifteen male patients with schizophrenia and 14 male controls were assessed using proton magnetic resonance spectroscopy, with regions of interest placed in the right and left dorsal and rostral cingulate. The metabolites of interest were N-acetylaspartate (NAA), a putative neuronal marker, and glutamate + glutamine (Glx), which may index synapse number. Schizophrenia patients had lower NAA concentrations throughout the dorsal and rostral portions of the anterior cingulate and in both hemispheres, but showed no changes in Glx. Anterior cingulate involvement in schizophrenia is likely to be a result of neuronal loss or dysfunction.

State, trait and biochemical influences on human anterior cingulate function.

The dorsal part of the human anterior cingulate cortex (dACC) is reliably activated in situations requiring cognitive control, especially during states of conflict. However, little is known about how individual differences in the neural characteristics of the dACC and major dimensions of behavior, affect this brain response. We recruited 28 healthy adults and employed a multi-modal neuroimaging approach combined with a task designed to specifically activate the human dACC and statistical path analysis to demonstrate clear roles for intelligence, personality and concentrations of neuronal N-acetylaspartate in determining dACC activation. These influences were comparable in magnitude to those associated with the experience of conflict. Our findings extend current understandings of the neural substrates of cognitive control by modeling the effect of neuronal viability, intelligence, and personality, on dACC activation. They also highlight the importance of considering enduring personal characteristics when mapping human brain-behavior relationships.

Plasma Epstein-Barr virus (EBV) DNA is a biomarker for EBV-positive Hodgkin's lymphoma.

PURPOSE: Latent Epstein-Barr virus (EBV) genomes are found in the malignant cells of approximately one-third of Hodgkin's lymphoma (HL) cases. Detection and quantitation of EBV viral DNA could potentially be used as a biomarker of disease activity. EXPERIMENTAL DESIGN: Initially, EBV-DNA viral load was prospectively monitored from peripheral blood mononuclear cells (PBMC) in patients with HL. Subsequently, we analyzed viral load in plasma from a second cohort of patients. A total of 58 patients with HL (31 newly diagnosed, 6 relapsed, and 21 in long-term remission) were tested. Using real-time PCR, 43 PBMC and 52 plasma samples were analyzed. RESULTS: EBV-DNA was detectable in the plasma of all EBV-positive patients with HL prior to therapy. However, viral DNA was undetectable following therapy in responding patients (P = 0.0156), EBV-positive HL patients in long-term remission (P = 0.0011), and in all patients with EBV-negative HL (P = 0.0238). Conversely, there was no association seen for the EBV-DNA load measured from PBMC in patients with active EBV-positive HL patients as compared with EBV-negative HL, or patients in long-term remission. EBV-DNA load in matched plasma/PBMC samples were not correlated. CONCLUSIONS: We show that free plasma EBV-DNA has excellent sensitivity and specificity, and can be used as a noninvasive biomarker for EBV-positive HL and that serial monitoring could predict response to therapy. Additional prospective studies are required to further evaluate the use of free plasma EBV-DNA as a biomarker for monitoring response to treatment in patients with EBV-positive HL.