Spinal dementia: Don't miss it, it's treatable.

BACKGROUND & PURPOSE: Around 5% of dementia patients have a treatable cause. To estimate the prevalence of two rare diseases, in which the treatable cause is at the spinal level. METHODS: A radiology information system was searched using the terms CT myelography and the operation and classification system (OPS) code 3-241. The clinical charts of these patients were reviewed to identify patients with a significant cognitive decline. RESULTS: Among 205 patients with spontaneous intracranial hypotension (SIH) and proven CSF leaks we identified five patients with a so-called frontotemporal brain sagging syndrome: Four of those had CSF venous fistulas and significantly improved by occluding them either by surgery or transvenous embolization. Another 11 patients had infratentorial hemosiderosis and hearing problems and ataxia as guiding symptoms. Some cognitive decline was present in at least two of them. Ten patients had ventral dural tears in the thoracic spine and one patient a lateral dural tear at C2/3 respectively. Eight patients showed some improvement after surgery. DISCUSSION: It is mandatory to study the (thoracic) spine in cognitively impaired patients with brain sagging and/ or infratentorial hemosiderosis on MRI. We propose the term spinal dementia to draw attention to this region, which in turn is evaluated with dynamic digital subtraction and CT myelography.

Neoadjuvant talazoparib in patients with germline BRCA1/2 mutation-positive, early-stage triple-negative breast cancer: exploration of tumor BRCA mutational status.

BACKGROUND: Talazoparib monotherapy in patients with germline BRCA-mutated, early-stage triple-negative breast cancer (TNBC) showed activity in the neoadjuvant setting in the phase II NEOTALA study (NCT03499353). These biomarker analyses further assessed the mutational landscape of the patients enrolled in the NEOTALA study. METHODS: Baseline tumor tissue from the NEOTALA study was tested retrospectively using FoundationOne®CDx. To further hypothesis-driven correlative analyses, agnostic heat-map visualizations of the FoundationOne®CDx tumor dataset were used to assess overall mutational landscape and identify additional candidate predictive biomarkers of response. RESULTS: All patients enrolled (N = 61) had TNBC. In the biomarker analysis population, 75.0% (39/52) and 25.0% (13/52) of patients exhibited BRCA1 and BRCA2 mutations, respectively. Strong concordance (97.8%) was observed between tumor BRCA and germline BRCA mutations, and 90.5% (38/42) of patients with tumor BRCA mutations evaluable for somatic-germline-zygosity were predicted to exhibit BRCA loss of heterozygosity (LOH). No patients had non-BRCA germline DNA damage response (DDR) gene variants with known/likely pathogenicity, based on a panel of 14 non-BRCA DDR genes. Ninety-eight percent of patients had TP53 mutations. Genomic LOH, assessed continuously or categorically, was not associated with response. CONCLUSION: The results from this exploratory biomarker analysis support the central role of BRCA and TP53 mutations in tumor pathobiology. Furthermore, these data support assessing germline BRCA mutational status for molecular eligibility for talazoparib in patients with TNBC.

Beyond overlap: Considering habitat preference and fitness outcomes in the umbrella species concept.

Umbrella species and other surrogate-species approaches to conservation provide an appealing framework to extend the reach of conservation efforts beyond single species. For the umbrella species concept to be effective, populations of multiple species of concern must persist in areas protected on behalf of the umbrella species. Most assessments of the concept, however, focus exclusively on geographic overlap among umbrella and background species, and not measures that affect population persistence (e.g., habitat quality or fitness). We quantified the congruence between the habitat preferences and nesting success of a high-profile umbrella species (greater sage-grouse, Centrocercus urophasianus, hereafter "sage-grouse"), and three sympatric species of declining songbirds (Brewer's sparrow Spizella breweri, sage thasher Oreoscoptes montanus, and vesper sparrow Pooecetes gramineus) in central Wyoming, USA during 2012 - 2013. We used machine-learning methods to create data-driven predictions of sage-grouse nest-site selection and nest survival probabilities by modeling field-collected sage-grouse data relative to habitat attributes. We then used field-collected songbird data to assess whether high-quality sites for songbirds aligned with those of sage-grouse. Nest sites selected by songbirds did not coincide with sage-grouse nesting preferences, with the exception that Brewer's sparrows preferred similar nest sites to sage-grouse in 2012. Moreover, the areas that produced higher rates of songbird nest survival were unrelated to those for sage-grouse. Our findings suggest that management actions at local scales that prioritize sage-grouse nesting habitat will not necessarily enhance the reproductive success of sagebrush-associated songbirds. Measures implemented to conserve sage-grouse and other purported umbrella species at broad spatial scales likely overlap the distribution of many species, however, broad-scale overlap may not translate to fine-scale conservation benefit beyond the umbrella species itself. The maintenance of microhabitat heterogeneity important for a diversity of species of concern will be critical for a more-holistic application of the umbrella species concept.

A next-generation BRAF inhibitor overcomes resistance to BRAF inhibition in patients with BRAF-mutant cancers using pharmacokinetics-informed dose escalation.

RAF inhibitors have transformed treatment for BRAF V600-mutant cancer patients, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAF V600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAF V600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in BRAF-mutant cancer patients refractory to approved RAF inhibitors.

Determining pre-procedure fasting alert time using procedural and scheduling data.

Before a medical procedure requiring anesthesia, patients are required to not eat or drink non-clear fluids for 6 h and not drink clear fluids for 2 h. Fasting durations in standard practice far exceed these minimum thresholds due to uncertainties in procedure start time. The aim of this retrospective, observational study was to compare fasting durations arising from standard practice with different approaches for calculating the timepoint at which patients are instructed to stop eating and drinking. Scheduling data for procedures performed in the cardiac catheterization laboratory of an academic hospital in Canada (January 2020 to April 2022) were used. Four approaches utilizing machine learning (ML) and simulation were used to predict procedure start times and calculate when patients should be instructed to start fasting. Median fasting duration for standard practice was 10.08 h (IQR 3.5) for both food and clear fluids intake. The best performing alternative approach, using tree-based ML models to predict procedure start time, reduced median fasting from food/non-clear fluids to 7.7 h (IQR 2) and clear liquids fasting to 3.7 h (IQR 2.4). 97.3% met the minimum fasting duration requirements (95% CI 96.9% to 97.6%). Further studies are required to determine the effectiveness of operationalizing this approach as an automated fasting alert system.

Latent Profiles of Co-occurring Sexual Problems and Posttraumatic Stress Symptoms Among Young Women Exposed to Sexual Violence.

Sexual dysfunctions (SDs) have been noted to occur following exposure to sexual violence although how these conditions covary with other mental health conditions, particularly posttraumatic stress disorder symptoms (PTSS), is relatively understudied. The current study examined patterns of co-occurring SDs and PTSS in a sample of 328 college-aged, female-identified survivors of adolescent/early adulthood sexual assault (ASA). Latent profile analysis was used to examine patterns of symptom endorsement of various types of SDs and PTSS at the symptom cluster level. Four profiles were identified: asymptomatic (41.2% of sample), sexually distressed + intrusions (24.7%), co-occurring (21%), and PTSS (13.1%). Profiles were compared to one another on various characteristics of sexual assault and social reactions from others following assault disclosure. Results indicated that those in the co-occurring symptom and PTSS profiles reported more severe ASA and more unsupportive social responses relative to the sexually distressed + intrusions and asymptomatic profiles. The asymptomatic profile was significantly less likely to have experienced rape relative to the other three profiles and was less likely to report instances where a close other treated them in a negative manner following assault disclosure. Results are discussed in light of mental health needs for young women who have experienced ASA, with implications discussed for future research and clinical services for university students.

Advanced diffusion MRI provides evidence for altered axonal microstructure and gradual peritumoral infiltration in GBM in comparison to brain metastases.

PURPOSE: In contrast to peritumoral edema in metastases, GBM is histopathologically characterized by infiltrating tumor cells within the T2 signal alterations. We hypothesized that depending on the distance from the outline of the contrast-enhancing tumor we might reveal imaging evidence of gradual peritumoral infiltration in GBM and predominantly vasogenic edema around metastases. We thus investigated the gradual change of advanced diffusion metrics with the peritumoral zone in metastases and GBM. METHODS: In 30 patients with GBM and 28 with brain metastases, peritumoral T2 hyperintensity was segmented in 33% partitions based on the total volume beginning at the enhancing tumor margin and divided into inner, middle and outer zones. Diffusion Tensor Imaging (DTI)-derived fractional anisotropy and mean diffusivity as well as Diffusion Microstructure Imaging (DMI)-based parameters Dax-intra, Dax-extra, V­CSF and V-intra were employed to assess group-wise differences between inner and outer zones as well as within-group gradients between the inner and outer zones. RESULTS: In metastases, fractional anisotropy and Dax-extra were significantly reduced in the inner zone compared to the outer zone (FA p = 0.01; Dax-extra p = 0.03). In GBM, we noted a reduced Dax-extra and significantly lower intraaxonal volume fraction (Dax-extra p = 0.008, V­intra p = 0.006) accompanied by elevated axial intraaxonal diffusivity in the inner zone (p = 0.035). Between-group comparison of the outer to the inner zones revealed significantly higher gradients in metastases over GBM for FA (p = 0.04) as well as the axial diffusivity in the intra- (p = 0.02) and extraaxonal compartment (p < 0.001). CONCLUSION: Our findings provide evidence of gradual alterations within the peritumoral zone of brain tumors. These are compatible with predominant (vasogenic) edema formation in metastases, whereas our findings in GBM are in line with an axonal destructive component in the immediate peritumoral area and evidence of tumor cell infiltration with accentuation in the tumor's vicinity.

Screening and surveillance recommendations for central nervous system hemangioblastomas in pediatric patients with Von Hippel-Lindau disease.

PURPOSE: Von Hippel-Lindau (VHL) disease is an autosomal-dominantly inherited tumor predisposition syndrome. One of the most common tumors are central nervous system (CNS) hemangioblastomas. Recommendations on the initiation and continuation of the screening and surveillance program for CNS tumors in pediatric VHL patients are based on small case series and thus low evidence level. To derive more robust screening recommendations, we report on the largest monocentric pediatric cohort of VHL patients. METHODS: We performed a retrospective analysis on a pediatric cohort of 99 VHL patients consulted at our VHL center from 1992 to 2023. Clinical, surgical, genetic, and imaging data were collected and statistically analyzed. RESULTS: 42 patients (50% male) developed CNS hemangioblastomas, of whom 18 patients (56% male) underwent hemangioblastoma surgery (mean age at first surgery: 14.9 ± 1.9 years; range 10.2-17). The first asymptomatic patient was operated on at the age of 13.2 years due to tumor progress. Truncating VHL mutation carriers had a significantly higher manifestation rate (HR = 3.7, 95% CI: 1.9-7.4, p < 0.0001) and surgery rate (HR = 3.3, 95% CI: 1.2-8.9, p = 0.02) compared with missense mutation carriers. CONCLUSION: We recommend starting MRI imaging at the age of 12 years with examination intervals every (1-) 2 years depending on CNS involvement. Special attention should be paid to patients with truncating variants. Affected families should be educated regularly on potential tumor-associated symptoms to enable timely MRI imaging and eventually intervention, as CNS hemangioblastoma may develop before screening begins. GERMAN CLINICAL TRIALS REGISTER REGISTRATION NUMBER: DRKS00029553, date of registration 08/16/2022, retrospectively registered.

Insights from a Multicenter Study on Adult H3 K27M-Mutated Glioma: Surgical Resection's Limited Influence on Overall Survival, ATRX as Molecular Prognosticator.

BACKGROUND: H3 K27M-mutated gliomas were first described as a new grade 4 entity in the 2016 WHO classification. Current studies have focused on its typical appearance in children and young adults, increasing the need to better understand the prognostic factors and impact of surgery on adults. Here, we report a multicentric study of this entity in adults. METHODS: We included molecularly confirmed H3 K27M-mutated glioma cases in patients >18 years diagnosed between 2016 and 2022. Clinical, radiological, and surgical features were analyzed. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Among 70 patients with a mean age of 36.1 years, the median overall survival (OS) was 13.6 + 14 months. Gross-total resection was achieved in 14.3% of patients, whereas 30% had a subtotal resection and 54.3% a biopsy.Tumors located in telencephalon/diencephalon/myelencephalon were associated with a poorer OS, while a location in the mesencephalon/metencephalon showed a significantly longer OS (8.7 vs. 25.0 months, p=0.007). Preoperative Karnofsky Performance Score (KPS) < 80 showed a reduced OS (4.2 vs. 18 months, p=0.02). Furthermore, ATRX loss, found in 25.7%, was independently associated with an increased OS (31 vs. 8.3 months, p=0.0029). Notably, patients undergoing resection showed no survival benefit over biopsy (12 vs. 11 months, p=0.4006). CONCLUSION: The present study describes surgical features of H3 K27M-mutated glioma in adulthood in a large multicentric study. Our data reveal that ATRX status, location and KPS significantly impact OS in H3 K27M-mutated glioma. Importantly, our dataset indicates that resection does not offer a survival advantage over biopsy.

Social problem-solving in intimate partner violence victims: Exploring the relative contributions of shame and PTSD symptoms.

OBJECTIVE: This study examined the contributions of shame and posttraumatic stress disorder (PTSD) symptoms to two dimensions of social problem-solving. METHOD: A sample of 426 women who were seeking mental health assistance following experiences of intimate partner violence completed self-report and clinician measures. Separate path analyses were conducted for problem orientation and problem-solving styles. RESULTS: In the model examining problem orientation, higher levels of shame were significantly associated with lower levels of positive problem orientation (f2 = 0.32) and higher levels of negative problem orientation (f2 = 0.92), with large effects noted. PTSD symptoms were significantly, positively associated with negative problem orientation (f2 = 0.3, large effect). When examining problem-solving styles, shame showed a significant negative association with rational style (f2 = 0.08, small effect) and significant positive associations with impulsive style (f2 = 0.45, large effect) and avoidant style (f2 = 0.48, large effect). PTSD symptoms did not return significant associations with any of the three problem-solving styles. CONCLUSION: Results indicate that shame holds notable associations with both dimensions of social problem-solving, relative to PTSD symptoms, and are discussed in light of current models of post-trauma functioning. Implications for clinical care and early intervention efforts are highlighted.

Multiple Imputation for Partial Recording Periodontal Examination Protocols.

AIM: Partial-mouth recording protocols often result in underestimation of population prevalence and extent of periodontitis. We posit that multiple imputation of measures such as clinical attachment loss for nonselected tooth sites in partial-mouth samples can reduce bias in periodontitis estimates. METHODS: Multiple imputation for correlated site-level dichotomous outcomes in a generalized estimating equations framework is used to impute site-level binary indicators for clinical attachment loss exceeding a fixed threshold in partial-mouth samples. Periodontitis case definitions are applied to the imputed "complete" dentitions, enabling estimation of prevalence and other summaries of periodontitis for partial-mouth samples as if for full-mouth examinations. A multiple imputation-bootstrap procedure is described and applied for point and variance estimation of these periodontitis measures. The procedure is evaluated with pseudo-partial-mouth samples based on random site selection protocols of 28 to 84 periodontal sites repeatedly generated from full-mouth periodontal examinations of 3,621 participants in the 2013 to 2014 National Health and Nutrition Examination Survey (NHANES) survey. RESULTS: Multiple imputation applied to partial-mouth samples overestimated periodontitis mean extent, defined as the number of sites with clinical attachment loss 3 mm or greater, by 9.5% in random site selection protocols with 84 sites and overestimated prevalence by 5% to 10% in all the evaluated protocols. CONCLUSIONS: In the 2013 to 2014 NHANES data, multiple imputation of site-level periodontal indicators provides less biased estimates of periodontitis prevalence and extent than has been reported from estimates based on the direct application of full-mouth case definitions to partial-mouth samples. Multiple imputation provides a promising solution to the longstanding, vexing problem of estimation bias in partial-mouth recording, with potential application to a wide array of case definitions, periodontitis measures, and partial recording protocols. KNOWLEDGE TRANSFER STATEMENT: Partial-mouth sampling, while a resource-efficient strategy for obtaining oral disease estimates, often results in underestimation of periodontitis metrics. Multiple imputation for nonselected periodontal sites produces pseudo-full-mouth data sets that may be analyzed and combined to produce estimates with small bias.

Do latent profiles of self-reported anxiety, depression, and PTSD map onto clinician ratings? An examination with intimate partner violence survivors.

OBJECTIVE: Studies exploring latent profiles of mental health in trauma survivors have largely relied on self-report, making it unclear whether these patterns correspond with clinician-assessed psychopathology. The purpose of the current study was to examine latent profiles of self-reported PTSD, depression, and anxiety in a sample of 387 women who had experienced intimate partner violence (IPV) and investigate whether profiles mapped onto clinician-rated measures of the same outcomes. METHOD: Participants completed a series of semi-structured interviews and self-report measures assessing PTSD, depression, and anxiety. RESULTS: Latent profile analyses revealed a 3-profile solution characterized by Low (22.48 %), Moderate (37.98 %), and High (39.53 %) self-reported symptomology. Clinician ratings were significant predictors of membership in the low vs. moderate vs. high symptomology profiles. However, normalized means showed discrepancies between self-report and clinician assessment regarding which issue was rated most severe. CONCLUSIONS: Results suggest that while latent modeling approaches relying on self-report may adequately approximate common underlying patterns of psychopathology, they have limitations in identifying which disorders are most salient for clinical intervention.

Examining the Content Validity of the Measure of Psychologically Abusive Behaviors: A Qualitative Approach.

The content validity of the Measure of Psychologically Abusive Behaviors (MPAB) was examined via qualitative content analysis of interviews conducted with 262 women who experienced intimate partner violence. Data were coded using MPAB categories and items. Approximately 73.4% of the data were represented by the MPAB at both the category and severity levels; half of the data mapped onto "severe" items. At the category level, 12.3% of the data did not map onto the MPAB; 15.5% of the data mapped onto a category but did not match a severity level. Results support the content validity of the MPAB.

Increased Utilization of Low-Dose CT for Lung Cancer Screening at an Arkansas Community Oncology Clinic.

BACKGROUND: Low-dose CT (LDCT) is underused in Arkansas for lung cancer screening, a rural state with a high incidence of lung cancer. The objective was to determine whether offering free LDCT increased the number of high-risk individuals screened in a rural catchment area. METHODS: There were 5,402 patients enrolled in screening at Highlands Oncology, a community oncology clinic in Northwest Arkansas, from 2013 to 2020. Screenings were separated into time periods: period 1 (10 months for-fee), period 2 (10 months free with targeted advertisements and primary care outreach), and period 3 (62 months free with only primary care outreach). In all, 5,035 high-risk participants were eligible for analysis based on National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Enrollment rates, incidence densities (IDs), Cox proportional hazard models, and Kaplan-Meier curves were performed to investigate differences between enrollment periods and high-risk groups. RESULTS: Patient volume increased drastically once screenings were offered free of charge (period 1 = 4.6 versus period 2 = 66.0 and period 3 = 69.8 average patients per month). Incidence density per 1,000 person-years increased through each period (IDPeriod 1 = 17.2; IDPeriod 2 = 20.8; IDPeriod 3 = 25.5 cases). Cox models revealed significant differences in lung cancer risk between high-risk groups (P = .012) but not enrollment periods (P = .19). Kaplan-Meier lung cancer-free probabilities differed significantly between high-risk groups (log-rank P = .00068) but not enrollment periods (log-rank P = .18). CONCLUSIONS: This study suggests that eligible patients are more receptive to free LDCT screening, despite most insurances not having a required copay for eligible patients.

CIMT 2023: report on the 20th Annual Meeting of the Association for Cancer Immunotherapy.

The Association for Cancer Immunotherapy (CIMT) celebrated the 20th anniversary of the CIMT Annual Meeting. CIMT2023 was held 3-5 May 2023 in Mainz, Germany. 1051 academic and clinical professionals from over 30 countries attended the meeting and discussed the latest advances in cancer immunology and immunotherapy research. This report summarizes the highlights of CIMT2023.

Alcohol Use and Mental Health Symptoms in Nurses during the Early Months of COVID-19.

OBJECTIVE: The current study examined associations of symptoms of posttraumatic stress disorder [PTSD], depression, and generalized anxiety disorder [GAD] with alcohol consumption and drinking to cope in a sample of 310 nurses during the first six months of the COVID-19 pandemic. METHOD: Using a cross-sectional design, nurses completed online surveys. RESULTS: Over 50% of the sample reported alcohol misuse and 12.2% reported drinking to cope. Further, 38.7% reported elevated symptoms of PTSD, 29.7% moderate-to-high symptoms of depression, and 56.8% elevated symptoms of GAD symptoms. Hierarchical regression analyses were conducted to examine how mental health symptoms were associated with alcohol outcomes, controlling for age, gender pronouns, education, and race. No significant predictors emerged for alcohol consumption. Significant associations of symptoms of PTSD and depression were found for drinking to cope, such that higher levels of mental health symptoms were associated with greater endorsement of drinking to cope. CONCLUSION: Results are discussed in light of increasing prevention and support services for nurses.

Cost-Effectiveness Analysis for Therapy Sequence in Advanced Cancer: A Microsimulation Approach with Application to Metastatic Prostate Cancer.

PURPOSE: Patients with advanced cancer may undergo multiple lines of treatment, switching therapies as their disease progresses. We developed a general microsimulation framework to study therapy sequence and applied it to metastatic prostate cancer. METHODS: We constructed a discrete-time state transition model to study 2 lines of therapy. Using digitized published survival curves (progression-free survival, time to progression, and overall survival [OS]), we inferred event types (progression or death) and estimated transition probabilities using cumulative incidence functions with competing risks. We incorporated within-patient dependence over time; first-line therapy response informed subsequent event probabilities. Parameters governing within-patient dependence calibrated the model-based results to a target clinical trial. We applied these methods to 2 therapy sequences for metastatic prostate cancer, wherein both docetaxel (DCT) and abiraterone acetate (AA) are appropriate for either first- or second-line treatment. We assessed costs and quality-adjusted life-years (5-y QALYs) for 2 treatment strategies: DCT → AA versus AA → DCT. RESULTS: Models assuming within-patient independence overestimated OS time, which corrected with the calibration approach. With generic pricing, AA → DCT dominated DCT → AA, (higher 5-y QALYs and lower costs), consistent for all values of calibration parameters (including no correction). Model calibration increased the difference in 5-y QALYs between treatment strategies (0.07 uncorrected v. 0.15 with base-case correction). Applying the correction decreased the estimated difference in cost (-$5,360 uncorrected v. -$3,066 corrected). Results were strongly affected by the cost of AA. Under a lifetime horizon, AA → DCT was no longer dominant but still cost-effective (incremental cost-effectiveness ratio: $19,463). CONCLUSIONS: We demonstrate a microsimulation approach to study the cost-effectiveness of therapy sequences for advanced prostate cancer, taking care to account for within-patient dependence. HIGHLIGHTS: We developed a discrete-time state transition model for studying therapy sequence in advanced cancers.Results are sensitive to dependence within patients.A calibration approach can introduce dependence across lines of therapy and closely match simulation outcomes to target trial outcomes.

Updated overall survival from the MONALEESA-3 trial in postmenopausal women with HR+/HER2- advanced breast cancer receiving first-line ribociclib plus fulvestrant.

BACKGROUND: The phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) in the final protocol-specified and exploratory (longer follow-up) OS analyses. At the time of these analyses, the full OS benefit of 1L ribociclib was not completely characterized because the median OS (mOS) was not reached. As CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) is now a preferred option for 1L HR+/HER2- ABC, we report an exploratory analysis (median follow-up, 70.8 months; 14.5 months longer than the prior analysis) to fully elucidate the OS benefit in the MONALEESA-3 1L population. METHODS: Postmenopausal patients with HR+/HER2- ABC were randomized 2:1 to 1L/2L fulvestrant + ribociclib or placebo. OS in 1L patients (de novo disease or relapse > 12 months from completion of [neo]adjuvant ET) was assessed by Cox proportional hazards model and Kaplan-Meier methods. Progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS) were analyzed. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615). RESULTS: At data cutoff (January 12, 2022; median follow-up time, 70.8 months), mOS was 67.6 versus 51.8 months with 1L ribociclib versus placebo (hazard ratio (HR) 0.67; 95% CI 0.50-0.90); 16.5% and 8.6% of ribociclib and placebo patients, respectively, were still receiving treatment. PFS2 (HR 0.64) and CFS (HR 0.62) favored ribociclib versus placebo. Among those who discontinued treatment, 16.7% and 35.0% on ribociclib or placebo, respectively, received a subsequent CDK4/6i. No new safety signals were observed. CONCLUSIONS: This analysis of MONALEESA-3 reports the longest mOS thus far (67.6 months) for 1L patients in a phase III ABC trial. These results in a 1L population show that the OS benefit of ribociclib was maintained through extended follow-up, further supporting its use in HR+/HER2- ABC.

Patterns of metastatic progression and association with clinical outcomes in canine osteosarcoma: A necropsy study of 83 dogs.

Osteosarcoma is a highly metastatic primary bone tumour that occurs spontaneously in both pet dogs and humans. Patterns of metastasis to organs beyond the most common site (lung) are poorly characterised and it is unknown whether specific associations between patterns of metastatic progression and patient features exist. This retrospective study characterised the necropsy findings of 83 dogs receiving standardised therapy and clinical monitoring in a prospective clinical trial setting to document patterns of metastasis and correlate outcomes with these patterns and other patient and tumour-specific factors. A total of 20 different sites of metastasis were documented, with lung as the most common site, followed by bone, kidney, liver, and heart. Two distinct clusters of dogs were identified based on patterns of metastasis. There was no significant association between site of enrollment, trial arm, sex, serum alkaline phosphatase (ALP) activity, or tumour location and clinical outcomes. A second cancer type was identified at necropsy in 10 dogs (10/83; 12%). These data showcase the extensive nature of osteosarcoma metastasis beyond the lung and provide a benchmark for clinical monitoring of the disease. Further, this study provides insight into transcriptional features of primary tumours that may relate to a propensity for osteosarcoma metastasis to specific organs and tissues.

Evaluating the role of the diagnostic radiographer in identifying child safeguarding concerns: A knowledge, attitude and practice survey approach.

INTRODUCTION: Child safeguarding and the appropriate identification of suspected victims represents a global phenomenon. Diagnostic imaging is acknowledged as a contributory diagnostic service but the role of the radiographer in the identification and escalation process is less well understood. METHOD: A Knowledge, Attitude and Practice (KAP) survey was constructed to evaluate knowledge base in the context of the patient-radiographer interaction, the shaping of attitude towards child safeguarding and attitudes held towards their role plus the actual practical experiences of managing child safeguarding concerns. RESULTS: Respondents demonstrated a inconsistent knowledge base with respect to physical, social and radiographic signs and symptoms of child safeguarding concern. A positive attitude towards the role of the radiographer in child safeguarding was demonstrated but one that was shaped more by experience than pre-registration education. Assessment of concerns was chiefly influenced by clinical history and appreciation of aetiology. Practically, radiographers have infrequent involvement with the identification and escalation of concerns. Whilst some statistically significant relationships between responses and demographics did exist, these were either sporadic or argued to be a result of natural variation. CONCLUSION: Assessment of physical and social signs of child safeguarding concern are argued to be becoming more challenging. Radiological signs continue to be visible to radiographers but with increasing use of other imaging modalities these signs are becoming more varied in nature and are providing new challenges. Radiographers are capable of escalation when required to do so. IMPLICATIONS FOR PRACTICE: To maximise the contribution of the profession, education needs to account for imaging modality worked with, in combination with an understanding of related aetiology. Previously existing concerns with respect to escalating processes are no longer in evidence and radiographers are both willing and able to contribute to that process.