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.

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.

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.

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.

Neoadjuvant Talazoparib in Patients With Germline BRCA1/2 Mutation-Positive, Early-Stage Triple-Negative Breast Cancer: Results of a Phase II Study.

BACKGROUND: The undetermined efficacy of the current standard-of-care neoadjuvant treatment, anthracycline/platinum-based chemotherapy, in patients with early-stage triple-negative breast cancer (TNBC) and germline BRCA mutations emphasizes the need for biomarker-targeted treatment, such as poly(ADP-ribose) polymerase inhibitors, in this setting. This phase II, single-arm, open-label study evaluated the efficacy and safety of neoadjuvant talazoparib in patients with germline BRCA1/2-mutated early-stage TNBC. PATIENTS AND METHODS: Patients with germline BRCA1/2-mutated early-stage TNBC received talazoparib 1 mg once daily for 24 weeks (0.75 mg for moderate renal impairment) followed by surgery. The primary endpoint was pathologic complete response (pCR) by independent central review (ICR). Secondary endpoints included residual cancer burden (RCB) by ICR. Safety and tolerability of talazoparib and patient-reported outcomes were assessed. RESULTS: Of 61 patients, 48 received ≥80% talazoparib doses, underwent surgery, and were assessed for pCR or progressed before pCR assessment and considered nonresponders. pCR rate was 45.8% (95% confidence interval [CI], 32.0%-60.6%) and 49.2% (95% CI, 36.7%-61.6%) in the evaluable and intent-to-treat (ITT) population, respectively. RCB 0/I rate was 45.8% (95% CI, 29.4%-63.2%) and 50.8% (95% CI, 35.5%-66.0%) in the evaluable and ITT population, respectively. Treatment-related adverse events (TRAE) were reported in 58 (95.1%) patients. Most common grade 3 and 4 TRAEs were anemia (39.3%) and neutropenia (9.8%). There was no clinically meaningful detriment in quality of life. No deaths occurred during the reporting period; 2 deaths due to progressive disease occurred during long-term follow-up (>400 days after first dose). CONCLUSIONS: Neoadjuvant talazoparib monotherapy was active despite pCR rates not meeting the prespecified threshold; these rates were comparable to those observed with combination anthracycline- and taxane-based chemotherapy regimens. Talazoparib was generally well tolerated. CLINICALTRIALS.GOV IDENTIFIER: NCT03499353.

Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer.

BACKGROUND: In an earlier analysis of this phase 3 trial, ribociclib plus fulvestrant showed a greater benefit with regard to progression-free survival than fulvestrant alone in postmenopausal patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival. METHODS: Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. RESULTS: This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed. CONCLUSIONS: Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.).

Gray-White Matter Blurring of the Temporal Pole Associated With Hippocampal Sclerosis: A Microstructural Study Involving 3 T MRI and Ultrastructural Histopathology.

Hippocampal sclerosis (HS) is often associated with gray-white matter blurring (GMB) of the anterior temporal lobe. In this study, twenty patients with unilateral temporal lobe epilepsy and HS were studied with 3 T MRI including T1 MP2RAGE and DTI/DMI sequences. Anterior temporal lobe white matter T1 relaxation times and diffusion measures were analyzed on the HS side, on the contralateral side, and in 10 normal controls. Resected brain tissue of three patients without GMB and four patients with GMB was evaluated ultrastructurally regarding axon density and diameter, the relation of the axon diameter to the total fiber diameter (G-ratio), and the thickness of the myelin sheath. Hippocampal sclerosis GMB of the anterior temporal lobe was related to prolonged T1 relaxation and axonal loss. A less pronounced reduction in axonal fraction was also found on imaging in GMB-negative temporal poles compared with normal controls. Contralateral values did not differ significantly between patients and normal controls. Reduced axonal density and axonal diameter were histopathologically confirmed in the temporopolar white matter with GMB compared to temporal poles without. These results confirm that GMB can be considered an imaging correlate for disturbed axonal maturation that can be quantified with advanced diffusion imaging.

Understanding the role of COVID-19-related workplace stress and institutional betrayal on mental health in nurses: Some heroes wear scrubs.

This study examined the association of three specific COVID-19-related workplace stressors (percentage of nursing work with COVID-positive [COVID+] patients, number of COVID-19-related patient deaths witnessed, and living separately from family for safety) and their associations with posttraumatic stress symptoms (PTSS) and symptoms of major depressive disorder (MDD) and generalized anxiety disorder (GAD) among 391 nurses (93.6% White, 93.4% utilize she/her pronouns). Cross-sectional data were collected via an online survey. Institutional betrayal (i.e., the perception that an institution failed to protect a member who depends on and trusts it) was examined as a moderator of these associations. Although institutional betrayal was not a significant moderator in the three individual models, it held small-to-medium-sized positive main effects with PTSS and symptoms of GAD and MDD in both the individual and combined models. In the individual models, the percentage of nursing work with COVID+ patients was significantly positively associated with all three mental health conditions, f2 = .019-.195, whereas it only showed a significant effect with PTSS in the combined model, f2 = .138. Living separately from family was significantly positively associated with PTSS and MDD symptoms in both the individual, f2 = .037 and .015, respectively, and combined models, f2 = .025 and .013, respectively. Number of patient deaths held a significant positive association with PTSS alone, f2 = .022, in the individual model only. The findings are discussed in light of ways in which health care settings can better support and prioritize mental health among nursing staff.

Predictors of treatment completion in group psychotherapy for male veterans with posttraumatic stress disorder.

Group therapy is a frequently used therapy format for posttraumatic stress disorder (PTSD). However, factors contributing to treatment completion remain understudied. The current study examined predictors of treatment completion, defined as having completed 10 out of 14 sessions within 16 weeks, in veterans with PTSD who engaged in a hybrid efficacy-effectiveness randomized controlled trial of group psychotherapy for PTSD. Veterans (N = 198) were randomly assigned to 14 sessions of either group cognitive behavioral treatment (GBCT; n = 98) or group present-centered treatment (GPCT; n = 100). Four primary domains of predictors were examined, encompassing sociodemographic factors, the severity of PTSD and comorbid conditions, modifiable predictors, and treatment condition. Multilevel binomial logistic regression models following the Fournier analysis approach were used to examine significant predictors within domains, which were then included in a final model. Overall, 70.7% of participants completed treatment (GCBT = 61.6%, GPCT = 79.8%). Participants in the GPCT condition were 2.389 times, 95% CI [1.394, 4.092], more likely to complete treatment than those in the GCBT condition. Older age, a higher income and level of educational attainment, more lifetime and current mental health diagnoses, and higher use of positive reappraisal ER skills predicted treatment completion. Higher levels of depressive symptoms, cumulative trauma burden, and use of positive refocusing ER skills predicted treatment noncompletion. These findings are discussed in the context of current clinical and research practices for examining treatment noncompletion, with attention to the inclusion of translational predictors.

Technical report: surgical preparation of human brain tissue for clinical and basic research.

BACKGROUND: The study of the distinct structure and function of the human central nervous system, both in healthy and diseased states, is becoming increasingly significant in the field of neuroscience. Typically, cortical and subcortical tissue is discarded during surgeries for tumors and epilepsy. Yet, there is a strong encouragement to utilize this tissue for clinical and basic research in humans. Here, we describe the technical aspects of the microdissection and immediate handling of viable human cortical access tissue for basic and clinical research, highlighting the measures needed to be taken in the operating room to ensure standardized procedures and optimal experimental results. METHODS: In multiple rounds of experiments (n = 36), we developed and refined surgical principles for the removal of cortical access tissue. The specimens were immediately immersed in cold carbogenated N-methyl-D-glucamine-based artificial cerebrospinal fluid for electrophysiology and electron microscopy experiments or specialized hibernation medium for organotypic slice cultures. RESULTS: The surgical principles of brain tissue microdissection were (1) rapid preparation (<1 min), (2) maintenance of the cortical axis, (3) minimization of mechanical trauma to sample, (4) use of pointed scalpel blade, (5) avoidance of cauterization and blunt preparation, (6) constant irrigation, and (7) retrieval of the sample without the use of forceps or suction. After a single round of introduction to these principles, multiple surgeons adopted the technique for samples with a minimal dimension of 5 mm spanning all cortical layers and subcortical white matter. Small samples (5-7 mm) were ideal for acute slice preparation and electrophysiology. No adverse events from sample resection were observed. CONCLUSION: The microdissection technique of human cortical access tissue is safe and easily adoptable into the routine of neurosurgical procedures. The standardized and reliable surgical extraction of human brain tissue lays the foundation for human-to-human translational research on human brain tissue.

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.

Reevaluating the Evidence for Intensive Postoperative Extracolonic Surveillance for Nonmetastatic Colorectal Cancer.

OBJECTIVES: The FACS, GILDA, and COLOFOL trials have cast doubt on the value of intensive extracolonic surveillance for resected nonmetastatic colorectal cancer and by extension metastasectomy. We reexamined this pessimistic interpretation. We evaluate an alternative explanation: insufficient power to detect a realistically sized survival benefit that may be clinically meaningful. METHODS: A microsimulation model of postdiagnosis colorectal cancer was constructed assuming an empirically plausible efficacy for metastasectomy and thus surveillance. The model was used to predict the large-sample mortality reduction expected for each trial and the implied statistical power. A potential recurrence imbalance in the FACS trial was investigated. Goodness of fit between model predictions and trial results were evaluated. Downstream life expectancy was estimated and power calculations performed for future trials evaluating surveillance and metastasectomy. RESULTS: For all 3 trials, the model predicted a mortality reduction of ≤5% and power of <10%. The FACS recurrence imbalance likely led to a large relative bias (>2.5) in the hazard ratio for overall survival favoring control. After adjustment, both COLOFOL and FACS results were consistent with model predictions (P>.5). A 2.6 (95% credible interval 0.5-5.1) and 3.6 (95% credible interval 0.8-7.0) month increase in life expectancy is predicted comparing intensive extracolonic surveillance-routine computed tomography scans and carcinoembryonic antigen assays-with 1 computed tomography scan at 12 months or no surveillance, respectively. An adequately sized surveillance trial is not feasible. A metastasectomy trial should randomize at least 200 to 300 patients. CONCLUSIONS: Recent trial results do not warrant de novo skepticism of metastasectomy nor targeted extracolonic surveillance. Given the potential for clinically meaningful life-expectancy gain and significant uncertainty, a trial of metastasectomy is needed.

The First FDA Approved Early Feasibility Study of a Novel Percutaneous Bone Anchored Prosthesis for Transfemoral Amputees: A Prospective 1-year Follow-up Cohort Study.

OBJECTIVE: Evaluate the safety and efficacy of a novel press-fit bone-anchored prosthesis in an FDA approved study. DESIGN: Single-center, prospective 1-year follow-up cohort study of a percutaneous bone anchored prosthesis. SETTING: Veterans Health Administration Hospital. PARTICIPANTS: Ten male Veterans with unilateral transfemoral amputation that occurred at least 6 months prior to enrollment and was not the result of dysvascular disease (N=10). INTERVENTIONS: All participants received the novel press-fit Percutaneous Osseointegrated Prosthesis (POP) and a minimum of 10 days supervised rehabilitation therapy. OUTCOME MEASURES: Adverse events and radiographs were collected to assess device safety. Temporal assessments of bone density, stomal skin, prosthetic don/doff, functional ambulation, and patient-reported outcome compared our POP to a socket suspension system. RESULTS: Ten male participants mean age 48.8±12.1 years (range, 32-68 y) with mean time since amputation of 9.4± years (range 1-18 y) completed a two-staged implantation protocol and progressed to ambulation with an assistive device by post-operative day 14. Eight of 10 completed all study procedures. One implant loosened at 5 weeks, requiring removal. A second was removed after periprosthetic fracture from a non-device-related fall at 28 weeks. One patient required oral antibiotics for superficial infection. There were significant (P<.05) increases in bone density in the lumbar spine and adjacent to the distal porous coating with no radiographic evidence of bone resorption. Compared to the socket system, the use of POP significantly (P<.05) reduced prosthetic don and doff times and patient-reported prosthetic problem scores. Significant improvements (P<.05) in mean mobility, global health, and walking test scores were also observed. CONCLUSIONS: Improvements in bone density, function, and patient reported outcomes were observed with the POP device when compared to a socket suspension system. This Early Feasibility Study established initial safety and effectiveness of the POP device, supporting expanded investigation as an alternative to socket prostheses.

Impact of a Musculoskeletal "Mini-Residency" Professional Development Program on Knee Magnetic Resonance Imaging Orders by Primary Care Providers.

BACKGROUND: The US Department of Veterans Affairs has created a portfolio of educational programs to train primary care providers (PCPs) in the evaluation and management of common musculoskeletal (MSK) conditions. Appropriate resource utilization for evaluation of knee pain, including limiting unnecessary magnetic resonance imaging (MRI) studies, is an important theme of these initiatives. The objective of this study was to report the utilization of knee MRI by PCP providers before and after the MSK education program and to determine the appropriateness of these MRI orders. METHODS: Twenty-six PCPs participated in the MSK Mini-Residency educational program held in Salt Lake City between April 2012 and October 2014. Knee MRI orders submitted by these providers 12 months before and 12 months after their participation were reviewed. Magnetic resonance imaging orders were categorized as "inappropriate," "probably inappropriate," or "possibly appropriate," based on accepted guidelines for knee MRI utilization. Differences in the numbers of precourse and postcourse MRI orders for each of these categories were compared using Student t test. RESULTS: Following our program, MRI orders decreased from 130 (precourse) to 93 (postcourse), a reduction of 28% ( p = 0.04). This reduction was observed entirely within the "inappropriate" and "probably inappropriate" categories; the number of orders categorized as "possibly appropriate" increased, but not significantly. CONCLUSIONS: The MSK Mini-Residency training program was a successful educational intervention and was associated with a reduction in inappropriate knee MRI utilization for some participants, while keeping appropriate MRI utilization stable.

Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive, HER2-negative advanced breast cancer.

BACKGROUND: This pooled analysis of MONALEESA trials evaluated the safety of ribociclib plus endocrine therapy (RIB + ET) with a focus on dose reductions in first-line patients. METHODS: In the dose reduction analysis, data were pooled from MONALEESA-2 (all patients), MONALEESA-3 (patients receiving treatment as first-line ET) and MONALEESA-7 (patients receiving combination therapy with an NSAI as initial ET). Efficacy was analysed by ribociclib relative dose intensity (DI). Safety was analysed in all patients in the trials (except those receiving tamoxifen in MONALEESA-7) and those with/without ≥1 ribociclib dose reduction. RESULTS: Of 818 women who received first-line RIB + ET, 41.8% required ≥1 dose reduction due to AEs (most commonly, neutropenia). Median RIB relative DI in patients without and with dose reductions was 99.3% and 65.6% in MONALEESA-2, 98.4% and 67.8% in MONALEESA-3 and 98·0% and 66·3% in MONALEESA-7. Median PFS was 24.8, 24.9 and 29.6 months for patients who received ≤71% (30th percentile), 72-96% (60th percentile) and 97-100% (90th percentile) RIB relative DI, respectively. No new safety signals emerged in the pooled safety analysis. CONCLUSIONS: This analysis provides reassuring data showing that the clinical benefit of RIB is preserved when dose modifications are undertaken to manage AEs. TRIAL REGISTRATION: MONALEESA-2 (NCT01958021) first posted October 8, 2013; MONALEESA-3 (NCT02422615) first posted April 21, 2015; MONALEESA-7 (NCT02278120) first posted October 29, 2014.

Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival.

BACKGROUND: Ribociclib plus fulvestrant demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). Here we present a new landmark in survival follow-up for a phase III cyclin-dependent kinases 4 and 6 inhibitor clinical trial in patients with ABC (median, 56.3 months). PATIENTS AND METHODS: This phase III, randomized, double-blind, placebo-controlled trial was conducted at 174 sites (30 countries). Patients were men and postmenopausal women (age ≥18 years) with histologically/cytologically confirmed HR+/HER2- ABC. Patients could have received ≤1 line of endocrine therapy (ET) but no chemotherapy for ABC. Patients, assigned 2:1, were stratified by the presence/absence of liver/lung metastases and previous ET. Patients received intramuscular fulvestrant (500 mg, day 1 of each 28-day cycle plus day 15 of cycle 1) with oral ribociclib (600 mg/day, 3 weeks on, 1 week off) or placebo. Efficacy analyses were by intention to treat. Safety was assessed in patients receiving ≥1 dose study treatment. OS was a secondary endpoint. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615; no longer enrolling). RESULTS: Between 18 June 2015 and 10 June 2016, 726 patients were randomly assigned (484, ribociclib; 242, placebo). At data cut-off (30 October 2020), median OS (mOS) was 53.7 months (ribociclib) versus 41.5 months (placebo) [hazard ratio (HR), 0.73; 95% confidence interval (CI) 0.59-0.90]. Subgroup analyses were consistent with overall population. In the first-line setting, most patients in the ribociclib arm (∼60%) lived longer than median follow-up; mOS was 51.8 months in the placebo arm (HR, 0.64; 95% CI 0.46-0.88). In the second-line setting, mOS was 39.7 months (ribociclib) versus 33.7 months (placebo) (HR, 0.78; 95% CI 0.59-1.04). No apparent drug-drug interaction between ribociclib and fulvestrant or new safety signals were observed. CONCLUSIONS: This analysis reported extended OS follow-up in MONALEESA-3. mOS was ∼12 months longer in patients with HR+/HER2- ABC treated with ribociclib plus fulvestrant compared with fulvestrant monotherapy.

The Use of Patient-Reported Outcome Measures in Phase I Oncology Clinical Trials.

OBJECTIVE: To investigate patient-reported outcome (PRO) usage in phase I oncology clinical trials, including types of PRO measures and changes over time. METHODS: We analyzed ClinicalTrials.gov records of phase I oncology clinical trials completed by December 2019. RESULTS: Of all eligible trials, 2.3% (129/5,515) reported ≥1 PRO, totaling 181 instances of PRO usage. PRO usage increased over time, from 0.6% (trials initiated before 2000) to 3.4% (trials starting between 2015 and 2019). The most common PRO measures were unspecified (29%), tumor-specific (24%), and generic cancer (19%). CONCLUSION: Although uncommon in phase I oncology clinical trials, PRO usage is increasing over time. PRO measures were often unspecified on ClinicalTrials.gov, suggesting that more precise reporting and standardization are needed.

Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series.

Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there are few reports about their use in clinical practice. Which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared with those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalisable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These data should provide a basis for more informed counselling and clinical decision making.

First-line surgery in prolactinomas: lessons from a long-term follow-up study in a tertiary referral center.

CONTEXT: Although consensus guidelines recommend dopamine agonists (DAs) as the first-line approach in prolactinomas, some patients may opt instead for upfront surgery, with the goal of minimizing the need for continuation of DAs over the long term. While this approach can be recommended in selected patients with a microprolactinoma, the indication for upfront surgery in macroprolactinomas remains controversial, with limited long-term data in large cohorts. We aimed at elucidating whether first-line surgery is equally safe and effective for patients with micro- or macroprolactinomas not extending beyond the median carotid line (i.e., Knosp grade ≤ 1). METHODOLOGY: Retrospective study of patients with prolactinomas Knosp grade ≤ 1 treated with upfront surgery. The primary endpoint was patients' dependence on DAs at last follow-up. The secondary endpoint was postoperative complications. Independent risk factors for long-term dependence on DAs were analyzed. RESULTS: A microadenoma was noted in 45 patients (52%) and a macroadenoma in 41 (48%), with 17 (20%) harboring a Knosp grade 1 prolactinoma. Median follow-up was 80 months. First-line surgery resulted in long-term remission in 31 patients (72%) with a microprolactinoma and in 18 patients (45%) with a macroprolactinoma (p = 0.02). DA therapy was ultimately required in 11 patients (24%) with microadenomas vs. 20 (49%) with macroadenomas (p = 0.03). As for the latter, DA was required in 13 patients (76%) with Knosp grade 1 macroadenomas vs. 7 patients (29%) with Knosp grade 0 macroadenomas (p = 0.004). There was no mortality, and morbidity was minimal. Knosp grade 1 prolactinomas (OR 7.3, 95% CI 1.4-37.7, p = 0.02) but not adenoma size (i.e., macroprolactinomas) were an independent predictor of long-term dependence on DAs. CONCLUSIONS: First-line surgery in patients with microprolactinomas or macroprolactinomas Knosp grade 0 resulted in a good chance of non-dependency on DA therapy. However, in patients with prolactinomas Knosp grade 1, first-line surgery cannot be recommended, as adjuvant DA therapy after surgery is required in the majority of them over the long term.

A cross-sectional analysis of investigator needs for non-communicable disease research at the University of the West Indies, Mona.

OBJECTIVE: To describe the needs of academic staff conducting non-communicable disease (NCD) research at the University of the West Indies, Mona Campus in Jamaica. METHODS: Utilizing a cross-sectional design an online survey was created using the research electronic data capture application (REDCap); it was disseminated via email to 708 academic staff members in the Faculties of Medical Sciences and Science & Technology between September and November 2018. Participants were asked to indicate their level of access to expertise, training and equipment for conducting research. Descriptive analysis was conducted using STATA version 14. RESULTS: Most respondents were women (74.2%), predominantly scientists (33.1%) or specialist physicians (22.6%). Less than 2/3 of respondents reported publishing research findings in peer reviewed journals, with a quarter not disseminating their research findings in any medium. Resources for field research/data collection, epidemiological methods and principles, and data management/data analysis were generally available. However, there was limited access to training, expertise and equipment in emerging techniques for NCD research such as metabolomics, bioinformatics/analysis of large-scale data sets and health economics. Additional challenges included limited access to financing for research, inadequate workspace and poor administrative support for conducting research. CONCLUSIONS: There is a need for more local research seed funding, stronger administrative support for researchers, and opportunities for training in cutting edge NCD research techniques. Jamaican researchers could benefit from being part of a regional research centre of excellence with critical research skills and equipment that builds research networks and strengthens the NCD research response.