Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.

BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

[Neuropsychology of psychoeducation in schizophrenia: results of the Munich COGPIP study]. / Neuropsychologie der Psychoedukation bei Schizophrenie: Ergebnisse der Münchner COGPIP-Studie.

BACKGROUND: The aim of the study was to examine whether the efficacy of psychoeducation in patients with schizophrenia is dependent on their cognitive performance and if a preceding cognitive training can enhance the therapeutic effects of psychoeducation. PATIENTS AND METHODS: A total of 116 inpatients were randomly assigned to either a standardized cognitive training (COGPACK) or to routine occupational therapy, followed by a psychoeducational group program of 8 sessions within 4 weeks for all study patients. The effects of cognitive training and psychoeducation were assessed directly afterwards and in a follow-up after 9 months. RESULTS: The patient knowledge and compliance improved. Neurocognition and especially memory acquisition significantly predicted illness knowledge after psychoeducation, whereas psychopathology did not. No differential effects of the COGPACK training were found. After 9 months 75% of the patients showed a very good compliance and the readmission rate was 18%. The results were comparable under both study conditions. CONCLUSION: Besides baseline illness knowledge neurocognition was the only significant predictor for illness knowledge after psychoeducation. Patients with cognitive deficits can profit from psychoeducation in the long run as well. In future it should be examined whether a modified cognitive training program could achieve a faster improvement of the illness knowledge.

[Pharmacological treatment for patients with borderline personality disorder: practice and study results]. / Pharmakotherapie der Borderline-Störung: Praxis und Studienlage.

Many patients with borderline personality disorder (BPD) receive pharmacological treatment. On account of the few treatment guidelines and the often changing symptoms, different substances are used. The present article summarises treatment-practice and study results concerning the pharmacological treatment of BPD.

Measurement of the proton-air cross section at √s=57 TeV with the Pierre Auger Observatory.

We report a measurement of the proton-air cross section for particle production at the center-of-mass energy per nucleon of 57 TeV. This is derived from the distribution of the depths of shower maxima observed with the Pierre Auger Observatory: systematic uncertainties are studied in detail. Analyzing the tail of the distribution of the shower maxima, a proton-air cross section of [505±22(stat)(-36)(+28)(syst)] mb is found.

Agomelatine improves sleep in a patient with fatal familial insomnia.

A young patient with FFI was started on agomelatine 25 mg to medicate nocturnal insomnia. Under this treatment sleep efficiency was improved, slow wave sleep was high and awakenings during sleep period time were far less than before. Clinically the patient was less restless during nighttime.

Neurocognitive prediction of illness knowledge after psychoeducation in schizophrenia: results from the Munich COGPIP study.

BACKGROUND: Many patients with schizophrenia exhibit neurocognitive impairments, namely, in attentional, mnestic and executive functions. While these deficits limit psychosocial rehabilitation, their effect on psychoeducation is unknown. Within the framework of the longitudinal Munich Cognitive Determinants of Psychoeducation and Information in Schizophrenic Psychoses (COGPIP) study, we examined: (a) whether illness knowledge after psychoeducation could be predicted more precisely from the neurocognitive than from the psychopathological status of the patients; (b) which neurocognitive domains are best predictors. METHOD: A total of 116 in-patients with schizophrenic or schizoaffective disorders were randomized to a neurocognitive training or control condition (2 weeks) followed by a manualized psychoeducational group programme (4 weeks) and then observed over a 9-month follow-up. Repeated measurements included - among others - the Positive and Negative Syndrome Scale and a comprehensive neuropsychological test battery from which normative T scores were used to calculate one global and five domain-specific neurocognitive composite scores. Illness knowledge was measured by a questionnaire (WFB-52) tailored to the psychoeducational programme. RESULTS: Multiple linear regression analyses showed that, apart from baseline illness knowledge, neurocognition significantly predicted knowledge outcome as well as knowledge gain (measured by reliable change indices) after psychoeducation. This was not true for psychopathology. Among the domain-specific neurocognitive composite scores, only memory acquisition was a significant predictor of knowledge outcome and gain. CONCLUSIONS: Neurocognition, not psychopathology, is a significant predictor of illness knowledge after psychoeducation in schizophrenia. This finding should guide efforts to tailor psychoeducational interventions more closely to the patient's needs and resources.

[Psychiatric effects and side effects of the alpha-2-antagonist yohimbine: a review of literature and case report]. / Yohimbin, ein Alpha-2-Antagonist: Literaturübersicht zu psychiatrisch relevanten Wirkungen und Nebenwirkungen mit aktuellem Fallbericht.

We describe a 21-year old female patient who had taken the alpha-2-antagonist yohimbine for weight-loss. The patient reported alterations in alcohol- and cocaine-seeking along with changes in defensive behaviour, including suicidal tendencies. Pre-clinical and clinical studies are discussed, which support the hypothesis of a causal relationship. We added an overview of relevant psychiatric effects and side effects of yohimbine.

The association of children's mathematic abilities with both adults' cognitive abilities and intrinsic fronto-parietal networks is altered in preterm-born individuals.

Mathematic abilities in childhood are highly predictive for long-term neurocognitive outcomes. Preterm-born individuals have an increased risk for both persistent cognitive impairments and long-term changes in macroscopic brain organization. We hypothesized that the association of childhood mathematic abilities with both adulthood general cognitive abilities and associated fronto-parietal intrinsic networks is altered after preterm delivery. 72 preterm- and 71 term-born individuals underwent standardized mathematic and IQ testing at 8 years and resting-state fMRI and full-scale IQ testing at 26 years of age. Outcome measure for intrinsic networks was intrinsic functional connectivity (iFC). Controlling for IQ at age eight, mathematic abilities in childhood were significantly stronger positively associated with adults' IQ in preterm compared with term-born individuals. In preterm-born individuals, the association of children's mathematic abilities and adults' fronto-parietal iFC was altered. Likewise, fronto-parietal iFC was distinctively linked with preterm- and term-born adults' IQ. Results provide evidence that preterm birth alters the link of mathematic abilities in childhood and general cognitive abilities and fronto-parietal intrinsic networks in adulthood. Data suggest a distinct functional role of intrinsic fronto-parietal networks for preterm individuals with respect to mathematic abilities and that these networks together with associated children's mathematic abilities may represent potential neurocognitive targets for early intervention.

Extensive and interrelated subcortical white and gray matter alterations in preterm-born adults.

Preterm birth is a leading cause for impaired neurocognitive development with an increased risk for persistent cognitive deficits in adulthood. In newborns, preterm birth is associated with interrelated white matter (WM) alterations and deep gray matter (GM) loss; however, little is known about the persistence and relevance of these subcortical brain changes. We tested the hypothesis that the pattern of correspondent subcortical WM and GM changes is present in preterm-born adults and has a brain-injury-like nature, i.e., it predicts lowered general cognitive performance. Eighty-five preterm-born and 69 matched term-born adults were assessed by diffusion- and T1-weighted MRI and cognitive testing. Main outcome measures were fractional anisotropy of water diffusion for WM property, GM volume for GM property, and full-scale IQ for cognitive performance. In preterm-born adults, reduced fractional anisotropy was widely distributed ranging from cerebellum to brainstem to hemispheres. GM volume was reduced in the thalamus, striatum, temporal cortices, and increased in the cingulate cortices. Fractional anisotropy reductions were specifically associated with GM loss in thalamus and striatum, with correlation patterns for both regions extensively overlapping in the WM of brainstem and hemispheres. For overlap regions, fractional anisotropy was positively related with both gestational age and full-scale IQ. Results provide evidence for extensive, interrelated, and adverse WM and GM subcortical changes in preterm-born adults. Data suggest persistent brain-injury-like changes of subcortical-cortical connectivity after preterm delivery.

Search for patterns by combining cosmic-ray energy and arrival directions at the Pierre Auger Observatory.

Energy-dependent patterns in the arrival directions of cosmic rays are searched for using data of the Pierre Auger Observatory. We investigate local regions around the highest-energy cosmic rays with [Formula: see text] eV by analyzing cosmic rays with energies above [Formula: see text] eV arriving within an angular separation of approximately 15[Formula: see text]. We characterize the energy distributions inside these regions by two independent methods, one searching for angular dependence of energy-energy correlations and one searching for collimation of energy along the local system of principal axes of the energy distribution. No significant patterns are found with this analysis. The comparison of these measurements with astrophysical scenarios can therefore be used to obtain constraints on related model parameters such as strength of cosmic-ray deflection and density of point sources.

The effect of family interventions on relapse and rehospitalization in schizophrenia--a meta-analysis.

Twenty-five intervention studies were meta-analytically examined regarding the effect of including relatives in schizophrenia treatment. The studies investigated family intervention programs to educate relatives and help them cope better with the patient's illness. The patient's relapse rate, measured by either a significant worsening of symptoms or rehospitalization in the first years after hospitalization, served as the main study criterion. The main result of the meta-analysis was that the relapse rate can be reduced by 20 percent if relatives of schizophrenia patients are included in the treatment. If family interventions continued for longer than 3 months, the effect was particularly marked. Furthermore, different types of comprehensive family interventions have similar results. The bifocal approach, which offers psychosocial support to relatives and schizophrenia patients in addition to medical treatment, was clearly superior to the medication-only standard treatment. The effects of family interventions and comprehensive patient interventions were comparable, but the combination did not yield significantly better results than did a treatment approach, which focused on either the patient or the family. This meta-analysis indicates that psychoeducational interventions are essential to schizophrenia treatment.

Doubleblind evaluation of the antimanic properties of carbamazepine as a comedication to haloperidol.

1. Today carbamazepine is the most important alternative to neuroleptic drugs for the treatment of manic psychoses. Often carbamazepine is administered as a comedication to a neuroleptic. 2. A doubleblind study with 20 patients suffering from manic or schizomanic psychoses was performed to determine whether carbamazepine and haloperidol in comedication are more effective than haloperidol alone. 3. Under the tested conditions (24 mg haloperidol p.d.) only the smaller amount of additional medication with levomepromazine in the experimental group gave evidence for the antimanic effect of carbamazepine in combination with haloperidol. 4. Especially the patients with pure manic psychoses seem to benefit from carbamazepine as an adjunct to haloperidol.

Early clinical results with the neuroleptic roxindole (EMD 49,980) in the treatment of schizophrenia--an open study.

The neuroleptic effect and tolerability of roxindole (EMD 49,980), an agonist of the dopamine-D2 autoreceptor, was studied during a 4 week treatment period in 7 patients with paranoid-hallucinatory schizophrenia (ICD-9: 295.3). In patients with a daily dosage of up to 4.5 mg/day, there was no improvement as measured with the total score of the BPRS scale. In contrast, patients with a daily dosage of up to 30 mg/day showed a slight improvement, especially in items associated with negative symptoms. In 3 patients there were slight adverse events (dizziness, hypersalivation, hypotonia, nausea/vomiting, miction disturbance) which were probably connected with the intake of roxindole.

Gender differences in patient and caregiver psychoeducation for schizophrenia.

OBJECTIVE: The aim of this research is to detect gender-related differences in patients and caregivers regarding knowledge about schizophrenia and attitudes towards drugs as well as gender as predictor for changes in these variables during psychoeducation. METHODS: Data sets of one randomised-controlled (study 1) and one naturalistic psychoeducation study (study 2) were reanalysed. Main outcome measures (knowledge about schizophrenia, drug attitude, confidence in medication) were assessed at baseline, post-intervention and 12 months after index discharge. RESULTS: The reanalysed samples consisted in total of 1002 patients and 176 caregivers. In study 2, baseline knowledge was significantly better in male patients and female caregivers. All participants improved significantly their knowledge. The amount of knowledge gain did not differ between genders in either study or either group. Gender was not a major predictor of baseline knowledge or knowledge gain. Only in study 1 did gender significantly impact the knowledge gain from baseline to follow-up. Regarding improvement of drug attitude, females seemed to benefit significantly better from psychoeducation. In both studies, however, changes in drug attitudes respectively confidence in medication were best explained by lower corresponding baseline scores, not gender. Patients' gender did not influence outcomes of their caregivers. CONCLUSION: Our findings suggest that psychoeducational programs might be better adapted to males in order to improve their drug attitude. Concerning knowledge, gender-related changes do not seem to be necessary.

[Chronic suicidality in depression due to untreated adrenogenital syndrome]. / Chronische Suizidalität bei organisch bedingter Depression infolge eines adrenogenitalen Syndroms.

A 38-year-old female suffered from adrenogenital syndrome with 21-hydroxylase deficiency requiring a corticosteroid substitution. The virilized patient claims to have discontinued treatment with corticosteroids since the age of 15. In the 12 months prior to admission, the patient experienced addisonian crises and repeated decompensation with depressive-suicidal symptoms. Due to the second suicide attempt within a short period, the patient underwent psychiatric treatment presenting an organic depressive syndrome. Under sufficient medication including corticosteroids, antidepressants, and mood stabilizing therapy, the psychopathologic findings improved impressively. Noncompliance after discharge led to a relapse and another suicide attempt, which remitted promptly after adequate therapy.

Genetic analysis of MAPT haplotype diversity in frontotemporal dementia.

The H1 haplotype of the tau gene, MAPT, has been linked to the sporadic tauopathies corticobasal degeneration and progressive supranuclear palsy; however, there have been inconsistent findings regarding association with frontotemporal dementia (FTD). We investigated MAPT haplotype diversity, in 171 sporadic FTD and 186 healthy controls individuals, and report no single marker or haplotype association with increased risk or changes in age at onset. These findings do not support an association of MAPT with FTD but do not rule out its association with other tauopathies.

Fine mapping of the MAPT locus using quantitative trait analysis identifies possible causal variants in Alzheimer's disease.

In addition to senile plaques, neurofibrillary tangles are characteristic of Alzheimer's disease (AD) pathology, suggesting a clear involvement of the microtubule-associated protein tau (MAPT) in AD. Recent findings, suggesting that the H1c haplotype is associated with increased risk, now also implicate MAPT genetically. In this study, we aim to clarify this association by a fine mapping approach using both a traditional phenotypic association analysis and a quantitative trait (QT) analysis using cerebrospinal fluid (CSF) tau protein levels in the German population. Here, we report that both methodologies identify that the H1c haplotype may play important role in AD (AD risk, P=0.007, uncorrected; CSF tau levels, P=0.027, uncorrected). Further, the use of a sliding window approach in the QT analysis allowed for the narrowing down of the region where a probable causal variant may be located. The data suggest that this may lie at or within close proximity to the rs242557 single nucleotide polymorphism as association with CSF tau levels seems to be primarily driven by rs242557 in a gene dosage-dependent manner (trend model: P=0.002, uncorrected). These findings provide functional evidence to support the genetic association of MAPT with AD.

[Psychoeducational intervention for schizophrenic patients and subsequent long-term ambulatory care. A four-year follow-up] . / Psychoedukative Gruppen bei schizophrenen Patienten und anschliessende ambulante Langzeitbehandlung. Eine 4-Jahres-Katamnese und Literaturübersicht.

A subset of schizophrenic inpatients and families participated in an eight-sessions bifocal psychoeducational intervention, followed by treatment in a corresponding outpatient department. These patients were a part of the multicenter and randomized Münchner Psychosis-Information-Project (PIP). The course of illness in 88 patients treated in the outpatient department of the Technical University of Munich has been recorded in a 4-year follow-up study. 60% of the patients continued outpatient treatment while 40% lost contact with the outpatient department. Predictors for patient drop-out were assessed and the course of illness of both groups was compared. There was no significant difference between the relapse rate of the patients who dropped out (66%) and those who continued the long-term treatment (53%). However, within the 4-year period the drop-out patients had more than twice as many hospital days compared to the patients who maintained the outpatient treatment. The improved social adjustment and quality of life of these patients, along with the 50% reduction of readmission days demonstrates the impact of the long-term treatment in this study.