First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: a single-arm, single-centre, phase 2 trial.

BACKGROUND: The addition of nivolumab to chemotherapy improves survival in patients with advanced oesophagogastric (oesophageal, gastric, or gastro-oesophageal junction) adenocarcinoma; however, outcomes remain poor. We assessed the safety and activity of regorafenib in combination with nivolumab and chemotherapy in the first-line treatment of advanced oesophagogastric adenocarcinoma. METHODS: This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with previously untreated, HER2-negative, metastatic oesophagogastric adenocarcinoma was done at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients had measurable disease or non-measurable disease that was evaluable (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received FOLFOX chemotherapy (fluorouracil [400 mg/m2 bolus followed by 2400 mg/m2 over 48 h], leucovorin [400 mg/m2], and oxaliplatin [85 mg/m2]) and nivolumab (240 mg) intravenously on days 1 and 15, and oral regorafenib (80 mg) on days 1-21 of a 28-day cycle. Treatment was continued until disease progression (defined by RECIST version 1.1), unacceptable toxicity, or withdrawal of consent. The primary endpoint was 6-month progression-free survival in the per-protocol population (ie, all participants who received a dose of all study treatments). The regimen would be considered worthy of further investigation if at least 24 of 35 patients were progression free at 6 months. Safety was assessed in all participants who received at least one dose of any study treatment. This trial is registered with ClinicalTrials.gov, NCT04757363, and is now complete. FINDINGS: Between Feb 11, 2021, and May 4, 2022, 39 patients were enrolled, received at least one dose of study drug, and were included in safety analyses. 35 patients were evaluable for 6-month progression-free survival. Median age was 57 years (IQR 52-66), nine (26%) patients were women, 26 (74%) were men, 28 (80%) were White, and seven (20%) were Asian. At data cutoff (March 3, 2023), median follow-up was 18·1 months (IQR 12·7-20·4). The primary endpoint was reached, with 25 (71%; 95% CI 54-85) of 35 patients progression free at 6 months. Nine (26%) of 35 patients had disease progression and one (3%) patient died; the death was unrelated to treatment. The most common adverse event of any grade was fatigue (36 [92%] of 39). The most common grade 3 or 4 adverse events were decreased neutrophil count (18 [46%]), hypertension (six [15%]), dry skin, pruritus, or rash (five [13%]), and anaemia (four [10%]). Serious treatment-related adverse events occurred in ten (26%) patients, which were acute kidney injury (three [8%]), hepatotoxicity (two [5%]), sepsis (two [5%]), dry skin, pruritus, or rash (one [3%]), nausea (one [3%]), and gastric perforation (one [3%]). There were no treatment-related deaths. INTERPRETATION: Regorafenib can be safely combined with nivolumab and chemotherapy and showed promising activity in HER2-negative metastatic oesophagogastric cancer. A randomised, phase 3 clinical trial is planned. FUNDING: Bristol Myers Squibb, Bayer and National Institutes of Health/National Cancer Institute.

Clinical Importance of Clonal Hematopoiesis in Metastatic Gastrointestinal Tract Cancers.

Importance: Clonal hematopoiesis (CH) has been associated with development of atherosclerosis and leukemia and worse survival among patients with cancer; however, the association with cancer therapy efficacy, in particular immune checkpoint blockade (ICB), and toxicity has not yet been established. Given the widespread use of ICB and the critical role hematopoietic stem cell-derived lymphocytes play in mediating antitumor responses, CH may be associated with therapeutic efficacy and hematologic toxicity. Objective: To determine the association between CH and outcomes, hematologic toxicity, and therapeutic efficacy in patients with metastatic gastrointestinal tract cancers being treated with systemic therapy, both in the first-line metastatic treatment setting and in ICB. Design, Setting, and Participants: This retrospective cohort study included 633 patients with stage IV colorectal (CRC) and esophagogastric (EGC) cancer who were treated with first-line chemotherapy and/or ICB at Memorial Sloan Kettering Cancer Center. Patients underwent matched tumor and peripheral blood DNA sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets next-generation sequencing assay between January 1, 2006, and December 31, 2020. Exposures: Clonal hematopoiesis-related genetic alterations were identified by next-generation sequencing of patients' tumor and normal blood buffy coat samples, with a subset of these CH alterations annotated as likely putative drivers (CH-PD) based upon previously established criteria. Main Outcomes and Measures: Patients with CH and CH-PD in peripheral blood samples were identified, and these findings were correlated with survival outcomes (progression-free survival [PFS] and overall survival [OS]) during first-line chemotherapy and ICB, as well as baseline white blood cell levels and the need for granulocyte colony-stimulating factor (G-CSF) support. Results: Among the 633 patients included in the study (390 men [61.6%]; median age, 58 [IQR, 48-66] years), the median age was 52 (IQR, 45-63) years in the CRC group and 61 (IQR, 53-69) years in the EGC group. In the CRC group, 161 of 301 patients (53.5%) were men, compared with 229 of 332 patients (69.0%) in the EGC group. Overall, 62 patients (9.8%) were Asian, 45 (7.1%) were Black or African American, 482 (76.1%) were White, and 44 (7.0%) were of unknown race or ethnicity. Presence of CH was identified in 115 patients with EGC (34.6%) and 83 with CRC (27.6%), with approximately half of these patients harboring CH-PD (CRC group, 44 of 83 [53.0%]; EGC group, 55 of 115 [47.8%]). Patients with EGC and CH-PD exhibited a significantly worse median OS of 16.0 (95% CI, 11.6-22.3) months compared with 21.6 (95% CI, 19.6-24.3) months for those without CH-PD (P = .01). For patients with CRC and EGC, CH and CH-PD were not associated with PFS differences in patients undergoing ICB or first-line chemotherapy. Neither CH nor CH-PD were correlated with baseline leukocyte levels or increased need for G-CSF support. Conclusions and Relevance: These findings suggest CH and CH-PD are not directly associated with the treatment course of patients with metastatic gastrointestinal tract cancer receiving cancer-directed therapy.

Olfactory and neurological outcomes of SARS-CoV-2 from acute infection to recovery.

Educational objective: To investigate the impact of SARS-CoV-2 on sinonasal quality of life, olfaction, and cognition at different stages of viral infection and evaluate the association between olfaction and cognition in this population cohort. Objectives: While olfactory dysfunction (OD) is a frequently reported symptom of COVID-19 (98% prevalence), neurocognitive symptoms are becoming more apparent as patients recover from infection. This study aims to address how different stages of infection [active infection (positive PCR test, symptomatic) vs. recovered (7 days post-symptoms)] compared to healthy control patients influence sinonasal quality of life, olfactory function, and cognition. Study design: Prospective, longitudinal, case-control. Methods: Participants completed the SNOT-22, University of Pennsylvania Smell Identification Test (UPSIT) and validated cognitive examinations to assess degree of smell loss and neurocognitive function at baseline and at 1 and 3 months for the active group and 3 months for the recovered group. Self-reported olfactory function and overall health metrics were also collected. Results: The recovered group had the lowest average UPSIT score of 27.6 compared to 32.7 (active) and 32.6 (healthy control). 80% (n = 24) of the recovered patients and 56.3% (n = 9) of the active patients suffered from smell loss. In follow-up, the active group showed improvement in UPSIT scores while the recovered group scores worsened. In terms of neurocognitive performance, recovered patients had lower processing speed despite an improving UPSIT score. Conclusion: SARS-CoV-2 infection was found to impact olfactory function in a delayed fashion with significant impact despite recovery from active infection. Although olfactory function improved, decrements in cognitive processing speed were detected in our cohort.

Cognitive and Neural Mechanisms of Social Communication Dysfunction in Primary Progressive Aphasia.

Mounting evidence suggests that, in parallel with well-defined changes in language, primary progressive aphasia (PPA) syndromes display co-occurring social cognitive impairments. Here, we explored multidimensional profiles of carer-rated social communication using the La Trobe Communication Questionnaire (LCQ) in 11 semantic dementia (SD), 12 logopenic progressive aphasia (LPA) and 9 progressive non-fluent aphasia (PNFA) cases and contrasted their performance with 19 Alzheimer's disease (AD) cases, 26 behavioural variant frontotemporal dementia (bvFTD) cases and 31 healthy older controls. Relative to the controls, the majority of patient groups displayed significant overall social communication difficulties, with common and unique profiles of impairment evident on the LCQ subscales. Correlation analyses revealed a differential impact of social communication disturbances on functional outcomes in patient and carer well-being, most pronounced for SD and bvFTD. Finally, voxel-based morphometry analyses based on a structural brain MRI pointed to the degradation of a distributed brain network in mediating social communication dysfunction in dementia. Our findings suggest that social communication difficulties are an important feature of PPA, with significant implications for patient function and carer well-being. The origins of these changes are likely to be multifactorial, reflecting the breakdown of fronto-thalamic brain circuits specialised in the integration of complex information.

Pancreas cancer and BRCA: A critical subset of patients with improving therapeutic outcomes.

BACKGROUND: Patients with germline/somatic BRCA1/BRCA2 mutations (g/sBRCA1/2) comprise a distinct biologic subgroup of pancreas ductal adenocarcinoma (PDAC). METHODS: Institutional databases were queried to identify patients who had PDAC with g/sBRCA1/2. Demographics, clinicopathologic details, genomic data (annotation sBRCA1/2 according to a precision oncology knowledge base for somatic mutations), zygosity, and outcomes were abstracted. Overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS: In total, 136 patients with g/sBRCA1/2 were identified between January 2011 and June 2020. Germline BRCA1/2 (gBRCA1/2) mutation was identified in 116 patients (85%). Oncogenic somatic BRCA1/2 (sBRCA1/2) mutation was present in 20 patients (15%). Seventy-seven patients had biallelic BRCA1/2 mutations (83%), and 16 (17%) had heterozygous mutations. Sixty-five patients with stage IV disease received frontline platinum therapy, and 52 (80%) had a partial response. The median OS for entire cohort was 27.6 months (95% CI, 24.9-34.5 months), and the median OS for patients who had stage IV disease was 23 months (95% CI, 19-26 months). Seventy-one patients received a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi), and 52 received PARPi monotherapy. For maintenance PARPi, 10 patients (36%) had a partial response, 12 (43%) had stable disease, and 6 (21%) had progression of disease as their best response. Six patients (21%) received maintenance PARPi for >2 years. For those with stage IV disease who received frontline platinum, the median OS was 26 months (95% CI, 20-52 months) for biallelic patients (n = 39) and 8.66 months (95% CI, 6.2 months to not reached) for heterozygous patients (n = 4). The median OS for those who received PARPi therapy was 26.5 months (95% CI, 24-53 months) for biallelic patients (n = 25) and 8.66 months (95% CI, 7.23 months to not reached) for heterozygous patients (n = 2). CONCLUSIONS: g/sBRCA1/2 mutations did not appear to have different actionable utility. Platinum and PARPi therapies offer therapeutic benefit, and very durable outcomes are observed in a subset of patients who have g/sBRCA1/2 mutations with biallelic status.

The interplay of emotional and social conceptual processes during moral reasoning in frontotemporal dementia.

Cooperative social behaviour in humans hinges upon our unique ability to make appropriate moral decisions in accordance with our ethical values. The complexity of the neurocognitive mechanisms underlying moral reasoning is revealed when this capacity breaks down. Patients with the behavioural variant of frontotemporal dementia (bvFTD) display striking moral transgressions in the context of atrophy to frontotemporal regions supporting affective and social conceptual processing. Developmental studies have highlighted the importance of social knowledge to moral decision making in children, yet the role of social knowledge in relation to moral reasoning impairments in neurodegeneration has largely been overlooked. Here, we sought to examine the role of affective and social conceptual processes in personal moral reasoning in bvFTD, and their relationship to the integrity and structural connectivity of frontotemporal brain regions. Personal moral reasoning across varying degrees of conflict was assessed in 26 bvFTD patients and compared with demographically matched Alzheimer's disease patients (n = 14), and healthy older adults (n = 22). Following each moral decision, we directly probed participants' subjective emotional experience as an index of their affective response, while social norm knowledge was assessed via an independent task. While groups did not differ significantly in terms of their moral decisions, bvFTD patients reported feeling 'better' about their decisions than healthy control subjects. In other words, although bvFTD patients could adjudicate between different courses of action in the moral scenarios, their affective responses to these decisions were highly irregular. This blunted emotional reaction was exclusive to the personal high-conflict condition, with 61.5% of bvFTD patients reporting feeling 'extremely good' about their decisions, and was correlated with reduced knowledge of socially acceptable behaviour. Voxel-based morphometry analyses revealed a distributed network of frontal, subcortical, and lateral temporal grey matter regions involved in the attenuated affective response to moral conflict in bvFTD. Crucially, diffusion-tensor imaging implicated the uncinate fasciculus as the pathway by which social conceptual knowledge may influence emotional reactions to personal high-conflict moral dilemmas in bvFTD. Our findings suggest that altered moral behaviour in bvFTD reflects the dynamic interplay between degraded social conceptual knowledge and blunted affective responsiveness, attributable to atrophy of, and impaired information transfer between, frontal and temporal cortices. Delineating the mechanisms of impaired morality in bvFTD provides crucial clinical information for understanding and treating this challenging symptom, which may help pave the way for targeted behavioural interventions.

Establishing two principal dimensions of cognitive variation in logopenic progressive aphasia.

Logopenic progressive aphasia is a neurodegenerative syndrome characterized by sentence repetition and naming difficulties arising from left-lateralized temporoparietal atrophy. Clinical descriptions of logopenic progressive aphasia largely concentrate on profiling language deficits, however, accumulating evidence points to the presence of cognitive deficits even on tasks with minimal language demands. Although non-linguistic cognitive deficits in logopenic progressive aphasia are thought to scale with disease severity, patients at discrete stages of language dysfunction display overlapping cognitive profiles, suggesting individual-level variation in cognitive performance, independent of primary language dysfunction. To address this issue, we used principal component analysis to decompose the individual-level variation in cognitive performance in 43 well-characterized logopenic progressive aphasia patients who underwent multi-domain neuropsychological assessments and structural neuroimaging. The principal component analysis solution revealed the presence of two, statistically independent factors, providing stable and clinically intuitive explanations for the majority of variance in cognitive performance in the syndrome. Factor 1 reflected 'speech production and verbal memory' deficits which typify logopenic progressive aphasia. Systematic variations were also confirmed on a second, orthogonal factor mainly comprising visuospatial and executive processes. Adopting a case-comparison approach, we further demonstrate that pairs of patients with comparable Factor 1 scores, regardless of their severity, diverge considerably on visuo-executive test performance, underscoring the inter-individual variability in cognitive profiles in comparably 'logopenic' patients. Whole-brain voxel-based morphometry analyses revealed that speech production and verbal memory factor scores correlated with left middle frontal gyrus, while visuospatial and executive factor scores were associated with grey matter intensity of right-lateralized temporoparietal, middle frontal regions and their underlying white matter connectivity. Importantly, logopenic progressive aphasia patients with poorer visuospatial and executive factor scores demonstrated greater right-lateralized temporoparietal and frontal atrophy. Our findings demonstrate the inherent variation in cognitive performance at an individual- and group-level in logopenic progressive aphasia, suggesting the presence of a genuine co-occurring cognitive impairment that is statistically independent of language function and disease severity.

Bedtime Stress Increases Sleep Latency and Impairs Next-Day Prospective Memory Performance.

The cognitive construct of prospective memory (PM) refers to the capacity to encode, retain and execute delayed intentions (e.g. to remember to buy milk on the way home). Although previous research suggests that PM performance is enhanced by healthy sleep, conclusions tend to be drawn based on designs featuring ecologically unnatural manipulations (e.g. total sleep deprivation). This study investigates whether a more common everyday experience (bedtime stress) affects next-day PM performance and, in so doing, also contributes to the heretofore inconsistent literature on stress and PM. Forty young adults received PM task instructions and were then assigned to either a stress condition (exposure to a laboratory-based stress-induction manipulation; n = 20, 9 women) or a non-stress condition (exposure to a non-stressful control manipulation; n = 20, 12 women). After completing the experimental manipulation, all participants had their objective sleep quality measured over a full night of polysomnographic monitoring. Upon awakening, they completed the PM task. Analyses detected significant between-group differences in terms of stress outcomes, sleep quality and PM performance: Participants exposed to the manipulation experienced heightened signs of stress (captured using a composite variable that included self-report, psychophysiological and endocrinological measures), had longer sleep latencies and poorer sleep depth and displayed significantly longer reaction times to PM cues. An interaction between experimental condition (being exposed to the stressor) and disrupted sleep (longer sleep latency) significantly predicted poorer next-day PM reaction time. We interpret these findings as indicating that bedtime stress, which leads to heightened presleep arousal, affects sleep processes and, consequently, the deployment of attentional resources during next-day execution of a delayed intention.

Acute Aortic Dissection Initially Suspected on 18F-FDG PET/CT.

A 64-year-old man with anal cancer underwent follow-up F-FDG PET/CT to evaluate chemoradiation therapy response 5 months after an initial PET/CT. The follow-up F-FDG PET/CT demonstrated new FDG-avid curvilinear soft tissue adjacent to the abdominal aorta, interpreted as an aortic dissection. Despite lack of clinical symptoms, the patient was directed to an emergency room the same day, where a contrast-enhanced CT confirmed an aortic aneurysm with dissection. The patient underwent endovascular surgical repair the following day. This case demonstrates that newly FDG-avid aortic soft tissue should be recognized and may need further evaluation to characterize clinically significant vascular pathology.

Scene construction impairments in frontotemporal dementia: Evidence for a primary hippocampal contribution.

The capacity to generate naturalistic three-dimensional and spatially coherent representations of the world, i.e., scene construction, is posited to lie at the heart of a wide range of complex cognitive endeavours. Clinical populations with selective damage to key nodes of a putative scene construction network of the brain have provided important insights regarding the contribution of medial temporal and prefrontal regions in this regard. Here, we explored the capacity for atemporal scene construction, and its associated neural substrates, in the behavioural-variant of frontotemporal dementia (bvFTD); a neurodegenerative brain disorder in which atrophy systematically erodes medial and lateral prefrontal cortices with variable medial temporal lobe involvement. Nineteen bvFTD patients were compared to 18 typical Alzheimer's Disease (AD), and 25 healthy older Control participants on a scene construction task. Relative to Controls, both patient groups displayed marked impairments in generating contextually detailed and spatially coherent scenes, with bvFTD indistinguishable from AD patients across the majority of task metrics. Voxel-based morphometry, based on structural brain MRI, revealed divergent neural substrates of scene construction performance in each patient group. Despite widespread medial and lateral prefrontal atrophy, the capacity to generate richly detailed and spatially coherent scenes in bvFTD was found to rely predominantly upon the integrity of right medial temporal structures, including the hippocampus and parahippocampal gyrus. Scene construction impairments in AD, by contrast, hinged upon the integrity of posterior parietal brain regions. Our findings in bvFTD resonate with a large body of work implicating the right hippocampus in the construction of spatially integrated scene imagery. How these impairments relate to changes in autobiographical memory and prospection in bvFTD will be an important question for future studies to address.

Regorafenib in Combination with First-Line Chemotherapy for Metastatic Esophagogastric Cancer.

BACKGROUND: Angiogenesis is critical to gastroesophageal adenocarcinoma growth and metastasis. Regorafenib is a multikinase inhibitor targeting angiogenic and stromal receptor tyrosine kinases. We evaluated whether regorafenib augments the antitumor effect of first-line chemotherapy in metastatic esophagogastric cancer. MATERIALS AND METHODS: Patients with previously untreated metastatic gastroesophageal adenocarcinoma received 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) every 14 days and regorafenib 160 mg daily on days 4 to 10 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS). To identify predictive biomarkers of outcome, we examined correlations between genomic characteristics of sequenced pretreatment tumors and PFS. RESULTS: Between August 2013 and November 2014, 36 patients with metastatic esophagogastric cancer were accrued to this single-center phase II study (NCT01913639). The most common grade 3-4 treatment-related adverse events were neutropenia (36%), leucopenia (11%) and hypertension (8%). The 6-month PFS was 53% (95% confidence interval [CI], 38%-71%), the objective response rate was 54% (95% CI, 37%-70%), and the disease control rate was 77% (95% CI, 67%-94%). Next-generation sequencing did not identify any genomic alterations significantly correlated with response, and there was no association between homologous recombination deficiency and PFS with platinum-based chemotherapy. CONCLUSION: Regorafenib (one week on-one week off schedule) is well tolerated in combination with first-line FOLFOX but does not improve 6-month PFS relative to historical control. IMPLICATIONS FOR PRACTICE: Prognosis for metastatic esophagogastric cancer remains poor despite modern systemic therapy regimens. This phase II trial indicates that the combination of regorafenib and FOLFOX is well tolerated but does not add to the efficacy of first-line chemotherapy in metastatic esophagogastric cancer. Notably, recently reported data suggest potential synergy between regorafenib and the PD-1 inhibitor nivolumab. As this study demonstrates that regorafenib plus FOLFOX is safe, and combined chemotherapy and immunotherapy show favorable toxicity profiles, future studies combining immunotherapy with regorafenib and chemotherapy may be feasible.

Efficacy of Combined VEGFR1-3, PDGFα/ß, and FGFR1-3 Blockade Using Nintedanib for Esophagogastric Cancer.

PURPOSE: VEGFR2-directed therapy is commonly used to treat metastatic esophagogastric cancer, but disease progresses in most patients within months. Therapeutic resistance is likely mediated in part by co-occurring amplifications of the genes for multiple oncogenic receptor tyrosine kinases (RTK). We therefore tested the efficacy of combined inhibition of VEGFR1-3, PDGFα/ß, and FGFR1-3 using nintedanib. PATIENTS AND METHODS: Patients with metastatic esophagogastric adenocarcinoma and disease progression on first-line chemotherapy were treated with nintedanib 200 mg twice daily. The primary endpoint was progression-free survival (PFS) at 6 months; secondary endpoints included tumor response and safety. Tumor biopsies were profiled by targeted capture next-generation sequencing (NGS) to identify molecular predictors of drug response. RESULTS: The study achieved its primary endpoint; 6 of 32 patients (19%) were progression-free at 6 months. With a median follow-up of 14.5 months among survivors, median overall survival (OS) was 14.2 months [95% confidence interval (CI), 10.8 months-NR]. Nintedanib was well tolerated; grade ≥ 3 toxicities were uncommon and included grade 3 hypertension (15%) and liver enzyme elevation (4%). FGFR2 alterations were identified in 18% of patients but were not predictive of clinical outcome on nintedanib therapy. Alterations in cell-cycle pathway genes were associated with worse median PFS (1.61 months for patients with cell-cycle pathway alterations vs. 2.66 months for patients without, P = 0.019). CONCLUSIONS: Nintedanib treatment resulted in modest disease stabilization in patients with metastatic esophagogastric cancer. Alterations in cell-cycle pathway genes and increased global copy-number alteration (CNA) burden warrant further study as prognostic or predictive biomarkers.

A Qualitative Analysis of Family Dynamics and Motivation in Sessions With 15 Women in Drug Treatment Court.

Women with substance use disorders (SUDs) often experience inadequate health care, mental and physical health problems, trauma, lack of social support, and undermining of support for psychological needs of autonomy, competence, and relatedness needed for motivation and well-being. For women with SUD trying to reclaim sobriety and a healthy life, family can present both barriers and support. The aim of this study is to gain a deeper understanding of the intersection of family relationships with motivation of women in Drug Treatment Court (DTC) to attain their health goals. Data consist of transcribed intervention sessions between trained peer interventionists and 15 DTC participants from The Women's Initiative Supporting Health DTC Intervention Study. This analysis uses a qualitative framework approach to analyze the data. The Self-determination Theory of human motivation and Family Systems Theory provide the conceptual framework to understand how participants' expressions of motivation-related basic needs of autonomy, competence, and relatedness and change-related behaviors interfaced with family support. Analysis revealed more mentions of family in motivation-supportive contexts than in motivation-thwarting contexts, but highlighted complex roles families can play in health of women in recovery from SUD. Providers may be able to incorporate this knowledge to address the needs of this challenging population.

Phase II study of trastuzumab with modified docetaxel, cisplatin, and 5 fluorouracil in metastatic HER2-positive gastric cancer.

BACKGROUND: Trastuzumab with cisplatin and fluoropyrimidine is the standard treatment in metastatic HER2-positive gastric or gastroesophageal (GE) junction adenocarcinoma; however, there is limited data on the efficacy of trastuzumab in combination with a three-drug regimen in this setting. We examined the efficacy and safety of modified docetaxel, cisplatin and 5 fluorouracil (mDCF) plus trastuzumab in a single-arm multicenter phase II trial. METHODS: Previously untreated patients with HER2-positive metastatic gastric or GE junction adenocarcinoma were treated with mDCF and trastuzumab every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS); secondary endpoints included objective response rate, overall survival (OS), and toxicity. RESULTS: We enrolled 26 patients with metastatic HER2-positive gastric or GE junction adenocarcinoma between February 2011 and June 2015. The median age of patients was 62 years; 96% had a Karnofsky performance status equal to or greater than 80%. With a median follow-up of 25.4 months, the 6-month PFS was 73% (95% CI 51-86%). The objective response rate was 65%, the median PFS was 13 months (95% CI 6.4-20.7) and the median OS was 24.9 months (95% CI 14.4-42.5). Grade 3/4 toxicities included neutropenia (42%), fatigue (23%), and hypophosphatemia (15%). There were no episodes of febrile neutropenia. CONCLUSION: The combination of mDCF and trastuzumab is effective and safe in patients with metastatic HER2-positive gastric or GE junction adenocarcinoma and can be considered as an option for selected patients. This trial is registered at ClinicalTrials.gov, number NCT00515411.

Age-related changes in the temporal focus and self-referential content of spontaneous cognition during periods of low cognitive demand.

An intriguing aspect of human cognition is the unique capacity to mentally retreat from our immediate surroundings to consider perspectives distinct from the here and now. Despite increasing interest in this phenomenon, relatively little is known regarding age-related changes in off-task, self-generated thought (often referred to as "mind-wandering"), particularly under conditions of low cognitive demand. While a number of studies have investigated the temporal orientation of mind-wandering with increasing age, findings have been largely inconsistent. Here, we explored the frequency, temporal focus, and self-referential/social content of spontaneous task-unrelated, perceptually decoupled thought in 30 young and 33 healthy older adults using the Shape Expectations task, a validated experimental paradigm in which discrete facets of inner mentation are quantified along a conceptual continuum using open-ended report. Participants also completed the daydreaming subscale of the Imaginal Process Inventory (IPI) as a trait measure of mind-wandering propensity. Significant group differences emerged on the Shape Expectations task, with reduced instances of mind-wandering in the context of elevated task-related thoughts relative to younger adults. In terms of temporal focus, a preponderance of present/atemporal off-task thoughts was evident irrespective of group; however, significantly higher levels of future-oriented thoughts were provided by younger adults, contrasting with significantly higher instances of retrospection in the older group. In addition, older adults displayed significantly fewer incidences of self-referential cognition relative to their younger counterparts. Our findings indicate a distinct attenuation of off-task, self-generated thought processes with increasing age, with evidence for a shift in temporal focus and self-referential quality, during periods of low cognitive demand.

Neural correlates of changes in sexual function in frontotemporal dementia: implications for reward and physiological functioning.

BACKGROUND: Frontotemporal dementia (FTD) is characterised by changes in behaviour including alterations in sexual function. While hypersexual behaviour is commonly thought to predominate, emerging evidence suggests that hyposexual behaviour is in fact most prevalent. The underlying mechanisms driving these behavioural changes remain unclear; however, likely reflect interactions between cognitive, emotional, reward processing and physiological functioning. We aimed to systematically quantify changes in sexual behaviour in behavioural variant FTD (bvFTD) and semantic dementia (SD) in contrast with Alzheimer's disease (AD) and to elucidate the neural correlates of these changes using whole-brain voxel-based morphometry. METHODS: Carers of 62 dementia patients (30 bvFTD, 12 SD, 20 AD) were interviewed using the Sexual Behaviour and Intimacy Questionnaire, which assesses changes in sexual function. Voxel-based morphometry analysis of structural MRI brain scans was used to determine the association between changes in grey matter intensity and the presence of hyposexual, hypersexual, and inappropriate sexual behaviour across groups. RESULTS: Widespread attenuation of sexual drive, intimacy and the display of affection were evident irrespective of dementia subtype. In contrast, hypersexual and inappropriate sexual behaviour was present in only a small proportion of patients. Neuroimaging analyses revealed an association between hyposexual behaviour and atrophy of the right supramarginal gyrus, middle frontal gyrus and thalamus, whilst hypersexual behaviour was associated with cerebellar atrophy. CONCLUSION: Counter to the prevailing view, younger-onset dementia syndromes predominantly display an attenuation in sexual drive. Changes in sexual function likely reflect the degeneration of cortical and subcortical neural circuits implicated in reward, autonomic function, empathy, and emotional processing.

Exploring the contribution of visual imagery to scene construction - Evidence from Posterior Cortical Atrophy.

Posterior Cortical Atrophy (PCA) is a rare neurodegenerative syndrome characterised by profound visuoperceptual processing disturbances, attributable to focal parieto-occipital cortical atrophy. Despite relative sparing of the medial temporal lobes, converging evidence reveals significant autobiographical memory impairments in this syndrome, underscoring the crucial role of visual imagery for episodic memory processes. The contribution of visual imagery to complex constructive endeavours, however, remains unclear. Here, we investigated the capacity for atemporal scene construction in 5 well-characterised cases of PCA and contrasted their performance with 10 typical amnestic Alzheimer's Disease (AD) and 10 healthy older Control participants. Behavioural data were analysed using case-Control statistics comparing each PCA patient's scene construction scores to the mean scores of AD and Control groups. In keeping with their clinical phenotype, PCA patients demonstrated significant visuoperceptual and episodic memory impairments on standard neuropsychological tasks. Scene construction performance was grossly impaired in PCA, at a level comparable to that observed in the AD group, manifesting in impoverished and spatially fragmented scenes. Structural neuroimaging confirmed prominent grey matter intensity decrease predominantly in posterior cortical regions in PCA, in the absence of frank hippocampal atrophy. Using an a priori motivated region-of-interest approach across all participants, scene construction performance was found to correlate with grey matter intensity in the left angular gyrus, right precuneus, and right hippocampus. This study is the first to reveal compromised scene construction capacity in PCA, extending our understanding of the cognitive profile of this rare syndrome and pointing towards the fundamental contribution of visual imagery to atemporal forms of imagination.