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Glioblastoma is immunologically "cold" and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we enrolled an additional 25 patients with a primary endpoint of evaluating the cell cycle gene signature associated with neoadjuvant pembrolizumab and performed bulk-RNA seq on resected tumor tissue (NCT02852655). Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent positive risk factor for survival. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not confirm a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma and our secondary endpoint of PFS-6 was 19.5% (95% CI: 9.29-41.2%) for the pooled neoadjuvant cohorts. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively. Glioblastoma is resistant to immune-checkpoint inhibitors. In this study, the authors report the results of an expansion cohort (n = 25) of a randomized testing neoadjuvant plus adjuvant pembrolizumab versus adjuvant pembrolizumab alone in patients with recurrent glioblastoma with resectable tumors. [ABSTRACT FROM AUTHOR]

The Hippo tumor suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some entering clinical trials for different cancers with Hippo pathway deregulation, most notably, mesothelioma. Using genome-wide CRISPR/Cas9 screens we reveal that mutations in genes from the Hippo, MAPK, and JAK-STAT signaling pathways all modulate the response of mesothelioma cell lines to TEAD palmitoylation inhibitors. By exploring gene expression programs of mutant cells, we find that MAPK pathway hyperactivation confers resistance to TEAD inhibition by reinstating expression of a subset of YAP/TAZ target genes. Consistent with this, combined inhibition of TEAD and the MAPK kinase MEK, synergistically blocks proliferation of multiple mesothelioma and lung cancer cell lines and more potently reduces the growth of patient-derived lung cancer xenografts in vivo. Collectively, we reveal mechanisms by which cells can overcome small-molecule inhibition of TEAD palmitoylation and potential strategies to enhance the anti-tumor activity of emerging Hippo pathway targeted therapies. Synopsis: Genome-wide CRISPR/Cas9 screens identify mechanisms by which mesothelioma cells respond to TEAD palmitoylation inhibitors, which are the first Hippo pathway targeted therapies. MAPK pathway targeted therapies enhance the anti-tumor activity of TEAD inhibitors. Mutating the Hippo, MAPK, and JAK-STAT pathways modulates the cellular response to TEAD inhibitors. MAPK pathway hyperactivation confers resistance to TEAD inhibition by reinstating expression of a subset of YAP/TAZ targets. Combined inhibition of TEAD and MEK synergistically blocks proliferation of mesothelioma and lung cancer cell lines. MEK inhibitors enhance the ability of TEAD inhibitors to suppress the growth of patient-derived lung cancer xenografts. Genome-wide CRISPR/Cas9 screens identify mechanisms by which mesothelioma cells respond to TEAD palmitoylation inhibitors, which are the first Hippo pathway targeted therapies. MAPK pathway targeted therapies enhance the anti-tumor activity of TEAD inhibitors. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol (PI) is the precursor lipid for the minor phosphoinositides (PPIns), which are critical for multiple functions in all eukaryotic cells. It is poorly understood how phosphatidylinositol, which is synthesized in the ER, reaches those membranes where PPIns are formed. Here, we used VT01454, a recently identified inhibitor of class I PI transfer proteins (PITPs), to unravel their roles in lipid metabolism, and solved the structure of inhibitor-bound PITPNA to gain insight into the mode of inhibition. We found that class I PITPs not only distribute PI for PPIns production in various organelles such as the plasma membrane (PM) and late endosomes/lysosomes, but that their inhibition also significantly reduced the levels of phosphatidylserine, di- and triacylglycerols, and other lipids, and caused prominent increases in phosphatidic acid. While VT01454 did not inhibit Golgi PI4P formation nor reduce resting PM PI(4,5)P2 levels, the recovery of the PM pool of PI(4,5)P2 after receptor-mediated hydrolysis required both class I and class II PITPs. Overall, these studies show that class I PITPs differentially regulate phosphoinositide pools and affect the overall cellular lipid landscape. Synopsis: Class I phosphatidylinositol (PI) transfer proteins (PITPs) have been proposed to supply PI to the lipid kinases that produce mono-phosphorylated phosphoinositides, PI4P and PI3P. A novel inhibitor of class I PITPs illuminates how these proteins contribute to the maintenance of various phosphoinositide pools in intact cells. PITPs provide PI to the plasma membrane and late endosomes for generation of PI4P in those organelle membranes. Acute PITP inhibition does not affect PI4P levels in the Golgi and only has a small impact on PI3P levels in early endosomes. PI(4,5)P2 maintenance in the plasma membrane upon phospholipase C activation requires both class I and class II PITPs. The crystal structure of inhibitor-bound PITPNA reveals an "open" structure identical to the reported cargo-free structures. PTIP Inhibition affects the levels of several lipid classes. Inhibition of specific lipid transfer proteins reveals how pools of key signalling lipids are maintained in the plasma membrane and late endosome. [ABSTRACT FROM AUTHOR]

A sensor chip that can detect enzyme electrode reactions with a sample volume as small as 20 μL has been developed using screen-printing technology with porous silica spheres (PSSs). PSSs are spherical particles of silica with mesoporous pores, a material with a large specific surface area. Other material properties of PSSs include good dispersibility, high mechanical strength, and the ability to be synthesized with precisely controlled mesopore sizes. These advantages support the increased adsorption of enzymes to create highly sensitive sensors. The electrode was designed as follows: carbon paste (CP) with PSSs was used as the working electrode, glucose dehydrogenase (GDH) was used as the enzyme, and quinoline-5,8-dione (QD) was used as the mediator of electron transfer to induce a glucose dehydrogenation reaction. The sensitivity of the sensor was demonstrated through the detection of glucose. The glucose sensor showed reliable sensitivity between 1 and 60 mM glucose, which is comparable to the detection range of a traditional working electrode such as platinum. Furthermore, the GDH had a minimal reduction in activity over repeated usage. This device demonstrates the ability to create an equally sensitive but less expensive and reusable sensor that has the potential to better suit general applications. [ABSTRACT FROM AUTHOR]

Background and Aims: Electronic nicotine delivery systems (ENDS) can help people to quit smoking combusted tobacco products (CTPs), but most current and former smokers who use ENDS also intend to quit ENDS. This analysis measured whether ENDS cessation among current and former CTP smokers is associated with changes in CTP smoking or abstinence. Design: Regression analysis of a nationally representative cohort from waves 4 (W4) and 5 (W5) of the Population Assessment of Tobacco and Health Study (December 2016–November 2019). Setting: United States. Participants: Adults (n = 1525) who reported W4 current or former use of ≥ 1 CTP and either currently using ENDS or quitting ENDS in the past year were included. Measurements Logistic regressions were performed separately among W4 current and former CTP smokers, controlling for demographic and tobacco use characteristics. First, we analyzed proximal outcomes by testing the association between ENDS quit status and CTP abstinence, both occurring during W5. Next, we analyzed long‐term outcomes by testing W4 ENDS quit status as a predictor of CTP abstinence at W5, approximately 1 year later. Findings Among W4 current CTP smokers, there was no evidence that CTP smoking abstinence differed between those quitting or continuing using ENDS, both in our proximal [adjusted odds ratio (aOR) = 1.37, 95% confidence interval (CI) = 0.90, 2.10] and long‐term (aOR = 0.90, 95% CI = 0.52, 1.53) analyses. Among former CTP smokers, quitting ENDS was associated with less CTP abstinence in our proximal analysis (aOR = 0.42, 95% CI = 0.20, 0.89), but there was no evidence that CTP smoking abstinence differed between those quitting or continuing using ENDS in our long‐term analysis (aOR = 0.86, 95% CI = 0.44, 1.67). Conclusions: There is no evidence that ENDS cessation is associated with CTP abstinence among current smokers, although mixed findings among former smokers indicate a possible risk for relapse to smoking associated with quitting ENDS. [ABSTRACT FROM AUTHOR]

Schwannoma tumours typically arise on the eighth cranial nerve and are mostly caused by loss of the tumour suppressor Merlin (NF2). There are no approved chemotherapies for these tumours and the surgical removal of the tumour carries a high risk of damage to the eighth or other close cranial nerve tissue. New treatments for schwannoma and other NF2-null tumours such as meningioma are urgently required. Using a combination of human primary tumour cells and mouse models of schwannoma, we have examined the role of the Hippo signalling pathway in driving tumour cell growth. Using both genetic ablation of the Hippo effectors YAP and TAZ as well as novel TEAD palmitoylation inhibitors, we show that Hippo signalling may be successfully targeted in vitro and in vivo to both block and, remarkably, regress schwannoma tumour growth. In particular, successful use of TEAD palmitoylation inhibitors in a preclinical mouse model of schwannoma points to their potential future clinical use. We also identify the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) as a Hippo signalling target, driven by the TAZ protein in human and mouse NF2-null schwannoma cells, as well as in NF2-null meningioma cells, and examine the potential future role of this new target in halting schwannoma and meningioma tumour growth. [ABSTRACT FROM AUTHOR]

Introduction: In response to reducing cigarette nicotine content, people who smoke could attempt to compensate by using more cigarettes or by puffing on individual cigarettes with greater intensity. Such behaviors may be especially likely under conditions where normal nicotine content (NNC) cigarettes are not readily accessible. The current within-subject, residential study investigated whether puffing intensity increased with very low nicotine content (VLNC) cigarette use, relative to NNC cigarette use, when no other nicotine products were available.Aims and Methods: Sixteen adults who smoke daily completed two four-night hotel stays in Charleston, South Carolina (United States) in 2018 during which only NNC or only VLNC cigarettes were accessible. We collected the filters from all smoked cigarettes and measured the deposited solanesol to estimate mouth-level nicotine delivery per cigarette. These estimates were averaged within and across participants, per each 24-h period. We then compared the ratio of participant-smoked VLNC and NNC cigarette mouth-level nicotine with the ratio yielded by cigarette smoking machines (when puffing intensity is constant).Results: Average mouth-level nicotine estimates from cigarettes smoked during the hotel stays indicate participants puffed VLNC cigarettes with greater intensity than NNC cigarettes in each respective 24-h period. However, this effect diminished over time (p < .001). Specifically, VLNC puffing intensity was 40.0% (95% CI: 29.9, 53.0) greater than NNC puffing intensity in the first period, and 16.1% (95% CI: 6.9, 26.0) greater in the fourth period.Conclusion: Average puffing intensity per cigarette was elevated with exclusive VLNC cigarette use, but the extent of this effect declined across four days.Implications: In an environment where no other sources of nicotine are available, people who smoke daily may initially attempt to compensate for cigarette nicotine reduction by puffing on individual cigarettes with greater intensity. Ultimately, the compensatory behavior changes required to achieve usual nicotine intake from VLNC cigarettes are drastic and unrealistic. Accordingly, people are unlikely to sustain attempts to compensate for very low cigarette nicotine content. [ABSTRACT FROM AUTHOR]

In this paper, we present the influence of a professional development, including a faculty learning community (FLC), on STEM teaching practices at a southern US liberal arts college. We used a quasi-experimental mixed-method design to collect information about teaching practices and the influence of the professional development. The Reformed Teaching Observation Protocol (RTOP) was used to evaluate the faculty teaching strategies. The RTOP ratings indicated that most faculty used some sort of active strategies. Further, faculty who attended the professional development had significantly higher RTOP scores than their counterparts. Results from interviews show that faculty were willing to make changes to their teaching approaches based on the workshop. Results from this study contribute to the knowledge base describing the influence of professional development on STEM college faculty teaching strategies. [ABSTRACT FROM AUTHOR]

Monoamine oxidase (MAO) activity is reduced in cigarette smokers and this may promote the reinforcing actions of nicotine, thereby enhancing the addictive properties of cigarettes. At present, it is unclear how cigarette smoking leads to MAO inhibition, but preclinical studies in rodents show that MAO inhibition increases nicotine self-administration, especially at low doses of nicotine. This effect of MAO inhibition develops slowly, likely due to plasticity of brain monoamine systems; studies relying on acute MAO inhibition are unlikely to replicate what happens with smoking. Given that MAO inhibition may reduce the threshold level at which nicotine becomes reinforcing, it is important to consider this in the context of very low nicotine content (VLNC) cigarettes and potential tobacco product regulation. It is also important to consider how this interaction between MAO inhibition and the reinforcing actions of nicotine may be modified in populations that are particularly vulnerable to nicotine dependence. In the context of these issues, we show that the MAO-inhibiting action of cigarette smoke extract (CSE) is similar in VLNC cigarettes and cigarettes with a standard nicotine content. In addition, we present evidence that in a rodent model of schizophrenia the effect of MAO inhibition to enhance nicotine self-administration is absent, and speculate how this may relate to brain serotonin systems. These issues are relevant to the MAO-inhibiting effect of cigarette smoking and its implications to tobacco product regulation. [ABSTRACT FROM AUTHOR]

Purpose: Caregivers of patients with malignant gliomas are at risk for psychological distress. However, factors associated with distress in this population have not been well described. We conducted a prospective study evaluating psychological distress in patients with malignant gliomas and their caregivers and exploring factors associated with caregiver distress.Methods: We enrolled patients with newly diagnosed malignant gliomas (N = 77) and their caregivers (N = 61). At baseline and 3, 6, and 9 months after diagnosis, we administered the Hospital Anxiety and Depression Scale to assess psychological distress and the Caregiver Reaction Assessment to evaluate caregiver burden. We performed multivariable regression analyses to investigate caregiver-related, patient-related, and tumor-related factors associated with caregivers' distress.Results: At baseline, 48.3% (29/60) and 26.2% (16/61) of caregivers reported clinically significant anxiety and depression symptoms, respectively. Anxiety and depression symptoms persisted over time. Greater caregiver depression was associated with male gender (B = 1.48, 95% CI 0.16-2.81, p = 0.03), higher caregiver burden (B = 0.08, 95% CI 0.01-0.15, p = 0.02), caregiver anxiety (B = 0.53, 95% CI 0.38-0.68, p < 0.0001), patient depression (B = 0.34, 95% CI 0.13-0.55, p = 0.002), and caring for a younger patient (B =  -0.07, 95% CI -0.15 to 0.00, p = 0.049). Factors associated with greater caregiver anxiety symptoms were caregiver depression (B = 0.91, 95% CI 0.71-1.12, p < 0.0001) and younger patient age (B =  -0.15, 95% CI -0.24 to -0.05, p = 0.003).Conclusion: Male gender, higher caregiver burden, greater patient depression symptoms, and younger patient age are associated with increased distress among caregivers of patients with malignant gliomas, underscoring the need for tailored supportive care interventions targeting caregivers at highest risk for psychological distress. [ABSTRACT FROM AUTHOR]

Aging is a risk factor for neurodegenerative disease, but precise mechanisms that influence this relationship are still under investigation. Work in Drosophila melanogaster identified the microRNA miR‐34 as a modifier of aging and neurodegeneration in the brain. MiR‐34 mutants present aspects of early aging, including reduced lifespan, neurodegeneration, and a buildup of the repressive histone mark H3K27me3. To better understand how miR‐34 regulated pathways contribute to age‐associated phenotypes in the brain, here we transcriptionally profiled the miR‐34 mutant brain. This identified that genes associated with translation are dysregulated in the miR‐34 mutant. The brains of these animals show increased translation activity, accumulation of protein aggregation markers, and altered autophagy activity. To determine if altered H3K27me3 was responsible for this proteostasis dysregulation, we studied the effects of increased H3K27me3 by mutating the histone demethylase Utx. Reduced Utx activity enhanced neurodegeneration and mimicked the protein accumulation seen in miR‐34 mutant brains. However, unlike the miR‐34 mutant, Utx mutant brains did not show similar altered autophagy or translation activity, suggesting that additional miR‐34‐targeted pathways are involved. Transcriptional analysis of predicted miR‐34 targets identified Lst8, a subunit of Tor Complex 1 (TORC1), as a potential target. We confirmed that miR‐34 regulates the 3' UTR of Lst8 and identified several additional predicted miR‐34 targets that may be critical for maintaining proteostasis and brain health. Together, these results present novel understanding of the brain and the role of the conserved miRNA miR‐34 in impacting proteostasis in the brain with age. [ABSTRACT FROM AUTHOR]

The introduction of alternative nicotine and tobacco products (such as e-cigarettes, heat-not-burn devices, nicotine pouches) warrants an updated framework from which to conceptualize tobacco use disorder (TUD). The following review provides considerations for TUD within the context of novel products. Historically, the tobacco industry falsely claimed that cigarettes were not addictive or harmful and that those who smoked simply chose to do so. This generated an inaccurate lay perception that smoking is a free or informed choice. Research on nicotine pharmacology demonstrates the powerful addictive potential of nicotine, which is shaped by dose, speed of delivery, and other constituents generated. In addition, non-pharmacologic reinforcers motivate and maintain tobacco use behaviors for both traditional cigarettes and novel products. The negative consequences of combustible tobacco use are well known; however, these outcomes may differ for alternative products. Strategies used for combustible product cessation may be adapted for novel products, and treatment recommendations for TUD should be made within the context of a harm reduction framework wherein alternative product use may be the desired outcome. Providers must therefore be willing to modify their perceptions of products and treatment recommendations accordingly. Better public health outcomes are accomplished through promotion of abstinence from combustible smoking. For those who cannot wean from nicotine entirely, switching to less risky modes of delivery might be a secondary goal, with an eventual aim of stopping use of the alternative product. Implications: Given the advent of novel, alternative tobacco products, tobacco use disorder (TUD) must be conceptualized within a contemporary framework that includes harm reduction and alternative outcomes. The unique contributions of nicotine pharmacology, non-pharmacologic reinforcers, and consequences of use can be used to inform treatments for TUD with the ultimate goal of improving the health of individuals who use tobacco. [ABSTRACT FROM AUTHOR]

MR spectroscopic imaging (MRSI) noninvasively maps the metabolism of human brains. In particular, the imaging of D‐2‐hydroxyglutarate (2HG) produced by glioma isocitrate dehydrogenase (IDH) mutations has become a key application in neuro‐oncology. However, the performance of full field‐of‐view MRSI is limited by B0 spatial nonuniformity and lipid artifacts from tissues surrounding the brain. Array coils that multiplex RF‐receive and B0‐shim electrical currents (AC/DC mixing) over the same conductive loops provide many degrees of freedom to improve B0 uniformity and reduce lipid artifacts. AC/DC coils are highly efficient due to compact design, requiring low shim currents (<2 A) that can be switched fast (0.5 ms) with high interscan reproducibility (10% coefficient of variation for repeat measurements). We measured four tumor patients and five volunteers at 3 T and show that using AC/DC coils in addition to the vendor‐provided second‐order spherical harmonics shim provides 19% narrower spectral linewidth, 6% higher SNR, and 23% less lipid content for unrestricted field‐of‐view MRSI, compared with the vendor‐provided shim alone. We demonstrate that improvement in MRSI data quality led to 2HG maps with higher contrast‐to‐noise ratio for tumors that coincide better with the FLAIR‐enhancing lesions in mutant IDH glioma patients. Smaller Cramér–Rao lower bounds for 2HG quantification are obtained in tumors by AC/DC shim, corroborating with simulations that predicted improved accuracy and precision for narrower linewidths. AC/DC coils can be used synergistically with optimized acquisition schemes to improve metabolic imaging for precision oncology of glioma patients. Furthermore, this methodology has broad applicability to other neurological disorders and neuroscience. [ABSTRACT FROM AUTHOR]

The 2016 revised fourth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors incorporated molecular features with histologic grading, revolutionizing how oncologists conceptualize primary brain and spinal cord tumors as well as providing new insights into their management and prognosis. The 2021 revised fifth edition of the WHO classification further integrates molecular alterations for CNS tumor categorization, updating current understanding of the pathophysiology of many of these disease entities. Here, the authors review changes in the new classification for the most common primary adult tumors—gliomas (including astrocytomas, oligodendrogliomas, and ependymomas) and meningiomas—highlighting the key genomic alterations for each group classification to help clinicians interpret them as they consider therapeutic options—including clinical trials and targeted therapies—and discuss the prognosis of these tumors with their patients. The revised, updated 2021 WHO classification also further integrates molecular alterations in the classification of pediatric CNS tumors, but those are not covered in the current review. The 2021 World Health Organization classification of tumors of the central nervous system increasingly relies on molecular alterations for central nervous system tumor categorization. The new classification will help improve diagnosis, prognosis, and treatment selection (including enrollment into relevant clinical trials) for patients with brain tumors. [ABSTRACT FROM AUTHOR]

Background: We sought to determine differences in the circulating metabolic profile of infants with or without acute kidney injury (AKI) following cardiothoracic surgery with cardiopulmonary bypass (CPB). Methods: We performed a secondary analysis of preoperative and 24-h postoperative serum samples from infants ≤ 120 days old undergoing CPB. Metabolic profiling of the serum samples was performed by targeted analysis of 165 serum metabolites via tandem mass spectrometry. We then compared infants who did or did not develop AKI in the first 72 h postoperatively to determine global differences in the preoperative and 24-h metabolic profiles in addition to specific differences in individual metabolites. Results: A total of 57 infants were included in the study. Six infants (11%) developed KDIGO stage 2/3 AKI and 13 (23%) developed stage 1 AKI. The preoperative metabolic profile did not differentiate between infants with or without AKI. Infants with severe AKI could be moderately distinguished from infants without AKI by their 24-h metabolic profile, while infants with stage 1 AKI segregated into two groups, overlapping with either the no AKI or severe AKI groups. Differences in these 24-h metabolic profiles were driven by 21 metabolites significant at an adjusted false discovery rate of < 0.05. Prominently altered pathways include purine, methionine, and kynurenine/nicotinamide metabolism. Conclusion: Moderate-to-severe AKI after infant cardiac surgery is associated with changes in the serum metabolome, including prominent changes to purine, methionine, and kynurenine/nicotinamide metabolism. A portion of infants with mild AKI demonstrated similar metabolic changes, suggesting a potential role for metabolic analysis in the evaluation of lower stage injury. [ABSTRACT FROM AUTHOR]

Introduction: As the FDA works to determine whether a nicotine reduction policy would benefit public health, one key question is whether to mandate an immediate or gradual reduction in nicotine levels in cigarettes. The aim of this study was to determine whether the effects of gradual versus immediate nicotine reduction on cigarettes per day (CPD), total nicotine equivalents, and subjective responses differed in younger adults versus older adults.Methods: Using data from a recent randomized trial conducted in the United States (N = 1250) that switched smokers over a 20-week period to very low nicotine content (VLNC) cigarettes either immediately, gradually (via monthly reductions in nicotine content), or not at all (control condition, normal nicotine content research cigarette), we analyzed the moderating effect of age (age 18-24 or 25+).Results: For both age groups, CPD in the immediate condition was significantly lower relative to gradual condition (estimated mean difference of 6.3 CPD in young adults, 5.2 CPD in older adults; p's < .05). Younger and older adults in the immediate and gradual reduction conditions had lower total nicotine equivalents at Week 20 (all p's < .05) than those in the control condition; age group did not moderate this effect. Positive subjective responses to cigarettes were lower among young adults relative to older adults in the immediate condition.Conclusions: These results indicate that an immediate reduction in nicotine would result in beneficial effects in both young and older adults. Young adults show less positive subjective effects of smoking following switching to VLNC cigarettes relative to older adults.Implications: As researchers work to understand how a potential reduced-nicotine product standard for cigarettes may affect public health, one question is whether nicotine should be reduced immediately or gradually. This study demonstrates that both young and older adults who were switched immediately to the lowest content of nicotine smoked fewer CPD and had lower nicotine intake than those in the gradual condition. Furthermore, young adults appear to show lower positive subjective effects following switching to VLNC cigarettes relative to older adults. This is consistent with previous work demonstrating that young people appear to show lower abuse liability for VLNC cigarettes. [ABSTRACT FROM AUTHOR]

Introduction: Medication sampling is a clinically useful tool to engage smokers in the quitting process. Whether varenicline is suitable for sampling purposes is unclear. The purpose of this study was to examine the feasibility, uptake, and preliminary outcomes of varenicline sampling.Methods: Smokers (N = 99), both motivated to quit and not, were recruited and randomized to varenicline sampling versus not, with 12 week follow-up. The intervention consisted of mailing one-time samples of varenicline (lasting 2-4 wks), with minimally suggestive guidance on use.Results: Uptake of varenicline was strong, at 2 weeks (54% any use, 66% daily use) and 4 weeks (38%, 46%), with 58% of medication users seeking additional medication. Most users followed conventional titration patterns, self-titrating from 0.5 mg to 2 mg. Relative to control, varenicline sampling increased motivation (p = 0.006) and confidence to quit (p = 0.02), and decreased cigarette smoking (p = 0.02). Smokers receiving varenicline samples were significantly more likely to achieve 50% reduction in cigarettes per day (CPD), both immediately following the sampling exercise (Adjusted Odds Ratio [AOR] = 4.12; 95% CI: 1.39 to 12.17) and at final follow-up (AOR = 4.50; 95% CI: 1.56 to 13.01). Though cessation outcomes were not statistically significant, there was a 1.5 to 3-fold increase in quit attempts and abstinence from varenicline sampling throughout follow-up. These outcomes were comparable among smokers motivated to quit and not.Conclusions: Unguided, user-driven sampling of varenicline sampling is a concrete behavioral exercise that is feasible to do and seems to suggest clinical utility. Sampling is a pragmatic clinical approach to engage more smokers in quitting.Implications: Use of evidence-based pharmacotherapies for smoking cessation is low. Medication sampling is a pragmatic behavioral exercise that allows smokers to experience the benefits of using them, while promoting positive downstream effects towards quitting. While previous studies have shown that nicotine replacement therapy (NRT) sampling is viable and effective, whether this extends to varenicline is unclear. Results from this trial demonstrate that varenicline sampling is feasible, safe, and suggestive of clinically important steps toward quitting, deserving of a larger trial.Clinical Trial Registration: NCT #03742154. [ABSTRACT FROM AUTHOR]

Background: Intracranial foreign body granuloma (FBG) is a rare inflammatory reaction to retained foreign material, manifesting acutely or months to years following neurosurgical procedures. Radiographically, FBG can mimic tumor progression, and tissue biopsy may be required to guide management. Materials and Methods: In this retrospective case series, we present unique clinico‐radiographic and histopathological features of six neuro‐oncological patients diagnosed with FBG between 2007 and 2019. Results: All six patients (4 women and 2 men, aged 29–54 [median, 30.5] years) had undergone surgical resection of a low‐ (n = 4) or high‐grade (n = 2) glioma. FBG manifestation postsurgery ranged from 1 day to 4 years and was predominantly asymptomatic (n = 5/6). Magnetic resonance imaging universally demonstrated one or multiple peripherally enhancing lesion(s) adjacent to the resection cavity. Histopathology in all (n = 4/4) resected specimens demonstrated an inflammatory reaction to foreign material, confirming FBG. Conclusion: Intracranial FBG constitutes a rare but challenging treatment‐related condition effectively managed by surgery, with important therapeutic implications in neuro‐oncology. Cancer treatment‐related effects remain a challenge in neuro‐oncology. This brief communication presents a case series of patients diagnosed with intracranial foreign body granuloma. [ABSTRACT FROM AUTHOR]

Summary: Primary central nervous system (CNS) lymphoma (PCNSL) represents 4% of all CNS malignancies and 4–6% of all extranodal lymphomas. Its low incidence is the main reason why it has been difficult to develop guidelines on the treatment and management of PCNSL patients. The lack of consensus around standard therapy and best diagnostic approach, inevitably, affected the outcome of these patients for many years. Current efforts are focusing on: (1) defining the optimal induction and consolidation therapies in fit and frail patients, (2) establishing when and how to use the new non-cytotoxic agents, (3) investigating innovative radiotherapy to mitigate treatment-related neurotoxicity, (4) limiting delays in diagnosis, and (5) improving response assessment with new biological markers and radiological tools. Finally, the complexity of the management of PCNSL patients compels clinicians to provide timely and efficient social, neuropsychological, and physiotherapy support, which is feasible only when there is effective collaboration between the multiple specialists involved in the care of these patients. Recent Findings: In the last decade, thanks to multicenter collaborations, important gains have been made, particularly in the front line therapy and in the biological understanding of this disease. The progressive knowledge on molecular profile of PCNSL has justified the recent use of targeted therapy also in these settings of patients. Purpose of Review: In this review, we discuss important advances in the management of PCNSL and we highlight unresolved questions that should be addressed in the future. [ABSTRACT FROM AUTHOR]

Introduction: The U.S. Food and Drug Administration (FDA) has proposed lowering the nicotine content of cigarettes to a minimally addictive level to increase smoking cessation and reduce initiation. This study has two aims: (1) to determine when cigarette manufacturers had the technical capability to reduce cigarette nicotine content and (2) to estimate the lost public health benefits of implementing a standard in 1965, 1975, or 1985.Methods: To determine the technical capability of cigarette companies, we reviewed public patents and internal cigarette company business records using the Truth Tobacco Industry Documents. To evaluate the impact of a very low nicotine content cigarette (VLNC) standard on smoking attributable deaths (SADs) and life-years lost (LYLs), we applied a validated (CISNET) model that uses past smoking data, along with estimates of the potential impact of VLNCs derived from expert elicitation.Results: Cigarette manufacturers recognized that cigarettes were deadly and addictive before 1964. Manufacturers have had the technical capability to lower cigarette nicotine content for decades. Our model projected that a standard implemented in 1965 could have averted 21 million SADs (54% reduction) and 272 million LYLs (64% reduction) from 1965 to 2064, a standard implemented in 1975 could have averted 18.9 million SADs and 245.4 million LYLs from 1975 to 2074, and a standard implemented in 1985 could have averted 16.3 million SADs and 211.5 million LYLs from 1985 to 2084.Conclusions: Millions of premature deaths could have been averted if companies had only sold VLNCs decades ago. FDA should act immediately to implement a VLNC standard.Implications: Prior research has shown that a mandated reduction in the nicotine content of cigarettes could reduce the prevalence of smoking and improve public health. Here we report that cigarette manufacturers have had the ability to voluntarily implement such a standard for decades. We use a well-validated model to demonstrate that millions of smoking attributable deaths and life-years lost would have been averted if the industry had implemented such a standard. [ABSTRACT FROM AUTHOR]

Sexual displays are some of the most dramatic and varied behaviors that have been documented. The elaboration of such behaviors often relies on the modification of existing morphology. To understand how display elaboration arises, we analyzed the laryngeal anatomy of three species of mice that vary in the presence and complexity of their vocal displays. Mice and rats have a specialized larynx that enables them to produce both low‐frequency "audible" sounds, perhaps using vocal fold vibration, as well as distinct mechanisms that are thought to enable higher frequency sounds, such as vocal membrane vibration and intralaryngeal whistles. These mechanisms rely on different structures within the larynx. Using histology, we characterized laryngeal anatomy in Alston's singing mouse (Scotinomys teguina), the northern pygmy mouse (Baiomys taylori), and the laboratory mouse (Mus musculus), which produce different types of vocalizations. We found evidence of a vocal membrane in all species, as well as species differences in vocal fold and ventral pouch size. Presence of a vocal membrane in these three species, which are not known to use vocal membrane vibration, suggests that this structure may be widespread among muroid rodents. An expanded ventral pouch in singing and pygmy mice suggests that these mice may use an intralaryngeal whistle to produce their advertisement songs, and that an expanded ventral pouch may enable lower frequencies than laboratory mouse whistle‐produced sounds. Variation in the laryngeal anatomy of rodents fits into a larger pattern across terrestrial vertebrates, where the development and modification of vocal membranes and pouches, or air sacs, are common mechanisms by which vocalizations diversify. Understanding variation in the functional anatomy of relevant organs is the first step in understanding how morphological changes enable novel displays. [ABSTRACT FROM AUTHOR]

Introduction: Participant noncompliance, in which participants do not follow their assigned treatment protocol, has long complicated the interpretation of randomized clinical trials. No gold standard has been identified for detecting noncompliance, but in some trials participants' biomarkers can provide objective information that suggests exposure to non-study treatments. However, existing methods are limited to retrospectively detecting noncompliance at a single time point based on a single biomarker measurement. We propose a novel method that can leverage participants' full biomarker history to detect noncompliance across multiple time points. Conditional on longitudinal biomarker data, our method can estimate the probability of compliance at (1) a single time point of the trial, (2) all time points, and (3) a future time point. Methods: Across time points, we model the biomarker as a mixture density with (latent) components corresponding to longitudinal patterns of compliance. To estimate the mixture density, we fit mixed effects models for both compliance and the biomarker. We use the mixture density to derive compliance probabilities that condition on the longitudinal biomarker data. We evaluate our compliance probabilities by simulation and apply them to a trial in which current smokers were asked to only smoke low nicotine study cigarettes (Center for the Evaluation of Nicotine in Cigarettes Project 1 Study 2). In the simulation, we investigated three different effects of compliance on the biomarker, as well as the effect of misspecification of the covariance structures. We compared probability estimators (1) and (2) to those that ignore the longitudinal correlation in the data according to area under the receiver operating characteristic curve. We evaluated estimator (3) by plotting its calibration lines. For Center for the Evaluation of Nicotine in Cigarettes Project 1 Study 2, we compared estimators (1) and (3) to a probability estimator of compliance at the last time point that ignores the longitudinal correlation. Results: In the simulation, for both compliance at the last time point and at all time points, conditioning on the longitudinal biomarker data uniformly raised area under the receiver operating characteristic curve across all three compliance effect scenarios. The gains in area under the receiver operating characteristic curve were smaller under misspecification. The calibration lines for the prediction of compliance closely followed 45°, though with additional variability under misspecification. For compliance at the last time point of Center for the Evaluation of Nicotine in Cigarettes Project 1 Study 2, conditioning on participants' full biomarker history boosted area under the receiver operating characteristic curve by three percentage points. The prediction probabilities somewhat accurately approximated the non-longitudinal compliance probabilities. Discussion: Compared to existing methods that only use a single biomarker measurement, our method can account for the longitudinal correlation in the biomarker and compliance to more accurately identify noncompliant participants. Our method can also use participants' biomarker history to predict compliance at a future time point. [ABSTRACT FROM AUTHOR]

Background Patients with malignant gliomas have a poor prognosis. However, little is known about patients' and caregivers' understanding of the prognosis and the primary treatment goal. Methods We conducted a prospective study in patients with newly diagnosed malignant gliomas (N = 72) and their caregivers (N = 55). At 12 weeks after diagnosis, we administered the Prognosis and Treatment Perceptions Questionnaire to assess understanding of prognosis and the Hospital Anxiety and Depression Scale to evaluate mood. We used multivariable regression analyses to explore associations between prognostic understanding and mood and McNemar tests to compare prognostic perceptions among patient-caregiver dyads (N = 48). Results A total of 87.1% (61/70) of patients and 79.6% (43/54) of caregivers reported that it was "very" or "extremely" important to know about the patient's prognosis. The majority of patients (72.7%, [48/66]) reported that their cancer was curable. Patients who reported that their illness was incurable had greater depressive symptoms (B = 3.01, 95% CI, 0.89-5.14, P =.01). There was no association between caregivers' prognostic understanding and mood. Among patient-caregiver dyads, patients were more likely than caregivers to report that their primary treatment goal was cure (43.8% [21/48] vs 25.0% [12/48], P =.04) and that the oncologist's primary goal was cure (29.2% [14/48] vs 8.3% [4/48], P =.02). Conclusions Patients with malignant gliomas frequently hold inaccurate perceptions of the prognosis and treatment goal. Although caregivers more often report an accurate assessment of these metrics, many still report an overly optimistic perception of prognosis. Interventions are needed to enhance prognostic communication and to help patients cope with the associated distress. [ABSTRACT FROM AUTHOR]

Introduction: Smoking to reduce negative affect has been identified as a key motivational feature of tobacco use. Our recent work suggests that smoking very low nicotine content (VLNC) cigarettes reduces the relationship between negative affect and smoking behavior over a 6-week period. Here, we sought to extend our findings by evaluating whether a gradual or immediate approach to switching to VLNC cigarettes led to a differential reduction in the relationship between affect and smoking behavior over a longer (20-week) period.Aims and Methods: Participants (n = 1250) were adult smokers from 10 US sites randomized to one of three groups: gradual nicotine reduction (15.5, 11.7, 5.2, 2.4, and 0.4 mg of nicotine per gram of tobacco [mg/g]), immediate nicotine reduction (0.4 mg/g), or standard nicotine content cigarettes (15.5 mg/g; control), for 20 weeks. We examined whether the relationship between affect-both negative and positive-and cigarettes per day differed as a function of reduction group.Results: We found that both negative and positive affect were associated with cigarette consumption in the control group, but not in the gradual or immediate reduction groups across the 20 weeks of exposure.Conclusions: Our results extend previous findings that switching to VLNC cigarettes disrupts the relationship between affect and cigarette consumption by showing that either gradually or immediately reducing cigarette nicotine content achieves this disruption. These findings provide further evidence that switching to VLNC cigarettes reduces nicotine-related reinforcement of cigarette smoking.Implications: These findings support the notion that switching to very low nicotine content cigarettes reduces the association between affect and smoking behavior, and that either a gradual or immediate nicotine reduction approach achieves this reduction. This provides further evidence that switching to very low nicotine content cigarettes weakens reinforcement mechanisms associated with nicotine dependence. [ABSTRACT FROM AUTHOR]

Background: Clinical experience is limited for primary central nervous system (CNS) lymphoma that arises from the dura mater, which is denoted with the term primary dural lymphoma (PDL). This study was aimed at determining the relative incidence, presentation, and outcomes of PDL.Methods: The institutional databases of the Divisions of Neuro-Oncology at the Massachusetts General Hospital and the Yale School of Medicine were retrospectively searched for patients with primary CNS lymphoma. Patients with pathologically confirmed dural lymphoma and no evidence of primary cerebral or systemic involvement were identified. Clinical data, diagnostic findings, treatments, and outcomes were recorded.Results: A total of 20 patients with PDL were identified, and they represented 6.3% of the individuals with primary CNS lymphomas (20 of 316). Histopathological examination of PDL revealed the following underlying subtypes: diffuse large B-cell lymphoma (10 of 20 patients), marginal zone lymphoma (6 of 20), follicular lymphoma (2 of 20), undefined B-cell non-Hodgkin lymphoma (1 of 20), and T-cell non-Hodgkin lymphoma (1 of 20). On imaging, all tumors appeared as extra-axial masses with avid contrast enhancement and mostly mimicked meningioma. The median apparent diffusion coefficient value was 667 ± 26 mm2 /s. Cerebrospinal fluid analyses and symptoms were nonspecific, and the diagnosis rested on tissue analysis. Therapeutic approaches included surgery, radiotherapy, and chemotherapy. The median overall survival was not reached after 5 years. Three patients were deceased at database closure because of tumor progression. The extent of tumor resection correlated positively with overall survival (P = .044).Conclusions: PDL is a rare variant of primary CNS lymphoma that can be radiographically mistaken for meningioma. The outcome is excellent with multimodality treatment, and aggressive surgery may convey a survival advantage in select cases. [ABSTRACT FROM AUTHOR]

Introduction: Electronic nicotine delivery systems (ENDS) vary on a wide range of characteristics that may affect reinforcement value and use. One characteristic is the ratio of two solvents commonly used in most e-liquids: propylene glycol (PG) and vegetable glycerin (VG). The goal of this study was to understand how PG/VG ratio affects subjective effects, reinforcement value, and tobacco use patterns among current smokers who try using ENDS.Aims and Methods: Current smokers with minimal ENDS use history (n = 30) sampled, in a double-blind fashion, three different e-liquids that varied in PG/VG ratio (70/30, 50/50, 0/100) while holding constant other aspects of the e-liquid and ENDS. Participants tried each e-liquid before rating the subjective effects on a modified version of the Cigarette Evaluation Questionnaire. Reinforcement value was assessed using a preference task where participants chose between the three e-liquids. The impact of each e-liquid on cigarette reinforcement was assessed using a modified version of the Cigarette Purchase Task. Participants were randomly assigned to receive one e-liquid to take home for 1 week.Results: PG/VG ratio had minimal impact on most of the tested outcomes. Participants rated the highest PG concentration as having a stronger "throat hit" than the other two. There was no significant difference between the number of participants who preferred each of the PG/VG ratios in the preference assessment. PG/VG ratio did not affect cigarette or ENDS use during the sampling week.Conclusions: These data suggest that PG/VG ratio has minimal impact on subjective effects and reinforcement value in ENDS naive current smokers.Implications: These data suggest that PG/VG ratio, within the range that is commonly used, has minimal impact on subjective effects, reinforcement value, or uptake in current smokers with minimal ENDS experience. [ABSTRACT FROM AUTHOR]

Introduction: E-cigarettes have risen in prevalence in recent years, and most public health experts agree they deliver fewer toxicants than combustible tobacco products such as cigarettes. Thus, it is important to understand how use of e-cigarettes by current smokers impacts dependence on combustible cigarettes.Methods: The present study is a secondary analysis of a randomized pilot trial of e-cigarette sampling. Nontreatment seeking current smokers were randomized in a 2:1 ratio to either receive or not receive a weekly supply of e-cigarettes for 3 weeks. Participants completed the Brief Wisconsin Inventory of Smoking Dependence Motives (WISDM) scale and the cigarette purchase task before and after the sampling period and at monthly follow-up visits for 3 months.Results: Individuals assigned to receive an e-cigarette had significantly lower mean WISDM scores at the end of sampling and the end of the follow-up period compared with those in the control group. Both frequency of e-cigarette use as well as nicotine concentration of the e-cigarette given to smokers were significant predictors of changes in the mean WISDM score. E-cigarette sampling significantly reduced the demand parameter Omax, which measures the maximum amount of money participants estimate they would spend on cigarettes in a single day.Conclusions: These data suggest that current smokers who try using an e-cigarette may experience reductions in dependence on combustible cigarettes.Implications: The present analysis suggests that providing an e-cigarette to current cigarette smokers is likely to reduce cigarette dependence, especially if the e-cigarette delivers sufficient nicotine and is used frequently. [ABSTRACT FROM AUTHOR]

Introduction: Because 30% of cigarettes sold in the United States are characterized as menthol cigarettes, it is important to understand how menthol preference may affect the impact of a nicotine reduction policy.Methods: In a recent trial, non-treatment-seeking smokers were randomly assigned to receive very low nicotine cigarettes (VLNC; 0.4 mg nicotine/g tobacco) or normal nicotine cigarettes (NNC; 15.5 mg/g) for 20 weeks. On the basis of preference, participants received menthol or non-menthol cigarettes. We conducted multivariable regression analyses to examine whether menthol preference moderated the effects of nicotine content on cigarettes per day (CPD), breath carbon monoxide (CO), urinary total nicotine equivalents (TNE), urinary 2-cyanoethylmercapturic acid (CEMA), and abstinence.Results: At baseline, menthol smokers (n = 346) reported smoking fewer CPD (14.9 vs. 19.2) and had lower TNE (52.8 vs. 71.6 nmol/mg) and CO (17.7 vs. 20.5 ppm) levels than non-menthol smokers (n = 406; ps < .05). At week 20, significant interactions indicated that menthol smokers had smaller treatment effects than non-menthol smokers for CPD (-6.4 vs. -9.3), TNE (ratio of geometric means, 0.22 vs. 0.10) and CEMA (ratio, 0.56 vs. 0.37; ps < .05), and trended toward a smaller treatment effect for CO (-4.5 vs. -7.3 ppm; p = .06). Odds ratios for abstinence at week 20 were 1.88 (95% confidence interval [CI] = 0.8 to 4.4) for menthol and 9.11 (95% CI = 3.3 to 25.2) for non-menthol VLNC smokers (p = .02) relative to the NNC condition.Conclusions: Although menthol smokers experienced reductions in smoking, toxicant exposure, and increases in quitting when using VLNC cigarettes, the magnitude of change was smaller than that observed for non-menthol smokers.Implications: Results of this analysis suggest that smokers of menthol cigarettes may respond to a nicotine reduction policy with smaller reductions in smoking rates and toxicant exposure than would smokers of non-menthol cigarettes. [ABSTRACT FROM AUTHOR]

Background: A recent clinical trial showed that an immediate transition to very low nicotine content (VLNC) cigarettes, compared with a gradual transition, produced greater reductions in smoking behavior, smoke exposure, and dependence. However, there was less compliance with the instruction to smoke only VLNC cigarettes in the immediate versus gradual reduction condition. The goal of this study was to test whether nicotine reduction method alters subjective ratings of VLNC cigarettes, and whether subjective ratings mediate effects of nicotine reduction method on smoking behavior, smoke exposure, dependence, and compliance.Methods: This is a secondary analysis of a randomized trial conducted across 10 sites in the United States. Smokers (n = 1250) were randomized to either a control condition, or to have the nicotine content of their cigarettes reduced immediately or gradually to 0.04 mg nicotine/g of tobacco during a 20-week study period. Participants completed the modified Cigarette Evaluation Questionnaire (mCEQ).Results: After Week 20, the immediate reduction group scored significantly lower than the gradual reduction group on multiple subscales of the mCEQ (ps < .001). The Satisfaction subscale of the mCEQ mediated the impact of nicotine reduction method on smoke exposure, smoking behavior, dependence, compliance, and abstinence. Other subscales also mediated a subset of these outcomes.Conclusions: An immediate reduction in nicotine content resulted in lower product satisfaction than a gradual reduction, suggesting that immediate reduction further reduces cigarette reward value. This study will provide the Food and Drug Administration with information about the impact of nicotine reduction method on cigarette reward value.Implications: These data suggest that an immediate reduction in nicotine content will result in greater reductions in cigarette satisfaction than a gradual reduction, and this reduction in satisfaction is related to changes in smoking behavior and dependence. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma is a rare subtype of non-Hodgkin lymphoma that is confined to the brain, leptomeninges, or the eye and is associated with a relatively poor prognosis compared to other extranodal diffuse large B-cell lymphomas. However, methotrexate-based induction chemotherapy followed by consolidative chemotherapy or high-dose therapy and autologous stem cell transplantation is associated with improved survival and reduced neurotoxicity. Aberrant activation of B-cell receptor signaling and activation of nuclear factor kappa beta is a frequent genetic alteration and offers opportunities for targeted therapies in this lymphoma subtype. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint blockade has systemic efficacy in patients with metastatic melanoma, including those with brain metastases (MBMs). However, immunotherapy‐induced intracranial tumoral inflammation can lead to neurologic compromise, requiring steroids, which abrogate the systemic efficacy of this approach. We investigated whether upfront neurosurgical resection of MBM is associated with a therapeutic advantage when performed prior to initiation of immunotherapy. Material and Methods: An institutional review board‐approved, retrospective study identified 142 patients with MBM treated with immune checkpoint blockade between 2010 and 2016 at Massachusetts General Hospital, of whom 79 received surgery. Patients were classified based on the temporal relationship between immunotherapy, surgery, and development of central nervous system metastases. Overall survival (OS) was calculated from the date of diagnosis of MBM until death from any cause. Multivariate model building included a prognostic Cox model of OS, the effect of immunotherapy and surgical sequencing on OS, and the effect of immunotherapy and radiation sequencing on OS. Results: The 2‐year overall survival for patients treated with cytotoxic T‐lymphocyte antigen 4, programmed death 1, or combinatorial blockade was 19%, 54%, and 57%, respectively. Among immunotherapy‐naïve melanoma brain metastases, surgery followed by immunotherapy had a median survival of 22.7 months (95% confidence interval [CI], 12.6–39.2) compared with 10.8 months for patients treated with immunotherapy alone (95% CI, 7.8–16.3) and 9.4 months for patients treated with immunotherapy followed by surgery (95% CI, 4.1 to ∞; p = .12). On multivariate analysis, immunotherapy‐naïve brain metastases treated with immunotherapy alone were associated with increased risk of death (hazard ratio, 1.72; 95% CI, 1.00–2.99) compared with immunotherapy‐naïve brain metastases treated with surgery followed by immunotherapy. Conclusion: In treatment‐naïve patients, early surgical resection for local control should be considered prior to commencing immunotherapy. A prospective, randomized trial comparing the sequence of surgery and immunotherapy for treatment‐naïve melanoma brain metastases is warranted. Implications for Practice: In this retrospective study of 142 patients with melanoma brain metastases treated with immune checkpoint blockade, the development of melanoma brain metastases following immunotherapy was associated with decreased survival compared with diagnosis of immunotherapy‐naïve brain metastases. The benefit of surgical intervention was seen in immunotherapy‐naïve brain metastases in contrast to brain metastases that developed on immunotherapy. These results suggest that upfront local control with surgery for immunotherapy‐naïve melanoma brain metastasis may provide a bridge toward immunotherapy‐mediated systemic control. Nearly 75% of patients with stage IV melanoma will develop brain metastases as a sequelae of their illness and approximately 50% will succumb to progression of their intracranial disease. Standard therapy includes surgery, but the therapeutic landscape for metastatic melanoma is being transformed by immunotherapy blockade treatment possibilities. Considering the limited data informing the combination of surgery and immunotherapy for metastatic melanoma, the study reported here investigated the timing of neurosurgical intervention and immune checkpoint blockade. [ABSTRACT FROM AUTHOR]

Background: Traditionally, small intestinal bacterial overgrowth (SIBO) is diagnosed when there is an early peak in breath hydrogen or methane. Given unclear intestinal transit time in Roux-en-Y gastric bypass (RYGB) patients, it is unknown if the traditional approach at diagnosing SIBO is adequate in this patient population.Aim: To assess oral-cecal transit time (OCTT) and its impact on the interpretation of breath tests in the diagnosis of SIBO in patients with RYGB.Methods: This study was a retrospective review of prospectively collected data on RYGB patients who underwent testing for SIBO using lactulose breath test (LBT) with or without small bowel follow-through (SBFT) to assess OCTT. Outcomes of SIBO test based on LBT alone versus LBT with OCTT were compared using a chi-squared test.Results: Sixty-two of the 151 RYGB patients who underwent LBT underwent an additional SBFT to assess OCTT. Median OCTT was 60 min. Of these, 59.7% had OCTT shorter than 90 min. Based on LBT alone, 36/62 patients (58.1%) were classified as positive SIBO. When LBT results were combined with OCTT, 26/36 patients (72.2%) had hydrogen or methane rise within OCTT, suggesting 27.8% false positive rate. Patients with true positive SIBO based on LBT and OCTT had a higher response rate to antibiotics compared to those with false positive SIBO (78.3% vs. 33.3%, p = 0.03).Conclusion: A personalized approach of combining LBT with SBFT to assess OCTT may improve the accuracy of SIBO testing and enhance clinical outcomes in patients with RYGB. [ABSTRACT FROM AUTHOR]

Background: The 2016 World Health Organization Classification of Central Nervous System Tumors categorizes gliomatosis cerebri growth pattern (GC) as a subgroup of diffuse infiltrating gliomas, defined by extent of brain involvement on magnetic resonance imaging (MRI). Clinical and radiographic features in GC patients are highly heterogeneous; however, prognosis has historically been considered poor. Subjects, Materials, and Methods: We performed a retrospective search for patients at our institution meeting radiographic criteria of primary, type I GC (defined as diffuse tumor infiltration without associated tumor mass and contrast enhancement on MRI) and analyzed their clinical, imaging, and histopathologic features. Results: A total of 34 patients met radiographic criteria of primary, type I GC, and 33 had a confirmed histologic diagnosis of an infiltrating glial neoplasm. Age >47 years at diagnosis was associated with worse overall survival (OS) compared with age ≤47 years (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.01–1.07, p =.003). Patients with grade 2 tumors demonstrated a trend for improved OS compared with those with grade 3 tumors (HR 2.65, 95% CI 0.99–7.08, p =.051). Except for brainstem involvement, extent or location of radiographic involvement did not detectably affect clinical outcome. IDH mutation status identified a subgroup of GC patients with particularly long survival up to 25 years and was associated with longer time to progression (HR 4.81, 95% CI 0.99–23.47, p =.052). Conclusion: Patients with primary, type I GC do not uniformly carry a poor prognosis, even in the presence of widespread radiographic involvement. Consistent with other reports, IDH mutation status may identify patients with improved clinical outcome. Molecular characterization, rather than MRI features, may be most valuable for prognostication and management of GC patients. Implications for Practice: Patients with gliomatosis cerebri growth pattern (GC) constitute a challenge to clinicians, given their wide range of clinical, histologic, and radiographic presentation, heterogeneous outcome patterns, and the lack of consensus on a standardized treatment approach. This study highlights that radiographic extent of disease—albeit category‐defining—does not detectably influence survival and that IDH mutations may impact clinical outcome. Practicing oncologists should be aware that select GC patients may demonstrate exceptionally favorable survival times and prognosticate patients based on molecular markers, rather than imaging features alone. Gliomatosis cerebri growth pattern (GC) is a rare presentation of a primary widely infiltrating glial tumor of the central nervous system. In this retrospective case series, the clinical, radiographic, and histopathologic findings of 34 patients with histologically proven primary, type I GC are evaluated. [ABSTRACT FROM AUTHOR]