CCR2 and CCR5 co-inhibition modulates immunosuppressive myeloid milieu in glioma and synergizes with anti-PD-1 therapy.

Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients.

Anaerobic Antibiotic Coverage in Aspiration Pneumonia and the Associated Benefits and Harms: A Retrospective Cohort Study.

BACKGROUND: Antibiotics with extended anaerobic coverage are used commonly to treat aspiration pneumonia, which is not recommended by current guidelines. RESEARCH QUESTION: In patients admitted to hospital for community-acquired aspiration pneumonia, does a difference exist between antibiotic therapy with limited anaerobic coverage (LAC) vs antibiotic therapy with extended anaerobic coverage (EAC) in terms of in-hospital mortality and risk of Clostridioides difficile colitis? STUDY DESIGN AND METHODS: We conducted a multicenter retrospective cohort study across 18 hospitals in Ontario, Canada, from January 1, 2015, to January 1, 2022. Patients were included if the physician diagnosed aspiration pneumonia and prescribed guideline-concordant first-line community-acquired pneumonia parenteral antibiotic therapy to the patient within 48 h of admission. Patients then were categorized into the LAC group if they received ceftriaxone, cefotaxime, or levofloxacin. Patients were categorized into the EAC group if they received amoxicillin-clavulanate, moxifloxacin, or any of ceftriaxone, cefotaxime, or levofloxacin in combination with clindamycin or metronidazole. The primary outcome was all-cause in-hospital mortality. Secondary outcomes included incident C difficile colitis occurring after admission. Overlap weighting of propensity scores was used to balance baseline prognostic factors. RESULTS: The LAC and EAC groups included 2,683 and 1,316 patients, respectively. In hospital, 814 patients (30.3%) and 422 patients (32.1%) in the LAC and EAC groups died, respectively. C difficile colitis occurred in five or fewer patients (≤ 0.2%) and 11 to 15 patients (0.8%-1.1%) in the LAC and EAC groups, respectively. After overlap weighting of propensity scores, the adjusted risk difference of EAC minus LAC was 1.6% (95% CI, -1.7% to 4.9%) for in-hospital mortality and 1.0% (95% CI, 0.3%-1.7%) for C difficile colitis. INTERPRETATION: Extended anaerobic coverage likely is unnecessary in aspiration pneumonia because it is associated with no additional mortality benefit, only an increased risk of C difficile colitis.

Comparative Effectiveness of First-Line and Alternative Antibiotic Regimens in Hospitalized Patients With Nonsevere Community-Acquired Pneumonia: A Multicenter Retrospective Cohort Study.

BACKGROUND: There are several antibiotic regimens to treat community-acquired pneumonia (CAP). RESEARCH QUESTION: In patients hospitalized to a non-ICU ward setting with CAP, is there a difference between first-line and alternative antibiotic regimens (ß-lactam plus macrolide [BL+M], ß-lactam [BL] alone, respiratory fluoroquinolone [FQ], or ß-lactam plus doxycycline [BL+D]) in terms of in-hospital mortality? STUDY DESIGN AND METHODS: This retrospective cohort study included consecutive patients admitted with CAP at 19 Canadian hospitals from 2015 to 2021. Taking a target trial approach, patients were categorized into the four antibiotic groups based on the initial antibiotic treatment within 48 h of admission. Patients with severe CAP requiring ICU admission in the first 48 h were excluded. The primary outcome was all-cause in-hospital mortality. Secondary outcome included time to being discharged alive. Propensity score and overlap weighting were used to balance covariates. RESULTS: Of 23,512 patients, 9,340 patients (39.7%) received BL+M, 9,146 (38.9%) received BL, 4,510 (19.2%) received FQ, and 516 (2.2%) received BL+D. The number of in-hospital deaths was 703 (7.5%) for the BL+M group, 888 (9.7%) for the BL group, 302 (6.7%) for the FQ group, and 31 (6.0%) for the BL+D group. The adjusted risk difference for in-hospital mortality when compared with BL+M was 1.5% (95% CI, -0.3% to 3.3%) for BL, -0.9% (95% CI, -2.9% to 1.1%) for FQ, and -1.9% (95% CI, -4.8% to 0.9%) for BL+D. Compared with BL+M, the subdistribution hazard ratio for being discharged alive was 0.90 (95% CI, 0.84-0.96) for BL, 1.07 (95% CI, 0.99-1.16) for FQ, and 1.04 (95% CI, 0.93-1.17) for BL+D. INTERPRETATION: BL+M, FQ, and BL+D had similar outcomes and can be considered effective regimens for nonsevere CAP. Compared with BL+M, BL was associated with longer time to discharge and the CI for mortality cannot exclude a small but clinically important increase in risk.

Ceftriaxone and the Risk of Ventricular Arrhythmia, Cardiac Arrest, and Death Among Patients Receiving Lansoprazole.

Importance: The combination of ceftriaxone and lansoprazole has been shown to prolong the corrected QT interval on electrocardiogram. However, it is unknown whether this translates to clinically important patient outcomes. Objective: To compare lansoprazole with another proton pump inhibitor (PPI) during ceftriaxone treatment in terms of risk for ventricular arrhythmia, cardiac arrest, and in-hospital mortality. Design, Setting, and Participants: A retrospective cohort study including adult medical inpatients receiving ceftriaxone with lansoprazole or another PPI in 13 hospitals in Ontario, Canada, was conducted from January 1, 2015, to December 31, 2021. Exposure: Lansoprazole during ceftriaxone treatment vs other PPIs during ceftriaxone treatment. Main Outcomes and Measures: The primary outcome was a composite of ventricular arrhythmia or cardiac arrest that occurred after hospital admission. The secondary outcome was all-cause in-hospital mortality. Propensity-score weighting was used to adjust for covariates including hospital site, demographic characteristics, comorbidities, risk factors for ventricular arrhythmia, illness severity, admitting diagnoses, and concomitant medications. Results: Of the 31 152 patients hospitalized on internal medicine wards who were treated with ceftriaxone while receiving a PPI, 16 135 patients (51.8%) were male, and the mean (SD) age was 71.7 (16.0) years. The study included 3747 patients in the lansoprazole group and 27 405 patients in the other PPI group. Ventricular arrhythmia or cardiac arrest occurred in 126 patients (3.4%) within the lansoprazole group and 319 patients (1.2%) within the other PPI group. In-hospital mortality occurred in 746 patients (19.9%) within the lansoprazole group and 2762 patients (10.1%) in the other PPI group. After weighting using propensity scores, the adjusted risk difference for the lansoprazole group minus other PPI group was 1.7% (95% CI, 1.1%-2.3%) for ventricular arrhythmia or cardiac arrest and 7.4% (95% CI, 6.1%-8.8%) for in-hospital mortality. Conclusions and Relevance: The findings of this cohort study suggest that combination therapy with lansoprazole and ceftriaxone should be avoided. More studies are needed to determine whether these findings could be replicated in other populations and settings.

Role of Guided FNA in Gallbladder Cancer: A Retrospective 3-Year Study.

Background: A majority of the patients with gall bladder cancer (GBCa) present at an advanced stage and have poor survival. The aim is to retrospectively study the role of guided FNA in the diagnosis of GBCa in a superspecialty institute and to describe the cytomorphologic spectrum of gall bladder (GB) lesions in the North Indian population. Materials and Methods: All suspected cases of GBCa who underwent guided FNA from the primary GB mass or metastatic liver space-occupying lesion from 2017 to 2019 were included. The aspirate smears were retrieved and analyzed for cytomorphological features independently by two cytopathologists. The neoplastic lesions were classified according to the WHO 2019 classification. Results: Of 489 cases, fine needle aspiration cytology (FNAC) was diagnostic in 463 cases (94.6%), of which 417 (90.1%) were positive for malignancy, 35 (7.5%) were inflammatory, and 11 (2.4%) were inconclusive for malignancy. Adenocarcinoma not otherwise specified (NOS) was the most common type seen in 330 cases (79.1%) and 87 (20.9%) were unusual variants. These included papillary adenocarcinoma (22, 5.2%), mucinous adenocarcinoma (12, 2.8%), signet ring carcinoma (2,0.4%), adenosquamous carcinoma (8, 1.9%), squamous cell carcinoma (10, 2.4%), neuroendocrine neoplasms (7, 1.7%), undifferentiated carcinoma (24, 5.7%) and non-Hodgkin lymphoma (2,0.4%), respectively. Immunohistochemistry on the cell block confirmed the diagnosis wherever possible. Histopathology was discordant in 5 out of 33 cases. Conclusion: Guided FNAC is a sensitive investigation that plays a crucial role in confirming the diagnosis and deciding the further treatment options in advanced-stage GBCa patients. The uncommon variants of GBCa can be reliably categorized on cytology.

Generative and discriminative training of Boltzmann machine through quantum annealing.

A hybrid quantum-classical method for learning Boltzmann machines (BM) for a generative and discriminative task is presented. BM are undirected graphs with a network of visible and hidden nodes where the former is used as the reading site. In contrast, the latter is used to manipulate visible states' probability. In Generative BM, the samples of visible data imitate the probability distribution of a given data set. In contrast, the visible sites of discriminative BM are treated as Input/Output (I/O) reading sites where the conditional probability of output state is optimized for a given set of input states. The cost function for learning BM is defined as a weighted sum of Kullback-Leibler (KL) divergence and Negative conditional Log-likelihood (NCLL), adjusted using a hyper-parameter. Here, the KL Divergence is the cost for generative learning, and NCLL is the cost for discriminative learning. A Stochastic Newton-Raphson optimization scheme is presented. The gradients and the Hessians are approximated using direct samples of BM obtained through quantum annealing. Quantum annealers are hardware representing the physics of the Ising model that operates on low but finite temperatures. This temperature affects the probability distribution of the BM; however, its value is unknown. Previous efforts have focused on estimating this unknown temperature through regression of theoretical Boltzmann energies of sampled states with the probability of states sampled by the actual hardware. These approaches assume that the control parameter change does not affect the system temperature; however, this is usually untrue. Instead of using energies, the probability distribution of samples is employed to estimate the optimal parameter set, ensuring that the optimal set can be obtained from a single set of samples. The KL divergence and NCLL are optimized for the system temperature, and the result is used to rescale the control parameter set. The performance of this approach, as tested against the theoretically expected distributions, shows promising results for Boltzmann training on quantum annealers.

Videoconferencing interventions and COPD patient outcomes: A systematic review.

INTRODUCTION: Videoconferencing circumvents various physical and financial barriers associated with in-person care. Given this technology's potential benefits and timely nature, we conducted a systematic review to understand how videoconferencing for chronic obstructive pulmonary disease (COPD) follow-up care affects patient-related outcomes. METHODS: We included primary research evaluating the use of bidirectional videoconferencing for COPD patient follow-up. The outcomes of interest were resource utilization, mortality, lifestyle factors, patient satisfaction, barriers, and feasibility. We searched MEDLINE, EMBASE, EBM Reviews, and CINAHL databases for articles published from January 1, 2010, to August 2, 2021. Relevant information was extracted and presented descriptively and common themes and patterns were identified. The risk of bias for each study was assessed using design-specific validated tools. RESULTS: We included 39 studies of 18,194 patients (22 quantitative, 12 qualitative, and 5 mixed methods). The included studies were grouped by type of intervention; 18 studies explored videoconferencing for exercise, 19 explored videoconferencing for clinical assessment/monitoring, and 2 examined videoconferencing for education. Generally, videoconferencing was associated with high levels of patient satisfaction. There were mixed results in terms of its effects on resource utilization and lifestyle-related factors. Additionally, 12 studies were at high risk of bias, indicating that these results should be interpreted with caution. CONCLUSIONS: The videoconferencing interventions resulted in high levels of patient satisfaction, despite facing technological issues. Overall, more research is needed to better understand the effects of videoconferencing interventions on resource utilization and other patient outcomes, quantifying their advantages over in-person care.

Oscillatory ERK Signaling and Morphology Determine Heterogeneity of Breast Cancer Cell Chemotaxis via MEK-ERK and p38-MAPK Signaling Pathways.

Chemotaxis, regulated by oscillatory signals, drives critical processes in cancer metastasis. Crucial chemoattractant molecules in breast cancer, CXCL12 and EGF, drive the activation of ERK and Akt. Regulated by feedback and crosstalk mechanisms, oscillatory signals in ERK and Akt control resultant changes in cell morphology and chemotaxis. While commonly studied at the population scale, metastasis arises from small numbers of cells that successfully disseminate, underscoring the need to analyze processes that cancer cells use to connect oscillatory signaling to chemotaxis at single-cell resolution. Furthermore, little is known about how to successfully target fast-migrating cells to block metastasis. We investigated to what extent oscillatory networks in single cells associate with heterogeneous chemotactic responses and how targeted inhibitors block signaling processes in chemotaxis. We integrated live, single-cell imaging with time-dependent data processing to discover oscillatory signal processes defining heterogeneous chemotactic responses. We identified that short ERK and Akt waves, regulated by MEK-ERK and p38-MAPK signaling pathways, determine the heterogeneous random migration of cancer cells. By comparison, long ERK waves and the morphological changes regulated by MEK-ERK signaling, determine heterogeneous directed motion. This study indicates that treatments against chemotaxis in consider must interrupt oscillatory signaling.

A systematic review of eHealth technologies for breast cancer supportive care.

Breast cancer places a substantial burden on patient physical and mental wellbeing, and the delivery of high-quality supportive care is essential at all stages of the disease. Given the increased uptake of technology in recent years, eHealth interventions may be a convenient and accessible method for supportive care. Within this context, we conducted a systematic review to describe and quantify the use of eHealth for breast cancer supportive care. We searched MEDLINE, EMBASE, and CINAHL databases for primary research studies published from 2016 to 2021 (present) that assessed the effects of eHealth interventions on adult patients with breast cancer. We explored the effects of the interventions on patient symptoms, lifestyle, satisfaction, and barriers, as well as factors related to feasibility and implementation. The risk of bias of each study was also assessed. Findings were presented according to stage of cancer care. We identified 43 relevant studies capturing n = 6,285 patients (30 randomized controlled trials and 13 non-randomized interventional studies); 5 evaluated patients who were newly diagnosed, 16 evaluated patients undergoing active treatment, and 22 evaluated patients in post-treatment follow-up. A total of 19 studies used mobile apps, 18 used online patient portals, 5 used text messaging, and 1 used both a patient portal and text messaging. We found that patients were broadly satisfied with the eHealth interventions; however, findings were less consistent for symptom and lifestyle-related outcomes. Eight studies were judged as high risk of bias. There was substantial between-study heterogeneity, which made it challenging to discern consistent trends. Overall, future research should continue to explore the use of eHealth for breast cancer supportive care, with a focus on improving patient symptoms.

Ogden material calibration via magnetic resonance cartography, parameter sensitivity and variational system identification.

Contemporary material characterization techniques that leverage deformation fields and the weak form of the equilibrium equations face challenges in the numerical solution procedure of the inverse characterization problem. As material models and descriptions differ, so too must the approaches for identifying parameters and their corresponding mechanisms. The widely used Ogden material model can be comprised of a chosen number of terms of the same mathematical form, which presents challenges of parsimonious representation, interpretability and stability. Robust techniques for system identification of any material model are important to assess and improve experimental design, in addition to their centrality to forward computations. Using fully three-dimensional displacement fields acquired in silicone elastomers with our recently developed magnetic resonance cartography (MR-u) technique on the order of greater than [Formula: see text], we leverage partial differential equation-constrained optimization as the basis of variational system identification of our material parameters. We incorporate the statistical F-test to maintain parsimony of representation. Using a new, local deformation decomposition locally into mixtures of biaxial and uniaxial tensile states, we evaluate experiments based on an analytical sensitivity metric and discuss the implications for experimental design. This article is part of the theme issue 'The Ogden model of rubber mechanics: Fifty years of impact on nonlinear elasticity'.

Virtual Care Access and Health Equity during the COVID-19 Pandemic, a qualitative study of patients with chronic diseases from Canada.

OBJECTIVES: The COVID-19 pandemic has led to the widespread uptake of virtual care in Canada; however, virtual care may also create new barriers to health care. The purpose of this paper was to explore patient perceptions and concerns around virtual care access. METHODS: Between February and April 2020, we conducted semi-structured interviews with participants from four chronic disease clinics (stroke, epilepsy, amyotrophic lateral sclerosis, obstetrics medicine) in a mid-sized academic hospital in Southern Ontario, Canada. Consecutive sampling was done by including the patients receiving virtual care in those months. Caregivers were invited to participate in the event that patients were unable to participate in the interview. Thematic analysis was employed to identify overarching themes, and codes were reviewed and refined using a consensus process. RESULTS: We interviewed 31 participants (27 patients, four caregivers) that had taken part in virtual care. Our findings suggested that the COVID-19 pandemic served to isolate participants and had negatively impacted their access to health care. However, virtual care did provide a safe avenue for patients to receive care and served as a reassuring option during the pandemic. Low technological literacy and access were identified as barriers to virtual care. Greater awareness and patient engagement is needed in future research to improve access. CONCLUSION: Certain populations can be disproportionately affected by differential access to virtual care. Future studies should examine how social determinants intersect to impact virtual health care access in different patient populations.

The safety and efficacy of dexamethasone in the perioperative management of glioma patients.

OBJECTIVE: In this single-institution retrospective cohort study, the authors evaluated the effect of dexamethasone on postoperative complications and overall survival in patients with glioma undergoing resection. METHODS: A total of 435 patients who underwent resection of a primary glioma were included in this retrospective cohort study. The inclusion criterion was all patients who underwent resection of a primary glioma at a tertiary medical center between 2014 and 2019. RESULTS: The use of both pre- and postoperative dexamethasone demonstrated a trend toward the development of postoperative wound infections (3% vs 0% in single use or no use, p = 0.082). No association was detected between dexamethasone use and the development of new-onset hyperglycemia (p = 0.149). On multivariable Cox proportional hazards analysis, dexamethasone use was associated with a greater hazard of death (overall p = 0.017); this effect was most pronounced for preoperative (only) dexamethasone use (hazard ratio 3.0, p = 0.062). CONCLUSIONS: Combined pre- and postoperative dexamethasone use may increase the risk of postoperative wound infection, and dexamethasone use, specifically preoperative use, may negatively impact survival. These findings highlight the potential for serious negative consequences with dexamethasone use.

Synergy between glutamate modulation and anti-programmed cell death protein 1 immunotherapy for glioblastoma.

OBJECTIVE: Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) have shown promise for the treatment of cancers such as melanoma, but results for glioblastoma (GBM) have been disappointing thus far. It has been suggested that GBM has multiple mechanisms of immunosuppression, indicating a need for combinatorial treatment strategies. It is well understood that GBM increases glutamate in the tumor microenvironment (TME); however, the significance of this is not well understood. The authors posit that glutamate upregulation in the GBM TME is immunosuppressive. The authors utilized a novel glutamate modulator, BHV-4157, to determine synergy between glutamate modulation and the well-established anti-PD-1 immunotherapy for GBM. METHODS: C57BL/6J mice were intracranially implanted with luciferase-tagged GL261 glioma cells. Mice were randomly assigned to the control, anti-PD-1, BHV-4157, or combination anti-PD-1 plus BHV-4157 treatment arms, and median overall survival was assessed. In vivo microdialysis was performed at the tumor site with administration of BHV-4157. Intratumoral immune cell populations were characterized with immunofluorescence and flow cytometry. RESULTS: The BHV-4157 treatment arm demonstrated improved survival compared with the control arm (p < 0.0001). Microdialysis demonstrated that glutamate concentration in TME significantly decreased after BHV-4157 administration. Immunofluorescence and flow cytometry demonstrated increased CD4+ T cells and decreased Foxp3+ T cells in mice that received BHV-4157 treatment. No survival benefit was observed when CD4+ or CD8+ T cells were depleted in mice prior to BHV-4157 administration (p < 0.05). CONCLUSIONS: In this study, the authors showed synergy between anti-PD-1 immunotherapy and glutamate modulation. The authors provide a possible mechanism for this synergistic benefit by showing that BHV-4157 relies on CD4+ and CD8+ T cells. This study sheds light on the role of excess glutamate in GBM and provides a basis for further exploring combinatorial approaches for the treatment of this disease.

Mutation status and postresection survival of patients with non-small cell lung cancer brain metastasis: implications of biomarker-driven therapy.

OBJECTIVE: Non-small cell lung cancer (NSCLC) is the most common primary tumor to develop brain metastasis. Prognostic markers are needed to better determine survival after neurosurgical resection of intracranial disease. Given the importance of mutation subtyping in determining systemic therapy and overall prognosis of NSCLC, the authors examined the prognostic value of mutation status for postresection survival of patients with NSCLC brain metastasis. METHODS: The authors retrospectively analyzed all cases of NSCLC brain metastasis with available molecular testing data that were resected by a single surgeon at a single academic center from January 2009 to February 2019. Mutation status, demographic characteristics, clinical factors, and treatments were analyzed. Association between predictive variables and overall survival after neurosurgery was determined with Cox regression. RESULTS: Of the included patients (n = 84), 40% were male, 76% were smokers, the mean ± SD Karnofsky Performance Status was 85 ± 14, and the mean ± SD age at surgery was 63 ± 11 years. In total, 23%, 26%, and 4% of patients had EGFR, KRAS, and ALK/ROS1 alterations, respectively. On multivariate analysis, survival of patients with EGFR (HR 0.495, p = 0.0672) and KRAS (HR 1.380, p = 0.3617) mutations were not significantly different from survival of patients with wild-type (WT) tumor. However, the subgroup of patients with EGFR mutation who also received tyrosine kinase inhibitor (TKI) therapy had significantly prolonged survival (HR 0.421, p = 0.0471). In addition, postoperative stereotactic radiosurgery (HR 0.409, p = 0.0177) and resected tumor diameter < 3 cm (HR 0.431, p = 0.0146) were also significantly associated with prolonged survival, but Graded Prognostic Assessment score ≤ 1.0 (HR 2.269, p = 0.0364) was significantly associated with shortened survival. CONCLUSIONS: Patients with EGFR mutation who receive TKI therapy may have better survival after resection of brain metastasis than patients with WT tumor. These results may inform counseling and decision-making regarding the appropriateness of resection of NSCLC brain metastasis.

Emerging Technologies for Non-invasive Monitoring of Treatment Response to Immunotherapy for Brain Tumors.

Glioblastoma is the most common primary malignant brain tumor and one of the most aggressive tumors across all cancer types with remarkable resistance to any treatment. While immunotherapy has shown a robust clinical benefit in systemic cancers, its benefit is still under investigation in brain cancers. The broader use of immunotherapy in clinical trials for glioblastoma has highlighted the challenges of traditional methods of monitoring progression via imaging. Development of new guidelines, advanced imaging techniques, and immune profiling have emerged to counter premature diagnoses of progressive disease. However, these approaches do not provide a timely diagnosis and are costly and time consuming. Surgery is currently the standard of care for diagnosis of pseudoprogression in cases where MRI is equivocal. However, it is invasive, risky, and disruptive to patient's lives and their oncological treatment. With its increased vascularity, glioblastoma is continually shedding tumor components into the vasculature including tumor cells, genetic material, and extracellular vesicles. These elements can be isolated from routine blood draws and provide a real-time non-invasive indicator of tumor progression. Liquid biopsy therefore presents as an attractive alternative to current methods to guide treatment. While the initial evaluation of liquid biopsy for brain tumors via identification of mutations in the plasma was disappointing, novel technologies and use of alternatives to plasma cell-free DNA analytes provide promise for an effective liquid biopsy approach in brain tumors. This review aims to summarize developments in the use of liquid biopsy to monitor glioblastoma, especially in the context of immunotherapy.

Comparison of frailty metrics and the Charlson Comorbidity Index for predicting adverse outcomes in patients undergoing surgery for spine metastases.

OBJECTIVE: Frailty-the state defined by decreased physiological reserve and increased vulnerability to physiological stress-is exceedingly common in oncology patients. Given the palliative nature of spine metastasis surgery, it is imperative that patients be healthy enough to tolerate the physical insult of surgery. In the present study, the authors compared the association of two frailty metrics and the widely used Charlson Comorbidity Index (CCI) with postoperative morbidity in spine metastasis patients. METHODS: A retrospective cohort of patients who underwent operations for spinal metastases at a comprehensive cancer center were identified. Data on patient demographic characteristics, disease state, medical comorbidities, operative details, and postoperative outcomes were collected. Frailty was measured with the modified 5-item frailty index (mFI-5) and metastatic spinal tumor frailty index (MSTFI). Outcomes of interest were length of stay (LOS) greater than the 75th percentile of the cohort, nonroutine discharge, and the occurrence of ≥ 1 postoperative complication. RESULTS: In total, 322 patients were included (mean age 59.5 ± 12 years; 56.9% of patients were male). The mean ± SD LOS was 11.2 ± 9.9 days, 44.5% of patients had nonroutine discharge, and 24.0% experienced ≥ 1 postoperative complication. On multivariable analysis, increased frailty on mFI-5 and MSTFI was independently predictive of all three outcomes: prolonged LOS (OR 1.67 per point, 95% CI 1.06-2.63, p = 0.03; and OR 1.63 per point, 95% CI 1.29-2.05, p < 0.01, respectively), nonroutine discharge (OR 2.65 per point, 95% CI 1.74-4.04, p < 0.01; and OR 1.69 per point, 95% CI 1.36-2.11, p < 0.01), and ≥ 1 complication (OR 1.95 per point, 95% CI 1.23-3.09, p = 0.01; and OR 1.41 per point, 95% CI 1.12-1.77, p < 0.01). CCI was found to be independently predictive of only the occurrence of ≥ 1 postoperative complication (OR 1.45 per point, 95% CI 1.22-1.72, p < 0.01). CONCLUSIONS: Frailty measured with either mFI-5 or MSTFI scores was a more robust independent predictor of adverse postoperative outcomes than the more widely used CCI. Both mFI-5 and MSTFI were significantly associated with prolonged LOS, higher complication rates, and nonroutine discharge. Further investigation in a prospective multicenter cohort is merited.

Combination checkpoint therapy with anti-PD-1 and anti-BTLA results in a synergistic therapeutic effect against murine glioblastoma.

Clinical trials involving anti-programmed cell death protein-1 (anti-PD-1) failed to demonstrate improved overall survival in glioblastoma (GBM) patients. This may be due to the expression of alternative checkpoints such as B- and T- lymphocyte attenuator (BTLA) on several immune cell types including regulatory T cells. Murine GBM models indicate that there is significant upregulation of BTLA in the tumor microenvironment (TME) with associated T cell exhaustion. We investigate the use of antibodies against BTLA and PD-1 on reversing immunosuppression and increasing long-term survival in a murine GBM model. C57BL/6 J mice were implanted with the murine glioma cell line GL261 and randomized into 4 arms: (i) control, (ii) anti-PD-1, (iii) anti-BTLA, and (iv) anti-PD-1 + anti-BTLA. Kaplan-Meier curves were generated for all arms. Flow cytometric analysis of blood and brains were done on days 11 and 16 post-tumor implantation. Tumor-bearing mice treated with a combination of anti-PD-1 and anti-BTLA therapy experienced improved overall long-term survival (60%) compared to anti-PD-1 (20%) or anti-BTLA (0%) alone (P = .003). Compared to monotherapy with anti-PD-1, mice treated with combination therapy also demonstrated increased expression of CD4+ IFN-γ (P < .0001) and CD8+ IFN-γ (P = .0365), as well as decreased levels of CD4+ FoxP3+ regulatory T cells on day 16 in the brain (P = .0136). This is the first preclinical investigation into the effects of combination checkpoint blockade with anti-PD-1 and anti-BTLA treatment in GBM. We also show a direct effect on activated immune cell populations such as CD4+ and CD8 + T cells and immunosuppressive regulatory T cells through this combination therapy.

Targeting of cyclin-dependent kinases in atypical teratoid rhabdoid tumors with multikinase inhibitor TG02.

OBJECTIVE: Atypical teratoid rhabdoid tumors (ATRTs) are aggressive pediatric brain tumors with no current standard of care and an estimated median patient survival of 12 to 18 months. Previous genetic analyses have implicated cyclin D1 and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase that is implicated in many cancers, as key drivers of tumorigenicity in ATRTs. Since the effects of EZH2 and cyclin D1 are facilitated by a host of cyclin-dependent kinases (CDKs), the authors sought to investigate the potential therapeutic effects of targeting CDKs in ATRTs with the multi-CDK inhibitor, TG02. METHODS: Human ATRT cell lines BT12, BT37, CHLA05, and CHLA06 were selected for investigation. The effects of TG02 on cell viability, proliferation, clonogenicity, and apoptosis were assessed via Cell Counting Kit-8 assays, cell counting, clonogenic assays, and flow cytometry, respectively. Similar methods were used to determine the effects of TG02 combined with radiation therapy (RT) or cisplatin. Synergism indices for TG02-cisplatin combination therapy were calculated using CompuSyn software. RESULTS: TG02 was observed to significantly impair ATRT cell growth in vitro by limiting cell proliferation and clonogenicity, and by inducing apoptosis. TG02 inhibited ATRT cell proliferation and decreased cell viability in a dose-dependent manner with nanomolar half maximal effective concentration (EC50) values (BT12, 207.0 nM; BT37, 127.8 nM; CHLA05, 29.7 nM; CHLA06, 18.7 nM). TG02 (150 nM) dramatically increased the proportion of apoptotic ATRT cells 72 hours posttreatment (TG02 8.50% vs control 1.52% apoptotic cells in BT12, p < 0.0001; TG02 70.07% vs control 15.36%, p < 0.0001). Combination therapy studies revealed that TG02 acted as a potent radiosensitizer in ATRT cells (BT12 surviving fraction, RT 51.2% vs RT + TG02 21.7%). Finally, CompuSyn analysis demonstrated that TG02 acted synergistically with cisplatin against ATRT cells at virtually all therapeutic doses. These findings were consistent in cell lines that cover all three molecular subgroups of ATRTs. CONCLUSIONS: The results of this investigation have established that TG02 is an effective therapeutic against ATRTs in vitro. Given the lack of standard therapy for ATRTs, these findings help fill an unmet need and support further study of TG02 as a potential therapeutic option for patients with this deadly disease.

Strategies to Prevent Readmissions to Hospital for COPD: A Systematic Review.

Patients with chronic obstructive pulmonary disease (COPD) experience high rates of hospital readmissions, placing substantial clinical and economic strain on the healthcare system. Therefore, it is essential to implement evidence-based strategies for preventing these readmissions. The primary objective of our systematic review was to identify and describe the domains of existing primary research on strategies aimed at reducing hospital readmissions among adult patients with COPD. We also aimed to identify existing gaps in the literature to facilitate future research efforts. A total of 843 studies were captured by the initial search and 96 were included in the final review (25 randomized controlled trials, 37 observational studies, and 34 non-randomized interventional studies). Of the included studies, 72% (n = 69) were considered low risk of bias. The majority of included studies (n = 76) evaluated patient-level readmission prevention strategies (medication and other treatments (n = 25), multi-modal (n = 19), follow-up (n = 16), telehealth (n = 8), education and coaching (n = 8)). Fewer assessed broader system- (n = 13) and policy-level (n = 7) strategies. We observed a trend toward reduced all-cause readmissions with the use of medication and other treatments, as well as a trend toward reduced COPD-related readmissions with the use of multi-modal and broader scale system-level interventions. Notably, much of this evidence supported shorter-term (30-day) readmission outcomes, while little evidence was available for longer-term outcomes. These findings should be interpreted with caution, as considerable between-study heterogeneity was also identified. Overall, this review identified several evidence-based interventions for reducing readmissions among patients with COPD that should be targeted for future research.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1955338 .

Patient perceptions of the benefits and barriers of virtual postnatal care: a qualitative study.

OBJECTIVE: The objective of this study is to understand the perceptions of new mothers using virtual care via video conferencing to gain insight into the benefits and barriers of virtual care for obstetric patients. METHODS: Semi-structured interviews were conducted with 15 patients attending the Kingston Health Sciences Centre. The interviews were 20-25 min in length and recorded through an audio recorder. Thematic analysis was conducted in order to derive the major themes explored in this study. RESULTS: New mothers must often adopt new routines to balance their needs and their child's needs. These routines could impact compliance and motivation to attend follow-up care. In our study, participants expressed high satisfaction with virtual care, emphasizing benefits related to comfort, convenience, communication, socioeconomic factors, and the ease of technology use. Participants also perceived that they could receive emotional support and build trust with their health care providers despite the remote nature of their care. Due to its ease of use and increased accessibility, we argue that virtual care shows promise to facilitate long-term compliance to care in obstetric patients. CONCLUSIONS: Virtual care is a useful modality that could improve compliance to obstetric care. Further research and clinical endeavours should examine how social factors and determinants intersect to determine how they underpin patient perceptions of virtual and in-person care.