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Nature Mar 2024Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when...
Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone. However, there remains little consensus on the mechanism(s) of response with this combination. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8 T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.
Topics: Animals; Humans; Mice; Antibodies, Monoclonal; Antineoplastic Agents; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Dendritic Cells; Drug Therapy, Combination; Immune Checkpoint Inhibitors; Macrophage Activation; Myeloid Cells; Neoplasms; Receptors, IgG; Receptors, Immunologic; T-Lymphocytes, Regulatory; Tumor Microenvironment; Tumor-Associated Macrophages
PubMed: 38418879
DOI: 10.1038/s41586-024-07121-9 -
Journal of Osteopathic Medicine Jun 2024Osteopathic treatments regulate the neurovegetative system through joint mobilizations and manipulations, and myofascial and craniosacral techniques. Despite the growing... (Randomized Controlled Trial)
Randomized Controlled Trial
Effectiveness of osteopathic manipulative applications on hypothalamic-pituitary-adrenal (HPA) axis in youth with major depressive disorder: a randomized double-blind, placebo-controlled trial.
CONTEXT
Osteopathic treatments regulate the neurovegetative system through joint mobilizations and manipulations, and myofascial and craniosacral techniques. Despite the growing body of research, the precise impact of osteopathic medicine on the autonomic nervous system (ANS) is not yet fully elucidated. As to Kuchera's techniques, the stimulation of the sympathetic trunk and prevertebral ganglia contributed to harmonization of the sympathetic activity. However, potential relationships between the harmonization of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis largely remain uncertain and warrant further exploration.
OBJECTIVES
This study was designed to evaluate the effectiveness of the osteopathic sympathetic harmonization (OSH) on the SNS and the HPA axis in youth with major depressive disorder (MDD).
METHODS
The study included 39 youths aged 15-21 years and diagnosed with MDD. The participants were randomly assigned into either the OSH or the placebo group. Stimulation was performed on the sympathetic truncus and prevertebral ganglia in the OSH group. The stimulation of the placebo group was performed with a lighter touch and a shorter duration in similar areas. Each participant completed the Beck Depression Inventory (BDI) and the State and Trait Anxiety Inventory (SAI and TAI) before the application. Blood pressure (BP) and pulse measurements were made, and saliva samples were taken before, immediately after, and 20 min after application.
RESULTS
The baseline BDI (p=0.617) and TAI (p=0.322) scores were similar in both groups. Although the SAI scores decreased in both groups postintervention, no statistically significant difference was found between the two groups. Subjects who received OSH had a decrease in α-amylase level (p=0.028) and an increase in cortisol level (p=0.009) 20 min after the procedure.
CONCLUSIONS
Following OSH application in depressed youth, SNS activity may decrease, whereas HPA axis activity may increase. Future studies may examine the therapeutic efficacy of repeated OSH applications in depressed individuals.
Topics: Humans; Depressive Disorder, Major; Adolescent; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Male; Female; Double-Blind Method; Young Adult; Manipulation, Osteopathic; Hydrocortisone; Sympathetic Nervous System; Treatment Outcome
PubMed: 38414339
DOI: 10.1515/jom-2023-0056 -
Multiple Sclerosis (Houndmills,... Jun 2024The coronavirus disease 2019 (COVID-19) pandemic offered an epidemiological opportunity to evaluate if isolation and masking affected John Cunningham (JC) virus...
BACKGROUND
The coronavirus disease 2019 (COVID-19) pandemic offered an epidemiological opportunity to evaluate if isolation and masking affected John Cunningham (JC) virus transmission.
OBJECTIVE
This study aimed to assess the proportion of natalizumab-treated patients who converted to a positive anti-JCV antibody serostatus before and during the pandemic.
METHODS
Data from TYSABRI Outreach: Unified Commitment to Health (TOUCH) for 22,375 US patients treated with natalizumab with anti-JCV antibody records were assessed in epochs annually from 2017 to 2022.
RESULTS
Pre-pandemic anti-JCV antibody serostatus change was observed for 7.4%-7.7%. During the first and second years of the pandemic, 7.3% and 7.2% of patients' serostatus changed, respectively.
CONCLUSION
The proportion of patients with anti-JCV antibody serostatus change did not significantly differ during the first 2 years of the pandemic compared with prior years. In contrast to seasonal influenza, masking and social distancing had no discernable effect on JCV serostatus change.
Topics: Humans; COVID-19; Multiple Sclerosis; Male; Female; Adult; Physical Distancing; Antibodies, Viral; Middle Aged; United States; JC Virus; Natalizumab; SARS-CoV-2; Immunologic Factors
PubMed: 38406828
DOI: 10.1177/13524585241232274 -
Viruses Jan 2024Pregnant women identified to carry hepatitis B surface antigen (HBsAg) should be linked to care for the determination of the need for long-term antiviral therapy (LTT)....
Pregnant women identified to carry hepatitis B surface antigen (HBsAg) should be linked to care for the determination of the need for long-term antiviral therapy (LTT). We assessed the performance of simplified criteria, free from HBV DNA quantification, to select women eligible for LTT using different international guidelines as a reference. A retrospective analysis of HBV-infected pregnant women enrolled in the phase 4 ANRS TA-PROHM study was conducted in Cambodia. Sensitivity, specificity, and AUROC were computed to compare three simplified criteria (TREAT-B, HBcrAg/ALT, and TA-PROHM) with the American (AASLD) and European (EASL) guidelines as a reference. An additional assessment was performed at 6 months postpartum. Of 651 HBsAg-positive women, 209 (32%) received peripartum antiviral prophylaxis using tenofovir disoproxil fumarate (TDF). During pregnancy, 9% and 12% of women were eligible for LTT according to AASLD and EASL guidelines, respectively; 21% and 24% of women were eligible for prophylactic TDF and 2% and 5% in those ineligible ( < 0.001). Using the AASLD guidelines, the AUROC of TREAT-B, HBcrAg/ALT, and TA-PROHM scores were 0.88 (95%CI, 0.85-0.90), 0.90 (95%CI, 0.87-0.92), and 0.76 (95%CI, 0.73-0.80), respectively. Using the EASL guidelines, the AUROCs were lower: 0.73 (95%CI, 0.69-0.76), 0.76 (95%CI, 0.73-0.80), and 0.71 (95%CI, 0.67-0.74), respectively. Among those ineligible for prophylactic TDF, only 2% to 6% present an indication for LTT at 24 weeks postpartum. Few pregnant women are eligible for LTT, and the use of simplified criteria could represent an efficient triage option in decentralized areas to identify those negative for whom there is no urgent indication for LTT and focus on those positive for whom other exams must be conducted to confirm LTT indication.
Topics: Humans; Female; Pregnancy; Pregnant Women; Hepatitis B, Chronic; Hepatitis B Surface Antigens; Cambodia; Retrospective Studies; Pregnancy Complications, Infectious; Hepatitis B e Antigens; DNA, Viral; Tenofovir; Antiviral Agents; Hepatitis B virus; Infectious Disease Transmission, Vertical
PubMed: 38399970
DOI: 10.3390/v16020194 -
Current Oncology (Toronto, Ont.) Feb 2024Fluorescence-guided oncology promises to improve both the detection and treatment of malignancy. We sought to investigate the temporal distribution of indocyanine green...
UNLABELLED
Fluorescence-guided oncology promises to improve both the detection and treatment of malignancy. We sought to investigate the temporal distribution of indocyanine green (ICG), an exogenous fluorophore in human colorectal cancer. This analysis aims to enhance our understanding of ICG's effectiveness in current tumour detection and inform potential future diagnostic and therapeutic enhancements.
METHODS
Fifty consenting patients undergoing treatment for suspected/confirmed colorectal neoplasia provided near infrared (NIR) video and imagery of transanally recorded and ex vivo resected rectal lesions following intravenous ICG administration (0.25 mg/kg), with a subgroup providing tissue samples for microscopic (including near infrared) analysis. Computer vision techniques detailed macroscopic 'early' (<15 min post ICG administration) and 'late' (>2 h) tissue fluorescence appearances from surgical imagery with digital NIR scanning (Licor, Lincoln, NE, USA) and from microscopic analysis (Nikon, Tokyo, Japan) undertaken by a consultant pathologist detailing tissue-level fluorescence distribution over the same time.
RESULTS
Significant intra-tumoural fluorescence heterogeneity was seen 'early' in malignant versus benign lesions. In all 'early' samples, fluorescence was predominantly within the tissue stroma, with uptake within plasma cells, blood vessels and lymphatics, but not within malignant or healthy glands. At 'late' stage observation, fluorescence was visualised non-uniformly within the intracellular cytoplasm of malignant tissue but not retained in benign glands. Fluorescence also accumulated within any present peritumoural inflammatory tissue.
CONCLUSION
This study demonstrates the time course diffusion patterns of ICG through both benign and malignant tumours in vivo in human patients at both macroscopic and microscopic levels, demonstrating important cellular drivers and features of geolocalisation and how they differ longitudinally after exposure to ICG.
Topics: Humans; Tissue Distribution; Indocyanine Green; Colorectal Neoplasms
PubMed: 38392057
DOI: 10.3390/curroncol31020063 -
Turkish Journal of Ophthalmology Feb 2024A 56-year-old man was referred to our clinic for unilateral nodular scleritis unresponsive to systemic corticosteroids. A localized, nodular hyperemia on the nasal...
A 56-year-old man was referred to our clinic for unilateral nodular scleritis unresponsive to systemic corticosteroids. A localized, nodular hyperemia on the nasal bulbar conjunctiva surrounding a central cyst-like lesion together with vascular engorgement was observed on slit-lamp examination of the left eye. No abnormal fundoscopic findings were noted. Surgical exploration revealed an embedded episcleral brown colored, soft to touch, splinter-like organic foreign body (FB) which was confirmed by the histopathological examination. Nodular hyperemia resolved during the postoperative follow-up period, and mild scar tissue accompanied by scleral thinning developed in the left nasal bulbar conjunctiva. Ocular injury associated with FBs may cause significant ocular morbidity depending on the nature and location of the FB. Severe visual disability may occur if left untreated. Subconjunctival FBs are rare and may present with a clinical picture mimicking episcleritis or scleritis. History of trauma involving a FB should always be assessed for an accurate differential diagnosis and appropriate management of patients with anterior scleritis.
Topics: Male; Humans; Middle Aged; Scleritis; Hyperemia; Sclera; Glucocorticoids; Foreign Bodies
PubMed: 38385320
DOI: 10.4274/tjo.galenos.2023.37460 -
Annals of Oncology : Official Journal... May 2024Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an...
BACKGROUND
Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd.
PATIENTS AND METHODS
Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC.
RESULTS
In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified.
CONCLUSIONS
In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; ErbB Receptors; Female; Receptor, ErbB-3; Middle Aged; Male; Aged; Mutation; Adult; Antibodies, Monoclonal, Humanized; Aged, 80 and over; Camptothecin; Antibodies, Monoclonal; Broadly Neutralizing Antibodies; Immunoconjugates
PubMed: 38369013
DOI: 10.1016/j.annonc.2024.02.003 -
ESMO Open Feb 2024In 2019, we reported the first efficacy and safety analysis of EUCROSS, a phase II trial investigating crizotinib in ROS1 fusion-positive lung cancer. At that time,...
BACKGROUND
In 2019, we reported the first efficacy and safety analysis of EUCROSS, a phase II trial investigating crizotinib in ROS1 fusion-positive lung cancer. At that time, overall survival (OS) was immature and the effect of crizotinib on intracranial disease control remained unclear. Here, we present the final analysis of OS, systemic and intracranial activity, and the impact of co-occurring aberrations.
MATERIALS AND METHODS
EUCROSS was a prospective, single-arm, phase II trial. The primary endpoint was best overall response rate (ORR) using RECIST 1.1. Secondary and exploratory endpoints were progression-free survival (PFS), OS, and efficacy in pre-defined subgroups.
RESULTS
Median OS of the intention-to-treat population (N = 34) was 54.8 months [95% confidence interval (CI) 20.3 months-not reached (NR); median follow-up 81.4 months] and median all-cause PFS of the response-evaluable population (N = 30) was 19.4 months (95% CI 10.1-32.2 months). Time on treatment was significantly correlated with OS (R = 0.82; P < 0.0001). Patients with co-occurring TP53 aberrations (28%) had a significantly shorter OS [hazard ratio (HR) 11; 95% CI 2.0-56.0; P = 0.006] and all-cause PFS (HR 4.2; 95% CI 1.2-15; P = 0.025). Patients with central nervous system (CNS) involvement at baseline (N = 6; 20%) had a numerically shorter median OS and all-cause PFS. Median intracranial PFS was 32.2 months (95% CI 23.7 months-NR) and the rate of isolated CNS progression was 24%.
CONCLUSIONS
Our final analysis proves the efficacy of crizotinib in ROS1-positive lung cancer, but also highlights the devastating impact of TP53 mutations on survival and treatment efficacy. Additionally, our data show that CNS disease control is durable and the risk of CNS progression while on crizotinib treatment is low.
Topics: Humans; Lung Neoplasms; Crizotinib; Carcinoma, Non-Small-Cell Lung; Protein-Tyrosine Kinases; Prospective Studies; Proto-Oncogene Proteins; Central Nervous System
PubMed: 38350336
DOI: 10.1016/j.esmoop.2024.102237 -
PloS One 2024Potentially inappropriate prescribing of medications in older adults, particular those with dementia, can lead to adverse drug events including falls and fractures,...
Developing a PRogram to Educate and Sensitize Caregivers to Reduce the Inappropriate Prescription Burden in the Elderly with Alzheimer's Disease (D-PRESCRIBE-AD): Trial protocol and rationale of an open-label pragmatic, prospective randomized controlled trial.
CONTEXT
Potentially inappropriate prescribing of medications in older adults, particular those with dementia, can lead to adverse drug events including falls and fractures, worsening cognitive impairment, emergency department visits, and hospitalizations. Educational mailings from health plans to patients and their providers to encourage deprescribing conversations may represent an effective, low-cost, "light touch", approach to reducing the burden of potentially inappropriate prescription use in older adults with dementia.
OBJECTIVES
The objective of the Developing a PRogram to Educate and Sensitize Caregivers to Reduce the Inappropriate Prescription Burden in Elderly with Alzheimer's Disease (D-PRESCRIBE-AD) trial is to evaluate the effect of a health plan based multi-faceted educational outreach intervention to community dwelling patients with dementia who are currently prescribed sedative/hypnotics, antipsychotics, or strong anticholinergics.
METHODS
The D-PRESCRIBE-AD is an open-label pragmatic, prospective randomized controlled trial (RCT) comparing three arms: 1) educational mailing to both the health plan patient and their prescribing physician (patient plus physician arm, n = 4814); 2) educational mailing to prescribing physician only (physician only arm, n = 4814); and 3) usual care (n = 4814) among patients with dementia enrolled in two large United States based health plans. The primary outcome is the absence of any dispensing of the targeted potentially inappropriate prescription during the 6-month study observation period after a 3-month black out period following the mailing. Secondary outcomes include dose-reduction, polypharmacy, healthcare utilization, mortality and therapeutic switching within targeted drug classes.
CONCLUSION
This large pragmatic RCT will contribute to the evidence base on promoting deprescribing of potentially inappropriate medications among older adults with dementia. If successful, such light touch, inexpensive and highly scalable interventions have the potential to reduce the burden of potentially inappropriate prescribing for patients with dementia. ClinicalTrials.gov Identifier: NCT05147428.
Topics: Humans; Aged; Inappropriate Prescribing; Alzheimer Disease; Caregivers; Potentially Inappropriate Medication List; Drug-Related Side Effects and Adverse Reactions; Polypharmacy; Randomized Controlled Trials as Topic
PubMed: 38346025
DOI: 10.1371/journal.pone.0297562