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Κυριακή 20 Νοεμβρίου 2022

CTIM-22. THE COMBINATION OF LOMUSTINE AND THE IMMUNOCYTOKINE L19TNF IS A PROMISING TREATMENT FOR RECURRENT GLIOBLASTOMA

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Abstract
Glioblastoma is the most aggressive primary brain tumor and adults and poorly immunogenic. Treatment options for recurrent glioblastoma after standard of care chemoradiation are limited Several immunotherapeutic strategies including peptide vaccination and immune checkpoint inhibition have so far failed to improve survival and except from potentially regorafenib, no other agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma. Here, we investigate a new treatment combination based on the alkylating chemotherapy lomustine and the tumor-stroma targeting antibody-cytokine fusion protein L19TNF in preclinical glioma models and patients with recurrent glioblastoma. The combination treatment with lomustine and L19TNF demonstrated strong synergistic anti-tumor activity in several immunocompetent orthotopic glioma models curing the majority of tumor-bear ing mice, whereas other mono- or combination therapies for example with anti-PD1 had only limited anti-glioma activity. Investigations of the mechanism of action revealed that lomustine plus L19TNF led to intratumoral necrosis, DNA damage and triggered a strong local anti-tumor immune response with increased MHC-I expression, presentation of neoepitopes and increased abundance of tumor-infiltrating lymphoid cells. In the first patients treated within a phase I/II clinical trial (NCT04573192), the treatment was well tolerated, and durable objective tumor responses and disease stabilizations could be observed also in patients with an unmethylated MGMT promoter.
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INNV-25. ASSESSING SLEEP AND CIRCADIAN RHYTHMS IN PRIMARY BRAIN TUMORS PATIENTS: AN OBSERVATIONAL STUDY

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Abstract
Sleep-wake disturbances are among the most common and severe symptoms in primary brain tumor (PBT) patients. Currently, no studies have quantified their physiological sleep measurements or compared these assessments to established patient reported outcome measures (PROs). Smart wearable devices, such as Fitbits, continuously monitor patient behaviors at home and provide detailed physiological measurements of sleep, activity, and heart rate. We hypothesized that smart wearable devices can accurately determine physiological sleep disturbances and circadian disruptions and will complement established PROs in a PBT patient population. This observational, cross-sectional trial monitors sleep and circadian rhythm variables using Fitbit smart wearable devices worn for 1 month. Additionally, participants will answer PROs questionnaires (PROMIS Sleep Disturbance and Sleep Related Impairment-Short Forms, Sleep Hygiene Index, Morningness-Eveningness questio nnaire, and Consensus Sleep Diary) at study entry and during the last week on-study. The present study is a planned interim analysis of 54 patients to assess feasibility, including evaluation of enrollment, attrition, study parameter completion and data missingness. 73 PBT patients were screened and approached. Of these patients, 54 (74%) were enrolled on study and 19 (26%) declined participation (8 lacked interest, 3 discomfort wearing watches, 3 lacked smart phone, 2 unable to wear device at work, 2 unable to attend consent calls, 1 pregnancy and 1 cognitive complication). The accrued patients were 56% male, 56%³ 50 years of age, and 81% had a KPS³ 90. Patients represented different stages of treatment: 6% of patients were newly diagnosed, 24% on active treatment (11% 1st recurrence, 13% 2nd recurrence), and 70% were on imaging surveillance. Feasibility was confirmed as there were no deviations reported and 100% of PROs and study timep oints completed. Quantified Fitbit data including percent time worn and physiologic sleep parameters will be reported. Study enrollment for efficacy measures continues.
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LTBK-08. Inferring cell type and cell state composition in glioblastoma from bulk DNA methylation profiles using multi-omic single-cell analyses

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Abstract
OBJECTIVE
Cellular heterogeneity determines tumor phenotype and response to therapy. This is particularly pronounced in glioblastoma (GBM), which is characterized by multiple malignant cell states with distinct proliferation potentials, and different cell types of the microenvironment. Ideally, cellular heterogeneity is characterized using single cell genomic profiling techniques. However, these techniques remain challenging to apply in a diagnostic setting and to large retrospective patient cohorts (TCGA, GLASS, DKFZ and clinical trials). Instead, clinicians routinely support their diagnosis with bulk DNA methylation profiling, which generates robust results from low quality material but does not inform on cellular heterogeneity. We have developed a powerful new computational method to deconvolute bulk DNA methylation data and infer cellular heterogeneity within individual tumors, to support prognostic accuracy and personalized treatme nt decisions.
METHODS
Using both bulk and single-cell multi-omic datasets, we created a DNA methylation-based reference of cell types (malignant, glial, neuronal, and immune) within GBM tumors, and the state of malignant cells therein (stem-like vs. differentiated-like). Using this reference, our computational approach accurately deconvolutes bulk DNA methylation profiles of individual query samples.
RESULTS
High deconvolution accuracy of GBM heterogeneity was achieved from frozen and FFPE tissue samples, including those of low quality or purity (Jensen Shannon divergence for composition similarity < 0.05). Our approach eliminates bias derived from the microenvironment, and results in patient stratification that harmonizes the DNA methylation- and RNA-based classifications of GBM. It also reveals the inter- and intra-tumoral links between the genetic, DNA methylation, and transcriptomic components of GBM pathology, and suggests their specific impacts on treatmen t efficacy. To facilitate clinical translation, we created a public website that allows clinicians to infer the relative abundance of different cell states within a tumor at the click of a button.
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Pediatric cancer‐associated thrombosis

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Abstract

Background and aims

Thrombotic events (TEs) have been extensively studied in adult cancer patients, but data in children are limited. We prospectively analyzed pediatric cancer-associated thrombosis (PCAT) in children with malignancies.

Methods

Children below 15 years of age with confirmed malignancies, treated at a large tertiary cancer center in India from July 2015 to March 2020 developing any TE were eligible. A standardized approach for detection and management was followed. Data were collected after informed consent.

Results

Of 6132 eligible children, 150 (2.44%) had 152 TEs, with median age 8.5 years and male:female of 1.83:1. Most TEs occurred on chemotherapy: 111 (74.0%). The most common site was central nervous system (CNS) 59 (39.3%), followed by upper-limb venous system 37 (24.7%). Hemato-lymphoid (HL) malignancies were more prone to PCAT than solid tumors (ST) (incidence 3.23% vs. 1.58%; odds ratio [OR] = 2.06, 95% confidence interval [CI] [1.36–2.88]; p < .001). Malignancies associated with PCAT were acute lymphoblastic leukemia (ALL) 2.94%, acute myeloid leukemia (AML) 6.66%, and non-Hodgkin lymphomas 5.35%. Response imaging done in 106 (70.7%) children showed complete to partial resolution in almost 90% children. Death was attributable to TE in seven (4.66%) children. Age above 10 years (OR 2.33, 95% CI [1.59–3.41]; p < .001), AML (OR 4.62, 95% CI [1.98–10.74]; p = .0062), and non-Hodgkin lymphoma (OR 4.01, 95 % CI [1.15–14.04]; p = .029) were significantly associated with TEs. In ALL, age more than 10 years (OR 1.86, 95% CI [1.06–3.24]; p < .03), T-ALL (OR 3.32, 95% CI [1.69–6.54]; p = .001), and intermediate-risk group (OR 4.97, 95% CI [1.12–22.02]; p = .035) were significantly associated with thrombosis. The 2-year event-free survival (EFS) for HL malignancies with PCAT was 55.3% versus 72.1% in those without PCAT (p = .05), overall survival (OS) being 84.6% versus 80.0% (p = .32).

Conclusion

Incidence of PCAT was 2.4%, and occurred predominantly in older children with hematolymphoid malignancies early in treatment. Most resolved completely with low molecular weight heparin (LMWH) and mortality was low. In hematolymphoid malignancies, PCAT reduce EFS, highlighting the need for prevention.
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18F‐fludeoxyglucose positron emission computed tomography (18F‐FDG‐PET/CT) versus 68Ga‐DOTATATE‐PET/CT in patients with head and neck cancer: Comparisons and implications for treatment

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Abstract

Background

Tumor-specific molecular imaging in head and neck squamous cell carcinoma (HNSCC) is not well established. Somatostatin receptors (SSTRs) are found in solid tumors, including HNSCC. 68Ga-DOTATATE, a commercially available radionuclide that binds SSTRs, may have utility in imaging HNSCC.

Methods

Patients with HNSCC received pretreatment imaging with 18F-FDG-PET/CT and 68Ga-DOTATATE. Imaging was compared for concordance. When available, surgical resection specimens were compared to pretreatment imaging findings. Historic HNSCC tumor specimens were assessed for both SSTR and p16/human papilloma virus (HPV) expression.

Results

Twenty patients were imaged. Fifteen had oropharyngeal cancer. Primary tumor site was concordant between imaging modalities for all patients. One of 45 lymph nodes was discordant. Retrospective specimen review showed a significant correlation with SSTR expression and HPV/p16 expression. No adverse events occurred.

Conclusions

68Ga-DOTATATE imaging is safe and effective in HNSCC. SSTR expression may be increased in HPV-mediated tumors. Targeted therapies to SSTR should be explored.
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Παρασκευή 18 Νοεμβρίου 2022

Emergence of recombinant norovirus GII.12[P16] and predominance of GII.3[P12] strains in pediatric patients with acute gastroenteritis in Thailand, 2019‐2020

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ABSTRACT

Norovirus (NoV) and sapovirus (SaV) are important pathogens that cause acute gastroenteritis (AGE) in all age groups, commonly in children worldwide. Recently, a number of studies have reported a wide variety of NoV recombinant strains. This study aimed to investigate the distribution of NoV and SaV recombinant strains circulating in Chiang Mai, Thailand during 2019-2020. One hundred and twenty-four NoV and seven SaV strains detected in children admitted to the hospital with AGE were included in this study. The partial RdRp/VP1 regions of these NoV and SaV strains were analyzed by phylogenetic analysis, Simplot and RDP softwares. Overall, eight recombination patterns of NoV were detected. NoV GII.4[P16] was the most common strain detected (39.1%), followed by GII.3[P12] (25.0%), GII.4[P31] (17.2%), and other recombinant strains were detected at lower rate. NoV GII.12[P16] strains were detected for the first time in Thailand. For SaV, none of the recombinant strains was detected. All SaV strains, GI.1/GI.1, GI.2/GI.2, and GII.5/GII.5, exhibited VP1 genotype corresponded to RdRp genotype. In conclusion, this study demonstrates the distribution and diversity of NoV and SaV recombinant strains circulating in pediatric patients with AGE in Chiang Mai, Thailand during 2019-2020 with the emergence of NoV GII.3[P12] and GII.12[P16].

This article is protected by copyright. All rights reserved.
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Busulfan, fludarabine, and melphalan are effective conditioning for pediatric and young adult patients with myeloid malignancies underdoing matched sibling or alternative donor transplantation

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Abstract

Background

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for patients with high-risk myeloid malignancies.

Procedure

We present our 10-year experience (October 2012 to October 2021) of consecutive allo-HCT in patients with myeloid malignancies treated on the pediatric HCT service and conditioned with myeloablative targeted dose—busulfan (BU), fludarabine (FLU), and melphalan (MEL). Twenty-three children, adolescents, and young adult patients (CAYA) (median age 15.4 years) with acute myeloid leukemia (AML, n = 17), myelodysplastic syndrome (MDS, n = 4), or chronic myeloid leukemia (CML, n = 2) underwent allo-HCT post-BU-FLU-MEL. Four patients had treatment-related AML/MDS. Donor/stem cell source was matched sibling donor (MSD) PBSC (n = 7), matched unrelated donor (MUD) PBSC (n = 2), umbilical cord blood (UCB) (n = 3), or haploidentical-BMT (n = 11). Risk stratification was low (n = 2), intermediate (n = 15), high (n = 3), and very high risk (n = 1). The two patients with CML had failed tyrosine kinase inhibitor t herapies.

Results

With a median follow-up of 41.6 months, the relapse rate is only 4.5% with an overall survival (OS) 100%, progression-free survival (PFS) 95.5%, and graft-versus-host-free-relapse-free survival (GRFS) 67.8%. The donor source and the acute graft-versus-host disease (GvHD) prophylaxis regimen significantly impacted grade II–IV aGvHD 66.7% versus 19.2% (p = .039) and chronic graft-versus-host-disease (cGvHD) 66.7% versus 0% (p = .002) in the patients receiving MSD or MUD PBSC compared to haplo-BMT, respectively, resulting in improved GRFS in haplo-BMT, 83.3% compared to 40% matched donor peripheral blood stem cell transplant (PBSCT) (p = .025).

Conclusions

Our results demonstrate that BU-FLU-MEL is efficacious conditioning for disease control in young patients with myeloid malignancies undergoing MSD or alternative donor allo-HCT, but in the setting of PBSC grafts with cyclosporine A-methotrexate (CSA-MTX) GvHD prophylaxis, it results in an unacceptably high incidence of GvHD.
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Dental implant failure rates with low insertion torque with a nonsubmerged surgical approach: A retrospective clinical study

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Abstract

Background

It is currently unclear if a low insertion torque (IT) should prompt a clinician to submerge the dental implant at time of placement.

Purpose

This study aimed to analyze implant failure rates and marginal bone loss (MBL) as a function of IT and surgical approach.

Materials and Methods

A total of 197 patients who had received 295 Mozo Grau (MG) implants were included in this study. The healing of submerged or nonsubmerged implants was evaluated in regular IT (≥20–25 Ncm) or low IT (<20–25 Ncm) cases. Implant failure and MBL were evaluated before prosthesis placement and at 6 and 12 months after functional loading with generalized estimating equations.

Results

The overall 12-month implant failure rate was 4.8% (95% confidence interval [CI]: 2.7%–8.2%). When successful at 12 months, dental implants placed with low IT and nonsubmerging had the same MBL as implants dental implants placed with other approaches (mean difference = −0.02 mm; 95% CI −0.05 to 0.02). Low IT combined with nonsubmerging of the dental implant was associated with a 30-fold increased odds for dental implant failure (95% CI: 3.8–236.6).

Conclusion

low IT and nonsubmerged healing was associated with a high failure rate.
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Naphazoline and oxymetazoline are superior to epinephrine in enhancing the cutaneous analgesia of lidocaine in rats

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Abstract

This study observed the cutaneous analgesic effect of adrenergic agonists when combined with lidocaine. We aimed at the usefulness of 4 adrenergic agonists and epinephrine as analgesics or as tools to prolong the effect of local anesthetics using a model of cutaneous trunci muscle reflex (pinprick pain) in rats. We showed that subcutaneous 4 adrenergic agonists and epinephrine, as well as the local anesthetic bupivacaine and lidocaine, developed a concentration-dependent cutaneous analgesia. The rank order of the efficacy of different compounds (ED50; median effective dose) was epinephrine [0.013 (0.012 – 0.014) μmol] > oxymetazoline [0.25 (0.22 – 0.28) μmol] > naphazoline [0.42 (0.34 – 0.53) μmol] = bupivacaine [0.43 (0.37 – 0.50) μmol] > xylometazoline [1.34 (1.25 – 1.45) μmol] > lidocaine [5.86 (5.11 – 6.72) μmol] > tetrahydrozoline [6.76 (6.21 – 7.36) μmol]. The duration of full reco very caused by tetrahydrozoline, oxymetazoline, or xylometazoline was greater (P<0.01) than that induced via epinephrine, bupivacaine, lidocaine, or naphazoline at equianesthetic doses (ED25, ED50 , and ED75). Co-administration of lidocaine (ED50) with 4 adrenergic agonists or epinephrine enhanced the cutaneous analgesic effect. We observed that 4 adrenergic agonists and epinephrine induce analgesia by themselves, and such an effect has a longer duration than local anesthetics. Co-administration of lidocaine with the adrenergic agonist enhances the analgesic effect, and the cutaneous analgesic effect of lidocaine plus naphazoline (or oxymetazoline) is greater than that of lidocaine plus epinephrine.
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Association of upper respiratory Streptococcus pneumoniae colonization with SARS-CoV-2 infection among adults

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ABSTRACT
Background
Streptococcus pneumoniae interacts with numerous viral respiratory pathogens in the upper airway. It is unclear whether similar interactions occur with SARS-CoV-2.
Methods
We collected saliva specimens from working-age adults receiving SARS-CoV-2 molecular testing at outpatient clinics and via mobile community-outreach testing between July and November 2020 in Monterey County, California. Following bact erial culture enrichment, we tested for pneumococci by quantitative polymerase chain reaction (qPCR) targeting the lytA and piaB genes, and measured associations with SARS-CoV-2 infection via conditional logistic regression.
Results
Analyses included 1,278 participants, with 564 enrolled in clinics and 714 enrolled through outreach-based testing. Prevalence of pneumococcal carriage was 9.2% (117/1,278) among all participants (11.2% [63/564] clinic-based testing; 7.6% [54/714] outreach testing). Prevalence of SARS-CoV-2 infection was 27.4% (32/117) among pneumococcal carriers and 9.6% (112/1,161) among non-carriers (adjusted odds ratio [aOR]: 2.73; 95% confidence interval: 1.58-4.69). Associations between SARS-CoV-2 infection and pneumococcal carriage were enhanced in the clinic-based sample (aOR = 4.01 [2.08-7.75]) and among symptomatic participants (aOR = 3.38 [1.35-8.40]), when compared to fin dings within the outreach-based sample and among asymptomatic participants. Adjusted odds of SARS-CoV-2 co-infection increased 1.24 (1.00-1.55)-fold for each 1-unit decrease in piaB qPCR CT value among pneumococcal carriers. Last, pneumococcal carriage modified the association of SARS-CoV-2 infection with recent exposure to a suspected COVID-19 case (aOR = 7.64 [1.91-30.7] and 3.29 [1.94-5.59]) among pneumococcal carriers and non-carriers, respectively).
Conclusions
Associations of pneumococcal carriage detection and density with SARS-CoV-2 suggest a synergistic relationship in the upper airway. Longitudinal studies are needed to determine interaction mechanisms between pneumococci and SARS-CoV-2.
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