The KRASG12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRASG12D mutant protein with MRTX1133, a non-covalent small ...molecule inhibitor of KRASG12D, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRASG12D-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+ T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of KRASG12D in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8+ T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials.
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•KRASG12D inhibition with MRTX1133 reverses early and advanced PDAC growth•MRTX1133 increases CD8+ T cells and reprograms cancer associated fibroblasts•Regression of advanced PDAC in response to MRTX1133 requires CD8+ T cells•KRASG12D inhibition induces FAS to facilitate CD8+ T cell mediated death
Mahadevan et al. demonstrate that the oncogenic KRASG12D inhibitor MRTX1133 reverses early and advanced PDAC growth and remodels the tumor microenvironment. MRTX1133 induces FAS expression in cancer cells and promotes CD8+ T cell mediated death.
The clinical significance of gangrenous, suppurative, or exudative (GSE) findings is poorly characterized in children with nonperforated appendicitis.
To evaluate whether GSE findings in children ...with nonperforated appendicitis are associated with increased risk of surgical site infections and resource utilization.
This multicenter cohort study used data from the Appendectomy Targeted Database of the American College of Surgeons Pediatric National Surgical Quality Improvement Program, which were augmented with operative report data obtained by supplemental medical record review. Data were obtained from 15 hospitals participating in the Eastern Pediatric Surgery Network (EPSN) research consortium. The study cohort comprised children (aged ≤18 years) with nonperforated appendicitis who underwent appendectomy from July 1, 2015, to June 30, 2020.
The presence of GSE findings was established through standardized, keyword-based audits of operative reports by EPSN surgeons. Interrater agreement for the presence or absence of GSE findings was evaluated in a random sample of 900 operative reports.
The primary outcome was 30-day postoperative surgical site infections (incisional and organ space infections). Secondary outcomes included rates of hospital revisits, postoperative abdominal imaging, and postoperative length of stay. Multivariable mixed-effects regression was used to adjust measures of association for patient characteristics and clustering within hospitals.
Among 6133 children with nonperforated appendicitis, 867 (14.1%) had GSE findings identified from operative report review (hospital range, 4.2%-30.2%; P < .001). Reviewers agreed on presence or absence of GSE findings in 93.3% of cases (weighted κ, 0.89; 95% CI, 0.86-0.92). In multivariable analysis, GSE findings were associated with increased odds of any surgical site infection (4.3% vs 2.2%; odds ratio OR, 1.91; 95% CI, 1.35-2.71; P < .001), organ space infection (2.8% vs 1.1%; OR, 2.18; 95% CI, 1.30-3.67; P = .003), postoperative imaging (5.8% vs 3.7%; OR, 1.70; 95% CI, 1.23-2.36; P = .002), and prolonged mean postoperative length of stay (1.6 vs 0.9 days; rate ratio, 1.43; 95% CI, 1.32-1.54; P < .001).
In children with nonperforated appendicitis, findings of gangrene, suppuration, or exudate are associated with increased surgical site infections and resource utilization. Further investigation is needed to establish the role and duration of postoperative antibiotics and inpatient management to optimize outcomes in this cohort of children.
College food insecurity is a known detriment to student success, but little is known about the implementation of campus‐based programmes to help address this issue on campus in the United States. The ...objective of this research study was to determine the types of food insecurity initiatives implemented and assess how such programmes are managed, funded, and evaluated. A cross‐sectional, 23‐item online survey was administered among individuals involved with campus food insecurity initiatives identified through professional networks. Food pantries were the most common (97.1%) and mobile food sharing applications were the least common (14.7%) food security initiatives. A majority of respondents (69.7%) stated that at least one programme on their campus was evaluated, although the methods varied and uncertainty about the methods used was common. An allocated budget was provided at some institutions (38.9%), but funding mechanisms varied. Student Life Offices were most commonly reported as being responsible for programme management. Most respondents (75.3%) reported there had been programme changes due to COVID‐19. This research confirmed that food insecurity programmes are widely available, although the type, funding, and leadership of these programmes vary. A coordinated approach on campus to align programming efforts is needed.
A wide range of patient health data is recorded in Electronic Health Records (EHR). This data includes diagnosis, surgical procedures, clinical laboratory measurements, and medication information. ...Together this information reflects the patient's medical history. Many studies have efficiently used this data from the EHR to find associations that are clinically relevant, either by utilizing International Classification of Diseases, version 9 (ICD-9) codes or laboratory measurements, or by designing phenotype algorithms to extract case and control status with accuracy from the EHR. Here we developed a strategy to utilize longitudinal quantitative trait data from the EHR at Geisinger Health System focusing on outpatient metabolic and complete blood panel data as a starting point. Comprehensive Metabolic Panel (CMP) as well as Complete Blood Counts (CBC) are parts of routine care and provide a comprehensive picture from high level screening of patients' overall health and disease. We randomly split our data into two datasets to allow for discovery and replication. We first conducted a genome-wide association study (GWAS) with median values of 25 different clinical laboratory measurements to identify variants from Human Omni Express Exome beadchip data that are associated with these measurements. We identified 687 variants that associated and replicated with the tested clinical measurements at p<5×10-08. Since longitudinal data from the EHR provides a record of a patient's medical history, we utilized this information to further investigate the ICD-9 codes that might be associated with differences in variability of the measurements in the longitudinal dataset. We identified low and high variance patients by looking at changes within their individual longitudinal EHR laboratory results for each of the 25 clinical lab values (thus creating 50 groups - a high variance and a low variance for each lab variable). We then performed a PheWAS analysis with ICD-9 diagnosis codes, separately in the high variance group and the low variance group for each lab variable. We found 717 PheWAS associations that replicated at a p-value less than 0.001. Next, we evaluated the results of this study by comparing the association results between the high and low variance groups. For example, we found 39 SNPs (in multiple genes) associated with ICD-9 250.01 (Type-I diabetes) in patients with high variance of plasma glucose levels, but not in patients with low variance in plasma glucose levels. Another example is the association of 4 SNPs in UMOD with chronic kidney disease in patients with high variance for aspartate aminotransferase (discovery p-value: 8.71×10-09 and replication p-value: 2.03×10-06). In general, we see a pattern of many more statistically significant associations from patients with high variance in the quantitative lab variables, in comparison with the low variance group across all of the 25 laboratory measurements. This study is one of the first of its kind to utilize quantitative trait variance from longitudinal laboratory data to find associations among genetic variants and clinical phenotypes obtained from an EHR, integrating laboratory values and diagnosis codes to understand the genetic complexities of common diseases.
Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK ...pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non-small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation
and caused tumor regression
. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC. SIGNIFICANCE: These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.
The
KRAS
G12D
mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRAS
G12D
mutant protein with MRTX1133, a non-covalent small ...molecule inhibitor of KRAS
G12D
, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRAS
G12D
-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8
+
effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8
+
T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of KRAS
G12D
in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8
+
T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials.
Mahadevan et al. demonstrate that the oncogenic KRAS
G12D
inhibitor MRTX1133 reverses early and advanced PDAC growth and remodels the tumor microenvironment. MRTX1133 induces FAS expression in cancer cells and promotes CD8
+
T cell mediated death.
The KRAS
mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRAS
mutant protein with MRTX1133, a non-covalent small molecule ...inhibitor of KRAS
, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRAS
-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8
effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8
T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of KRAS
in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8
T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials.
Purpose: The Collaborative Ocular Tuberculosis Study (COTS) Group sought to address the diagnostic uncertainty through retrospective cohort analysis of treatment regimens and therapeutic outcomes for ...patients with tubercular Anterior Uveitis (TAU) across international centers.
Methods: Multicentre retrospective analysis of patients diagnosed with TAU between January 2004 to December 2014 that had a minimum follow-up of 1 year.
Results: One hundred and sixty-five patients were included. One hundred and seven subjects received antitubercular therapy (ATT) (n = 107/165; 64.9%) with all the patients receiving topical steroid therapy. Treatment failure was noted in 17 patients (n = 17/165; 10.3%), more frequently described in patients that received ATT (n = 13/107, 12.2%), than those that did not receive ATT (n = 4/58, 6.9%).
Conclusion: In this retrospective study, addition of ATT did not have any statistically significant impact on outcome in patients with TAU.
Objective: Aim of the study was to examine extent, natural history, and clinical features associated with visual impairment (VI) in patients diagnosed with ocular tuberculosis (OTB) by the ...Collaborative Ocular Tuberculosis Study (COTS)-1.
Methods: Multi-center retrospective cohort study. Main outcomes were VI.
Results: A total of 302 patients were included in the study, including 175 patients whose data related to BCVA were available throughout the 2 years of follow up. Mean BCVA grossly improved at 12, 18, and 24 months of follow-up (p < .001). Mean BCVA was worse at 12-18th month follow-up for patients treated with ATT versus patients who were not treated with ATT, but patients treated with ATT had a statistically significant improvement in BCVA at the 24-month endpoint.
Conclusions: OTB is associated with significant visual morbidity, future well-designed prospective studies are warranted to establish the causal association between OTB and visual loss.
Autoimmune Encephalitis Misdiagnosis in Adults Flanagan, Eoin P; Geschwind, Michael D; Lopez-Chiriboga, A Sebastian ...
JAMA neurology,
01/2023, Letnik:
80, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Autoimmune encephalitis misdiagnosis can lead to harm.
To determine the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis.
This retrospective multicenter study ...took place from January 1, 2014, to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics including Mayo Clinic (n = 44), University of Oxford (n = 18), University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), University of Washington in St Louis (n = 6), and University of Utah (n = 4). Inclusion criteria were adults (age ≥18 years) with a prior autoimmune encephalitis diagnosis at a participating center or other medical facility and a subsequent alternative diagnosis at a participating center. A total of 393 patients were referred with an autoimmune encephalitis diagnosis, and of those, 286 patients with true autoimmune encephalitis were excluded.
Data were collected on clinical features, investigations, fulfillment of autoimmune encephalitis criteria, alternative diagnoses, potential contributors to misdiagnosis, and immunotherapy adverse reactions.
A total of 107 patients were misdiagnosed with autoimmune encephalitis, and 77 (72%) did not fulfill diagnostic criteria for autoimmune encephalitis. The median (IQR) age was 48 (35.5-60.5) years and 65 (61%) were female. Correct diagnoses included functional neurologic disorder (27 25%), neurodegenerative disease (22 20.5%), primary psychiatric disease (19 18%), cognitive deficits from comorbidities (11 10%), cerebral neoplasm (10 9.5%), and other (18 17%). Onset was acute/subacute in 56 (52%) or insidious (>3 months) in 51 (48%). Magnetic resonance imaging of the brain was suggestive of encephalitis in 19 of 104 patients (18%) and cerebrospinal fluid (CSF) pleocytosis occurred in 16 of 84 patients (19%). Thyroid peroxidase antibodies were elevated in 24 of 62 patients (39%). Positive neural autoantibodies were more frequent in serum than CSF (48 of 105 46% vs 7 of 91 8%) and included 1 or more of GAD65 (n = 14), voltage-gated potassium channel complex (LGI1 and CASPR2 negative) (n = 10), N-methyl-d-aspartate receptor by cell-based assay only (n = 10; 6 negative in CSF), and other (n = 18). Adverse reactions from immunotherapies occurred in 17 of 84 patients (20%). Potential contributors to misdiagnosis included overinterpretation of positive serum antibodies (53 50%), misinterpretation of functional/psychiatric, or nonspecific cognitive dysfunction as encephalopathy (41 38%).
When evaluating for autoimmune encephalitis, a broad differential diagnosis should be considered and misdiagnosis occurs in many settings including at specialized centers. In this study, red flags suggesting alternative diagnoses included an insidious onset, positive nonspecific serum antibody, and failure to fulfill autoimmune encephalitis diagnostic criteria. Autoimmune encephalitis misdiagnosis leads to morbidity from unnecessary immunotherapies and delayed treatment of the correct diagnosis.
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